sign in sign up
<<
Home , A1CF, ABCC5, AGPAT9, Auxology, DARS (gene), Forkhead box protein O1

Late Breaking Abstracts

June 2015 | Volume 64 | Suppl. 1A | www.diabetes.org/diabetes

Late Breaking Abstracts LB1

Subject Index LB85

Abstract Author Index LB88

Abstract Author Disclosure Information LB98

scientificsessions.diabetes.org

ComLatepli catBreaiokingns—Hy Abstractspoglycemia

Complications— 3‑LB

Coordination of Inpatient Food Delivery and Mealtime Administration Improves On-Time Insulin Dosing and Reduces Hypo­ 1‑LB glycemia The Effect of Hypoglycemia on Progression of Atherosclerosis in MICHAEL G. JAKOBY, SWATHI BEERAVOLU, SU AH BAE, SUMMI PARGAL, AMINA VA Diabetes Trial (VADT) JAFFAR, VEENA KESIREDDY, SHWETHA MALLIKARJUNA, LINDA READ, CHERYL ARAMESH SAREMI, GIDEON BAHN, PETER D. REAVEN, Phoenix, AZ, Hines, IL BURNS, Springfield, IL, Cincinnati, OH, Milwaukee, WI, San Leandro, CA We examined whether hypoglycemia predicted the progression of Basal/bolus insulin is the best approach for hospitalized patients with atherosclerosis in a substudy of the VADT. The effect of hypoglycemia (severe POSTERS diabetes mellitus, but little is published on strategies to synchronize delivery Complications episodes with loss of consciousness/requiring assistance, or documented of food and mealtime insulin. The SIU Hospital Diabetes Team implemented Acute and Chronic <50 mg/dl) on progression of coronary artery (CAC) was and evaluated a program to link food delivery and prandial insulin at St. determined in 197 participants with baseline and follow-up CT scans. During an John’s Hospital (Springfield, IL). Food Service personnel were equipped with average follow-up time of 4.5 years between scans, a total of 97 participants wireless phones and trained to contact nurses of tray drops during a three reported severe hypoglycemia (n=23) or glucose <50 (n=74). Frequency of month run in period. Primary study endpoint was proportion of hypoglycemia was higher in the intensive compared to the standard treatment doses administered within 20 minutes of food delivery. Secondary endpoints group (77% vs. 24%, P <0.01). Hypoglycemia did not predict progression of were frequency of insulin dosing errors, defined as a meal without insulin or CAC in the entire group. However, there was a significant hypoglycemia by insulin without food, glycemic control measured by median capillary blood treatment interaction (P=0.08 for hypoglycemia x treatment and P=0.01 for glucose (CBG), and frequency of CBG below the diabetes team target of 80- severe hypoglycemia x treatment, respectively). People with hypoglycemia 140 mg/dL. A prospective study with historical controls was performed, with in the standard group had significantly higher progression of CAC (Figure). intervention data collected June 2014-January 2015 and June 2013-January Age adjusted hypoglycemia predicted progression of CAC only in the 2014 serving as a historical control. All patients were managed by the standard group ( =3.51 ± 1.71, P=0.04 and = 6.46 ±2.71, P=0.01 for severe β β diabetes team. Nurses were notified at 96.1% of tray deliveries. Time hypoglycemia, respectively). Adjustment for all baseline differences including between meal and insulin was evaluated for 2,199 meals, 1,318 in the control baseline CAC, or on trial risk factors did not change the results. In conclusion, period and 881 after intervention. Mealtime insulin administered on time although hypoglycemic episodes were more frequent in the intensive group, increased from 49.7% to 57.7% for all meals (P = 0.0002), with significant they were associated with progression of CAC in the standard group only. improvements at breakfast (58.8% vs. 44.0%, P < 0.0001) and lunch (60.9% vs. 51.5%, P = 0.012). Insulin errors were reduced two-fold (2.4% to 1.2%), a clinically meaningful result that was not quite statistically significant (P = 0.06). Median CBG was equivalent before and after the notification system (159 mg/dL vs. 163 mg/dL, P = 0.46), but frequency of CBG < 80 mg/dL was reduced two-fold (9.8% vs. 4.9%, P < 0.0001). A program to coordinate food and prandial insulin improved diabetes management and in hospital by increasing on time insulin administration, decreasing insulin errors, and decreasing hypoglycemia rate. Supported By: Friends of St. John’s Hospital 2‑LB Pharmacokinetic (PK) and Pharmacodynamic (PD) Profiles of 4‑LB BIOD-961 Compared with Marketed Unreported Therapeutic Effect of in Dumping Syndrome LILIANA URIBE-BRUCE, LINDA MORROW, LORI CANNEY, PHILIP PICHOTTA, CHRISTINE K. STIER, Frankfurt, Germany MARCUS HOMPESCH, ALAN KRASNER, ERROL DE SOUZA, Chula Vista, CA, 7 patients with a new onset of a hyperinsulinemic hypoglycemia after Danbury, CT Roux-en-y gastric bypass were treated with Liraglutide to improve their Multiple formulations for use in user-friendly devices are severe dumping symptoms. Liraglutide is an anti-diabetic GLP-1 (Glucagon currently in development for the treatment of severe hypoglycemia; like 1) mimetic, which modulates pancreatic insulin production. Its however, formulations that are not reconstituted immediately prior to use spectrum of activity embraces neuro- and cardio protection, a decrease of have been associated with impaired absorption from the subcutaneous stomach emptying, glucagon secretion, hepatic glucose production, and (SC) space. BIOD-961 is a lyophilized glucagon formulation developed b-cell and an increase of b-cell proliferation, insulin secretion and for use in an auto-reconstitution device. The PK and PD profiles of BIOD- biosynthesis, as well as glucose uptake and storage. Against doctrine, the 961 were compared to those of two marketed glucagon formulations in use of Liraglutide in these patients showed a remarkable decrease in insulin a Phase 1 randomized, six-period study. On separate dosing secretion together with a better synchronization of corresponding plasma days, each subject received 1 mg of BIOD-961, Lilly glucagon, and Novo glucose levels as measured by repeated oral glucose tolerance tests (OGTT). glucagon delivered either SC or intramuscularly (IM). Fifteen normal, healthy subjects were randomized into the study and 10 completed all dosings. There were no statistically significant differences in maximal glucose concentration (BGmax), area under the glucose concentration vs. time curve (BGAUC0-240min), maximal glucagon concentration (Cmax) or area under the curve for glucagon concentration vs. time curve (AUC0-240min) (Table). Furthermore, standard criteria for PK and PD bioequivalence were met when comparing BIOD-961 to Lilly glucagon (IM) and to Novo glucagon (SC). The incidence of adverse events was similar among treatments. In summary, BIOD-961 PK and PD profiles are substantially similar to both comparator glucagons and likely to also show BE in a pivotal trial. Table. Pharmacokinetic and Pharmacodynamic Parameters. Parameter SC BIOD-961 SC Lilly SC Novo IM BIOD-961 IM Lilly IM Novo (n=12) (n=11) (n=12) (n=11) (n=11) (n=12)

Cmax (µg/L) 9.01 ± 0.75 7.87 ± 0.79 9.16 ± 0.59 6.80 ± 0.52 6.75 ± 0.31 7.22 ± 0.44

AUC0-240 min 559.5 ± 28.7 520.8 ± 29.8 570.5 ± 26.8 409.5 ± 39.2 402.6 ± 27.8 441.4 ± 42.7 (µg*min/L)

Tmax (min) 26.7 ± 3.76 23.2 ± 1.82 20.8 ± 1.83 15.5 ± 2.07 17.7 ± 4.39 14.6 ± 2.64

BGmax (mg/dL) 178.2 ± 7.3 170.9 ± 5.3 175.3 ± 5.9 182.9 ± 6.5 171.1 ± 6.7 174.8 ± 5.5

BGAUC0-240 min 26118 ± 630 25915 ± 685 25240 ± 424 26184 ± 607 24960 ± 568 25274 ± 485 (mg*min/dL)

Time to BGmax 41.7 ± 4.1 43.6 ± 4.2 34.6 ± 3.2 40.5 ± 2.5 40.5 ± 3.4 44.6 ± 3.8 (min)

ADA-Funded Research For author disclosure information, see page LB98.

LB1 Complications—Macrovascular—Atherosclerotic Cardiovascular Disease and Diabetes

The SHARE system was able to identify and quantify the frequency of RH

in a real-life use environment. Cloud based health information provides the opportunity for learning about actual diabetes management practices and facilitate prompt actions on appropriate hypoglycemia treatment. POSTERS Complications Acute and Chronic

Complications—Macrovascular— Atherosclerotic Cardiovascular Disease and Human Diabetes

6‑LB The Cardiac Deficiency of Pyruvate Dehydrogenase Complex Alters Cardiac Glucose Oxidation and Sensitizes Heart to Ischemic Insults WANQING SUN, QUAN LIU, JIYAN LENG, YANG ZHENG, JI LI, Changchun, China, Buffalo, NY Pyruvate Dehydrogenase Complex (PDH), plays a key role in aerobic energy . We found that cardiac PDH deficiency mice easily die and the PDH deficiency heart demonstrate significant hypertrophy phenotype. We hypothesized that glucose oxidation regulated by PDH is critical for the heart’s energy metabolism. The objectives of this study is to characterize the signaling mechanisms by which PDH deficiency sensitizes heart to myocardial infarction. The myocardial infarction was conducted by ligation of left anterior descending coronary artery (LAD) in mice. The results showed that PDH deficiency significantly increased myocardial infarct area (p<0.01 versus WT groups), and the immunohistochemistry data showed that cardiac PDH deficiency increased macrophage infiltration (p<0.01 vs. WT groups). The staining of wheat germ agglutinin (WGA) and Masson trichrome revealed greater hypertrophy and fibrosis in the PDH deficiency than WT hearts (p<0.05). It indicated the importance of PDH’s modulation of glucose metabolism in response to ischemic insults. Furthermore, we measured the substrate metabolism of hearts in a working heart perfusion system. The glucose oxidation rate was impaired in the cardiac PDH deficiency hearts as compared to WT hearts during ischemia and reperfusion (I/R), while the PDH activator, dichloroacetate (DCA), can augment glucose oxidation in WT hearts during I/R. The AMP-activated kinase (AMPK) signaling can lead to an increased glucose metabolism under ischemic stress in the heart. Intriguingly. The immunoblotting data demonstrated that cardiac 5‑LB PDH deficiency attenuates ischemic AMPK activation while DCA treatment Incidence of Hypoglycemia Overtreatment in the SHARE Real Life enhances the ischemic AMPK activation. Therefore, the present results Use Population strongly suggest that PDH deficiency cause impaired ischemic AMPK KATHERINE NAKAMURA, TOMAS WALKER, JAKE LEACH, LUCAS BOHNETT, signaling response that could sensitize heart to ischemic injury induced by JORGE VALDES, ANDREW BALO, San Diego, CA ischemia and reperfusion. Hypoglycemia (≤ 70 mg/dL) can occur with insulin use and should Supported By: American Diabetes Association (1-14-BS-131 to J.L.) be treated with rapid acting carbohydrates. Over-treatment results in “ ” (RH) (≥180 mg/dL). The frequency of RH is not well understood. Identification of hypoglycemia and RH now can be made 7‑LB Phosphodiesterase Type-5 Inhibitor Use in Is in real-life using the commercial Dexcom SHARE system. CGM glucose data Associated with a Reduction in All-Cause Mortality stored on SHARE was used to identify hypoglycemic events along with the GEOFFREY I. HACKETT, Lichfield, United Kingdom subsequent glycemic rise. Hypoglycemic events occurring within a half hour We retrospectively analysed the pseudoanonymised records of 42 GP of each other were considered the same event. Over 50,000 hypoglycemic practices in Cheshire, UK and identified all 7860 men diagnosed with T2DM events were identified from 1,177 users. Per person, on average, there were before 1 January 2007. Data search was performed through the centralised 0.96 events/day overall with 0.4 of the events/day occurring overnight (8p to data facility afforded by Egton Medical Information Systems (EMIS®), a 8a). Events were more common during the day (59%) vs. the night (41%). The commercial organization that provides health information systems for the proportion of overall hypoglycemic events that were followed by RHs within majority of practices in the Cheshire county of the UK. Baseline 60 min was 18%, and within 90 min was 26%. RHs occurred more often during clinical characteristics and PDE5i treatment data for erectile dysfunction the day (21%) vs. the night (13%). This analysis suggests that hypoglycemia is (ED) were obtained. All analyses were conducted using the Stata statistical frequent and that RH is not uncommon. The higher frequency of RH during the software based on available patient data through January 31 2014. Amongst day may be related to meals; RH at night is more likely due to overtreatment. those PDE5i treated individuals with a of AMI there were fewer

ADA-Funded Research For author disclosure information, see page LB98.

LB2 Complications—Macrovascular—ALtherosclerotate Breakingi Ac bstractsCardiovascular Disease and Human Diabetes deaths compared to those never treated with a PDE5i (24.1% (51/161) versus A vs. B 0.62 ( CI 0.41 – 0.95- P=0.027). For PDE5Is the HR was 0.17 (CI 0.05 -

31.1% (332/1066) respectively). In the cohort of 432 men that had an incident 0.56-) p=0.004 and for statin use HR was 0.59 (CI 0.36 0.97-) p=0.038. MI, those who used a PDE5i had a 50% reduction in the risk of mortality In this cohort of type 2 diabetes men at high cardiovascular risk, low (HR 0.50 (0.29-0.85); P=0.01). In this cohort of type 2 diabetes men at high baseline T was associated with increased mortality. After Cox analysis, T cardiovascular risk, PDE5i use was seemingly associated with a significant therapy showed 62% reduction in mortality. Regular use of “on demand” reduction in both overall mortality and mortality in those with a history of PDE5I use was associated with an independent reduction in all-cause AMI. mortality. Supported By: Bayer POSTERS 8‑LB Complications The MicroRNAs in the Pathogenesis of Metabolic Memory 10‑LB Acute and Chronic YUNFEI LIAO, LULU CHEN, XUEYU ZHONG, Wuhan, China The Tumour Suppressor CDKN2A/p16INK4a Control Perivascular “Metabolic memory” is identified as a phenomenon that prior exposure to Adipose Tissue Development hyperglycemia results in the long-lasting deleterious effects on cardiovascular SARAH HANNPU, KRISTIAAN WOUTERS, CÉLINE CUDEJKO, JONATHAN VAN- events. More and more researches show that epigenetics play an important HOUTTE, ANTHONY LUCAS, EMANUEL BOUCHAERT, CASPER G. SCHALKWIJK, role in the pathogenesis of metabolic memory. It remains unclear whether ANNE TAILLEUX, BART STAELS, RÉJANE PAUMELLE, Boston, MA, Maastricht, microRNA (miRNA) dysfunctions participate in the event. In this study, the Netherlands, Lille, France miRNA arrays were adopted to seek the miRNAs which may be involved Genome wide association studies (GWAS) have linked variants on chro- in the metabolic memory and verified in vivo and in vitro. Sixteen miRNAs mosome 9p21.3 situated near the CDKN2A/B with the risk for cor- were found differentially expressed. Among these miRNAs, the expressions onary artery disease (CAD) and type 2 diabetes (T2D). Both diseases are of miR-125b, miR-146a-5p and miR-29a-3p were associated with persistent characterized by accumulation of inflamed perivascular adipose tissue (pAT), impaired endothelial function and altered inflammatory expressions which contributes to the onset of endothelial dysfunction, atherosclerosis including nuclear factor-κB (NF-κB) subunit p65. Direct inhibition of miR- and thrombosis. The CDKN2A/B locus encodes, amongst other , for 125b expression or increased miR-146a-5p expression blunted NF-κB signals p16INK4A a well known tumor suppressor protein. As a regulator, and improved the endothelial function. Luciferase reporter assays confirmed p16INK4a is involved in senescence and aging. p16INK4a regulates fasting the biochemical relationship for miR-125b targeting on tumor necrosis induced hepatic . Moreover, p16INK4a is a modulator of factor alpha-induced protein 3 (TNFAIP3), and miR-146a targeting on TNF macrophage activation and polarization. Altogether these data suggest that -associated factor 6 (TRAF6) and interleukin-1 receptor-associated CDKN2A/B gene products may modulate the inflammatory response and glu- kinase 1 (IRAK1) during the activation of NF-κB pathway. Thus our findings cose homeostasis leading to T2D development. However, whether it plays a demonstrate that glucose induced changes in miR-125b and miR-146a-5p are role in and pAT formation and/or phenotype is still unknown. related to the long-lasting activation of NF-κB pathway and contribute to Using 3T3L1 preadipocytes cells and primary mouse embryonic fibroblasts follow-up metabolic memory. (MEF), we demonstrate that p16INK4a deficiency increased expression of key marker (CEBPa, PPARg, ) and fat storage without affecting clonal expansion. To study in vivo adipogenesis, we treated p16+/+ and p16-/- mice with . Aortas of treated p16-/- mice displayed increased expression of markers of adipogenesis and precursor, interestingly this effect was not observed in the other AT depots. As bone marrow is a niche of preadipocyte precursor cells and since rosiglitazone has been shown to mobilize these cells for peripheral adipogenesis, we tested whether bone marrow p16-deficiency affects pAT depots by using chimeric p16+/+Ldlr-/- and p16-/-Ldlr-/- mice fed a western diet. Bone marrow p16- deficiency increased pAT around the aortic root. To conclude, we identify a new role of p16INK4a in adipogenesis and pAT development which could explain the link between genetic variants on 9p21 and CVD development. Supported By: European Genomic Institute for Diabetes

11‑LB Type 2 Diabetes Mellitus in Insulinization: Biochemical, Haemo‑ static, and Inflammatory Markers NADMY A.Z. GONÇALVES, RENATA T. PETRI, RITA DE CÁSSIA R. GONÇALVES, DANIELA A.M.G. DO BEM, BIOQUIMICA CLÍNICA UFES, Vitória, Brazil The aim of this study was to investigate biochemical, haemostatic and inflammatory markers in patients with diabetes mellitus type 2 (DM2) who evolved into insulinization. This study was composed by 80 patients attended in Primary Care Unit at Vitória (Brazil). The evaluated group was composed by 40 patients with DM2 in insulinization, and 40 controls were selected without DM2. There was no difference between groups regarding age (57.05 ± 2.386 x 57.33 ± 1.819 years), sex and insulin resistance. In DM2 Supported By: National Natural Foundation of China group 85% had diabetes for more than five years and the time of insuliniza- tion was around 5.54 (± 5.85) years. Markers of , hypercoagula- 9‑LB bility and fibrinolysis were studied: high-sensitive C reactive protein (hsCRP), Replacement Therapy and PDE5 Inhibitor Use in Type fibrinogen, D-dimer (D-Di) and plasminogen activator type 1 inhibitor (PAI- 2 Diabetes Are Independently Associated with a Reduction in All- 1). The polymorphism (-675 4G / 5G) of the PAI-1 gene has been correlated Cause Mortality with plasma levels. Biochemical parameters included: glucose (G), glycated GEOFFREY I. HACKETT, Lichfield, United Kingdom hemoglobin (A1C), total cholesterol (TC), HDL cholesterol (HDL-C), LDL cho- The diabetes registers of 5 UK general practices (n=857, mean age 63) lesterol (LDLc), triglycerides (TGC), urea and serum creatinine. There was were screened for baseline total (TT), 12 nmol/l or less and free testosterone significant difference between groups for HDL-C, VLDL-C, TGC, urea, hsCRP (FT) 0.25nmol/l or less levels according to current EAU guidelines, between and fibrinogen. DM2 group in insulinization presented correlations between: April 2007 and April 2009 and allocated to 1 of 3 groups: A Normal T. B Low fibrinogen and D-Di, hsCRP and fibrinogen, PAI-1 and triglycerides, D-Di and T untreated, and C low T (treated with long acting G (negative). In controls these correlations were observed: fibrinogen and in a RCCT ). We report follow up data after mean 5.8 years. G, fibrinogen and hsCRP and PAI-1 and G. PAI-1 levels were higher in con- Unadjusted death rates were A 11.2% (36/320), B 16.85% (61/362) and C trols with genotype 4G4G. Binary logistic regression showed hypertensive 3.43% (6/175) analyzed on an ITT basis. Men treated with T were a mean patients have a risk 4.18 (1.426 to 12.28, p=0.009) times more likely to have 5.4 years younger, had higher BMI, BP, HbA1c, baseline cholesterol and DM2 with insulinization and that individuals with hyperfibrinogenemia have were twice as likely (36.6 vs. 15.5%) to be taking a PDE5 inhibitor. After Cox a 3.29 (1.006 to 10.775, p=0.049) times greater risk. According to our results, regression, the HR (CI) for C vs. B was 0.33 (CI 0.12 – 0.92- P=0.033) and for it is possible to suggest that patients with DM2 in insulinization have an

ADA-Funded Research For author disclosure information, see page LB98.

LB3 Complications—Macrovascular—Atherosclerotic Cardiovascular Disease and Human Diabetes

exacerbated inflammatory state in addition to an increased thrombotic risk 14‑LB

being more favorable for the development of cardiovascular disease. Within-Visit Blood Pressure Variability Predicts Increase in Glyce‑ Supported By: FAPESP mia KAUMUDI J. JOSHIPURA, MARIBEL CAMPOS, FRANCISCO MUNOZ-TORRES, 12‑LB ALBA D. RIVERA, JUAN C. ZEVALLOS, San Juan, PR The Involvement of PKC-theta-NF-kB in Regulating PAI-1 Expres‑ There is a bi-directional relationship between high blood pressure and sion in Vascular Smooth Muscle Cells diabetes. Within-visit blood pressure variability (BPV) may impact autonomic

POSTERS HONG-CHI CHEN, YI-CHUN LIAO, YUNG-CHIEH LIN, JONG-KAI HSIAO, Hualien, and humoral response, and is associated with pre-diabetes/diabetes in a Complications Taiwan, Taipei, Taiwan few cross-sectional studies, and the direction of the association is unclear. Acute and Chronic Increased expression/activity of protein kinase C (PKC) isoforms in vascu- This study evaluates within-visit systolic (SBPV) and diastolic (DBPV) vari- lar smooth muscle cells (VSMC) have been shown to cause vasoconstriction, ability as risk factors for increased glycemia over a 3 year follow-up, within leading to hypertension. The activation of PKC resulted from high concentra- the ongoing San Juan Overweight Longitudinal Study (SOALS). The analysis tions of glucose and nonesterified fatty acids has been shown in vascular includes 634 overweight/obese, 40-65 year old Hispanics who completed cells of diabetic and insulin resistant patients, and of animal models, sug- follow-up to date. Within-visit SBPV and DBPV are defined as the maximum gesting that it has significant roles in microvascular complication, cardiac difference between the three baseline measures taken few minutes apart hypertrophy, and in promoting atherosclerosis. Since its discovery, PKC-the- using standard blood pressure techniques. Increased glycemia was defined ta has been recognized as a master regulator for the activation and survival as > 20% increase from baseline in fasting glucose, 2 hour post load glucose of T cells. However, current understanding of PKC-theta’s role in VSMC is or HbA1c. The SBPV ranged from 0-36 mmHg (mean=4.1, SD=3.6), and DBPV still very limited. In this study, we showed that Angiotensin II (Ang II) treat- from 0-28 (mean=3.4, SD=3.0). Participants with SBPV >10 had significantly ment stimulated a rapid and transient 5-fold increase of PKC-theta phospho- increased risk of progression in glycemia compared to those with SBPV < rylation in rat VSMC in two minutes and this increase was reduced to two 10 (RR=1.34, 95% CI: 1.02-1.76), and with increased risk of progression to fold in five minutes, suggesting that PKC-theta might be an effector in Ang II pre-diabetes/diabetes (RR=1.82, 95% CI: 1.10-3.00) within the 3 year follow- signaling in VSMC. Further investigation showed that both Ang II-stimulated up. Both models adjusted for age, gender, smoking, physical activity, waist mRNA and protein expressions of plasminogen activator inhibitor-1 (PAI-1), circumference, reported hypertension diagnosis, and hypertension medica- the major regulator of both tissue and urokinase plasminogen activators, tion that may impact BPV. Additional control of SBP and DBP influenced the were inhibited by a myristoylated PKC-theta pseudosubstrate. Accordingly, estimates by <10%. The DBPV >10 did not show any association. The systolic the reporter gene assay revealed that the expression of a constitutively ac- blood pressure variability, which can be easily assessed in routine office vis- tive PCK-theta mutant enhanced PAI-1 activity, suggesting that its, may be an independent predictor of increased glycemia and progression PKC-theta is mediating the Ang II-stimulated PAI-1 in VSMC. In to pre-diabetes/diabetes. addition, while pretreatment of BAY 11-7082, an inhibitor of nuclear factor- Supported By: R01DE020111, U54MD007587 κB (NF-κB), completely blocked Ang II-stimulated PAI-1 protein expression, the PKC-theta inhibition reduced the Ang II-induced of IκB, 15‑LB suggesting that NF-κB is downstream of PKC-theta signaling in VSMC. In Cardiovascular Outcomes of Saxagliptin Treatment in African summary, our data suggest that PKC-theta-NF-κB signaling plays an impor- Americans with Type 2 Diabetes: Results from the SAVOR-TIMI 53 tant role in regulating PAI-1 transcriptional activation. Trial SAMUEL DAGOGO-JACK, KWAME OSEI, BENJAMIN M. SCIRICA, LAWRENCE 13‑LB A. LEITER, KYUNGAH IM, BOAZ HIRSHBERG, ITAMAR RAZ, DEEPAK L. BHATT, Effects of Sitagliptin plus Granulocyte-Colony Stimulating Factor SAVOR-TIMI 53 STEERING COMMITTEE AND INVESTIGATORS, Memphis, TN, Co- in Patients after Acute Myocardial Infarction (Sitagrami Trial)— lumbus, OH, Boston, MA, Toronto, ON, Canada, Wilmington, DE, Jerusalem, Israel Cardiac and Vascular Outcomes African Americans (AA) have higher prevalence of type 2 diabetes (T2DM) CHRISTOPH BRENNER, HANS D. THEISS, CHRISTINE ADRION, ULRICH GRAB- and higher mortality from cardiovascular disease (CVD) than Whites, but MAIER, DANIEL THEISEN, FRANZ VON ZIEGLER, ALEXANDER LEBER, ALEXAN- race-specific data on CVD outcomes from prospective studies are scant. DER BECKER, HAE-YOUNG SOHN, ELLEN HOFFMANN, ULRICH MANSMANN, The SAVOR-TIMI 53 trial randomly assigned T2DM patients with high CVD GERHARD STEINBECK, WOLFGANG-MICHAEL FRANZ, Innsbruck, Austria, Munich, risk to receive saxagliptin (SAXA) or placebo (PLO) and followed them for a Germany median of 2.1 yr. enrollees (N=5136) self-identified as non- In previous pre-clinical studies we have shown that G-CSF based mobi- Hispanic Black/AA (N=459); non-Hispanic White (WA) (N=3750), Hispanic lization of bone marrow stem cells in combination with genetic or pharma- (HA) (N=785) or non-Hispanic Asian (N=142). The primary endpoint was the cological DPP4 inhibition mediates an enhanced recruitment of these stem composite of CV death, myocardial infarction (MI), or ischemic stroke. The cells into the ischemic myocardium via the SDF1/CXCR4 axis after acute secondary composite endpoint was CV death, MI, stroke, hospitalization for myocardial infarction. This led to an improved cardiac remodeling, enhanced unstable angina, heart failure (HF), or coronary revascularization. A primary heart function and increased survival. We have translated these promising endpoint occurred in 38 (8.3%) AA, 46 (6.4%) HA, 289 (7.7%) WA, and 12 results into a phase III, multi-center, randomized, double-blind and placebo- (9.2%) Asians (P=0.37). Secondary composite endpoint occurred in 16.2%, controlled efficacy and safety trial. As treatment effect we hypothesized 11.5%, 15%, and 15%, respectively (P=0.06). Hospitalization for heart fail- an absolute increase in left/right ventricular ejection fraction of 3.5% six ure occurred in 6.3% of AA, 2.7% of HA, 4.1% of WA, and 3.1% of Asians months after acute myocardial infarction mediated by cardiac regeneration (P=0.01); other secondary endpoints did not differ significantly by race/eth- after application of G-CSF and the DPP4 inhibitor Sitagliptin (SITAGRAMI tri- nicity. SAXA treatment (vs. PLO) did not increase or decrease the risk of the al; EudraCT: 2007-003941-34; clinicaltrials.gov: NCT00650143). We enrolled primary (8.4% vs. 8.2%, P=0.72) or secondary composite endpoints (17.6% a total of 174 patients that suffered from large myocardial infarction (either vs. 14.9%, P=0.61) in AA or other racial/ethnic groups studied. SAXA treat- ST-segment elevation infarction or total occluded coronary vessel, maxi- ment (vs. PLO) was associated with increased risk of hospitalization for HF mum creatine kinase elevation (mean 3081, SD 2106 U/l)) and underwent in WA (4.9% vs. 3.3%, P=0.008) but not in AA (5.4% vs. 7.0%, P=0.47), HA successful percutaneous coronary intervention within 24 hours. Patients (2.5% vs. 2.8%, P=0.90), or others. In conclusion, Blacks in the SAVOR-TIMI were stratified (diabetes, sex) and randomized in a 1:1 ratio. Individuals were 53 study had a higher risk of hospitalization for heart failure compared to treated with either placebo or G-CSF (10μg/kg/d) over a period of 5 days other racial groups, but that risk was not exacerbated by SAXA treatment. together with Sitagliptin (100mg/d) for 28 days. Cardiac MRI was performed Although actual events were few, SAXA neither increased nor decreased at screening visit and after 6 months, additional clinical follow-up visits were the risk of the primary and secondary composite endpoints in AA or other scheduled after 6 weeks and 12 months. Regarding the primary endpoint subgroups. (ClinicalTrials.gov: NCT01107886). in the final analysis, we could not find a beneficial effect of our therapy on the mean change in left ventricular EF after 6 months (4.5% treatment vs. 4.7% placebo). Besides primary endpoint data we will present planned and unplanned secondary endpoints with focus on gender differences and the effect of GCSF plus Sitagliptin treatment on vascular outcomes. Supported By: Heinz Nixdorf Foundation

ADA-Funded Research For author disclosure information, see page LB98.

LB4 Complications—Macrovascular—Cellular Complications—Nephropathy— mECHAnisms of Atherogenesis in Diabetes Basic and Experimental Science

Complications—Macrovascular—Cellular Complications—Nephropathy—Basic and

Mechanisms of Atherogenesis in Diabetes Experimental Science

16‑LB 18‑LB Circulating Microvesicles from Diabetic Patients Carry Less miR- Activating of GLP-1 Ameliorates Obesity-related Kidney Disease via 126 and Have Detrimental Effects on Endothelial Progenitor Cells Improving the Metabolism of Triglyceride in Renal Mesangial Cells HALA AMMAR, XIAOTANG MA, ABOAJELA AJENA, THOMAS M. KOROSCIL, YAOMING XUE, MEIPING GUAN, YANMEI ZENG, FUPING LYV, Guangzhou, China YANFANG CHEN, JI C. BIHL, Dayton, OH, Zhanjiang, China DPP-4 inhibitors have been shown to ameliorate diabetic nephropathy, in POSTERS Complications

Endothelial progenitor cells (EPCs) are reduced in number and dysfunc- which metabolic disorder may involve. However, it is unknown whether Acute and Chronic tional in diabetic patients. Determining the factors that impair EPC function GLP-1 can improve obesity-related kidney disease through the regulation could provide therapy targets for diabetes. Our previous study has demon- of local lipid metabolism of kidney. First, the mice model of obesity-related strated that circulating microvesicles (cMVs) from diabetic mouse have det- kidney disease were established in apoE gene knockout C57BL/6J mice rimental effects on EPCs. In this study, we compared the effects of cMVs (6-week-old, apoE-/-) fed with a high fat diet (HFD). Sitagliptin, a DPP-4 in- from diabetic patients and healthy subjects on EPCs from healthy subjects or hibitor was mixed in the diet at 0.3% of concentration. At 16th week the diabetic patients. After co-incubation with cMVs for 24 hours, the EPCs were kidney tissues of mice were harvested. In sitagliptin-treated group, the renal collected to determine the migration ability by an assay kit, the apoptotic oil-red O staining (+) area was significantly decreased compared with con- rate and reactive oxidative species (ROS) production by flow cytometry. The trol group. Then we investigate the effects of Exendin-4, a GLP-1 analog, in levels of miR-126 in cMVs were measured by qPCR. The levels of miR-126 triglyceride metabolism of renal mesangial cells. Rat mesangial cells (MCs) target protein (VEGFR2) in EPCs were also analyzed after co-incubation. To were treated by oleate (200uM) combinated with exendin-4 of different determine whether miR-126 was involved in MVs-mediated effects, miR-126 concentrations. The triglyceride contents in MCs were determined by oil- inhibitor or mimic was added during the co-incubation. Our results showed: red O staining and glyceridase assay. The gene expressions of SREBP, FAS, (1) Compared to EPCs from healthy subjects, EPCs from diabetic patients PPARα, CPT-1 and ATGL were analyzed by qRT-PCR. Exendin-4 inhibited displayed a decrease in migration ability and an increase in apoptotic rate the triglycerides accumulation induced by oleate. The mRNA expressions and ROS production; (2) Co-incubation with cMVs from healthy subjects was of SREBP and FAS were significantly downregulated, while PPARα, CPT-1 able to improve the migration ability and decreased apoptosis and ROS pro- and ATGL gene expressions were upregulated by Exendin-4. We conclude duction in EPCs from diabetic patients; (3) In contrast, co-incubation with that Exendin-4 improves the lipid metabolism of MCs, which is a potential cMVs from diabetic patients had the opposite effects on EPCs from healthy mechanism through which Exendin-4 ameliorates the obesity-related kidney subjects; (4) The expression of miR-126 in cMVs from diabetic patients was disease. These results help to explain some of the beneficial effects of exen- decreased, and the expression of VEGFR2 in EPCs from healthy subjects was din-4 on obesity-related kidney disease. decreased after co-incubation with cMVs from diabetic patients; (5) miR-126 Supported By: National Natural Science Foundation of China (81470047) inhibitor significantly decreased the protective effects of cMV in healthy subjects, while the miR-126 mimic diminished the detrimental effects of 19‑LB cMVs in diabetic patients. In conclusion, cMVs from diabetic patients are Effect of on the Development of Diabetic Nephropathy detrimental to EPCs partially due to the reduction of their carried miR-126. in Streptozotocin-induced Diabetic Rats BAHAA AL-TRAD, IBRAHEEM ASHANKYTY, Ha’il, Saudi Arabia 17‑LB Previous studies reported that 17β- may influence the progres- Effect of Long-Term Interventions in the Diabetes Prevention Pro‑ sion of diabetic renal disease in females. The present study was intended gram (DPP) and Its Outcome Study on Coronary Artery Calcium to provide insight into the specific effects of progesterone, the other female (CAC) sex , in diabetic renal complications. Adult female wistar rats were RONALD GOLDBERG, MARINELLA TEMPROSA, VANITA R. ARODA, ELIZABETH divided into four groups (n=5-6/group): intact control (non-diabetic, ND), in- L. BARRETT-CONNOR, MATTHEW BUDOFF, JILL CRANDALL, DANA DABELEA, tact diabetic (D), ovariectomized diabetic (OVX-D) and ovariectomized dia- EDWARD S. HORTON, KIEREN J. MATHER, TREVOR J. ORCHARD, DAVID S. betic treated with progesterone (OVX-D+P; 10 mg/kg, s.c, every second day) SCHADE, KAROL E. WATSON, Miami, FL, Rockville, MD, Hyattsville, MD, San Diego, for 10 weeks. Diabetes was induced by a single dose injection of 55 mg/kg CA, Torrance, CA, Bronx, NY, Aurora, CO, Boston, MA, Indianapolis, IN, Pittsburgh, PA, streptozotocin. Diabetes was associated with increases in urinary albumin to Albuquerque, NM, Alhambra, CA creatinine ratio (ACR; mean± SEM; ND, 20.5±1.6; D, 94.6±12.9 mg/g; P<0.05), Despite intensive management of cardiovascular (CV) risk factors, coro- the index of glomerulosclerosis (GSI; ND, 0.16±0.08; D, 2.41±0.57; P<0.05), nary heart disease remains a major cause of morbidity and mortality in the mRNA expression of TGF-β (ND, 1.12±0.31; D, 2.85±0.60; P<0.05) and type 2 diabetes. Intervention in the prediabetic phase may have a greater with a significant decreases in the mRNA expression of podocyte markers; long-term impact on atherosclerosis than waiting for diabetes to develop nephrin (ND, 1.26±0.41; D, 0.26±0.15; P<0.05) and podocin (ND, 0.88±0.09; D, before intervening. The DPP demonstrated that intensive lifestyle (ILS) and 0.34±0.07; P<0.05). The expression and localization of TGF-β, nephrin, and (MET) reduced diabetes incidence vs. placebo (PLBO) in high risk podocin were also confirmed by immunohistochemistry. In the OVX-D rats, participants (ppts). During long term follow-up, MET ppts continued to re- these changes were exacerbated while progesterone supplementation mark- ceive study metformin and all received group lifestyle. After a mean study edly attenuated the increases in the ACR (59.4±12.9 mg/g), GSI (1.05±0.31) duration of 14 years, we assessed subclinical atherosclerosis by CAC in 2029 and TGF-β mRNA expression (1.04±0.29) compared to D and OVX-D groups. ppts using multidetector CT, read centrally, as an Agatston score. For as- Furthermore, the reduced expressions of nephrin and podocin in the D and sessment of treatment and covariate effects, Tobit regression models were OVX-D groups were significantly reversed by progesterone supplementation used to estimate age-adjusted CAC severity expressed as log (CAC+1). At (0.45±0.16 and 0.64±0.18, respectively). These results provide evidence, for the time of CAC assessment, 58% and 67% received lipid- and BP-lower- the first time, that progesterone replacement can ameliorate renal damage ing respectively, and 55% had developed diabetes. CAC was in experimental models of diabetic nephropathy through improve the renal greater in men (mean range was 39.5-66.9 in the 3 groups) than women function; downregulation of renal expressions of TGF-β; along with amelio- (4.7-5.2). While there were no overall differences in CAC between ILS, MET ration of podocyte injury. and PLBO, in a pre-specified subgroup analysis, CAC was significantly lower Supported By: King Abdulaziz City for Science and Technology (M-S-34/44) in MET vs. PLBO in men (ILS=58.3, MET=39.5, PLBO=66.9; p<0.05) especially in the youngest baseline age group (25-44 yrs: MET vs. PLBO 3.0 vs. 17.6; 20‑LB p<0.05) and MET was lower than ILS in subjects who had diabetes (p=0.02). Synip Phosphorylation Is Necessary for Insulin-stimulated Glut4 CAC prevalence (CAC>0) was also lower in men in MET vs. PLBO (ILS=85%, Translocation and Glucose Uptake in Podocyte MET=75%, PLBO=84%; p<0.05). In multivariate models in men, the MET as- SHUICHI OKADA, TSUGUMICHI SAITO, EIJIRO YAMADA, YOKO SHIMODA, AYA sociated effect on CAC was independent of age, race, baseline CV risk fac- OSAKAI, RYO SHIBUSAWA, JUNICHI OKADA, JEFFREY E. PESSIN, MASANOBU tors and diabetes status, but lost significance when diabetes duration was YAMADA, Maebashi, Japan, Bronx, NY added. Among men, lower CAC in the MET group suggests that metformin Previously we reported that the phosphorylation of Synip on serine 99 may delay atherosclerosis development in prediabetes and in early diabetes, is required for Synip dissociation from Syntaxin4 and insulin-stimulated independent of lipid- and BP-lowering therapy. Glut4 translocation in cultured 3T3-L1 adipocytes. We also reported that the dissociated Synip remains anchored to the plasma membrane by bind- ing to Phos­pha­tidylinositol (3,4,5)-triphosphate. Recently Synip was reported

ADA-Funded Research For author disclosure information, see page LB98.

LB5 Complications—Nephropathy—Clinical and Translational Research

to arrest SNARE-dependent membrane fusion as a selective t-SNARE bind- Complications—Nephropathy—Clinical and

ing inhibitor. In this study, we have newly found that Synip is expressed Translational Research in podocytes although at a somewhat lower level than in adipocytes. To determine whether phosphorylation of Synip on serine 99 is required for insulin-stimulated Glut4 translocation and glucose uptake in podocytes 23‑LB we expressed a phosphorylation deficient Synip mutant (S99A-Synip) that Mesenchymal Stem Cell Therapy for Diabetic Nephropathy: A Phase inhibited insulin-stimulated Glut4 translocation and 2-deoxyglucose uptake 2 Randomized Controlled Trial in adipocytes. We confirmed that S99A-Synip significantly inhibited insulin- DAVID K. PACKHAM, IAN FRASER, PETER G. KERR, JASON LICHLITER, SILVIU POSTERS ITESCU, DONNA SKERRETT, KAREN R. SEGAL, Melbourne, Australia, Richmond, Complications stimulated Glut4 translocation and 2-deoxyglucose uptake in podocyte too.

Acute and Chronic We conclude that serine 99 phosphorylation of Synip is required for Glut4 Australia, Clayton, Australia, New York, NY translocation and glucose uptake in both adipocytes and podocytes, sug- The etiology of diabetic nephropathy (DN) includes renal inflammation and gesting that defects in Synip phosphorylation may underlie insulin resis- endothelial dysfunction. Allogeneic bone marrow derived mesenchymal pre- tance and associated diabetic nephropathy. cursor cells (MPC), can modulate both inflammatory cells and microvascula- ture. We conducted a randomized, placebo (PBO) controlled, dose-escalating trial of MPC at 4 Australian sites in 30 type 2 diabetes/DN subjects (24 men, 21‑LB 6 women) with an estimated serum creatinine (SCr) based glomerular filtra- A Glucose-activated Sodium Transporter in the Vasculature tion rate (eGFR) of 20-50 ml/min/1.73/m2 and on a stable regimen of renin- PAUL HANNA, CHRISTINE DURIS, KEVIN R. REGNER, JOHN D. IMIG, JULIAN H. angiotensin inhibition. Subjects were randomized to a single IV infusion of LOMBARD, PAULA E. NORTH, NILOOFAR M. TABATABAI, Milwaukee, WI PBO (saline) or 150 million (M) or 300M MPCs (N=10 per group). Primary study Diabetes is the leading cause of chronic kidney disease, and diabetic kidney period was 12 w with follow-up to 60 w. Renal function was measured by disease is the major cause of end-stage renal disease. SLC5A4 is a member of 99mTc diethylenetriamine pentaacetate (mGFR) at baseline and 12 w, and the sodium-glucose cotransporter (SGLT) family and is known as SGLT3. How- by eGFR at all visits. Baseline mean age was 70 years, mean eGFR was ever, SGLT3 is a glucose-activated sodium transporter. Rodents have two 34.6, 35.7 and 34.6 ml/min/1.73/m2 for PBO, 150M and 300M, and 19/30 SLC5A4 -homologous genes encoding SGLT3a and SGLT3b. The physiological patients (63%) had eGFR>30. The infusions were well tolerated and there role of SGLT3 is not well studied and its role in the pathogenesis of diabetes were no treatment-related adverse events. For mGFR change from baseline is not known. Previously, we showed the expressions of SGLT3 mRNA and at 12 w, the adjusted least squares mean (LSM) differences (+SE) from PBO protein in human kidney specimens and that of mRNA for SGLT3a in mouse were 4.0+2.8 ml/min1.73/m2 (+8%) for 150M and 3.9+2.8 (+8%) for 300M. kidney. To investigate SGLT3 role in the kidney, we examined the localization In subjects with baseline eGFR >30, the LSM difference from PBO (n=7) in of SGLT3 in the human kidney tissue and compared that to that of SGLT3a in mGFR change from baseline at 12 w was 6.2+3.3 (+13%) in the pooled MPC kidneys of C57BL/6 mouse using a panel of our specific antibodies against (n=12), p=0.07. For eGFR change from baseline at 12 w, the LSM differences SGLTs. In Western blot analysis, SGLT3a antibody hybridized to ~72 kDa from PBO were 4.4+2.2 (+11%), p=0.05, in 150M, 1.6+2.2 (+5%) in 300M and protein band in mouse kidney homogenate. Immunohistochemical analysis 4.5+2.8 (+11%) in pooled MPC with baseline eGFR>30. Interleukin-6 (IL-6) showed SGLT3 was strongly expressed in arterial blood vessels in the human was elevated at baseline, and was reduced at 12 w in 300M vs. PBO (-0.21 kidney. Similarly, in mouse kidney, strong SGLT3a signals were observed in vs. 2.5 pg/dl; p=0.01). Baseline IL-6 correlated with SCr and eGFR improve- arteries but neither SGLT1 nor SGLT2 antibody stained the vasculature. Vas- ment at 12 w in the MPC groups (r= -0.57 and 0.50; both p<0.05) but not in cular expression of SGLT3a was also observed in mouse aorta. Next, the ef- PBO. In this exploratory study, a single MPC infusion improved or stabilized fect of SGLT3 agonist, imino sugar deoxynojirimycin (DNJ), was examined on GFR over 12 w, most notably in those with baseline eGFR>30. Mechanisms isolated mouse kidney arterioles and aortic tissue ex vivo. The results showed may include effects on inflammatory cytokines and renal microvasculature. that exposure to 10-150 μM DNJ caused dose-dependent vasoconstriction in micro- and macrovasculature. This study identified the vascular localizations of human SGLT3 and mouse SGLT3a. The results suggest that SGLT3 may play 24‑LB role in the development of vascular diseases in diabetes. Environmental Contaminant Perfluorooctane Sulfonate and Kidney Supported By: R01DK085031, R01ES004026, R25DK098104 Function by Diabetes Status BAQIYYAH CONWAY, KAREN INNES, TINA COSTACOU, JOHN ARTHUR, Morgan- town, WV, Pittsburgh, PA, Charleston, SC 22‑LB Although perfluroakyl acids are environmental contaminants linked to Adiponectin Alters the Kidney-Bone Axis of Mineral Balance certain adverse health outcomes, they are also potent oxygen transport- JOSEPH M. RUTKOWSKI, NYNKE VAN POLANEN, PHILIPP E. SCHERER, Dallas, TX ers used in organ preservation and synthetic blood development. Data are Diabetes is the primary cause of kidney failure and diabetic nephropathy is scarce on the effect of perfluroakyls on kidney function and chronic kidney a concurrent pathological manifestation of the obesity . The insulin- disease (CKD), especially in diabetes (DM). We assessed these associations sensitizing adipokine adiponectin is protective and aiding in recovery of renal by DM status in a large cohort. Participants were from the C8 Health Project function following injury; however, unlike other adipokines, adiponectin is (n=5,270 and 48,832 w/and w/out DM, respectively, age≥20 ys). eGFR was reduced in obesity. High adiponectin levels have been correlated with bone assessed by the MDRD formula. CKD was defined as eGFR <60. Perfluorooc- loss, suggesting an additional role in regulating mineral balance. The kidney tane sulfonate (C8s) was log-transformed before analysis. Adjusting for age controls calcium and levels with disruptions leading to osteoporo- and sex, C8s was directly related w/eGFR in those w/DM and inversely in sis or vascular calcification. Using adiponectin knockout (KO), wildtype, and those w/out DM (all p<0.0001; P interaction <0.0001). Further adjusting for adiponectin overexpressing transgenic (Tg) mice, we sought to identify how DM duration (in DM) BMI, HDLc, WBC, CRP, serum iron and hemoglobin (hb), adiponectin may regulate renal calcium and phosphate balance. At baseline, these associations remained significant (Fig. 1a). CKD was present in 21.6% adiponectin KO mice exhibited lower serum Ca2+, lower Ca2+ excretion, and w/and 7.2% w/out DM. Fig. 1b shows the C8s - CKD associations. When higher circulating klotho concentrations than wildtype littermates. Adiponec- stratified by CKD, C8s was directly associated w/eGFR in CKD and inversely tin-Tg mice on chow diet had markedly lower FGF23 and increased Ca2+ excre- in those w/out CKD (Fig. 1c) regardless of DM status. Our data suggest C8s tion. Challenging these mice with a 2% phosphate (Pi)-enriched diet resulted may have beneficial effects on kidney function in those w/CKD and DM, in expected increases in serum PTH and FGF23, decreases in secreted klotho, conditions where low hb is common, perhaps by protecting against hypoxia- and, unexpectedly, increased 1, 25-vitamin D in all mice. Adiponectin-Tg mice induced kidney damage. The inverse relation of C8s in those w/out CKD, were, however, hyper responsive to Pi challenge exhibiting 2-fold higher se- where low hb is less common, is likely due to reverse causation. rum FGF23 and concomitant increase in fractional Pi excretion. These mice also excreted more Ca2+ with Pi-enriched diet and less klotho protein was present in kidney. Adiponectin KO mice exhibited a 50% smaller increase in PTH; serum FGF23 was increased, but significantly less so than in their study mates. While all mice displayed a loss in bone mass over time, adiponectin-Tg mice exhibited disproportionately lower bone strength and mass. Adiponec- tin thus alters calcium and phosphate balance and impacts renal function and mineral excretion. This work highlights the profound effects of adipose tissue on renal function and has identified a new mechanism by which adiponectin may regulate bone mass. Supported By: National Institutes of Health (R01DK55758, P01DK088761 to P.E.S.); American Heart Association (12SDG12050287 to J.M.R.)

ADA-Funded Research For author disclosure information, see page LB98.

LB6 Complications—Neuropathy

tubular kidney damage were used. Longitudinal weights accounted for MEPS

complex survey design. Logistic regression models assessed the likelihood of harmful drug use. Generalized linear regression models assessed expenses. Of 809 eligible adults with kidney disease (weighted frequency: 14,665,892 U.S. non-institutionalized population), 72% had medications termed harmful. Of those, 47.2% and 52.8% were prescribed one and at least two harmful medications, respectively. In co-existent chronic conditions, hypertension dominated (72.3%), then diabetes (49.5%), coronary heart disease (33%), POSTERS

arthritis (23.6%), and COPD (17.6%). Being older, from the southern U.S. re- Complications

gion, and greater comorbidity significantly increased the likelihood of using a Acute and Chronic drug that may induce renal tubular harm. Renally harmful drug use vs. none showed significantly greater all-cause health services utilization and health expenses. No significant differences existed in kidney disease-related utiliza- tion or expense. Vigilance is needed when prescribing medications in kidney disease, particularly for comorbid conditions, the elderly, or uninsured. Supported By: National Institutes of Health (U54GM1049)

25‑LB Complications—Neuropathy Elevated Soluble Urokinase-type Plasminogen Activator Is a Pre‑ dictor of Incident Renal Disease 27‑LB SALIM S. HAYEK, SANJA SEVER, YI-AN KO, STAMATIOS LERAKIS, LAURENCE S. SPERLING, ARSHED A. QUYYUMI, JOCHEN REISER, Atlanta, GA, Boston, MA, Withdrawn Chicago, IL Background: Soluble urokinase-type plasminogen activator receptor (Su- PAR) is implicated in the pathogenesis of kidney disease but whether it pre- dicts incident renal dysfunction is unknown. Methods: The relationship between suPAR levels and renal function was investigated in 3683 patients recruited in the Emory Cardiovascular Biobank (mean age 63, 66% males, 17% Blacks, 32% diabetic, median suPAR 3040 pg/mL). Creatinine at enrollment and all subsequent values acquired during follow-up were collected. Incident kidney disease was defined as a decrease in eGFR<60 mL/min. The relationship between suPAR levels and eGFR at baseline and its change with time were analyzed using linear mixed model- ing adjusting for clinical covariates. Results: suPAR levels correlated with baseline levels of eGFR (r=-0.45, p<0.0001) and urine protein (r=0.22, p<0.0001), independently of demo- graphic and clinical characteristics. Higher suPAR levels were associated with a more rapid decline in eGFR with time irrespective of age, diabetes status or race (Figure 1A). Patients with the highest quartile of suPAR level had a three-fold increased incidence of CKD (Figure 1B). Conclusions: suPAR level is independently associated with parameters of renal function, decrease in eGFR and incident kidney disease. Whether suPAR is a modifiable risk factor for renal disease and therefore a potential treatment target needs further study.

28‑LB Role of TLR4 and HMGB1 in Changes in Pain in Type 1 and Type 2 Diabetic Animals 26‑LB MUNMUN CHATTOPADHYAY, El Paso, TX Comparing Medications that Can Cause Renal Tubular Harm vs. Peripheral sensory neuropathy is one of the most common complica- Nonharmful: Their Use Patterns, Health Services Utilization, and tions of diabetes. Accumulating evidence suggests that chronic low-grade Expenses inflammation involved in the pathogenesis of the disease. We hypothesize MARY L. DAVIS-AJAMI, JUN WU, JEFFREY C. FINK, Richmond, VA, Greenville, that continuous release of inflammatory mediators in the peripheral ner- SC, Baltimore, MD vous system causes the sensory neuropathy in diabetic animals; therefore The study compared population-level characteristics, individual-level blocking this increase will prevent or delay the development of neuropathy. use, health services utilization and expenses between individu- High mobility group box 1 (HMGB1), a nuclear protein released by injured als prescribed medications that can cause renal tubular harm versus those and severely stressed cells, promotes cytokine release via its interaction with any other or no medication(s) and compared them by co-existent chronic with the Toll-like receptor (TLR). In this study we investigated the changes in disease in adults with pre-dialysis kidney disease. This retrospective study cytokine/chemokine profiles in the dorsal root ganglia (DRG) and compared used Medical Expenditure Panel Survey (MEPS) household component lon- the changes in behavior with treatment with TLR4 inhibitor in type 1 diabetic gitudinal files (years 2006-2012; panels: 11-16) including adults > 18 years (T1D) model of pain and HMGB1 inhibitor in type 2 diabetic (T2D) model of with pre-dialysis kidney disease. Two groups were created: 1) those pre- pain. At 6 weeks after hyperglycemia, diabetic rats demonstrated significant scribed medications that can cause acute tubular nephritis and/or tubular changes in thermal hyperalgesia manifested by a decrease in withdrawal toxicity (termed “harmful”) and 2) those with any other or no prescription latency to heat, mechanical hyperalgesia measured by the Randall Sellito medication(s). From published work, select drugs cited as possibly inducing method of paw pressure. Both T1D and T2D rats exhibited marked increases in IL1β and TLR4, TNFα, pp38, HMGB1, RAGE by 6 weeks after diabetes as ADA-Funded Research For author disclosure information, see page LB98.

LB7 Complications—Neuropathy

determined by the Western blot analysis. To determine whether increased

TLR4 level is responsible for the painful neuropathy in diabetic animals, we injected TLR4 antagonist TAK242 for 5 days at a dose of 1.5 mg/kg per day I.P. in T1D animals. We injected HMGB1 inhibitor Glycyrrhizin for 5 days/ week up to 2 weeks at a dose of 50mg/kg per day I.P. to T2D rats. Diabetic animals treated with TLR4 and HMGB1 inhibitors had significant decrease in mechanical hyperalgesia. This study suggests that TLR4/HMGB1 plays an important role in the inflammatory aspect of the painful neuropathy in POSTERS

Complications T1D and T2D animals. Understanding the mechanisms of diabetic neuropathy

Acute and Chronic may provide a novel treatment approach for this difficult-to-treat complica- tion of diabetes. Supported By: American Diabetes Association (7-12-BS-021 to M.C.)

29‑LB 31‑LB Autoantibodies to Calcium Channels in Type 1 Diabetes Mediate MRS-based In Vivo Biomarkers Characterizing Chronic Uncon‑ in Pancreatic Beta Cells trolled Hyperglycemia at Ultra-high Field (9.4 Tesla) DAISY MOHANASUNDARAM, DEVANGI MODI, SKYE PEARS, TOM GORDON, SAKTHIVEL SEKAR, SANKAR SERAMANI, BOOMINATHAN RAMASAMY, PETER MICHAEL JACKSON, Adelaide, Australia CHENG LEE PING, KISHORE KUMAR BHAKOO, Singapore, Singapore Type 1 diabetes (T1D) is an autoimmune disease caused by the loss of Impact of metabolic changes in the brain due to hyperglycemia and/or dia- significant numbers of functional beta cells, resulting in loss of blood glucose betes are poorly understood due to difficulty in measuring the brain metabo- regulation. Autonomic neuropathy is a common but poorly understood com- lism in-vivo. Recent advances in ultra-high field MR spectroscopy allow us plication of T1D resulting in significant morbidity. Previously, we have demon- to observe metabolic changes with increased spectral resolution. The study strated that autoantibodies derived from T1D patients and directed against aimed to identify in-vivo biomarker(s) of neurodegeneration due to chronic L type Voltage gated calcium channels (VGCC) contribute to autonomic dys- uncontrolled hyperglycemia using a 9.4T MRI scanner. Hyperglycemia was function of the and bladder. We further demonstrated induced in a cohort of male Wistar rats (~300g, n=6) with STZ (60 mg/kg, IV). that these antibodies directly alter the function of the rat line, Rin Blood glucose and HbA1c levels were documented. MRS data were acquired A12, however the mechanism behind this effect was not clear. In the current on 2, 6, 10, 14, 18 and 40 weeks post STZ injection employing a PRESS se- study, we have attempted to address how these anti-VGCC antibodies cause quence with a voxel (2.5×4×4 mm3) localized in the hippocampus [TR/TE/ disruption of Rin cell function, by examining the effect of anti-VGCC autoan- TA/NA: 4000ms/13ms/8 min/128]. Metabolite quantitation was performed tibodies on the induction of oxidative stress in pancreatic beta cells using using LC Model. Amongst the various brain metabolites (glucose, glutamate, a novel method. Immunoglobulin from patients and healthy controls were , GABA, , myo-, NAA and taurine) quantitated, purified from serum using the caprylic acid method. Rin m5F and Min 6 cells significant reduction (p<0.05) in glutathione and increase in glucose and were treated with 2’, 7’-Dichlorofluorescein Diacetate (DCFDA) at a final Myo-inositol were apparent with the progression of the condition. Glutathi- concentration of 5uM for 5 min in the dark. DCFDA treated cells were then one has major role in sequestering free radicals and toxins from normal tis- incubated for 2 hrs at 37C with patient or control IgG at a final concentration sues; glutathione depletion in the brain plays a major role in oxidative stress of 0.4 mg/ml. The cells were then analysed by flow cytometry to detect the (Koji et al, 2013) and an accumulation of destructive free radicals, which then level of Reactive Oxygen Species production (ROS) in terms of mean DCFDA progressively leads to neurodegeneration. Furthermore, myo-inositol has intensity. We found a significant increase in the level of ROS production in been reported as a biomarker for glial cells; elevated level of myo-inositol both Rin and MIN cells treated with patient IgG compared to cells treated in the hippocampus has been associated with mild cognitive impairment in with controls. This preliminary work is the first to demonstrate that anti- Alzheimer’s disease (Miller et al, 1993). We report that levels of glutathione VGCC autoantibodies mediate a stress response in pancreatic beta cells, and myo-inositol may serve as in-vivo biomarkers for identifying progres- and suggest that these antibodies, in addition to contributing to autonomic sive oxidative stress and cognitive impairments respectively, as a result of dysfunction, may also form part of the immunological insult responsible for chronic uncontrolled hyperglycemia; thereby emphasizing the need for early destruction of pancreatic beta cells. therapeutic interventions. Furthermore our study exemplifies the value of 1H-MR spectroscopy to characterize neuronal metabolism in-vivo. 30‑LB Correlates of Somatic and Autonomic Neuropathy in Colombian Pa‑ 32‑LB tients with Type 2 Diabetes Role of Peroxynitrite in the Progression of Small Nerve Fiber Func‑ CARLOS O. MENDIVIL, CLAUDIA R. TIQUE, ARTURO ORDUZ, JOSE L. CÁRDENAS, tion in Diabetes Mellitus JORGE E. PATIÑO, WILLIAM KATTAH, Bogotá, Colombia JOSH EDWARDS, CAROLINA M. CASELLINI, ELLYN KORNFEIND, HENRI PAR- Diabetic neuropathy is greatly under-recognized, and its causes insuf- SON, IRINA G. OBROSOVA, MARK A. YOREK, AARON I. VINIK, Norfolk, VA, Baton ficiently understood. We assessed factors associated with cardiovascular Rouge, LA, Iowa City, IA autonomic neuropathy (CAN), distal symmetric polyneuropathy (DSP) and Accumulation of nitrotyrosine (NT) has been associated with nerve dys- sudomotor dysfunction (SD) in 154 patients with type 2 diabetes (DM2), function in diabetes mellitus (DM). The objective of this study was to evaluate age 61.4 +/- 9.5, diabetes duration 12.2 +/- 11.4 years. CAN diagnosis was the relationship between NT and nerve dysfunction in healthy controls (HC), made with the Ewing Battery of autonomic tests. DSP diagnosis was defined diabetic patients with (DM-DPN) and without diabetic peripheral neuropathy as a Total Symptoms Score (TSS) ≥ 5 or a Michigan Neuropathy Disability (DM-Non-DPN). We hypothesized that an association would exist between ® Score (NDS) ≥ 3. SD was diagnosed using the Neuropad test. The overall NT levels and the progression of neuropathy. This was a two year prospec- prevalence of CAN, DSP and SD was very high at 68.0%, 45.0% and 67.5%, tive study of 60 patients (20 HC, 14 DM Non-DPN, and 26 Definite DM-DPN). respectively. Prevalence increased across quartiles of diabetes duration for Neuropathy diagnosis was stratified according to the Toronto Consensus CAN (from 56.8 to 86.3%, p-trend: 0.008), and NDS-defined DSP (from 33.3 guidelines. Individuals were assessed at baseline and after two years using to 58.3%, p-trend: 0.0036). Mutually-adjusted logistic models including 12 clinical neuropathy scores, quantitative autonomic function tests (QAFT), in- predictors showed significant associations of age (OR 1.08, 95% CI: 1.02- traepidermal nerve fiber (IENF), and nerve conduction studies (NCS). 1.14) and A1c (OR 4.34, 95% CI: 1.13-16.6) with CAN. Plasma triglycerides and Mean NT levels (pmol/mg protein) in serum were 3.17 ± 0.29 for HC, 4.22 ± BMI were significantly associated with SD. No variable was associated with 0.36 for DM Non-DPN, and 4.83 ± 0.38 for Definite DM-DPN. Mean NT levels DSP. Our results highlight the extreme importance of good glycemic control in diabetic subgroups were significantly higher than controls. A deterioration in the prevention of CAN, and suggest that in many patients with DM2 CAN of small nerve fiber (SNF) function was observed in the DM Non-DPN group and DSP are allowed to progress over time without effective interventions. after two years for total neuropathy scores (p=0.007), neuropathy impair- ment scores of the lower limbs (NIS-LL) sensory scores (p=0.004) and NIS-LL total scores (p=0.004) as well as QAFT measures of heart rate variability (p=0.02). However, baseline NT levels, HbA1C, triglyceride levels, HDL, LDL, and blood pressure values were found to not be predictors of SNF deteriora- tion upon simple and multivariable . Our findings suggest in this preliminary study none of the traditional predictors of SNF, including

ADA-Funded Research For author disclosure information, see page LB98.

LB8 Complications—Ocular

NT, proved to be significant contributors of the progression of neuropathy. are associated with pathologies of disease including diabetes, diabetic com-

Larger studies are needed to further explore the relationship between NT plications, aging, and neurodegenerative diseases. In the present work, we levels and the progression of SNF neuropathy. found that MG significantly induced the expression of Supported By: National Institutes of Health SP1 (specific protein 1) and NF-Y (nuclear transcription factor Y) using Cig- nal finder reporter array in human retinal pigment epithelial cells (ARPE-19). Cytotoxicity were performed using the MTT assay in MG (5, 10 μM) or high Complications—Ocular glucose (HG, 30 mM)-treated ARPE-19. According to the FACS analysis with Annexin V staining, apoptotic cells were significantly increased in MG, HG, POSTERS 33‑LB and MG-HG-cotreated cells. MG induced the expressions of SP1 (1.54 fold) Complications and NF-Y (2.29 fold) and activated ERK1/2 and c-Jun in a dose dependent Acute and Chronic Differential Profiling in the Retina of Diabetic manner in ARPE-19. The C/EBP homologous protein (CHOP), activated by Rats ER stress, and interaction of SP1 and NF-Y also were increased in MG- HONG-LIANG WANG, JING HAN, TIANTIAN LV, YAN WU, GAIMEI HAO, JIE HE, treated cells. Further, tight junction such as ZO-1, occluding, and WEI WANG, Beijing, China Diabetic retinopathy (DR) is a common microvascular complication of claudin-1 were significantly increased by MG or HG. Taken together, these diabetes characterized by high disability rate and low . In this results demonstrate that SP1 and NF-Y transcription factors are involved in study, we aim to investigate mRNA expression changes in the retina of rats the regulation of ER stress and expressions of tight junction by MG or HG. with diabetes induced by streptozocin (STZ) and probe into the mechanism Therefore, our finding that MG triggers the expression and direct binding of of DR, then provide experimental basis to the prophylaxis and treatment of SP1 and NF-Y and MG-induced SP1 signaling pathway may serve as novel DR. Six male SD rats were randomly divided into normal group and model mechanisms against diabetic retinopathy. group. A single intraperitoneal injection of STZ 65mg/kg was used to in- Supported By: K14040 duce diabetic rats. The normal group was given isopyknic sodium citrate. mRNA of the retina was extracted after 32 weeks of diabetes. The mRNA 36‑LB expression changes were identified using rat genome microarrays, and gene RPE Barrier Breakdown in Diabetes: Is It Real? ontology (GO) analysis and the KyotoEncyclopedia of Genes and Genomes YUN-ZHENG LE, MEILI ZHU, Oklahoma City, OK (KEGG) were used to select target genes by function and pathway. Several Diabetic retinopathy (DR) is traditional regarded as a microvascular key up-regulated genes were CCR6, IL10RA, CXCL9, SOCS3 and TPO, which disorder. However, it is increasingly clear that the retinal pigment epithe- were further validated by Quantitative Real-time PCR (qPCR). Microarray da- lium (RPE) plays a critical role in “vascular leakage” in DR. To investigate ta analysis revealed that DR induced 138 genes up-regulated and 137 genes the significance of RPE barrier breakdown in DR, we developed an imaging down-regulated compared with the normal group. GO and Pathway analysis assay for RPE barrier-specific leakage (IOVS, 52:2160). To explore the role showed that the majority of change genes were associated with cytokine- of the RPE barrier in diabetic macular edema (DME), a major vision loss in interaction, cellular signal transduction and neuroactive DR, we examined the dynamics of fluorescein isothiocyanate (FITC)-dextran ligand-receptor interaction. Five genes were confirmed with qPCR, consis- passed through the RPE barrier in diabetic rodents. RPE barrier leakage was tent with the results from microarray. DR changed expression of many genes measured de novo by florescent microscopy of retinal sections from diabetic which regulated various biological functions. These findings might advance rodents injected intravenously with FITC-dextran. Computer-assisted quan- our understanding of the regulatory mechanisms underlying the evolution of tification was used to determine the relative levels of RPE- or endothelial DR, and might provide the novel therapeutic target in DR. barrier-specific leakage. The RPE barrier leakage was detected immediately after intravenous injection of FITC-dextran, indicating that the leakage from 34‑LB choroidal circulation to the retina was more efficient than that from retinal vessels. While the RPE barrier leakage occurred everywhere, there were P-MST and P-YAP Decreased in Rats with Diabetic Retinopathy clearly severe leakage sites (image: 6 mo diabetic rats). In addition, the RPE JING HAN, YAN WU, TIANTIAN LV, HONGLIANG WANG, JIE HE, GAIMEI HAO, barrier leakage appeared to be comparable, if not more, to that from the WEI WANG, Beijing, China The Hippo signaling pathway is a core kinase cassette that consists of endothelial barrier. Our data suggest a prominent role for the RPE barrier MST1/2, LATS1/2, SAV1 and MOB1. And YAP is a downstream target of this breakdown in “vascular leakage” in DR, which provides a cellular mechanism pathway. The Hippo-YAP signaling pathway plays crucial roles in organ size for DME patients with the cellular lesion near the RPE. control and development through modulating cell proliferation. Dia- betic retinopathy is one of the most prominent complications of diabetes and is characterized by vascular proliferation. But whether Hippo-YAP signaling pathway altered in diabetic retinopathy is not elucidated. In this study, SD rats were fasted for 14 hours before STZ injection. STZ was dissolved in citrate buffer and intraperitoneally injected at 65 mg/kg body weight. Age matched control rats received equal volume of vehicle (citrate buffer). Rats with blood glucose levels higher than 16.7 mmol/L were considered to be diabetic and used for studies. After diabetes was induced for 32 weeks, ocu- lar blood flow velocities in central retinal artery were determined by Color Doppler imaging and the eyes were isolated for retinal digest preparations and transmission electron microscope. The expression of P-MST1/2 and P-YAP in retinas were determined by immunohistochemistry. The results showed that compared with normal group, the blood flow in central retinal artery decreased, basement membrane of blood vessel thickened, capillary density increased and the ratio of endothelial cells to pericytes elevated in diabetic group. Meanwhile P-MST1/2 distributed mainly in inner Supported By: American Diabetes Association (1-10-BS-94 to Y-Z.L.); National plexiform layer and P-YAP distributed mainly in pigment epithelium layer of Institutes of Health (GM104934, EY020900, EY021725); Presbyterian Health Founda- retinas in rats. In diabetic group, P-MST1/2 and P-YAP decreased compared tion; Oklahoma Center for Adult Stem Cell Research; Choctaw Nation with normal group. In conclusion, Hippo-YAP pathway maybe participates in the process of diabetic retinopathy. These findings will contribute to provide 37‑LB new mechanism underlying diabetic retinopathy and lay a foundation for im- Improvements in Diabetic Retinopathy (DR) following Ranibizumab proving new drugs to ameliorate diabetic retinopathy. (RBZ) Medical Therapy JEFFREY S. HEIER, CHIRAG P. SHAH, PIN-WEN WANG, SHAMIKA GUNE, ANNE 35‑LB FUNG, Boston, MA, South San Francisco, CA DR, a diabetic microvascular complication of the retina, is a leading cause Methylglyoxal Induces Expressions of CHOP and Tight Junction via of blindness in American adults. DR worsens over time and diabetic macular SP1 and NF-Y Transcription Factors in ARPE-19 edema (DME) can develop at any stage of DR. Panretinal photocoagulation BO-JEONG PYUN, Daejeon, Republic of Korea Methylglyoxal (MG), a highly reactive metabolite of glucose, is a major (PRP) has been the standard of care since the early 1990s to treat prolif- cell-permeant precursor of advanced glycation end products (AGEs). AGEs erative DR (PDR) but leads to irreversible loss of tissue and visual field. In Feb 2015, the FDA approved RBZ (Lucentis®) for the treatment of DR (non-

ADA-Funded Research For author disclosure information, see page LB98.

LB9 Diabetic Dyslipidemia

proliferative DR [NPDR] and PDR) in patients (pts) with DME; the first medical HOMA-R, FFA or BMI, suggesting that decreased FFA with ipragliflozin is not

therapy to receive that label. This analysis summarizes changes in DR sever- a consequence for lowered blood glucose levels or enhanced beta-cell func- ity with RBZ therapy in pts with DME in RIDE and RISE, 2 parallel phase 3 tion. Significant negative correlations between the changes (Δ) of FFA and trials. Pts (N = 759) were randomized to monthly 0.3 mg RBZ, 0.5 mg RBZ, ΔHOMA-B (R=-0.434), and positive correlations between ΔFFA and ΔHbA1c or sham injection. At mo 24, pts in the sham arm crossed over to monthly (R=0.432) were observed only in ipragliflozin group, indicating that reduction 0.5 mg RBZ. At mo 36, 500 pts entered an open label extension (OLE) and of FFA is linked to enhancement of beta-cell function and decreased blood received 0.5 mg RBZ PRN based on worsening vision and retinal thickness. glucose levels with this drug. By contrast, no correlations were observed DR severity was graded on the ETDRS DR Severity Scale using color fundus between ΔFFA and ΔHOMA-R or between ΔHOMA-B and ΔHOMA-R in ip- POSTERS

Complications photos. Pts received PRP at investigator discretion. At mo 24, significantly ragliglozin group, implying that decreased FFA and/or increased beta-cell

Acute and Chronic more DR improvement was observed with RBZ vs. sham: for 0.3 mg RBZ, function are not related to reduced insulin resistance with this drug. Taken 0.5 mg RBZ, and sham, rates of ≥ 2-step improvement were 38%, 36%, and together, these results implicate that beta-cell function is activated partly 5%, respectively; respective rates of ≥ 3-step improvement were 13%, 15%, through reduced lipotoxicity (FFA) with ipragliflozin. and 1%. At mo 36, 12 mo after sham-arm pts crossed to active treatment, rates of ≥ 2-step improvement were 39%, 39%, and 24% for 0.3 mg RBZ, 0.5 40‑LB mg RBZ, and sham/crossover, respectively; rates of ≥ 3-step improvement Acute Treatment Reduces PCSK9 in ob/ob Mice and Leptin- were 15%, 13%, and 4%, respectively. When pts switched to less frequent deficient Patients therapy in the OLE, 75% of pts receiving some treatment and nearly 60% of AMY E. LEVENSON, MARY HAAS, JI MIAO, REBECCA J. BROWN, RANGANATH pts not receiving any RBZ injections maintained their mo 36 DR scores at MUNIYAPPA, SUDHA B. BIDDINGER, Boston, MA, Bethesda, MD mo 48. By mo 24, 1%, 1%, and 12% of pts received PRP in the 0.3 mg RBZ, Proprotein convertase subtilisin/kexin type 9 (PCSK9) promotes degrada- 0.5 mg RBZ, and sham arms, respectively. Monthly RBZ therapy resulted in tion of the Low Density Lipoprotein Receptor (LDLR), and thereby increases meaningful improvements in DR severity and decreased the need for PRP serum cholesterol levels. Currently, there are several emerging pharmaco- laser when compared with sham. Some patients maintained improvements therapies aimed at inhibiting PCSK9 to decrease Low Density Lipoprotein with less-than-monthly RBZ dosing. Cholesterol (LDL-C) in patients. However, the endogenous regulation of PCSK9 is poorly understood. Leptin is a cytokine-like hormone that plays a key role in the regulation of energy metabolism and body weight, as well Diabetic Dyslipidemia as in lipid metabolism. Indeed, leptin treatment has been shown to reduce LDL-C and total plasma cholesterol in leptin deficient patients. In this study, 38‑LB we examined the effects of leptin on PCSK9 expression in both leptin defi- Exposure to Common Carrageenan Alone Leads to cient ob/ob mice and with , a hypoleptinemic state. Fasting Hyperglycemia and in Combination with High-Fat Diet Ex‑ In ob/ob mice, four days of recombinant mouse leptin treatment (24 mcg/ acerbates Glucose Intolerance and Hyperlipidemia without Effect day, delivered by an osmotic pump) decreased plasma PCSK9 concentra- on Weight tions (15.3±1.9 ng/mL versus 155.9±12.6 ng/mL in vehicle treated mice; SUMIT BHATTACHARYYA, LEO FEFERMAN, TERRY G. UNTERMAN, JOANNE K. n=5/group; p=0.001). In parallel, leptin treatment decreased hepatic Pcsk9 TOBACMAN, Chicago, IL mRNA expression by 93% (p=0.003). However, hepatic Ldlr mRNA and Exposure to the common food additive carrageenan caused glucose LDLR protein levels were also reduced with leptin treatment, and LDL-C was intolerance, insulin resistance, and impaired insulin signaling in human slightly increased. Lipodystrophic patients, treated for four to six months hepatocytes and C57BL/6J mice. Current experiments were performed to with a synthetic leptin analog (, ~4.4 mg/day via subcutaneous determine: the minimal amount of carrageenan which produced glucose in- injection), showed a 26% decrease in plasma PCSK9 concentration (221±102 tolerance; the impact of carrageenan in combination with high fat diet on ng/mL post-leptin treatment versus 298 ± 109 ng/mL pre-leptin treatment; glucose tolerance; and whether carrageenan alone increased fasting blood n=8; p=0.008). This decrease in PCSK9 was associated with a decrease in glucose and hemoglobin A1c. Carrageenan (10 µg/ml) was added to the wa- LDL-C (r=0.751, p=0.03). In summary, these data indicate that leptin replace- ter of C57BL/6J mice, and the impact compared to control mice on a regular ment can suppress PCSK9 levels in both mice and humans. In humans, the diet, mice on a high fat diet, and mice on the combination of carrageenan decrease in PCSK9 is associated with a decrease in LDL-C, suggesting that and high fat diet. Carrageenan exposure led to abnormal glucose tolerance some of the beneficial effects of leptin on plasma could be mediated after 6 days, and to elevated fasting blood glucose at 23 weeks. Effects of by PCSK9. carrageenan were similar to those in mice on the high fat diet, but without Supported By: National Institutes of Health-National Institute of Diabetes and weight gain, suggesting that carrageenan intake may be a useful mouse Digestive and Kidney Diseases (K125K12DK094721-03) model for non-obese diabetes. The combination of carrageenan and high fat diet shortened the interval to fasting hyperglycemia and increased levels 41‑LB of total cholesterol and triglycerides, compared to high fat diet alone. The American Diabetes Association 2015 and American Heart Associa‑ amount of carrageenan intake (~50 µg/day/25 gm mouse = 2 µg/g) is about tion 2013 Lipid Guidelines: Are They Interchangeable? half the anticipated daily intake in the average adult diet (250 mg/day/60 FATEMA H. AL HAMMADI, ASMA A. AL NUAIMI, JAMILA S. AL DHUHOURI, SAR- kg adult = ~4.2 µg/kg), suggesting that carrageenan intake may contribute AH AL SHAIKH, SARA BEULA, TAREK M. FIAD, Abu Dhabi, United Arab Emirates to the development of diabetes in association with the Western diet and Conventional practice of treating dyslipidaemia entails titration of sta- may exacerbate the effects of the high fat diet on glucose tolerance, insulin tin therapy aiming at achieving a goal LDL-C level. Two new guidelines, the resistance, and hyperlipidemia. ADA1 and the American Heart Association (AHA) 2 moved away from this Supported By: American Diabetes Association (1-12-BS-216 to J.K.T.) practice, instead, both introduced a risk-based decision-making on grounds of which, either moderate-intensity (M-I) or high-intensity (H-I) statin therapy 39‑LB is recommended 1, 2. This study aimed at assessing whether the 2 guidelines Effect of Ipragliflozin on Lipotoxicity and Beta Cell Function yields similar rates of statin initiation and dose-intensity. In the context of EIJI KUTOH, MITSURU HIRATE, ASUKA WADA, Tokyo, Japan primary CVD prevention, the impact of adopting the ADA guidelines among Besides genetic elements, several modifiable factors are linked to beta- 445 diabetics aged 40-75 years was: 1) all patients (100%) qualified for sta- cell deterioration including chronic hyperglycemia (glucotoxicity) and elevat- tins therapy; b) 97% of subjects were considered for H-I statin therapy. In ed free (FFA, lipotoxicity). Ipragliflozin, a SGLT-2 inhibitor, exerts its contrast, the impact of adopting the AHA guidelines to this age group is: 1) effects by facilitating glucose excretion through the kidneys, thereby reduc- all patients qualified for statins therapy; b) the proportion of patients con- ing glucotoxicity. However, effects of SGLT-2 inhibitors on beta-cell function sidered for H-I and M-I statins was 56% and 46% respectively. Among the 2 involving lipotoxicity remain unknown. The aim of this study is to explore this other age groups e.g. 20-39 years (n=99) and >75 years (n=24), specific rec- question. Treatment naïve subjects with T2DM were administered either 25- ommendations were made by the ADA but not by the AHA guidelines. Based 50 mg/day ipragliflozin (n=25) or 12.5-25 mg/day alogliptin (as a control, n=26) on the ADA guidelines, the proportion of patients between the ages of 20-39 monotherapy. The baseline characteristics were similar in these two groups. years being considered for M-I and H-I statins was estimated as 36% and At 3 months, in ipragliflozin group, significant reductions of HbA1c (from 30% respectively. Among the >75 years age group, 100% of patients will be 10.35% to 8.46%, NGSP), HOMA-R (-23.9%), FFA (-33.5%) and BMI (-2.9%) considered for statins initiation, the options being either M-I or H-I statins. were observed, while significant increases of HOMA-B (32.8%) were noted. In the setting of CVD secondary prevention, all 129 patients (100%) quali- In alogliptin group, similar reductions of HbA1c and increases of HOMA-B fied for H-I statin therapy according to both guidelines. In conclusion, the from those of ipragliflozin were observed, while no changes were noted in ADA and AHA guidelines on lipid management are not interchangeable with ADA-Funded Research For author disclosure information, see page LB98.

LB10 Foot Care—Lower Extremities much greater likelihood of using H-I statins in diabetic subjects aged 40- Foot Care—Lower Extremities

75 years when the ADA guidelines are used. Furthermore, the ADA but not the AHA/ACC guidelines provides specific guidance on statins treatment in 44‑LB the younger and the older age groups. (1) ADA. Diabetes Care 2015;38(suppl A Urea, Arginine, and Cream Shows Greater Efficacy in 1):S52 (2) AHA Guidelines. Circulation 2014;129(25 Suppl 2):S1-45. the Treatment of Severe Feet Xerosis in Type 2 Diabetic Patients in Comparison with Standard Emollient Glycerol Cream: A Random‑ 42‑LB ized, 8-Month, Assessor-blinded, Controlled Trial

Contrasting the Impact of the ADA 2014 and 2015 Guidelines on the MASSIMO MILANI, ADALBERTO FEDERICI, GIOVANNI FEDERICI, Milan, Italy, POSTERS Practice of Lipid Management Rome, Italy Complications Acute and Chronic FATEMA H. AL HAMMADI, ASMA A. AL NUAIMI, JAMILA S. AL DHUHOURI, SAR- An effective hydration of foot skin in diabetics is a relevant preventive AH AL SHAIKH, SARA BEULA, TAREK M. FIAD, Abu Dhabi, United Arab Emirates strategy in to maintain a healthy foot, contributing to reduce the risk The ADA 2014 guidelines, recommended the widely practiced approach of ulcers development. No long-term data are available regarding effects of whereby stain therapy is titrated, aiming at defined LDL-C goal1. The ADA emollient in treating severe lower limb skin xerosis (SS) in type 2 diabetics. 2015 Guidelines introduced a risk-based decision making for which moder- We evaluated efficacy of 8-month topical urea 5% with arginine and carnos- ate-intensity (M-I) or high-intensity (H-I) statin therapy is advocated2. This ine cream (UC) in comparison with a glycerin-based cream (SEC) in type 2 study aimed at assessing the impact of adopting the ADA 2015 Guidelines diabetic patients with moderate-severe SS of feet. We assessed the effect on an unselected diabetic population currently been treated in accordance of UC on feet skin hydration in a randomized, assessor-blinded compara- with the ADA 2014 guidelines1. Analysis included 698 diabetic patients. In tive study in 50 diabetic patients, aged 40-75 years, treated with UC (N=25) the context of primary CVD prevention, the impact of adopting the 2015 ADA or comparator (N=25) for 32 consecutive weeks. Primary study outcomes guidelines2 among diabetics aged 40-75 years (n=445) is: 1) the proportion were a 9-point grading Xerosis Assessment Scale (XAS) score and a 4-point of patients eligible for statins increased from 87% to 100%; b) H-I statin grading overall cutaneous score (OCS) evaluated at baseline, at weeks 4, 12, therapy usage increased from current level of 25% to 97%. Among the 20- and 32 by an investigator unaware of treatment allocation. In addition skin 39 years age group (n=99), the new guidelines will result in: a) an increase hydration and desquamation were objectively evaluated by means of Hydr8 in eligibility for statin initiation from current level of 40% to 66%; b) H-I bio-impedance analysis device at baseline and at week 32. statin use will increase from a current level of 3% to 30%. Among the >75 Results: UC induced significantly greater hydration than SEC (p=0.01) with years age group (n=24), the new guidelines will result in: a) proportion of a 91% reduction at week 32 in XAS score (from 5.5 to 0.5; p < 0.001) in statin eligible patients will increase from 92 to 100% b) in contrast to cur- comparison with baseline values. After 4 weeks, compared with the SEC rent use of H-I statins in 17% of subjects, the new ADA guidelines considers treated group, XAS score in UC treated group was significantly lower (1.0 vs. the options of either M-I or H-I statins initiation in 100% of subjects. Among 3.9; p= 0.048). At month 8 Skin hydration (+75%) and desquamation (-77%) subjects with history of CVD (n= 129), adopting the new ADA guidelines man- evaluated by Hydr8 statistically improved in UC treated subjects both in dates that all patients (100%) being considered for H-I statin therapy (up comparison with baseline and in comparison with SEC group. Application of from 46%). In conclusion, adopting the ADA 2015 lipid guidelines will lead urea 5%, arginine and carnosine cream for 8 consecutive months increases to a striking increase in proportion of patients initiated on statin therapy as skin hydration and alleviates the condition of SS in type 2 diabetic patients well as those offered H-I statins among all age groups. The highest impact in comparison with a control glycerol-based emollient cream with a greater will affect subjects aged ≤75 years, where the implementation of the new efficacy observed as soon as 4 weeks of treatment. recommendation will lead to an additional 13-26% of diabetic subjects be- Supported By: Isdin ing initiated on statin therapy as well as 3-10 fold increase in the use of H-I statins. (1) ADA. Diabetes Care 2014;37 (Suppl 1) S14-S80. (2) ADA. Diabetes 45‑LB Care 2015;38 (Suppl 1):S52. Topical Administration of Pirfenidone Increases Healing of Chronic Diabetic Foot Ulcers: A Randomized Crossover Study 43‑LB MARCELA JANKA-ZIRES, ANA C. URIBE-WIECHERS, PALOMA ALMEDA-VALDES, JOEL LOPEZ-GUTIERREZ, SONIA C. JUAREZ-COMBONI, FRANCISCO J. GOMEZ- Withdrawn PEREZ, Mexico City, Mexico Introduction: Diabetic foot is one of the most common and devastating complications of diabetes mellitus and the most frequent cause of amputa- tion of the lower extremity. With conventional treatment, diabetes ulcers heal in 30% of cases in 20 weeks. Pirfenidone is a topical medication with biological, anti-inflammatory and anti-fibrotic effects, which can be useful in chronic diabetic foot ulcers by activating the healing process. Methods: This is a randomized crossover study. Patients with diabetic foot ulcer Wagner 1 or 2, with at least 4 weeks duration were randomly assigned into two groups. Group 1 was first treated with topic pirfenidone treatment (PT) plus conventional treatment (CT) for 8 weeks. After this period, they continued with CT for additional 8 weeks. Patients assigned to group 2 were first treated with CT and subsequently with PT for the remaining 8 weeks. All patients attended the Diabetic Foot Clinic every week for 16 weeks. The primary end points were the complete ulcer healing and the percentage of size reduction. Results: Final data were obtained from 36 ulcers in 27 patients, 20 men and 7 women. The mean age was 57.4±12.5 and diabetes evolution 16.5 [14.5-23.7] years. Baseline ulcer size and depth were not different between groups. Fifty percent of patients in treatment with PT healed before eight weeks vs. 14.3% of patients in CT (P= 0.032). Between 8 and 16 weeks, 30.8% of patients with PT healed vs. 0% in CT group (P= 0.067). By week 8, the reduction in ulcer size was 98% [73-100] with PT vs. 57.5% [28.9-74] with CT, P= 0.012. By week 16, the reduction in ulcer size was 93% [42.7-100] with PT and 20% [8-72.1] with CT (P= 0.032). Conclusions: In diabetic chronic foot ulcers the addition of topical pirfeni- done to conventional treatment is associated with a superior percentage of ulcer healing and a significant reduction in the percentage size.

ADA-Funded Research For author disclosure information, see page LB98.

LB11 Diabetes Education

Diabetes Education 48‑LB The Beneficial Effect of Mediterranean Diet on Glycaemic Control 46‑LB in Youths with Type 1 Diabetes Mellitus: A Controlled Study THEOFANEIA TSACHALINA, IOANNIS KYRGIOS, EFTHIMIA EFSTRATIOU, MI- Withdrawn CHAIL MELISSINOS, KYRIAKOS KAZAKOS, ASSIMINA GALLI-TSINOPOULOU, Thessaloniki, Greece Mediterranean Diet (MedDiet) has been reported as an optimal diet for the prevention of chronic diseases and maintaining good health. Despite the fact that impact of MedDiet on type 2 diabetes and the metabolic syndrome in adults has been previously described, no data concerning MedDiet and young patients with type 1 diabetes mellitus (T1DM) have been reported. American Diabetes Association’s guidelines in 2014 recommended MedDiet for the management of T1DM. We aimed with this control study to inves- tigate the influence of MedDiet on glycaemic control in youngsters with T1DM. Twenty four adolescents with T1DM were consecutively enrolled and divided to follow either a 7 day Med- Diet or an ad libitum diet (ALD).

POSTERS The two groups did not differ statistically in gender, age, BMI, glycated haemoglobin (HbA1c) and required insulin dose (RID). Patients were asked to perform 6 blood glucose (BG) measurements daily for 2 weeks. The first week was for both group ALD and only 6 BG measurements. During the study

Behavioral M edicine, Clinical period a reduction in the second week was noted which was statistically

N utrition, Education, and Exercise significant greater in the intervention group (IG), at post prandial BG values (159 mg/dL vs. 117 mg/dL p=<0.001) at daily rates (163 mg/dL vs. 127 mg/dL p=<0.001) hypothetical HbA1c (7.2% vs. 6.0% p=<0.001) and RID (0.96 IU/kg vs. 0.92 IU/kg p=0.001). Also a significantly greater decrease in preprandial, average prandial, total daily BG, hypothetical HbA1c and RID was noted in the IG, as compared to the control group (p<0.05). As regards the 1-h and 2-h postprandial BG, although the decrease in the IG was greater, this difference did not reach the level of statistical significance (p>0.05). The increase in the number of total daily hypoglycaemias tended to be greater in the IG (2.77 vs. 0.45 p=0.09). Our study demonstrates that adopting a diet containing foods from the pyramid of MedDiet is recommended in adolescents with T1DM in order to maintain euglycaemia which thereby reduces the risk of long-term complications. 47‑LB Impact of a Type 2 Diabetes Education Program on Clinical Out‑ comes during Ramadan 49‑LB MAHMOUD IBRAHIM, LAURA N. MCEWEN, NAHED ALI, SAMIR H. ASSAAD- The Relationship between Online Activity and Biometric Tracking KHALIL, HYAM R. TANTAWI, GAMELA NASR, SHAYAN MOHAMMAD MORADI, and Medication Adherence among Members with Diabetes ALY A. MISHA’L, FIRAS A. ANNABI, EBTESAM M. BA-ESSA, SUHAD M. BAHIJRI, MICHAEL TAITEL, JENNY JIANG, OSAYI AKINBOSOYE, GREGORY ORR, Deerfield, IL JAAKKO TUOMILEHTO, WILLIAM H. HERMAN, McDonough, GA, Ann Arbor, MI, In 2013, Walgreen Co., a national community pharmacy and retailer, Ismaïlia, Egypt, Alexandria, Egypt, Cairo, Egypt, Lexington, KY, Amman, Jordan, Dam- launched an online rewards program to help rewards program members mam, Saudi Arabia, Jeddah, Saudi Arabia, Helsinki, Finland track physical activity and biometrics. In April 2014, the program expanded Muslims who fast during Ramadan abstain from eating and drinking from to reward members for connecting devices and logging blood glucose (BG). before dawn until after sunset. The ADA has recommended that people with The study is to determine the relationship between program member en- diabetes who fast receive education to achieve a safer fast. The objective gagement and adherence to oral diabetes medications (ODMs), with focus of this study was to determine if pre-Ramadan education resulted in a safer on physical activity and BG tracking. This is a retrospective cohort study fast for people with type 2 diabetes (T2DM). Participating clinics in Egypt, of members newly enrolled in the Walgreens Balance Rewards for healthy ™ Iran, Jordan, and Saudi Arabia were randomized to provide patients with choices (BRhc) program between May and June 2014 who logged activities T2DM who intended to fast during Ramadan 2014 an individualized educa- such as steps (walking, running) and biometrics (body weight, BG) within 6 tion program or usual care. There were 8 intervention and 8 control clinics. months of enrollment and filled at least one medication in 2014. Steps logged The education program addressed meal planning, physical activity, blood were converted into miles on a 2,000:1 basis. Proportion of Days Covered glucose monitoring, and acute metabolic complications, and provided an (PDC) was used to measure adherence and calculated from each member’s individualized diabetes treatment plan. Pre-Ramadan surveys were admin- first prescription fill date (Index) in 2014 to December 31, 2014. A total of istered to 1010 people, 857 (85%) of whom also completed post-Ramadan 1,855 new BRhc members met the study criteria. Of these, 735 members surveys. Of these, 774 reported having T2DM and fasting during Ramadan. tracked their BG and 1,309 tracked steps, with 235 members logging steps In the latter group, age (mean±SD) was 48±10 years, 59% were female, BMI more than 1 mile/day. BRhc members who filled ODMs were older and had was 30±4 kg/m2, and HbA1c was 8.8±1.4%. After Ramadan, those who at- more co-morbidity compared to the general BRhc member population with tended clinics that provided individualized education were more likely to any prescription in 2014 (median age = 46.9 years vs. 38.1 years; median have modified their diabetes treatment plan during Ramadan (97% vs. 88%, maintenance medication count = 5 vs. 2). Members who tracked their BG p<0.0001), to perform self-monitoring of blood glucose at least twice daily levels had significantly higher adherence to ODMs compared to non-trackers (70% vs. 51%, p<0.0001), and to have improved knowledge about hypogly- (82.9% vs. 77.5%; Diff = 5.4%; Increase = 6.97%, P<0.001). And, compared to cemic signs and symptoms (p=0.0007). Those who attended clinics that pro- members who logged less than 1 mile/day, members who logged at least 1 vided education also reduced their BMI (-1.1±2.4 kg/m2 vs. -0.2±1.7 kg/m2, mile/day over the 180-day tracking period had significantly higher adherence p<0.0001) and HbA1c (-0.7±1.1% vs. -0.1±1.3%, p<0.0001) during Ramadan to ODMs (vs. 86.4% vs. 78.5%; Diff = 7.9%; Increase = 10.05%, P<0.0001). compared to those who attended control clinics. There were more mild (77% This study demonstrated a significant relationship between higher levels of vs. 67%, p=0.0031) and moderate (38% vs. 19%, p<0.0001) hypoglycemic member engagement in healthy activities and biometric tracking through ™ events reported by those who attended intervention clinics, however, they BRhc program and greater adherence to prescribed ODMs. reported fewer severe hypoglycemic events (23% vs. 34%, p=0.0017). In conclusion, this individualized education and diabetes treatment program helped patients with type 2 diabetes achieve a safer Ramadan fast.

ADA-Funded Research For author disclosure information, see page LB98.

LB12 Exercise

50‑LB Table. Myths in IT and in Non-IT Groups. Accessible Care Model to Improve Glycemic Control in High Risk Teens and Young Adults with Type 1 Diabetes (T1D): Lessons from Myth % Non-IT % IT OR IC 95% P the Take Charge Clinic (TCC) Group Group KATHERINE WENTZELL, ASHLEY ATKINS, JULIE GRIFFITH, JOYCE KEADY, - (1) Insulin use is similar 51.7% 25.4% 3.41 1.91-5.16 0.0001 TANY MARTIN, KERRY MILASZEWSKI, CINDY PASQUARELLO, ELLA STEPHENS, that use illegal drugs. LORI M. LAFFEL, Boston, MA (2) The insulin injections 25.6% 12.1% 2.49 1.29-4.77 0.005 Older teens and young adults with T1D experience suboptimal glycemic are painful. control and often miss clinic appointments; the Take Charge Clinic (TCC) was (3) The use of insulin means 45.7% 26.0% 2.40 1.48-3.88 0.0001 created as a quality improvement effort to overcome these challenges. TCC that I will not be able to was a nurse-led weekly walk-in clinic, providing increased care accessibility have a normal life. and support (in-person and by text messaging), directed at high risk young (4) The use of insulin brings 35.4% 19.8% 2.21 1.25-3.89 0.005 persons with T1D, ages 16-25 with A1c >9%, missed appointments or a re- complications such as cent DKA episode. During the TCC, patients saw either an RN/CDE or NP for blindness, amputation standard diabetes education and care. A trained non-medical staff member and even death. met briefly with each patient during the TCC to provide support; each patient (5) If I start using insulin, 58.5% 50.0% 1.41 0.89-2.27 0.141

received a $10 gift card after meeting with support staff. During the 6-month I will need to use it for POSTERS pilot, 23 young persons had 40 unique TCC encounters. Participants (35% the rest of my life. male, 35% pump users) had a mean age of 18.7±2.2 years, T1D duration of (6) The use of insulin leads 17.0% 22.0% 0.73 0.39-1.34 0.311 9.1±4.6 years and initial A1c of 11.0±1.8%. Participants attended between 1 to weight gain. and 6 visits (both regular and TCC visits) during the 6 months (mean 2.3±1.6 Behavioral M edicine, Clinical visits, median 2 visits). Participants attending ≥2 visits (n=13) had a mean N utrition, Education, and Exercise A1c improvement of 0.45±0.8 (p=0.06). Additionally, if the study window is 52‑LB extended 30 days to see effect beyond 6 months, there was a significant Associations between Diabetes Knowledge and Glycemic Control improvement in A1c for this cohort (n=17) from a baseline A1c of 11.0±1.6% among Incarcerated Persons with Diabetes to 10.3±1.2% (p=0.001). Support staff sent 118 text messages (reminders to LOUISE A. REAGAN, WILLIAM BARTA, New York, NY, Storrs, CT attend clinic, support for diabetes goals set at visits) to 20 patients and 7 pa- While there is abundant research in the community describing how fac- tients replied with 44 texts. The clinic was designed to be walk-in, yet only 1 tors such as knowledge about diabetes, and race/ethnicity influence glyce- patient attended without scheduling. Participants reported that short-notice mic control, research of this nature in the incarcerated diabetic population appointment availability and increased visit frequency were helpful. These is nonexistent. In order to develop effective diabetes programming and pre- pilot results suggest that the TCC for high risk young persons with T1D may vent complications, it is imperative that we begin to understand the factors improve glycemic control; the combination of increased care accessibility, that influence glycemic control in this population. In a prior cross-sectional support from non-medical staff and text messaging may enhance engage- study of 124 incarcerated persons (M age 47.3 years, SD 9.46) with diabetes ment and empowerment with care. (12.9% type 1, 59.7% type 2 and 27.4% unaware of type), we found that dia- betes knowledge (Spoken Knowledge for Low Literacy in Diabetes) (SKILLD) 51‑LB was positively associated (p<0.001). This result is contrary to findings from Myths about Insulin Therapy in Latin Patients with Type 2 Diabetes research with community dwelling individuals that has shown diabetes JUAN C. LIZARZABURU, JOSE VALERA, GABRIELA VARGAS, SOFIA VILLANES, knowledge to have no relationship or an inverse relationship to glycemic FLOR VENTO, LORENA VILLENA, YOBANA BELTRAN, BLANCA FUENTES, JOSE control. For this secondary analysis, we hypothesized that race/ethnicity, LACA, EIKO WATANABE, LIZARDO TORRES, Lima, Peru and length of incarceration were moderating factors on the relationship A barrier to insulin therapy (IT) in diabetic patients is the presence of between diabetes knowledge (SKILLD) and glycemic control (log10 HbA1c). myths about its use. There are few publications about this topic in Latins. Participants were 93.5% male, 40% black, 37% white and 23% Latino with We reviewed six myths described in the literature. The aim of the study was 77% having HS, GED or less education, M HbA1c 8.2 and on 85% on insulin. to describe the presence of myths about IT in patients with type 2 diabetes Results confirm our hypothesis that length of incarceration and race/ethnic- (T2D), at the Central Air Force Hospital in Lima-Peru. We conducted a cross- ity moderate the association of diabetes knowledge (SKILLD) and glycemic sectional study from January-December of 2014. Summary statistics for 360 control. Consideration of the influence of duration of incarceration and race/ from 5236 T2D patients was evaluated. Patients with type 1 diabetes mel- ethnicity should be explored when developing diabetes programming for in- litus, gestational diabetes, illiterate were excluded. We used a survey, us- carcerated persons with diabetes. ing Likert-scale, grouped in: agree, disagree or indifferent respect the myth. Stepwise logistic regression was used. Of the study population with a mean age of 67.4±10.7 years, 37.2% were on IT and 60.8% were female. The mean Exercise disease duration was 10.3±9.2 years. In the IT group, 67.3% had received Education in Insulin Use (EIU). We found that the most common myth was 53‑LB (5) with 48%, while the myth less frequent was (2) with 13.9%. The Non-IT Interrupting Prolonged Sitting Modulates Glycemic Control in group had greater presence of myths. The myth (1) was 3.4 times more pres- Adults with Type 2 Diabetes ent in Non-IT group regarding the IT group with p <0.05. Greater presences PADDY C. DEMPSEY, JENNIFER M. BLANKENSHIP, NEVILLE OWEN, NORA of myths were in patients with non-EIU, but not significant differences re- STRAZNICKY, NEALE COHEN, BARRY BRAUN, BRONWYN A. KINGWELL, DAVID garding EIU patients among the IT group The presence of myths in the Latin DUNSTAN, Melbourne, Australia, Amherst, MA, Fort Collins, CO patient with T2D is high. It was higher in the patient on Non- IT than patients Interrupting prolonged sitting with light activity lowers postprandial plas- on IT, but its presence was independently if they received or not education. ma glucose in overweight/obese adults, but the effect in individuals with type 2 diabetes (T2D) is unknown. We studied the effect of uninterrupted sitting compared to sitting broken up by brief bouts of light intensity walking or by simple resistance activities on glycemic control in T2D patients. In a randomized crossover trial, inactive adults with T2D consumed a standard- ized eucaloric diet over 22 h (9am - 7am) while wearing a continuous glucose monitor system for 3 x 8 h conditions (6-day washout): i) SIT: uninterrupted sitting (control); ii) LW: sitting + 3 min bouts of light-intensity walking at 3.2 km/h every 30 min; and iii) SRA: sitting + 3 min bouts of simple resistance activities (alternating half-squats, calf raises, brief gluteal contractions and knee raises) every 30 min. Over 22 h, both LW and SRA significantly reduced mean [interstitial] glucose, time in hyperglycemia (glucose > 10 mmol/L) and glycemic variability (quantified via the SD of mean glucose and mean ampli- tude of glycemic excursions) relative to uninterrupted sitting (Table). These simple interruptions to sitting significantly reduced the time in hyperglyce- mia, mean glucose and glycemic variability in adults with T2D. With the ubiq-

ADA-Funded Research For author disclosure information, see page LB98.

LB13 Exercise

uity of sedentary behaviours and the low adherence to structured exercise, pants showed significantly higher insulin levels compared with moderately this approach has the potential to be beneficial and practical. fit (8.20±4.80 vs. 6.17±2.59 μU/ml, p=0.024) and highly fit (vs. 5.32±3.57 μU/ Table. (A) Participant Characteristics and (B) Effects of the Three Trial ml, p=0.008). Circulating adiponectin and chemerin levels were also asso- Conditions on Glycemic Control. ciated with fasting insulin levels after adjustment for gender, age, stage, and BMI. To study combined impact of adiponectin and chemerin levels on (A) Participant characteristics (B) Effects of the three trial conditions on measures of glycemic control over 22 h fasting insulin levels participants were divided into four groups according to their adiponectin and chmerin levels. Participants in high adiponectin Characteristic N or mean Measure SIT LW SRA and low chemerin group showed lower fasting insulin level (4.79±2.14 vs.

(95% CI) of glycemic (control) control 8.49±4.64 μU/ml, p=0.006) compared with participants with low adiponec- tin and high chemerin levels. Multiple linear regression analysis confirmed Number of study 14 M 10 F Time in hyper‑ 60.3 37.5 26.5 that adiponectin and cardiopulmonary fitness (β=-0.224, p=0.009; β=-0.267, participants glycemia (%) (49.2, 71.3) (26.5, 48.6)** (15.5, 37.6)** p=0.006) were independently associated with fasting insulin level. Our re- Age (yr) 62.3 (64.8, 59.8) Time in hyper- 13.3 8.3 5.8 sults suggest that physical fitness, adiponectin and chemerin levels may glycemia (hr) 0.8, 15.7) (5.8, 10.7)** (3.4, 8.3)** contribute to circulating levels of insulin. Findings from the current study BMI (kg/m2) 33 (34.4, 31.7) Mean interstitial 11 9.4 8.6 may suggest that exercise influences the prognosis of colorectal cancer pa- glucose (mmol/L) (10.2, 11.8) (8.5, 10.2)** (7.8, 9.4)** tients by influencing circulating levels of adiponectin and chemerin as well HbA1c (%) 7.2 (7.5, 7) SD of mean 2.2 1.9 1.7 as physical fitness level. POSTERS interstitial (2, 2.5) (1.7, 2.2)** (1.5, 2)** Supported By: National Research Foundation of Korea (NRF-2010-0009048); glucose National R&D Program for Cancer Control, Ministry of Health and Welfare, Repub- Note: All participants were Metformin/diet MAGE (mmol/L) 104.94 85.5 76.18 lic of Korea (1120230)

Behavioral M edicine, Clinical controlled individuals with type 2 diabetes. (92.11, 117.78) (72.66, 98.34)** (63.35, 89.02)** N utrition, Education, and Exercise SD=standard deviation; MAGE=mean amplitude of glycemic 56‑LB excursions. *difference from SIT (P < 0.05); **difference from SIT Exercise Increases Insulin-induced Microvascular Recruitment in (P < 0.001); Analysed using multi-level mixed models, controlling for the Myocardium during Nutrient Overload age and BMI. Data are mean (95% CI). ERIK M. VAN POELGEEST, ERIK H. SERNÉ, VICTOR W.M. VAN HINSBERGH, YVO Supported By: National Health and Medical Research Council (1081734) M. SMULDERS, FEMKE M.P. HOEVENAARS, ETTO C. ERINGA, Amsterdam, Neth- erlands 54‑LB Impaired microvascular perfusion in muscle contributes to insulin resistance Effect of a 12-Week Home-Based Exercise Intervention on Fasting and, in the heart, determines susceptibility to ischemia. In healthy individu- Insulin and Adipocytokine in Colorectal Cancer Survivors: A Ran‑ als, insulin is known to induce vasodilatation of arterioles which subsequently domized Controlled Trial leads to an increase in muscle microvascular perfusion. This response is im- MI KYUNG LEE, JI-YOUNG KIM, DONG-IL KIM, DONG-WOO KANG, JI-HYE PARK, paired in obese individuals, and may be improved by exercise. We studied KI-YONG AHN, NAM-KYU KIM, JUSTIN Y. JEON, Seoul, Republic of Korea whether exercise prevents insulin-induced microvascular recruitment in skel- High circulating insulin levels are associated with an increased risk of re- etal muscle and the heart during nutrient overload. During two weeks, C57Bl/6 currence and mortality in early colorectal cancer (CRC). We conducted a ran- mice were fed chow (control), a western diet, alone (WD) or combined with domized controlled trial to determine the effect of a 12-week home-based treadmill running (WD+Ex). Microvascular perfusion was studied using con- exercise program on fasting insulin, adipocytokines, and physical function trast ultrasonography during a hyperinsulinemic euglycemic clamp. In mice fed in stage II-III CRC survivors. One hundred and twenty-three stage II-III CRC a normal diet insulin increased microvascular blood flow in skeletal muscle survivors were randomly assigned to either a home-based exercise (n=62) or (1.00+0.29 to 1.18+0.48, p<0.05) and myocardium (1.00+0.43 to 1.39+0.61, usual care (n=61) group for 12 weeks. The goal of the home-based exercise p<0.05). Insulin enhanced blood volume and blood velocity in myocardium, program was to increase the levels of exercise to 18 metabolic equivalent while increasing only blood volume in skeletal muscle. Western diet reduced task hours per week. The primary outcome was fasting insulin levels and peripheral insulin sensitivity and exercise partially restored that reduction secondary outcomes were adipocytokine levels and physical function, mea- (GIR in µm/kg/min: control: 85.24+-22.92; WD: 52.07+-26.94, p<0.05; WD+Ex: sured by 6 minute walk test. A total of 99 (80.5%) participants completed 65.83+-38.57, ns). Western diet impaired insulin-induced enhancement of myo­­ the trial. Intention-to-treat analysis indicated that fasting insulin level was cardial blood volume, and exercise prevented this impairment (1.00+0.63 to significantly decreased by 1.0 µU/ml (-16.67%) in exercise group while no 1.05+0.51, 1.03+0.36 to 1.21+0.46, p<0.05). In skeletal muscle western diet change was observed in the control group (between group difference, mean impaired insulin-induced increase of blood flow, but this was not prevented by -0.9, 95% CI: -1.8 to -0.01, p=0.042). Further analysis showed that tumor exercise. Running distance correlated with blood volume during hyperinsuline- necrosis factor (TNF)-α level was significantly reduced in exercise group mia in myocardium (r=0.51, p=0.05), but not in skeletal muscle. Exercise did not compared with control group (between group difference, mean -0.5, 95% increase muscle perfusion in mice fed a normal diet. In conclusion, exercise CI: -0.9 to -0.1, p=0.029). Physical function and fitness level measured by prevents western diet-induced impairment of insulin-induced microvascular 6-min walk test, chair to standing test, and push up test were significantly perfusion in myocardium, but not in skeletal muscle. Our findings highlight a improved in the exercise group compared with control group (p<0.05). protective effect of exercise in the coronary microcirculation. Home-based exercise program was effective in reducing fasting insulin, TNF-α levels and improving physical function. 57‑LB Supported By: National Research Foundation of Korea (NRF-2010-0009048); Protective Association of Physical Activity with Sexual Dysfunc‑ National R&D program for Cancer Control, Ministry of Health and Welfare, Repub- tion in Men with 50 or More Years of Type 1 Diabetes lic of Korea (1120230), Yonsei University Research Fund of 2014 STEPHANIE D’EON, LIANE TINSLEY, STEPHANIE M. HASTINGS, DAVID POBER, GEORGE L. KING, HILLARY A. KEENAN, Boston, MA 55‑LB Sexual dysfunction (SD) has been recognized in those with diabetes as an ear- Associations between Adiponectin, Chemerin, Physical Fitness, ly sign of impending cardiovascular disease (CVD), as progressive vascular dis- and Fasting Insulin level in Colorectal Cancer Patients ease should manifest earlier in penile microvasculature than in systemic conduit KI-YONG AHN, MI KYUNG LEE, DONG-IL KIM, JIHYE PARK, JIHEE MIN, HYUK IN vessels. However, few protective factors have been identified for either condi- YANG, JUNGA LEE, MINSUK OH, NAM-KYU KIM, JUSTIN Y. JEON, Seoul, Re- tion. Our previous analyses demonstrated physical activity (PA) protects against public of Korea CVD in men with 50 or more years of type 1 diabetes (Joslin 50-Year Medalists) Since high levels of insulin and insulin resistance are associated with (Adjusted OR: 0.25, 95% CI: 0.12, 0.52). SD and PA were assessed by self-report colorectal cancer prognosis, it is important to identify factors contributing and validated by the International Index of Erectile Function and Paffenbarger to fasting insulin level in colorectal cancer patients. The purpose of the cur- questionnaires, respectively. Males in this cohort (46%, n=442/968) had a mean rent study is to investigate the associations of adiponectin, chemerin, physi- (standard deviation) age of 67.0 (7.9) y, BMI of 26.5 (3.9) kg/m2, total cholesterol cal fitness, and fasting insulin level in colorectal cancer patients. A total of 148.0 (30.7) mg/dL and HbA1c of 7.0 (0.9)%. SD prevalence was 69.4% and of 123 colorectal cancer patients who completed standard treatment were was associated with elevated HbA1c (7.1 vs. 6.8%, p≤0.001), higher BMI (26.8 recruited. Anthropometric parameters, physical fitness, fasting insulin level, vs. 25.5 kg/m2, p≤0.001) and lower HDL (52.0 vs. 59.0 mg/dL, p≤0.001). SD was homeostasis model assessment of insulin resistance, lipid profiles, adi- not associated with diabetic nephropathy, retinopathy or neuropathy (p>0.05). ponectin, and chemerin levels were measured and analyzed. Low fit partici- PA was reported by 83.1% of males, BMI (28.4 vs. 26.1 kg/m2, p≤0.001) was significantly higher and HDL was lower (47.0 vs. 55.0 mg/dL, p≤0.001) in those re-

ADA-Funded Research For author disclosure information, see page LB98.

LB14 —Clinical porting PA. Total Testosterone, binding globulin, C-Reactive Protein Surprisingly, the level of ISGU was maintained high in the exercised leg on day 2 levels, as well as antilipidemic use, HbA1c and hypertension prevalence did not and 5. Exercise resulted in marked dephosphorylation and activation of muscle differ between PA groups (p>0.05). In an unadjusted model, those who reported synthase (GS) on day 1. This enhanced effect of exercise on GS was being physically active were 2 times less likely to report SD (OR: 0.48, 95% CI: preserved the subsequent day. Hexokinase II, but not GLUT 4, protein content 0.26, 0.90). This relationship persisted with adjustment for age and CVD factors was increased (~ + 30%) in the prior exercised muscle throughout the super- (Adjusted OR: 0.50 (0.26, 0.96)). This analysis demonstrates a strong, protective compensation regime. We hypothesize that the mechanism leading to muscle association of PA with SD, independent of CVD and metabolic risk factors in men supercompensation involves enhanced ISGU mediated by enhanced capacity for with long duration of type 1 diabetes. glucose phosphorylation and glucose storage. The apparent glycogen indepen- Supported By: National Institutes of Health; JDRF dent regulation of these events is novel and questions current thoughts on the regulatory role of glycogen in human muscle insulin action. 58‑LB Withdrawn Nutrition—Clinical

60‑LB Red Wine as Treatment for Obesity-associated Insulin

Resistance: A Randomized, Placebo-Controlled, Double-Blind Clini‑ POSTERS cal Trial JORN WOERDEMAN, RICK I. MEIJER, ETTO C. ERINGA, YVO M. SMULDERS, ERIK H. SERNÉ, Amsterdam, Netherlands Red wine consumption is associated with reduced incidence of type 2 dia- Behavioral M edicine, Clinical betes. Preclinical studies suggest that polyphenols extracted from red wine N utrition, Education, and Exercise (RWPs) favorably affect insulin sensitivity. Controversy exists whether RWPs exert beneficial effects in humans. This study was undertaken to investigate whether RWPs improve insulin sensitivity and post-meal glycemia in obese volunteers. Obese (BMI>30) volunteers were randomly allocated to RWPs 600mg/day (n=14) or matched placebo (n=15) in a double-blind fashion. Sub- jects were investigated at baseline and after 8 weeks supplementation. Insulin sensitivity was the primary endpoint and measured using the hyperinsuline- mic-euglycemic clamp, and expressed as M-value. To study whether insulin sensitivity was also affected in a more physiological setting, all participants underwent a mixed meal test to measure postprandial glucose, and lipid levels (after 4 hours). Both groups were well matched and none of the volunteers experienced . No differences were observed in weight or body fat. Red wine polyphenols elicited no significant changes in M-value, postprandial glucose, or postprandial lipid levels. We conclude that eight weeks of RWPs supplementation do not improve insulin sensitivity, postprandial glycemia or lipid levels in obese mildly insulin resistant volunteers. Table 1. Study Results (Change from Baseline). RWP (mean±SD Placebo (mean±SD p-value or median [IQR]) or median [IQR]) Weight (kg) 0.4 ± 2.1 0.2 ± 2.6 0.88 Body fat (%) -0.1 ± 2.0 1.3 ± 2.4 0.13 M-value (mg/kg/min) 0.4 ± 1.1 0.3 ± 1.5 0.65 AUCglucose (mmol/L*4h) 10.2 ± 116.0 -0.9 ± 88.7 0.99 Total-cholesterol (mmol/L) 0.2 [0;0.4] -0.1 [-0.5;0.4] 0.33 HDL-cholesterol (mmol/L) -0.04 ± 0.17 -0.03 ± 0.11 0.65 LDL-cholesterol (mmol/L) 0.2 [-0.3;0.3] -0.3 [-0.4;0.3] 0.50 Triglycerides (mmol/L) 0.2 ± 0.8 0.1 ± 0.5 0.12 Supported By: Dutch Heart Foundation (2010T041)

61‑LB Is Exposure to Famine in Childhood and Economic Development in Adulthood Associated with Diabetes? Two-Hit Hypothesis from 59‑LB Spect-China Study Molecular Signaling and Insulin Sensitivity of Human Skeletal Mus‑ NINGJIAN WANG, XIAOJIN WANG, BING HAN, QIN LI, YI CHEN, CHUNFANG cle during Glycogen Supercompensation ZHU, YINGCHAO CHEN, FANGZHEN XIA, XIAOQI PU, ZHEN CANG, CHAOXIA ZHU, JANNE R. HINGST, MADS BAU HANSEN, ANDERS GUDIKSEN, JESPER MENG LU, YING MENG, HUI GUO, CHI CHEN, DONGPING LIN, WEIPING TU, BIN BIRK, HENRIETTE PILEGAARD, BENTE KIENS, ERIK A. RICHTER, JØRGEN F.P. LI, LING HU, BINGSHUN WANG, MICHAEL D. JENSEN, YINGLI LU, Shanghai, WOJTASZEWSKI, Copenhagen, Denmark China, Zhejiang, China, Nanchang, China, Rochester, MN The phenomenon of glycogen supercompensation after exercise is not Background: The middle-aged and elderly Chinese experienced severe fam- mechanistically understood. To investigate this, nine healthy male subjects were ine between 1959 and 1962 and subsequent rapid economic development studied 3 times during 5 days following knee-extensor exercise of one leg while from 1978 to now. Now diabetes has attained epidemic proportions in China. the other leg served as resting control. Insulin action was evaluated in each leg Objective: We hypothesized that exposure to at early age and by euglycemic hyperinsulinemic clamps and leg catherization on day 1 (4 h post economic development in adulthood might increase diabetes risk. exercise), day 2 and day 5 (28 and 100 h post exercise, respectively) while the Design: We analyzed the association of exposure to famine at different age subjects consumed an isocaloric carbohydrate rich diet (80% CHO) between stages and economic development with risk of diabetes in adulthood. Our data clamps. In the prior exercised leg glycogen content was decreased (65%, day of 6897 adults was from population-based SPECT-China study in 2014. Among 1), normalized (day 2) and supercompensated (+ 30%, day 5) compared to the them, 3844 adults were exposed to famine when they were between -4 (fetus) rested leg. Insulin stimulated glucose uptake (ISGU) was markedly (~+ 40%) in- and 37 years old and lived in areas with different economic development levels creased in the exercise leg 4 h after exercise (day 1) compared to the rested leg. in adulthood. Diabetes was defined as previous diagnosis by health care pro- fessionals, fasting plasma glucose ≥7.0mmol/L and/or HbA1c ≥6.5%. ADA-Funded Research For author disclosure information, see page LB98.

LB15 Psychosocial, Behavioral

Results: Compared with non-exposed subjects, famine exposure during Psychosocial, Behavioral Medicine fetal development (age -1~-4, OR 1.53, 95% CI 1.09-2.14) and childhood (age 0~9, OR 1.82, 95% CI 1.21-2.73) was associated with an increased diabe- 63‑LB tes risk after adjustment for age and sex. Further adjustment for adiposity, Physician–Patient Communication at Prescription of an Additional insulin resistance, lipid profile and blood pressure did not attenuate this as- Oral Agent for Type 2 Diabetes (T2D): Link Between Key Conversa‑ sociation. Living in rural area (severely affected famine area) and under high tion Elements, Physician Empathy, and Patient Outcomes—Insights economic status, subjects had higher diabetes risk in adulthood (OR 1.22, from the Global IntroDia™ Study 95% CI 1.02-1.46 and OR 1.46, 95% CI 1.20-1.78, respectively). No interaction

MATTHEW CAPEHORN, ANNE BELTON, SUSAN DOWN, AUS ALZAID, VICTORIA was found between age classification and economic development status. GAMERMAN, FRIEDERIKE NAGEL, JISOO LEE, STEVEN EDELMAN, WILLIAM H. Conclusions: The rapid increase in diabetes prevalence in middle-aged POLONSKY, Rotherham, United Kingdom, Toronto, ON, Canada, Bridgwater, United and elderly people in China may be due to the combination of severe malnu- Kingdom, Riyadh, Saudi Arabia, Ridgefield, CT, Ingelheim, Germany, San Diego, CA trition during fetus and childhood (age 0~9) (the first hit) and high economic IntroDia™ is investigating physician-patient communication during the development level in adulthood (second hit). Avoiding central obesity could early treatment of T2D and how such conversations may be linked to critical overcome the second hit. Our findings are in line with the two-hit hypothesis patient outcomes. Here we investigate patient experiences of the “add-on” of diabetes etiology. moment, i.e. the consultation when, typically months or years after the T2D Supported By: National Natural Science Foundation of China (81270885, diagnosis, another oral agent is first prescribed, and how this conversation 81070677); Clinical Potential Subject Construction of Shanghai Jiaotong Uni- POSTERS is associated with patient self-care and quality of life outcomes. A total of versity School of Medicine (2014); Ministry of Science and Technology in China 4235 patients from 26 countries (52% male, median age 46 years) completed (2012CB524906); Science and Technology Commission of Shanghai Municipality a self-report survey examining the content of the conversation with their (14495810700); Fund for Outstanding Academic Leaders in Shanghai (12XD1403100) physicians at add-on (via a 24-item scale of conversation elements specific Behavioral M edicine, Clinical for add-on). Perceived physician empathy (PPE) was measured with CAHPS, N utrition, Education, and Exercise 62‑LB TIPS and IPC items. Current psychosocial status (WHO-5, DDS) and self-care Eugenia Dysenterica DC (Brazilian Fruit) Juices Reduce Postpran‑ behavior (SDSCA) were also evaluated. Three key elements of the physi- dial Glucose and Insulin Plasma Concentrations cian-patient conversation were identified by factor analysis - Collaborative RENATA ARAUJO, ROSA FERREIRA SANTOS, LUCIANO GIACAGLIA, MARIA ELIZ- (e.g. “Encouraged me to ask him/her questions”), Encouraging (e.g. “Told me ABETH ROSSI SILVIA, MARIA INES GENOVESE, São Paulo, Brazil that the new medication would improve my quality of life”) and Discourag- Eugenia dysenterica DC (EDDC) is a Brazilian fruit rich in polyphenols, and ing (e.g. “Told me that my diabetes was getting worse”). PPE was positively previous study have shown its action on . This study associated with Collaborative (β=1.16, p < 0.001) and Encouraging (β=1.39, evaluated the effect of EDDC juices without fiber (clarified C) and with fiber (non- p < 0.001) and negatively linked with Discouraging (β=-0.92, p < 0.001). clarified NC) on postprandial glycaemia and insulinemia, in patients with glucose Further, PPE was associated with less diabetes distress (DDS: β=-0.39, intolerance (GI). Fourteen patients (male/female: 2/12); age ( 46 ± 8) years, were p < 0.001), greater well-being (WHO-5: β=0.54, p < 0.001) and better self-care conducted to three meal tests of 30 g of carbohydrate plus 300 mL water (Test (SDSCA - exercise: β=0.56, p < 0.001; diet: β=0.94, p < 0.001; medication tak- 1), or 300 mL of C- EDDC juice (Test 2), or 300 mL of NC- EDDC juice (Test 3), ing: β=0.76, p < 0.001). Thus, physician use of collaborative/encouraging con- after 8 hours fasting, 7 days interval between them. Blood glucose and insulin versation elements when prescribing an additional oral agent may enhance were measured at 0, 30, 60, 90, and 120 min for glucose and insulin, and at 0 and communication with T2D patients and lead to better self-care and quality of 120 min for Ferric reducing power (FRAP). Data (mean ± SEM) were life. Conversely, discouraging elements may have the opposite effect. analyzed by ANOVA and Friedman, p ≤0.05. The results showed that AUC were Supported By: Boehringer Ingelheim/ lower in C and NC-EDDC Juices for glucose (14935 ± 1604 x 12968 ± 1237 x 12291 ± 979 mg/dL/min, p ≤ 0.0001) and insulin: (6049 ± 3617 x 3710 ± 1757 x 3331 ± 64‑LB 1337 µU/ml/min, p 0.0013. The insulin secretion index ( Ins0-120/ gluc0-120) ≤ Δ Δ Development and Validation of an Instrument to Measure Collabora‑ decreased with both EDDC juices: (0.3972 ± 0.2156 x 0.2859 ± 0.1323 x 0.2692 ± tive Goal Setting in the Care of Patients with Diabetes 0.1020 p < 0.0035). Also, both EDDC juices increased plasma antioxidant capac- HEATHER L. MORRIS, LEVENT DUMENCI, JENNIFER ELSTON LAFATA, Gaines- ity (FRAP) p < 0.05. In conclusion, C and NC-EDDC juices decreased significantly ville, FL, Richmond, VA post prandial glucose and insulin secretion index during meal tests. Despite known benefits of patient-perceived collaborative goal setting, we have limited ability to monitor this process in practice. We developed the Pa- tient Measure of Collaborative Goal Setting (PM-CGS) to evaluate the use of collaborative goal setting from the patient’s perspective. A random sample of 400 patients aged 40 years or older, receiving diabetes care from the Virginia Commonwealth University between 8/2012 - 8/2013 were mailed a survey containing potential PM-CGS items (n=41) as well as mea- sures of patient demographics, self-efficacy, trust in their physician, and self- management behaviors. Confirmatory factor analysis was used to evaluate instrument construct validity. External validity was evaluated via a structural equation model (SEM) that tested the association of the PM-CGS with self- management behaviors. The direct and two mediated (via trust and self ef- ficacy) pathways were tested. A total of 259 patients responded to the survey (64% response rate), of whom 192 were eligible for inclusion. Results from the factor analysis supported a 37-item measure of patient-perceived col- laborative goal setting spanning five domains: listen and learn; share ideas; caring relationship; measurable objective and goal achievement support (χ = 4366.13, p<.001; RMSEA = .08). Results from the SEM confirmed a relation- ship between the collaborative goal setting measure and self-management (p<.001), which was partially mediated by self-efficacy (p<.05). Collaborative goal setting can be validly measured by the 37-item PM-CGS. Use of the PM- CGS can help illustrate actionable deficits in goal setting discussions. Supported By: National Institutes of Health (1R36HS022202-01)

65‑LB Glucose Variations Are Strongly Coupled to Sleep Disruption in Young Adults with Type 1 Diabetes (T1DM) SARAH S. FARABI, DAVID W. CARLEY, LAURETTA T. QUINN, Chicago, IL Sleep quality is reduced in individuals with T1DM, which may negatively impact ongoing disease management. Glucose variability has been postu- Supported By: CAPES; FAPESP lated to impair sleep continuity in individuals with T1DM, but this has not

ADA-Funded Research For author disclosure information, see page LB98.

LB16 Clinical Therapeutics/New Technology—Glucose Monitoring and Sensing been systematically investigated. Actigraphy is a validated quantitative tool or the DDS (N=1,705: n=693 type 1 diabetes; n=1,012 type 2 diabetes). Rasch used to assess sleep disruption that rarely has been used in individuals with analysis was used to explore key parameters, namely category threshold or- T1DM. Here, we employed actigraphy and continuous glucose monitoring dering, precision, unidimensionality, item and person “fit,” targeting, and dif- (CGM) to define the coupling between variations in glucose and sleep dis- ferential item functioning. In the type 2 diabetes sample, the PAID total scale ruption in young adults with T1DM. 21 participants with T1DM (8 males), had satisfactory psychometric properties, which were optimized by the dele- aged 18-30, wore a CGM system and a wrist actigraph for an 8-hour over- tion of responses from persons with extreme minimum scores and ‘“misfit” night period. The cross correlation function was used to objectively quan- (9% and 12%, respectively), and the exclusion of item 15. However, the DDS tify coupling between glucose and activity and to estimate the global delay total scale had disordered thresholds, multidimensionality, and person misfit, between these processes. Because this coupling is/may be both frequency which could not be remedied by removing misfitting items or extreme scores. dependent and time varying, wavelet coherence analysis was employed to All four DDS subscales failed initially to reach adequate precision; only the capture these dynamics. The greatest mean cross-correlation (r2) was 0.44 ± Emotional burden and Regimen-related distress subscales achieved adequate 0.03 (p < 0.00005) with zero lag between glucose and activity. Mean coher- precision following removal of a substantial proportion of the sample (25% ence (C) was greatest for the fluctuations with periods of 10 to 20 min (0.39 ± and 11%, respectively) due to floor effects or misfit. Psychometric concerns 0.016, p < 0.00005) with very high coherence (VHC; C > 0.7,) observed for 16.2 were similar but less marked in the type 1 diabetes sample. In conclusion, ± 3.5% of recording time (VHC%). Furthermore, hemoglobin A1c and mean the DDS requires substantial revisions to resolve multidimensionality and item overnight glucose were negatively associated with VHC% (r = -0.45, p =0.04 misfit within the total scale, and poor precision in its subscales. The results of for each). Among our subjects with T1DM, glucose variations accounted for the present psychometric study support use of the PAID to measure diabetes nearly half of the variance in sleep disruption measured by overnight activ- distress. ity, with increasing glucose aligned with increasing activity. Moreover, this Supported By: National Diabetes Services Scheme; Sanofi Aventis; National coupling was consistently strongest for rapid fluctuations and the presence Health and Medical Research Council (1072987 to E.K.F.); National Health and of very high coherence between glucose and activity was negatively as- Medical Research Council (1061801 to G.R.); Centre for Eye Research sociated with A1c and overnight mean glucose. This suggests an important physiologic connection between glucose homeostasis and sleep continuity, 68‑LB which may be weakened by poor glucose control. Smartphone Skills Enhances Cognitive Behavioral Therapy (CBT) Supported By: American Association of Diabetes Educators Intervention Addressing Adherence and Distress with Type 2 Dia‑

betes (T2D) POSTERS 66‑LB JUDITH A. CALLAN, GREG J. SIEGLE, LINDA SIMINERIO, KATHLEEN M. MCTIGUE, Therapeutics Clinical Diabetes/ “It Is Definitely a Game Changer”: Closed Loop Technology in the SUSAN M. SEREIKA, Pittsburgh, PA Home Experienced by Adults with Type 1 Diabetes Non-adherence and distress are associated with poor clinical outcomes in CHRISTEL HENDRIECKX, JANE SPEIGHT, LUCINDA A. POOLE, AMIN SHARIFI, T2D. To modify negative adherence appraisals, a pilot feasibility study was MARGARET LOH, JODIE C. HORSBURGH, STEVE TRAWLEY, ALICIA J. JENKINS, conducted using a 30-minute phone CBT intervention with a skills practice KAVITA KUMARESWARAN, RICHARD J. MACISAAC, GLENN M. WARD, PETER smartphone application (app) for T2D (6 vs. 8 vs. 12 sessions or usual treat- COLMAN, LEON A. BACH, ANDREW KYOONG, NATALIE KURTZ, BENYAMIN ment). Outcomes included: medication adherence (measured via MEMs cap GROS­­MAN, ANIRBAN ROY, DAVID O’NEAL, Melbourne, Australia, Fitzroy, Austra- and Morisky self-report), diabetes distress and HbA1c levels. The sample lia, Northridge, CA included 12 subjects taking oral diabetes medication, aged 30 to 65 years, This qualitative study explored participants’ experiences after four nights HbA1c of > 8, with self-management and distress issues. Subjects were ran- Home Closed Loop (CL) Insulin Delivery System use vs. Sensor Augmented Pump domly assigned to equal groups of the 3 intervention conditions or usual Therapy with Low-Glucose Suspend (SAPT-LGS) in a randomised cross-over trial. care. Outcome measures were collected at baseline and post-intervention. Ten adults (≥18 years) completed the trial between April 2014 and March 2015; At fourteen weeks, all subjects had a follow-up HbA1c. Subjects also docu- median age 37.5 years (range 32-62) and diabetes duration 31 years (range 8-36); mented feasibility, ease of learning, T2D-relevance, and desire to use the five were women. Semi-structured interviews were conducted on day five, after app via ratings from 1 (very favorable) to 7 (very unfavorable). four consecutive nights of CL at home. Interviews were audio-recorded, with Table. Post-Intervention Clinical Outcomes. transcriptions imported into NVivo 10 for thematic analysis. A coding frame- work was developed to identify the main themes and subthemes. When asked CBT HbA1c MEM Doses Diabetes Duration Total HbA1c Adherence (Morisky5-item) Distress about the four nights’ CL experience, the most common observation was the (weeks) (Change) (% Change) (%) (% Change) (% Change) “flat-line,” showing stable overnight glucose levels. Although most reported technical glitches during one or more nights, few safety concerns were raised. If 6 -0.6o -6.62 37.73 88.89 -17.98 any, these related to feeling unsure whether the system would respond in time 8 -2.3o -20.46 35.73 26.67 -8.33 to falling glucose. However, confidence increased when they observed how the 12 -2.33 -22.34 88.69 46.67 -40.92 CL stopped insulin delivery when their glucose was trending down, how (when Usual Tx -2.15 -20.46 84.06 6.25 -36.22 switching to CL at night) the CL dealt with high glucose levels. Compared with their current insulin pumps (and, for some, sensors), participants reported the Mean feasibility rating was 1.84+0.64. Subjects used the app regularly, following benefits: less decision making, resulting in few human errors; fewer with mean daily actions of 33.27+19.73. Overall app rating was 3.00+2.07, alarms, as the CL kept glucose levels within target overnight; not having to indicating they found the app highly usable. The data demonstrates feasibil- cope with the consequences of hypo- and hyperglycaemia (e.g. feeling sick post ity and usability. All intervention subjects had improved adherence, reduced event), due to less glucose variability. Participants found the CL was easy to use, distress, and reduced HbA1c. Usual Tx subjects had higher than usual moti- but they mentioned that this might be different for people who are less “tech vation to improve clinical status. savvy.” In conclusion, participants gave a very positive evaluation of CL in the Supported By: 8KL2TR00014608 home. They were impressed with how well the CL system responded to their glucose levels and noted that further improvements of the technology will en- hance the user’s experiences. Clinical Therapeutics/New Technology— Supported By: JDRF Glucose Monitoring and Sensing

67‑LB 69‑LB What Is the Best Measure for Assessing Diabetes Distress? A Ra‑ Lanthionine Synthetase C-like Receptor 2 (LANCL2): A Novel Thera‑ sch Analysis Comparing the Problem Areas in Diabetes and Diabe‑ peutic Target for Type 2 Diabetes tes Distress Scale: Results from Diabetes MILES—Australia ADRIA CARBO, RAQUEL HONTECILLAS, JULIAN COOPER, RICHARD GANDOUR, EVA K. FENWICK, GWYN REES, ELIZABETH HOLMES-TRUSCOTT, JESSICA L. PATRICK HEIZER, MARION EHRICH, JOSEP BASSAGANYA-RIERA, Blacksburg, VA BROWNE, FRANS POUWER, JANE SPEIGHT, East Melbourne, Australia, Mel- There is an urgent need for developing type 2 diabetes (T2D) drugs that bourne, Australia, Tilburg, Netherlands are more effective and safer than existing medications. Lanthionine Syn- The aim of this study was to compare the psychometric properties of the thetase C-like Receptor 2 (LANCL2) is a novel T2D therapeutic target that Problem Areas In Diabetes (PAID) scale and the Diabetes Distress Scale (DDS) exerts potent anti-inflammatory and anti-diabetic effects. We generated to determine the optimal tool for measuring diabetes distress. A total of 3,338 libraries of derivatives and analogs of parent LANCL2-binding compounds adults with diabetes participated in the Diabetes MILES - Australia study, and 61610 belonging to the class of bis (benzimidazoyl) terephthalanilides (BTTs), completed the PAID (N=1,609: n=675 type 1 diabetes; n=934 type 2 diabetes) and identified BT-11 as our top lead compound. Molecular modeling studies

ADA-Funded Research For author disclosure information, see page LB98.

LB17 Clinical Therapeutics/New Technology—Glucose Monitoring and Sensing

were used to predict LANCL2 binding and predictions were validated experi- of the time while at home use subjects demonstrated a frequency of 12.2% mentally by Surface Plasmon Resonance (SPR) data, demonstrating that 3 for the same error threshold. The lack of variance in home use suggests that top leads, strongly bind to LANCL2. Our pre-clinical efficacy studies in db/db subjects may be entering the same BG value twice when calibration. Pa- and diet-induced obesity (DIO) mice showed that daily oral administration tient SMBG testing demonstrates significantly more variability at home than of BT-11 significantly reduces fasting blood glucose and improves glucose when conducted in the optimized clinical environment highlighting a lack normalization during a glucose tolerance test. Oral BT-11 administration sig- of precision of SMBG during actual use. Because replicate measurements nificantly decreased the infiltration of macrophages and pro-inflammatory are only obtained at initial calibration, it is unknown if the observed SMBG Ly6chigh GR1+ granulocytes as well as decreasing the expression of TNF- imprecision affects patient perception of SMBG accuracy. alpha and MCP1 in white adipose tissue. To assess the safety profile of BT-11, we performed a single high-dose and a 14-day repeated daily dose 72‑LB studies in rats, both of which confirmed the excellent initial safety profile of Comparative Accuracy of 17 Glucometers BT-11. Rats treated with BT-11 orally during a 14-day period showed no dif- LAYA EKHLASPOUR, MANASI SINHA, DEBBIE MONDESIR, NORMAN LAUTSCH, ferences in Functional Observational Battery endpoints, clinical pathology, COURTNEY BALLIRO, MALLORY HILLARD, KENDRA MAGYAR, STEVEN J. RUS- and histopathological examination in 15 tissues. In sum, BT-11 is a promising SELL, Boston, MA, Cambridge, MA LANCL2-binding anti-inflammatory and anti-diabetic drug efficacious and The accuracy of blood glucose (BG) meters is important for the detection safe for treating T2D. of dysglycemia and for calculation of insulin doses. The safety and effec- tiveness of automated glucose management with a bionic is also 70‑LB dependent on accurate BG measurements for calibration of the continuous Patient Home Experiences Using the OneTouch Reveal® Web Ap‑ glucose monitor. To evaluate the comparative accuracy of commercially ®

plication with the OneTouch Verio Glucose Meter Demonstrates available glucometers across a wide range of reference BG and hemoglobin Improved Glycemic Control values. Fresh, discarded blood samples from a hospital STAT laboratory were MIKE GRADY, GRAHAM WARREN, LAURENCE B. KATZ, BRIAN L. LEVY, Inverness, spiked with a glucose solution or incubated them at 37 C to produce 351 United Kingdom, West Chester, PA samples with an even distribution across reference BG levels from 20 - 440 Cloud-connected diabetes applications enable health care profession- mg/dl and hemoglobin values from 9-16 g/dl. We measured the BG of each als (HCPs) to monitor patient progress in real time and offer remote con- sample with 17 different available glucometers and the reference method ®

POSTERS sultations. OneTouch Reveal (OTR) is a cloud-based web application that (YSI 2300) at the same time. Reference whole blood measurements were Therapeutics aggregates data from a patient’s blood glucose (BG) meter and/or insulin converted to plasma glucose values. We determined the mean absolute - Clinical Diabetes/ pump. OTR tracks, analyzes and interprets patient blood glucose and insulin tive difference (MARD) for each glucometer and determined whether they data to help patients and HCPs make more informed treatment and lifestyle met ISO 2003 and 2013 criteria for accuracy. Seven meters met ISO 2003 decisions. This study assessed the experience of patients using OTR in criteria for accuracy but only 2 met ISO 2013 criteria. All meters meeting conjunction with the OneTouch Verio® (OTV) meter. 40 subjects with type ISO 2003 criteria had a MARD <10% and all utilize glucose dehydrogenase 1 (23 T1DM) or type 2 diabetes mellitus (17 T2DM) uploaded BG meter re- chemistry. Accuracy did not differ markedly with blood hemoglobin level. sults every 2 weeks to the OTR web application on their home computer for There was no correlation between accuracy and strip cost. The accuracy 12 weeks. At baseline, HCPs customized individual target BG ranges. HCPs of commercially available glucometers varies widely. Most of the meters remotely reviewed progress using OTR and delivered telephone consulta- tested did not meet current accuracy criteria. tions at 4 and 8 weeks based on OTR insights. After 12 weeks, mean A1c decreased from 8.3% to 7.9% (SD=0.725, p=0.001 paired t-test) with 25% of subjects having an A1c reduction of ≥1.0%. In subjects with T2DM, mean BG decreased from 175 to 161 mg/dl (p< 0.001), and the percentage of above- range BG results decreased from 33.0% to 23.9% (p=0.002), whilst in-range BG results increased from 65.5% to 75.0% (p=0.001). During phone con- sultations, 80% of subjects confirmed OTR detected out-of-range glucose patterns, and 84% of these subjects were able to correct the underlying pattern to get BG back in-range. 82.5% of subjects agreed OTR helped them “see the big picture and motivated them to stick to their plan,” and 92.5% agreed the OTV meter “made it clear when to take action.” In summary, OTR in combination with the OTV meter enabled subjects with T1DM and T2DM to effectively manage their diabetes and improve BG control over 12 weeks. Real-time visibility to subject data enabled HCPs to deliver focused and ef- fective remote consultations.

71‑LB Imprecision of SMBG Values Used for CGM Calibration during Opti‑ mal Conditions or Home Use ARTURO GARCIA, TOMAS WALKER, DAVID A. PRICE, San Diego, CA As real-time continuous glucose monitoring (CGM) requires twice daily calibrations with self-monitored blood glucose (SMBG) values patients are 73‑LB repeatedly reminded of differences between the CGM and the SMBG. The Pressure-induced Sensor Attenuation Testing on a Fully Implant‑ frequent comparison may impact the perception of CGM accuracy. In con- able Continuous Glucose Monitoring System trast, patients relying on SMBG rarely perform a direct comparison between ANDREW D. DEHENNIS, XIAOLIN WANG, SORIN IOACARA, Germantown, MD, meters or sequential SMBG measurements. Initial calibration of the Dexcom Bucharest, Romania CGM, requires patients to enter 2 SMBG values, obtained from separate This abstract presents the results of clinical testing on a Continuous Glu- fingersticks. We compared differences between the two initial calibration cose Monitoring (CGM) based on an implantable sensor to assess its sus- SMBG values performed during clinic sessions (subjects washed their hands, ceptibility to Pressure Induced Sensor Attenuation (PISA). The system under were instructed on proper blood application, and used fresh strips) and dur- evaluation is composed of a long term, subcutaneously inserted sensor, a ing home use. Clinic session data came from three clinical studies, 2 adult smart wearable transmitter, and a Mobile Medical App. Although previous studies with 69 subjects (n=62 T1D, n=7 T2D) and 1 pediatric study with reports on transcutaneous devices has shown the need to develop PISA de- 24 subjects (n=24 T1D). The home use data was derived Dexcom technical tection capability into the CGM system, a system that is not susceptible to support data. A total of 1126 fingerstick pairs were evaluated. The SMBG PISA will not need an algorithm to detect PISA or cause pump shut-offs due imprecision was measured by calculating an absolute proportional error if to PISA. In this study, 20 subjects with type 1 diabetes (T1DM) with mean both SMBG values ≥ 100 mg/dl and an absolute difference error for SMBG < age 37±8 years, mean disease duration 11±6 years were implanted with the 100 mg/dl. The subjects in the clinical study demonstrated errors > 10%/10 investigational continuous glucose sensor in the upper arm for up to 90 days. mg/dl and > 20%/20 mg/dl 7.6% and 3.3% respectively; home use subjects During the clinical session, which as 30 days after sensor insertion for 7 demonstrated a > 10%/10 mg/dl and > 20%/20 mg/dl of 17.6% and 3.6% subjects and 90 days after sensor insertion for 13 subjects, pressure was respectively. Clinical study subjects demonstrated 0%/0 mg/dl error 2.2% applied to the area above the implanted sensors for about 30 minutes, and

ADA-Funded Research For author disclosure information, see page LB98.

LB18 Clinical Therapeutics/New Technology—Glucose Monitoring and Sensing upon interviewing, the subjects felt the pressure was significant. The data individuals treated with intensive insulin therapy: average age 42.9 years analysis calculated the rate of change during the pressure tests of all the (range: 23-71 years); 49% male; 76.6% 10-25+ years diabetes duration; participating subjects to detect any PISA and all the glucose rates of change 79.7% insulin pump use. Participation was restricted to individuals who used were within physiological limits, no rate of change below -4 mg/dL/minute the Dexcom G4 device to avoid confounding responses due to differences was seen. The summary of rate of change during the pressure test is shown between various CGM systems. Respondents completed a 16-item survey, in Table 1. which queried them about their frequency of CGM use and primary reasons for persistence of use. Among the 74 respondents, 58 (78.3%) reported CGM use on most days. A 50.0% reduction in average number of daily blood glu- cose tests was reported after 1 year of CGM use vs. prior to use. (Figure 1A). An 85.7% reduction in the number of emergency hospitalization/paramedic visits after 1 year of CGM use vs. prior to use was reported. (Figure 1B). Fre- quent, persistent CGM use was associated with notable reductions in daily SMBG frequency and emergency hospitalizations. Reductions in emergency hospitalizations and SMBG utilization may offset the cost of CGM without jeopardizing patient safety.

74‑LB

Frequent, Persistent CGM Use May Reduce Hypoglycemia Fear POSTERS among Individuals Treated with Intensive Insulin Regimens Therapeutics Clinical Diabetes/ JAMES J. CHAMBERLAIN, EMILY GILGEN, DANA DOPITA, Salt Lake City, UT Fear of hypoglycemia remains a significant obstacle to achieving and maintaining optimal glycemic control. The impact of continuous glucose monitoring (CGM) use on hypoglycemia fear has not been well studied. We conducted a survey to assess the concerns of individuals about hypo- glycemia after one year of CGM use. This single-center study included 74 individuals treated with intensive insulin therapy: average age 42.9 years (range: 23-71 years); 49% male; 76.6% 10-25+ years diabetes duration; 76‑LB 79.7% insulin pump use. Participation was restricted to individuals who used Continuous Glucose Monitoring at the Site of Subcutaneous (SC) the Dexcom G4 device to avoid confounding responses due to differences Insulin Delivery: Building a Durable Sensing Catheter between various CGM systems. Respondents completed a 16-item survey, W. KENNETH WARD, SHEILA BENWARE, MATTHEW BREEN, TYLER MILHEM, which queried them about their frequency of CGM use and primary reasons KRISTIN MORRIS, CHAD KNUTSEN, KAMESH MULLAPUDI, JOHN CONLEY, ROB- for persistence of use. Among the 74 respondents, 58 (78.3%) reported CGM ERT S. CARGILL, Portland, OR, Corvallis, OR use on most days. A notable number of these respondents (n=45, 77.6%) New evidence suggests that CGM can be carried out in proximity to insu- reported worrying about hypoglycemia “most of the time” (n=20, 34.5%) or lin delivery. One method of creating a combined sensing + insulin delivery de- “frequently” (n=25, 43.1%) prior to CGM use. After one year, no respondents vice is to place thin metal electrode films on a polymer substrate that forms reported worrying about hypoglycemia “most of the time” and one (1.7%) the catheter wall. However, these films may not be durable. We hypoth- reported frequent worry, a 97.8% decrease (Figure 1). Our findings show that esized that depositing the thin metal films on a substantial metal foil would frequent, persistent use of CGM reduced hypoglycemia fear among survey increase durability. We evaluated 2 constructions of sensing catheters, each respondents. of which were indwelled in pigs x 24 h: GEN 1: Thin metal films of Pt and Ag deposited on a polymer. GEN 2: Thin metal films of Pt and Ag deposited over a 12 µm thick titanium foil. We also evaluated 2 tube architectures: GEN 1: a sharp steel needle. GEN 2: a blunt steel tube with retractable insertion stylet. In the pigs, after a period of equilibration, high rate aspart insulin was delivered continuously for 4 h at a rate of 0.02 u/kg/h SC. In control tubes, no insulin was given. After explant, 3 observers graded electrode integrity and tissue trauma using photomicrographs. Indicating electrode integrity was greater in titanium foil devices than in thin film devices (95% +/- 3 (n=46) vs. 76% +/- 4 (n=15), p < 0.001). Similar results were found in reference elec- trodes (90% +/- 4 (n=43) vs. 81% +/- 2 (n=14), p < 0.05). Mean tissue trauma score for the blunt tubes was one-fifth that of the sharp needle. There was no clear time-related decline of the glucose signal from the sensing tubes through which insulin was delivered. There was a trend for sensed glucose levels to be slightly (10-20%) lower in insulin tubes (n=19) vs. non-insulin tubes (n=22). A base layer of titanium foil improved electrode durability in glucose sensing tubes. Use of a retractable stylet within a blunt tube led to a much lower mean tissue trauma score than a sharp needle. The delivery of high basal rates of insulin via the tubes led to relatively small declines of local glucose levels. We conclude that continuous measurement of glucose 75‑LB in close proximity to the site of insulin delivery is feasible. Frequent CGM Use May Reduce Daily Blood Glucose Testing Fre‑ Supported By: National Institute of Diabetes and Digestive and Kidney Dis- quency and Emergency Hospitalizations/Paramedic Visits eases; The Leona M. and Harry B. Helmsley Charitable Trust EMILY GILGEN, DANA DOPITA, JAMES J. CHAMBERLAIN, Salt Lake City, UT Continuous glucose monitoring (CGM) is indicated as an adjunct to self- monitoring of blood glucose (SMBG). The impact of CGM use on daily SMBG habits has not been well studied. We assessed changes in SMBG frequency and emergency hospitalizations/paramedic visits in individuals who fre- quently and persistently use CGM. This single-center study included 74

ADA-Funded Research For author disclosure information, see page LB98.

LB19 Clinical Therapeutics/New Technology—Glucose Monitoring and Sensing

77‑LB member and clinicians using pre- and post-surveys. Two sites participated Performance of Dario Blood Glucose Monitoring System Evaluated in Time in Motion (TIM) and work flow mapping; to ensure that the AGP pro- in a Clinical Study in Compliance with the New ISO 15197:2013 Stan‑ cess was an enhancement to clinical care. Both clinics had patient download dard self-serve kiosks in their lobbies during this study. Patients entered minimal BILLY PERY, PAUL M. ROSMAN, Caesarea, Israel, New York, NY data and connected the device(s) for download. Download software sent Blood glucose monitoring systems (BGMS) are an in basic tool for diabetes data to the AGP cloud, clinic staff logged onto the AGP system and printed patients. The innovative DarioTM BGMS enables convenient self-monitoring the report. The average patient time to download from sitting down at the by adding a proprietary smart phone application. We evaluated accuracy and computer to a complete download has historically been 4 minutes, 54 sec- user performance in a clinical trial of 368 type 1 and type 2 diabetic patients, onds. The average time to print a report by the staff is 4 minutes, 45 seconds each of whom tested fresh capillary finger prick blood glucose levels while including time to log onto the AGP site and collect the report from the printer. using this BGMS for the first time, as instructed only by the manufacturer’s The staff time for the prior work flows was 8 minutes, 15 seconds (site 1) and directions for using the device. Glucose value accuracy was determined in 20 minutes (site 2). The AGP process saved on average 3.5 to 15 minutes per one sample obtained from each subject measured both on the BGMS by in- patient. Therefore, with practices seeing on average 20 patients per clini- dividual subjects and by a reference analysis of the identical sample. We cian per day; a time savings of 3 minutes result in a per day time savings of 1 documented sample collection or measurement errors. When needed, re- hour staff time per clinician. Clinics with 4 clinicians could expect to save 0.5 peat sampling by each subject was limited to 3 per subject. The interval of FTE medical assistant (avg. salary $30,000/yr.) by implementing a standard- glucose levels tested were BGMS range 43.0-477.0 mg/dL, and YSI range ized AGP download. Additional time saved in the clinical encounter since 42.3-435.5 mg/dL. There were no outliers. We used all 368 lay subjects’ standardized AGP reporting may facilitate efficient shared decision making. samples. Accuracy for this BGMS met ISO 15197:2013 criteria. Below 100 Supported By: The Leona M. and Harry B. Helmsley Charitable Trust mg/dL, 97.8% of values were within ±15mg/d of YSI reference glucose val-

ues. For samples with glucose above or equal to 100 mg/dL, 96.4% of values 80‑LB were within ± 15% of YSI glucose levels. Lay subject performance assess- Long-Term Follow-up of Sensor-augmented Pump Therapy with ment of the Dario BGMS’ instruction clarity and usefulness showed 97.1% of Low Glucose Suspend Function (SAP-LGS) in Type 1 Diabetes (T1D) subjects found instructions easy to follow with 70.7% rating they were very Patients with High Risk of Hypoglycemia satisfied (5/5) and 26.4% rating they were satisfied (4/5). Reading the result ANA MARIA GOMEZ, OSCAR MUÑOZ, DIANA HENAO, EDWIN MORA, CARLOS on the smart mobile device was rated easy to understand by 99.1% of lay POSTERS AUGUSTO YEPES, MARTIN RONDON, Bogotá, Colombia Therapeutics subjects, with 86.1% rated it very easy (5/5) and 13% rated it easy (4/5). If To assess the efficacy and safety of long term use of SAP-LGS in T1D Clinical Diabetes/ an error message displayed on the report screen, 96.4% of lay subjects were patients who initiated this therapy because of hypoglycemia and poor meta- clear about what to do, with 50% reporting is was very clear (5/5) and 46.4% bolic control. The second objective was to compare the frequency of severe reported it was clear (4/5). The Dario BGMS meets ISO 15197:2013 standards hypoglycemia and perception of hypoglycemic symptoms before and after for clinical performance as determined by lay user accuracy and by satisfac- SAP-LGS therapy. The study was an observational prospective cohort study tory experience with the BGMS instructions clarity and system utility. from August 2010 until February 2015 of T1D patients with hypoglycemia, older than 14 years of age, who started SAP - LGS at Hospital Universitario 78‑LB San Ignacio, Bogotá - Colombia. The main indication was hypoglycemia and Evaluation of Hematocrit and Hypoglycemia in a University Hos‑ poor metabolic control. Demographic and clinic variables were registered as pital: Blood Glucose Monitoring Experience Using Retrospective well as A1c levels at the beginning, 3 month and 1 year follow-ups. 94 T1D Data Analysis patients with hypoglycemia were included with an average baseline A1c of RICHARD J. BALTARO, BRYAN J. DANGOTT, ROBERT J. TANENBERG, APARNA 8.84 ± 1.93%. The mean follow-up was 2, 2 years (range 4.5 - 1, 02 years); THOMBARE, SU FAN LIN, Greenville, NC sensor use was 80 - 100% of the time in 94% of the patients. At the end of We evaluated the effect of hematocrit on waived point of care blood the follow-up, the decrease of A1C was statistically significant at 7.3% ± glucose values and the number of hypoglycemic events, using concurrent 1.03% (p<0.0001), this decrease was found at the third month of follow-up main laboratory glucose and hematocrit. At Vidant Medical Center, a 941 A1c 7.6%±1.7% (p<0.0001), with decreased incidence of severe hypoglyce- bed university hospital, a Roche Accu-Chek II Inform blood glucose monitor- mia in the last year to 0.02 episodes per patient per year (p= 0.0032). Only ing system (BGMS) is used for metabolic control. The BGMS was evaluated 2% of the patients presented severe hypoglycemia, which is statistically using EHR data for 14 months (October 2013-December 2014). During the different from the baseline (p <0.0001) and 12% of patients remain with hy- sample period, there were 590,000 point of care adult patient blood glucose poglycemia unawareness (p <0.0001) after initiating therapy. The patient tests (POC BG), 332,000 chemistry analyzer blood glucose tests (CA BG) and proportion at the beginning with A1C less than 7% was 16%. 87% had se- 332,000 hematocrit tests (HCT). We correlated all BGMS values that had vere hypoglycemia. At the end of the follow-up, it was 44.7%. Only 4.8% had a concurrent glucose performed by laboratory chemistry analyzer (Siemens severe hypoglycemia (p<0.0001) In conclusion, SAP-LGS therapy reduces in a Advia) within 3 minutes and a laboratory hematocrit (Coulter) within 6 hours. statistically significant quantity the severe hypoglycemic and unawareness Hypoglycemic events where defined as a POC BG laboratory < 70 mg/dl pre- of hypoglycemia in T1D patients with failure to MDI and a high risk of hypo- ceded by a POC BG > 180 mg/dl in the previous 6 hrs. At hematocrits < 40, the glycemia. This allows better metabolic control in a safe way. This effect was lower the hematocrit, the higher the percent POC BG increase against the CA observed early and was maintained during the follow-up time. BG. At lower hematocrits, the average POC BG was higher than the CA BG. At hematocrit of <20, 88% of the POC BG values were elevated and only 12% 81‑LB were decreased. The average increase bias was + 9.4%. At hematocrits > 50, Can Use of Continuous Glucose Monitoring (CGM) Prior to Initiating there was a slight negative bias (-1.7%). 860 hypoglycemic events were iden- Insulin Pump Therapy Result in Greater Glycemic Improvements? tified out of 159,416 patients for an average of 0.54% events per patient. The AIMEE JOSE, RUTH SPIRAKIS, CHRISTOPHER G. PARKIN, Palo Alto, CA, Boulder patient population with hematocrit < 30 had 380 hypoglycemic events for City, NV 29,023 patients, or 1.39% events per patient. This value is almost ten times Initiating continuous glucose monitoring (CGM) prior to insulin pump ther- higher than 72 hypoglycemic events for 46,528 patients with hematocrits > apy has been shown to increase frequency of CGM use, however, the im- 40 or 0.16% events per patient. Retrospective data analysis demonstrated pact of this approach on clinical outcomes has not been well studied. In this increased bias of POC BG readings by lower hematocrit and the subsequent single-center, retrospective, pilot study, we assessed changes in HbA1c over increased incidence of hypoglycemic episodes. 6 months in patients with type 1 diabetes treated with CSII and CGM. HbA1c values at baseline (before starting CGM) and 6 months after combined device 79‑LB (CGM/pump) use were available for 13 patients: 7 used CGM before pump Reducing Staff Time with Optimized Work Flows and Standardized (BP) initiation (baseline HbA1c 7.7±1.5, age 52.3±10.6 years, 86% female, Ambulatory Glucose Profile (AGP) Reporting 186.1±151.0 CGM days [range: 26-441 days] before pump); 6 patients started DEBORAH M. MULLEN, RICHARD M. BERGENSTAL, AGP WORK FLOW STUDY CGM after pump (AP) initiation (baseline HbA1c 7.9±1.1, age 45.3±14.7 years, GROUP, Minneapolis, MN 83% female, 75.5±93.1 pump months [range: 0-252 months] before CGM. At This research aimed to evaluate feasibility, utility and preference of stan- 6 months post CGM/pump use, BP patients showed a clinically significant dardized cloud-based glucose reporting using AGP reports. Seven diverse reduction in HbA1c from baseline compared with AP patients: -0.7±1.1% vs. sites were recruited (n = 144 patients and 16 clinicians). Measures of AGP vs. -0.2±1.0%, respectively. (Figure 1) Although not conclusive due to the small traditional glucose data acquisition were collected from the patient/family sample size, our results suggest that use of CGM prior to initiation of insulin

ADA-Funded Research For author disclosure information, see page LB98.

LB20 Clinical Therapeutics/New Technology— pump therapy may lead to greater glycemic improvement. Larger studies are kg). C-peptide secretion also improved significantly in this population with needed to assess the efficacy of this approach. very advanced long-standing disease. Table.

Clinical Therapeutics/New Technology— Supported By: Novo Nordisk Insulins 84‑LB 82‑LB A New Ultra-Long-Acting Glargine Analog with Improved Pharma‑ Sustainable Effects of Basal Insulin Have Favorable Outcomes on co-kinetic (PK) and Pharmacodynamic (PD) Profiles Compared with Fasting Blood Glucose Control in Patients with Type 2 Diabetes Lantus® SHIZUKA KANEKO, YUMIKO TAHARA, YORIHIRO IWASAKI, Takatsuki, Japan YOU-PING CHAN, GUILLAUME NOEL, Oullins, France, Marcy l’Etoile, France We investigated the difference in the sustainable effect of longer acting Ultra-long acting insulins, characterized by a duration of action greater formulations on blood glucose control in T2DM. We compared insulin deglu- than 36 hours, are the next generation basal insulins that could potentially POSTERS dec therapy (IDeg) which has the longest effect of 42 hours with convention- provide a better glucose control by delivering an infusion-like profile insulin Therapeutics al basal insulins (NPH, ditemir or glargine (IGla)) therapies of which the effect at steady state following daily injection. The objective of the study was to Clinical Diabetes/ is less than 24 hours. We conducted two different retrospective analyses, investigate PK and PD performances in the Dog model of a new insulin ana- 1) comparison of the newly introduced IDeg and conventional insulin, and 2) log that has the potential to be an ultra-long acting insulin. The new insulin substitution of IDeg for conventional insulin. The duration needed to achieve is made from glargine by addition of one histidine moiety. The new molecule, the target FPG and the quantity of insulin needed in both groups were ana- formulated with the same excipients as those used in Lantus® and at the lyzed. Out of 332 patients with T2DM, 114 patients (60 males, 64.4±9.8 years same molar concentration of insulin analog, has been administered subcuta- old, disease duration of 7.6±7.4 years, HbA1c 10.1±2.1%, BMI 26.7±3.7, FPG neously to normal fasted beagle dogs (n=9, 10-15 Kg) and the glucose level 201±52 mg/dl) were newly administered IDeg once-daily, and 218 patients measured over a period of 36 hours. The study has been conducted in a (95 males, 57.4±13.0 years old, disease duration of 5.6±5.6 years, HbA1c crossover manner using Lantus® as the comparator and both are adminis- 10.4±1.8%, BMI 27.1±4.6, FPG 200±56mg/dl) were newly administered IGla tered at 4.2 nmol/kg. The glucose lowering results, displayed in Figure A, once-daily. Patients newly treated with IDeg achieved the target FPG earlier show that the duration of action for the new molecule is at least 36 hours (6.7±6.9 days) than those with IGla (8.9±11.7 days) (p<0.01). Total doses of compared to about 20-24 hours for Lantus®. The c-peptide corrected insulin IDeg (104.4±75.3 unit) needed to achieve the target FPG tended to be less levels, consistent with the glucose lowering results, also last for at least 36 than those of IGla (122.5±93.4 unit) (NS). Sixty-nine patients undergoing con- hours as shown in Figure B. These results suggest that the new analog has ventional therapy were switched to IDeg for more than 30 days and then the potential to deliver basal insulin with efficacy for at least 36 hours in switched back to conventional therapy. The average and variability (SD) of this animal model. FPG for 14 days prior to and after both switches were analyzed. After switch- ing from conventional therapy to IDeg therapy, both the average and SD of FPG decreased in 47.8% of patients (the average decreased in 72.4% and the SD of FPG decreased in 68.1%), and the amount of insulin was reduced by 10%. Nocturnal hypoglycemia occurred in 1% and 5% of patients undergo- ing IDeg and conventional therapy, respectively. Longer active basal insulin therapy, i.e. IDeg, provides more effective and safer control of blood glucose in T2DM. It might also be expected to reduce medical costs. Supported By: Japan Vascular Disease Research Foundation

83‑LB Adding Liraglutide to High-Dose Insulin: Breaking the Cycle ANNA VANDERHEIDEN, LINDSAY HARRISON, BEVERLEY ADAMS HUET, ILDIKO LINGVAY, Dallas, TX, Austin, TX Treatment with high dose insulin has become much more common in the type 2 diabetes population. These patients often experience treatment related weight gain and an increase in insulin resistance, leading to even 85‑LB higher insulin requirements. We evaluated if addition of liraglutide is effec- Delay of Insulin Initiation in Patients with Type 2 Diabetes Mellitus tive and safe in this difficult to control population with advanced disease. Inadequately Controlled on Oral Glucose-Lowering Agents (Analy‑ We conducted a randomized, double-blinded, placebo-controlled study in sis of Patient- and Physician-related Factors): A Prospective, Ob‑ patients with uncontrolled (HbA1c>7.5%) type 2 diabetes using >1.5 units servational Dipp-Factor Study in Korea of insulin/day, who received liraglutide 1.8 mg/day or matching placebo in SIN GON KIM, KYOUNG SOO HA, BON JEONG KU, HO SANG SHON, DOO MAN addition to their background insulin regimen, for a total of 6 months. All KIM, TAE SUN PARK, YONG-SEONG KIM, IN JOO KIM, DONG SEOP CHOI, Seoul, measurements, including a 4 hr mixed meal challenge test were performed Republic of Korea, Daejeon, Republic of Korea, Daegu, Republic of Korea, Jeonju, at baseline and end of treatment. We randomized 71 patients (age 54 yrs, Republic of Korea, Incheon, Republic of Korea, Busan, Republic of Korea diabetes duration 18 yrs, insulin treatment duration 10 yrs), 93% completed Objective: To assess the time to initiation of insulin therapy, and concur- the study. Results are in the Table. The rate of hypoglycemia (<70mg/dl) was rently investigate both patients- and physicians-factors associated with 0.91 per person/month (ppm) in the liraglutide vs. 0.59 ppm in the placebo delaying insulin therapy in Korean patients with type 2 diabetes (T2D) un- group (p=0.07), this occurred in 84.9% of patients in liraglutide and 71.4% controlled on oral hypoglycemic agents (OHAs). in the placebo group (p=0.25). Addition of liraglutide to a high dose insulin Research Design and Methods: This prospective, observational disease regimen significantly improved glycemic control (placebo-subtracted HbA1c registry was conducted across 69 centers in Korea. T2DM patients who had -1.0%) and caused weight loss (placebo-subtracted weight difference -2.1 received two or more OHAs within last 5 years, had HbA1c ≥8% in last 6

ADA-Funded Research For author disclosure information, see page LB98.

LB21 Clinical Therapeutics/New Technology—Insulins

months and had not received insulin were included. Data were collected in a data collection form during a 12-month period. Results: Of 2,168 patients enrolled, 1,959 were evaluated and classified as insulin-initiated or insulin-delayed group. Insulin was prescribed for only 20% of the patients during one year follow-up and less than half (44.5%) of the patients who were on two OHAs started insulin after 6 years. Patient- related factors for delay in insulin initiation included older age, shorter du- ration of diabetes, and a lower HbA1c. Physician-related factors included age (50 ~ <60 years), gender (women), number (<1000) of patients consulted per month, Patient refusal (33.6%) and physician’s concerns of patient’s non-compliance (26.5%) were the other major reasons of delaying insulin therapy. Inconvenience due to insulin therapy (51.6%) was the major reason for patient refusal. Conclusions: Insulin initiation is delayed in patients with T2D uncontrolled on two or more OHAs in Korea. Patient- and physician-related factors associ- ated with this delay need to be addressed for better diabetes management. Supported By: Sanofi-Aventis Supported By: Sanofi-Aventis 86‑LB 88‑LB Use of PKPD Model to Design and Analyze Results of a Euglycemic Clamp Study for a Very Long-Acting Insulin Analogue HM12470 Clinical Pharmacokinetics (PK) and Renal Elimination of Basal In‑ YEAMIN HUH, JAHOON KANG, NARI YUN, SIYOEN KIL, JEEWOONG SON, SUN- sulin Peglispro (BIL) and Its Polyethylene Glycol (PEG)-Containing NY , Ann Arbor, MI, Seoul, Republic of Korea Products HM12470 is a novel very long-acting insulin analogue developed for weekly PARAG GARHYAN, SIAK LENG CHOI, ELIZABETH S. LABELL, MARY P. KNADLER, dosing, by conjugating a soluble insulin and a non-glycosylated Fc carrier via a MELVIN J. PRINCE, Indianapolis, IN, Singapore, Singapore BIL is a novel basal insulin with a prolonged duration of action consisting of

POSTERS non-peptidyl linker. The extended half-life of HM12470 was confirmed in sev- Therapeutics eral species; mice, rats, dogs, and monkeys. Due to an expected prolonged insulin lispro covalently linked to 20 kDa PEG. In rats, BIL was eliminated primar- Clinical Diabetes/ glucose lowering efficacy from the extended pharmacokinetic (PK) profile, ily via catabolism with total-PEG (BIL and PEG-containing catabolism products) choosing the right time for a euglycemic clamp study becomes an issue to excreted about equally via biliary and renal routes. In this analysis, BIL population capture an onset, peak, and offset of insulin action. The purpose of this study PK was evaluated using data from 15 Phase 1, 2, and 3 studies in healthy subjects is to select the timing of clamp study for a very long-acting insulin analogue and patients with type 1 diabetes or type 2 diabetes (T2D). BIL and total-PEG using a PKPD (pharmacodynamic) modeling. A PKPD model to describe a rela- exposure and renal elimination were evaluated in a subset of T2D patients in a tionship between concentration and glucose infusion rate (GIR) of HM12460A, 26-week Phase 3 study; BIL and total-PEG were measured in urine at week 26 another very long-acting insulin analogue having a similar molecular structure (n=35) and plasma (total-PEG, n=47) or serum (BIL, n=190) at week 2, 4, 12, and to HM12470, was previously developed. From results of animal studies, a ratio 26. The PK of BIL was well described by a 2-compartment model with absorp- of HM12470 half-life (t ) to HM12460A t in human was predicted as 2.4 (132 tion-limited first-order elimination kinetics. Rate of absorption was estimated at 1/2 1/2 -1 hrs vs. 55 hrs). The elimination rate constant (Ke) of HM12470 was then esti- 0.022 hr , clearance was 1.79 L/h and central and peripheral volumes of distribu- tion were 31.5 L and 23.4 L, respectively. Body weight was the only significant mated as 0.0055/hr based on the ratio of t1/2 and Ke of HM12460A (0.0132/hr). By assuming that a base PK model structure is the same between HM12470 predictor of BIL PK, and the effects of body weight, age, BMI, sex, race/ethnicity, and HM12460A except Ke, a concentration vs. time profile of single dose of renal function and disease status were not clinically relevant. At steady state, HM12470 was predicted. The predicted concentration vs. time profile enabled mean renal excretion of BIL and total-PEG was 1.6% and 23.9% of BIL dose, re- to predict a GIR vs. time profile based on an assumption that the potency of spectively. Serum BIL and plasma total-PEG concentrations increased over time HM12470 is the same as the one for HM12460A. Based on these predictions, during dose titration and remained stable during the remainder of the dosing the maximum GIR is expected to be at 62 hr post-dose and the GIR is reduced period. Total-PEG plasma concentrations decreased after cessation of BIL dos- by 40% 10 days later. Therefore, performing a clamp study on day 1 and day ing. These findings show low urinary excretion of intact BIL and suggest that in 5 was recommended to capture an onset and elimination phase of GIR for the patients with T2D the majority of total-PEG was excreted via nonrenal routes. ongoing Phase I study of HM12470. In conclusion, PKPD modeling could be a At steady state, total-PEG plasma concentrations did not increase over time, as useful tool to design and analyze results of a euglycemic clamp study for a very total-PEG continued to be excreted. The PK of BIL supports once-daily dosing, long-acting insulin analogue, whose prolonged glucose lowering effect cannot and dose adjustments are not needed based on patient factors. be fully monitored using current standard methods. Supported By: Eli Lilly and Company

87‑LB 89‑LB Basal Insulin Treatment in Patients with Type 2 Diabetes Uncon‑ Basal Insulin Peglispro (BIL) Demonstrates Hepato-Preferential trolled on Oral Antihyperglycemic Agents: ORBIT Study in China Action vs. (GL) in Patients with Type 1 Diabetes LINONG JI, PUHONG ZHANG, JIANPING WENG, SATISH K. GARG, Beijing, China, Mellitus (T1DM) Guangzhou, China, Aurora, CO SUNDER MUDALIAR, ROBERT R. HENRY, THEODORE P. CIARALDI, DEBRA A. Basal insulin (BI) treatment is usually delayed in patients with T2DM de- ARMSTRONG, PAIVI M. BURKE, JEREMY H. PETTUS, PARAG GARHYAN, SIAK spite its proven efficacy. We report the largest 6-month prospective study in LENG CHOI, SCOTT J. JACOBER, MARY P. KNADLER, ERIC CHEN QUIN LAM, MEL- China to evaluate the safety and glucose control after introduction of BI in VIN J. PRINCE, NAMRATA BOSE, NIELS PORKSEN, VIKRAM P. SINHA, HELLE LIN- real-life in the 2nd or 3rd tier hospitals. Inadequately controlled with OADs NEBJERG, San Diego, CA, Indianapolis, IN, Singapore, Singapore, Silver Spring, MD (A1C ≥7%), adults (N=18,995) with T2DM were enrolled at 209 hospitals (dif- BIL, a novel, long-acting basal insulin, has previously demonstrated ferent regions of China) and had 3 visits (baseline, 3 and 6 months). Type of BI hepato‑preferential action in healthy subjects. This randomized, open-label, used was at the physician’s discretion. Mean age was 55.4±10.4 years, with 4-period, crossover study evaluated effects of therapeutic (BIL and GL) and 6.4±5.3 diabetes duration (~50% men). Long-acting BI was most commonly supratherapeutic concentrations (BIL) on (endogenous glucose production used (82.5%-visit 1, 69.9%-visit 2, 64.2%- visit 3; Figure), with intermediate- [EGP]) and peripheral tissues (glucose disposal rate [GDR] and lipolysis) in pa- acting NPH insulin used by <18% at all visits. Long-acting BI-glargine was tients with T1DM. Patients (n=14; 22-48 years) had 4 euglycemic clamps of 8-10 used by 70% at visit 1, 59% at visit 2, and 54% at visit 3 of patients, whereas hours duration with primed, continuous infusions of BIL (15.3 and 74.1 mU/min) 2 3 detemir was used in <13% at each visit. >70% of glargine and detemir users and GL (10 and 20 mU/m /min). D-[3- H]-glucose infusion assessed EGP and continued to use the same insulin throughout the study. 40% of patients GDR. To correct for differences in binding, equivalent human did not change their insulin dose at all in the first 3 months. There was a insulin concentrations (EHIC) were calculated by dividing each insulin concen- significant improvement in A1c values at 3 months, which was maintained tration by its Ki (binding constant) and multiplying by the Ki of human insulin. at 6 months (Figure). Target FBG (<7.0 mmol/L) and A1C (<7%) were achieved At both low and high doses, BIL showed similar effects on EGP suppression in 43% and 41% of patients, respectively. Hypoglycemia was higher with (endpoint EGP) compared to GL, but had an attenuated effect on GDR (endpoint no weight gain for long-acting BI. We conclude that BI initiation in real-life GDR) (Table). Lipolysis, assessed by free fatty acids (FFA) and glycerol, was improves glucose control at 3 and 6 months in the ORBIT study. suppressed at low and high GL doses but only at the high BIL dose (Table).

ADA-Funded Research For author disclosure information, see page LB98.

LB22 Clinical Therapeutics/New Technology—Insulins

BIL has similar hepatic activity (EGP suppression) but less peripheral activity 91‑LB (GDR stimulation, lipolysis suppression) at clinically relevant concentrations Improved Glycemic Control with Lesser Daily Dose with insulin compared to GL, confirming hepato-preferential action. Glargine on Retransition from Table. UDAYA M. KABADI, Iowa City, IA Background: We documented lapse of glycemic control, despite higher daily insulin dose, 2 SC injections, and increased number of daily blood glucose mon- itoring with less convenience on switching from Insulin Glargine (GI) to Insulin Detemir (DI) in subjects with type 1 and type 2 DM (Iowa Medicaid 1 and 2). Objective: Assess impact of retransition from DI to GI in subjects with type 1 and type 2 DM. Subjects and Methods: 8 men and 6 women with type 1 (36 ± 3 years) and 12 men and 10 women with type 2 DM (62 ± 5 years). Duration of DM (years) was 15 ± 2 in type 1 and 12± 3 in type 2. DI was discontinued in both groups. (AI) was continued premeal 3 times daily in type 1 and Metformin and SU were continued in same daily dose in type 2. GI was re- initiated at 0700-0800 AM in the same daily dose as DI. Daily dose of insulin DI, GI and AI, no of injections, HbA1c, body Weight (BW) and hypoglycemia (Hypo) were assessed at 6 months. Results: Type 1 DM: Daily insulin dose, 58±6 and DI, 31±6 declined to 48±6 and GI, 23±5 units respectively (p<0.05). AI daily dose was not significantly

altered. No of injections with DI, 4.6±0.3 declined to 4.0 ±0 with GI. HbA1c, BW and Hypo were not significantly different (GI: HbA1C, 7.2 ± 0.2; BW, 70 ± 4; Hypo, 0.5 ± 0.2) vs. DI: HbA1c, 7.4 ± 0.3; BW, 71 ± 5 Kg; Hypo, 0.6 ± 0.2). Type 2 DM: On transition to GI, Daily DI dose,70±11 units, no. of injections, 1.4±0.2 and HbA1c, 7.6±0.3 declined to 56±6 units, 1±0, and 7.1±0.2 (p<0.01). No significant changes occurred in BW (93±5 with DI vs. 91±3 with GI) and POSTERS hypo (0.2±0.1 with DI vs. 0±0 with GI). Therapeutics Conclusion: Insulin Glargine is more cost effective than Insulin Detemir Clinical Diabetes/ due to lower daily dose, less equipment, (syringes, needles, pads) needed for once daily administration (more convenient with better quality of life) in type 1 and type 2 Once daily blood sugar testing may further lower cost in type 2. Thus, Insulin Glargine and Detemir are not bioequivalent and transition from one to another may be detrimental.

92‑LB Ultra-Rapid-Acting/Basal Concentrated Insulin BIOD-531 Demon‑ strates Superior Postprandial Glucose Control and Potential for Flexible Post-meal Dosing Compared with Marketed Prandial/Bas‑ al Insulins in Insulin-Resistant Patients with Type 2 Diabetes LINDA MORROW, LORI CANNEY, PHILIP PICHOTTA, MARCUS HOMPESCH, ALAN KRASNER, ERROL DE SOUZA, Chula Vista, CA, Danbury, CT BIOD-531, a 400 U/ml formulation of recombinant human insulin, EDTA, citrate, and sulfate is associated with ultra-rapid onset and basal duration of action. Twelve subjects with type 2 diabetes who used a mean of 205 units Supported By: Eli Lilly and Company of insulin/day were evaluated in this randomized, four-arm cross-over study. On 90‑LB separate days, following glucose standardization, each subject underwent the Simple Fortnightly Intravenous Nonpump Insulin Therapy to Treat following 4 treatments administered with a standardized breakfast (921 kcal) Diabetic Gastroparesis and with a standardized dinner (963 kcal): (a) BIOD-531 immediately before ® ® PRASHANT K. PRAKASH, PRADEEP K. MAHESHWARI, DAYA K. HAZRA, PRAB- meals (pre-meal); (b) Humalog Mix 75/25 (HMix) pre-meal; (c) Humulin R U-500 HAT K. AGRAWAL, AYUSH K. AGARWAL, Agra, India (U-500) pre-meal; and (d) BIOD-531 20 min after the start of the meals (post- Diabetic gastroparesis is characterised by a delay in gastric emptying after meal). The insulin dose was 1.2 U/kg with breakfast and 0.8 U/kg with dinner. a meal in the absence of a mechanical gastric outlet obstruction. Chronic inter- Lunch (669 kcal) was given without insulin treatment 330 min after the breakfast mittent intravenous insulin therapy (CIIIT) was originally described as deliver- dose. The primary endpoint was average glucose concentration in the breakfast ing insulin intravenously over a 6-12 hour period in a pulsatile fashion adjusting to lunch interval. BIOD-531 was associated with superior glucose control com- dosages based on frequent blood sugar monitoring and has been claimed to be pared to HMix and U-500 during this period. The mean post-breakfast glucose beneficial in diverse diabetic syndromes. The aim of the study was to evaluate concentration (mg/dl) was 164.6±11.8 with BIOD-531 treatment compared to the efficacy of a modified non-pump insulin regime “MOD CIIIT” in patients 179.9±10.0 with HMix (p=0.009) and 178.0±7.3 with U-500 (p=0.019). Over the of diabetic gastroparesis Fifty euglycemic cases of diabetes mellitus having entire 24 hours of observation, pre- and post-meal BIOD-531 resulted in superior signs and/or symptoms of diabetic gastroparesis not relieved with conven- glucose concentrations (155.7±15.7 and 149.8±11.8, respectively) compared to tional pharmacotherapy were studied. 12 units of human regular insulin were pre-meal HMix (172.6±14.0, p < 0.05 for both comparisons) and comparable to added to a half litre bottle of 5% Dextrose in 0.9% Normal Saline and infused pre-meal U-500 (154.0±13.1). There were no unexpected safety findings. In sum- intravenously over a period of 6-8 hours using a microdrip set. This was repeat- mary, BIOD-531 dosed pre-meal twice daily resulted in superior prandial control ed fortnightly The symptoms were compared at the commencement of the compared to HMix and U-500 in insulin-resistant patients with type 2 diabetes. study and after 6 sessions of MOD CIIIT (i.e. after 3 months) and finally after Post-meal dosing of BIOD-531 resulted in superior or comparable overall glyce- 12 sessions (6 months) by asking the patient to grade their symptoms numeri- mic control compared to pre-meal treatment with HMix and U-500. cally viz Belching, Bloating, Constipation, Diarrhoea, Nausea and Vomiting on a Visual Analogue Scale (VAS) on each visit. We found that patients who were 93‑LB previously refractory to conventional pharmacotherapy, showed considerable Inpatient Diabetes on Corticosteroids Study response to MOD CIIIT with most patients giving history of improvement in JAMIL B. ALKHADDO, LISA FISH, AMEER KHOWAJA, Minneapolis, MN their symptoms after therapy and during follow up. The VAS scores showed Despite marked hyperglycemia in diabetes patients receiving corticoster- statistically significant decline in the composite score of all symptoms (p< oids (CS), there are no published protocols tested to address insulin manage- 0.001) and HbA1c levels also remained in the euglycemic range throughout. ment. We tested a simple protocol using NPH insulin for inpatient diabetes MOD CIIIT is extremely beneficial in patients presenting with complaints of (IPDM) patients on CS (Table 1). In a prospective, randomized, non-blinded diabetic gastroparesis can be managed by MOD CIIIT. MOD CIIIT is a simple study of IPDM adults receiving CS, 31 patients have been randomized to and inexpensive method of delivering intermittent insulin therapy.

ADA-Funded Research For author disclosure information, see page LB98.

LB23 Clinical Therapeutics/New Technology—Insulins

date to receive either NPH insulin using the protocol or standard care (con- aAcross the study, TI doses were individualized and ranged from 15-90 U; trol). The mean daily blood glucose was 276.8 and 219.47 for the control and therefore, calculating mean FDKP and insulin AUC, mean insulin and C-peptide treatment group, respectively, and the incidence of severe hyperglycemia concentrations, or PK parameters were not meaningful. bFor diagnosis of URTIs, was lower in the intervention arm (Table 2). In conclusion, implementing an patients had to have ≥ 3 URTI symptoms within the 24 hours prior to clinic visit insulin protocol in IPDM patients receiving CS is straightforward and will and/or on the day of clinic visit (runny nose, nasal stuffiness, sneezing, sore throat, scratchy throat, hoarseness, cough [new onset], sinus pain/pressure, increase the use of basal insulin, resulting in better glycemic control. How- c d ever, optimal care may necessitate further insulin adjustment. head congestion/headache, and plugged ears/ear discomfort). n = 19. For 5 patients, TI doses during and after URTI resolution were different. AUC was Table 1. NPH Insulin Protocol. normalized for these patients to the lower of the 2 TI doses; the ratio was e Low dose High dose performed on the log-transformed normalized AUC. Difference (after URTI − CS CS * during URTI); as differences were small and variation large, statistical analysis was limited. AUC0-4h, AUC from 0-4 hours; Cmax, maxium serum concentration; NPH insulin dose with every Eating and 6 am to 8 pm 0.15 u/kg 0.3 u/kg C , minimum serum concentration; FDKP, fumaryl diketopiperazine; NA, not CS dosing min applicable; tmax, time to reach Cmax. NPO or 8 PM to 6 am 0.1 u/kg 0.2 u/kg Supported By: MannKind Corporation (NCT00642681); Sanofi US, Inc.; Excerpta * High dose CS defined as Prednisone > 40 mg/day, hydrocortisone >160 mg/ Medica day, > 32mg/day, and > 6mg/day.

Table 2. 95‑LB New Insulin Glargine 300 U/mL (Gla-300) in Combination with Di‑ Control Intervention P value peptidyl Peptidase IV Inhibitors in T2DM (EDITION 2 and 3): Glyce‑ 17 pts 14 pts mic Control and Hypoglycemia Total # of readings 185 133 RAFFAELLA BUZZETTI, JEREMY H. PETTUS, MIGUEL BRITO-SANFIEL, FERNAN- BG 70 to 180 34 (18.4%) 46 (33.6%) 0.0028 DO J. LAVALLE-GONZÁLEZ, ANA MERINO-TRIGO, PETER STELLA, SOAZIG CHE- BG >180 151 (81.6%) 34 (63.5%) 0.0004 VALIER, JEAN-FRANÇOIS YALE, Rome, Italy, San Diego, CA, Majadahonda, Spain, Monterrey, Mexico, Paris, France, Chilly-Mazarin, France, Montreal, QC, Canada BG >300 73 (39.5%) 26 (19.0%) 0.0001 In people with T2DM treated with oral antihyperglycemic drugs (insulin-

POSTERS BG >400 17 (9.2%) 5 (3.6%) 0.0846

Therapeutics naïve [EDITION 3, N=878] or on basal insulin [EDITION 2, N=811]), starting

Clinical Diabetes/ with or switching to Gla-300 provided comparable glycemic control to in- sulin glargine 100 U/mL (Gla-100), with a lower risk of hypoglycemia at any 94‑LB time of day and during the night over 6 months. This post hoc patient-level Inhalation of Insulin: Effect of Symptomatic Upper Respiratory Tract In‑ meta-analysis of EDITION 2 and EDITION 3 data evaluated glycemic control fections on Pharmacokinetic/Pharmacodynamic (PK/PD) Properties and hypoglycemia with Gla-300 vs. Gla-100, with or without concomitant PHILIP A. LEVIN, LUTZ HEINEMANN, ANDERS BOSS, PAUL D. ROSENBLIT, Balti- DPPIVi use. Among treated patients, 107 (13%, Gla-300) and 133 (16%, Gla- more, MD, Düsseldorf, Germany, Bridgewater, NJ, Huntington Beach, CA 100) participants received DPPIVi therapy. A comparable decrease in HbA1c Uncomplicated, acute upper respiratory tract infections (URTIs), i.e. com- from baseline to month 6 was observed for Gla-300 vs. Gla-100, irrespective mon colds, occur in patients with diabetes at a similar frequency to the gen- of DPPIVi use (Table). Risk of confirmed ≤( 70 mg/dL) or severe hypoglycemia eral population. We studied the effect of URTIs on the PK/PD properties of at any time of day (24 h) or at night (00:00–05:59 h) was consistently lower Technosphere Insulin Inhalation Powder (TI) in patients with type 1 or type 2 for Gla-300 vs. Gla-100, regardless of DPPIVi use. The concomitant use of diabetes (N = 20, mean age 50 years, 60% men). The trial included patients DPPIVi did not have an impact on basal insulin dose change in the different who developed a URTI while treated with TI in a phase 3 study (see Table treatment arms. Weight gain was minimal in all groups. In conclusion, the for URTI definition). Patients underwent two 4-hour meal challenges during comparable glycemic control with less hypoglycemia at any time of day (24 h) which blood samples were drawn to measure serum FDKP (the dry powder and during the night of Gla-300 vs. Gla-100 observed in the overall EDITION excipient), serum insulin, serum C-peptide, and plasma glucose. The primary 2 and EDITION 3 study populations was consistently shown in this pooled outcome was the ratio of serum FDKP AUC0-4h during URTI to after clinical analysis, irrespective of administration of DPPIVi. resolution of URTI symptoms (≥ 15 to ≤ 45 days). There were no significant differences in PK parameters during URTI versus after resolution of URTI (Table). Plasma glucose concentrations (unadjusted and baseline-corrected) were similar during and after URTI resolution. No adverse events (including hypoglycemia) occurred during meal challenge visits. URTIs had no impact on the PK/PD properties of TI. However, study observations are are limited to patients with URTI, as individuals with lower respiratory tract infection were not studied. If a patient is unable to conduct proper inhalation they should administer insulin subcutaneously. Table. FDKP Ratio and Insulin/Glucose Parameters During a Meal Challenge During and After URTI (N = 20). During After Parameter, mean (SD)a URTIb URTI Comparison P value c,d FDKP ratio AUC0-4h during URTI: NA NA 1.1 (0.63) 0.4462 AUC0-4h after URTI (ng*min/mL) c c c FDKP tmax (minutes) 15.8 (26.2) 15.5 (14.8) −0.3 (31.97) 0.9725

c Insulin ratio AUC0-4h during URTI: NA NA 0.9 (0.37) 0.1754 AUC0-4h after URTI (ng*min/mL)

Insulin tmax (minutes) 25.5 (44.42) 21.3 (25.12) −4.3 (52.12) 0.7194

e e Glucose Cmax (mg/dL) Baseline- 212.0 (65.6) 198.8 (69.7) −13.2 (75.6) NA e corrected Cmax (mg/dL) 81.0 (57.2) 69.7 (69.9) −11.3 (72.7) Supported By: Sanofi (NCT01499095, NCT01676220)

e e Glucose Cmin (mg/dL) Baseline- 116.7 (41.7) 111.1 (41.2) −5.7 (57.8) NA e corrected Cmin (mg/dL) 5.9 (14.6) 1.9 (7.9) −4.0 (12.5)

ADA-Funded Research For author disclosure information, see page LB98.

LB24 Clinical Therapeutics/New Technology—Insulin Delivery Systems

Clinical Therapeutics/New Technology— 98‑LB Insulin Delivery Systems Bi-hormonal Closed-Loop Treatment of Type 1 Diabetes with Exer‑ cise Announcement to Prevent Hypoglycemia 96‑LB PETER G. JACOBS, JOSEPH EL YOUSSEF, NAVID RESALAT, RAVI REDDY, DEBO- Efficacy and Safety of Technosphere Inhaled Insulin: Systematic RAH BRANIGAN, NICHOLAS PREISER, JOHN CONDON, JESSICA R. CASTLE, Review and Meta-analysis Portland, OR Exercise significantly increases the risk of hypoglycemia in individuals GREGORY P. WESTCOTT, ETHAN M. BALK, ANASTASSIOS G. PITTAS, Boston, MA, with type 1 diabetes (T1D). To reduce exercise-related hypoglycemia, we Providence, RI Introduction: Technosphere inhaled insulin (TI) recently became available for developed and tested a wireless bi-hormonal artificial pancreas system that clinical use as a non-invasive alternative to subcutaneous insulin in adult pa- delivers insulin and glucagon and adjusts dosing after an exercise announce- tients with diabetes. The purpose of this systematic review and meta-analysis ment. In random order, adult subjects with T1D underwent three 20 h ses- was to determine the efficacy, safety, and patient acceptability of TI. sions: open-loop (OL), closed-loop (CL), and CL with exercise announcement. Methods: We searched MEDLINE, the Cochrane Clinical Trials Register, Exercise announcement stopped insulin for 30 m, then 50% reduction for and the Food and Drug Administration review documents of TI through Janu- 60 m and increased glucagon by 2 fold for 1.5 h. Parameters were selected ary 31, 2015 for randomized control trials that compared TI with placebo, based on in silico testing using a glucoregulatory model with an exercise subcutaneous insulin, or oral anti-diabetic drugs. Two reviewers indepen- component. Glucose values from a Dexcom G4 sensor were pushed every dently assessed trials for inclusion and extracted data on study characteris- 5 m to a Google Nexus phone running the controller. Delivery commands tics, participant baseline characteristics, efficacy, and safety outcomes. were sent to 2 t:slim pumps for subcutaneous insulin and glucagon infusion. Results: 12 trials met eligibility criteria (n=5,273, mean age range 38-61). Capillary blood glucose levels were measured every 2 h during the day and every 3 h at night. After an overnight stay, subjects exercised for 45 m at Among patients with type 1 or insulin-requiring type 2 diabetes, hemoglobin A1c improvement from baseline favored subcutaneous insulin over TI (net 60% VO2max. Subjects were given 2 meals and carbohydrate amounts were difference 0.16% [95% CI 0.06, 0.25]). TI was associated with less weight entered into the controller, which automatically delivered pre-meal insulin. gain (net difference -1.6 kg [-2.1, -1.6]) and less risk of hypoglycemia (odds Subjects wore a Zephyr heart rate monitor and accelerometer. Four (of 24 ratio 0.61 [0.35, 0.92]) compared to subcutaneous insulin. There was an planned) adult subjects with T1D participated in 7 (of 72 planned) 20 h stud- increased incidence of mild, transient, dry cough in patients treated with ies. BG during CL control was 152±46 mg/dl (mean±SEM); daytime BG was 161±51; overnight BG was 135±29. Automated delivery of glucagon success- POSTERS

TI (odds ratio 7.82 [6.14, 10.15]) and greater decline in FEV1 (net difference Therapeutics fully prevented BG values from falling below 70 mg/dL in 100% of cases.

-0.038 liters [-0.049, -0.026]). There was no difference in quality of life or Clinical Diabetes/ overall patient satisfaction. Many trials were designed for non-inferiority, Rescue CHO doses were given for BG values <70 mg/dL. No treatments were which may introduce bias, and most of the trials were 24 weeks duration or needed in any of the 5 CL studies. Five treatments were needed between the less, thus limiting assessment of long-term safety. 2 OL studies. Preliminary results show that automated insulin and glucagon Conclusions: Until long-term safety data are available, TI should be re- delivery effectively controlled glucose levels and prevented hypoglycemia, served for non-pregnant, non-smoking, adult patients with diabetes, free of including during and after exercise. Testing is ongoing to complete a total of pulmonary disease, who are needle-phobic and would otherwise delay ini- 24 subjects. Future work will incorporate heart rate and accelerometry to tiating or intensifying insulin therapy. For patients who are needle-tolerant, automatically detect exercise. subcutaneous insulin appears to be a better option. Supported By: National Institutes of Health-National Institute of Diabetes and Digestive and Kidney Diseases (DP3DK101044-01, K23DK090133) 97‑LB A Feed-Forward Control Approach Capable of Substantially Tight 99‑LB Variation of Blood Glucose Level Closed-Loop Control with DIAS vs. Sensor-Augmented Pump Thera‑ py in Adolescents and Young Adults with Type 1 Diabetes at Camp DERRICK K. ROLLINS, YONG MEI, Ames, IA An artificial pancreas (AP) must be capable of tight glucose control for ma- TRANG T. LY, DANIEL CHERÑAVVSKY, MARTA SATIN-SMITH, DANIEL J. DESAL- jor disturbances. Feedforward control (FFC) has the potential to completely VO, SATYA SHANMUGHAM, PATRICK KEITH-HYNES, MARC D. BRETON, BRUCE cancel the effect of any disturbance that it models. Thus, our objective is A. BUCKINGHAM, Stanford, CA, Charlottesville, VA, Norfolk, VA the evaluation of our novel nonlinear parametrized FFC approach that seeks The DIAS system utilizes a control to range based algorithm for glucose to directly nullify the effects of eating, activity and stress. In this work, 11 control in type 1 diabetes. The system includes a Dexcom G4 sensor, a Roche cases of two weeks of free-living data collection on subjects with type 1 AccuCheck pump and an Android-based DIAS controller. The objective of diabetes are modeled with 13 input variables. The activity variables were this study was to test the safety and efficacy of DIAS in subjects with type collected using the SenseWear® Pro3 Body Monitoring System. For a FFC 1 diabetes, aged 10-35y, over 5 days at diabetes camp. There were 33 sub- model, the critical performance measure is the correlation of the measured jects randomized to either closed-loop with DIAS (intervention) or sensor- BGC and the fitted BGC (rfit). The average rfit values of the 11 cases for augmented pump (control) for 5 days at diabetes camp. Both groups utilized training, validation and testing were 0.64, 0.63, and 0.61, respectively. The premeal boluses. The mean±SD age of all subjects was 17.9±5.5y, A1C was closeness of the values for each of the three sets is an indication that the 8.2±1.5% (range 6.2-11%) and insulin dose 0.9±0.3 u/kg/day. Glucose control models did not significantly over-fit the data on unmeasured disturbances. for the two groups is shown in the Table. The primary outcome of overall per- To understand the potential impact of this approach at this level of rfit we cent time in range, 70-180mg/dL, was greater with DIAS, 78.6% vs. 65.4% show how the variation would be reduced in the figure using the fit of Sub- in the control group, p=0.003. This was associated with both a reduction ject 11. As shown, the variability is substantially reduced, with the standard in time spent < 70 mg/dL and > 180 mg/dL. Closed-loop control with DIAS deviation dropping from 73.9 (left plot) to 8.7 (right plot) mg/dL, a decrease was effective in reducing both hypoglycemia and hyperglycemia as well as of 88.3%. Thus, an AP based on this approach has the potential to reduce the increasing the percent time spent in range in this cohort of adolescents and variation to the level of those without diabetes. young adults with variable baseline glucose control. The improvement in glu- cose control was most prominent at night. Table. Glycemic Outcomes. Results are Man±SE. OVERALL Control Group DIAS Closed- P-Value 07:00 - 07:00 (SAP) n= 16 Loop n=17 Mean glucose 156±5 143±3 0.040 Percent time between 70-180 mg/dL 65.4±5.3 78.6±2.2 0.003 Percent time between 80-150 mg/dL 46.5±3.2 60.0±2.6 0.002 Percent time < 70 mg/dL 4.2±0.8 1.8±0.4 0.008 Percent time > 180 mg/dL 30.7±3.4 19.8±2.2 0.011 Average number of meter glucose 5.4±0.8 4.0±0.7 0.212 values < 70 mg/dL Supported By: The Leona M. and Harry B. Helmsley Charitable Trust

ADA-Funded Research For author disclosure information, see page LB98.

LB25 Clinical Therapeutics/New Technology—Non-Insulin Injectables

100‑LB weeks vs. 8.245 ± 0.72 at baseline with P ≤ 0.034), fasting C-peptide levels Medtronic’s Hybrid Closed-Loop System—An Evaluation of Meal (1.095 ± 0.215 at 12 weeks vs. 0.245 ± 0.069 at baseline with P ≤ 0.003) Dosing and C-peptide response following a 75-g oral glucose tolerance test (1.817 BENYAMIN GROSMAN, ANIRBAN ROY, GAYANE VOSKANYAN, NATALIE KURTZ, ± 0.27 at 12 weeks vs. 0.504 ± 0.065 at baseline with P ≤ 0.004). Patients of DI WU, NEHA PARIKH, REBECCA GOTTLIEB, KRISTEN HUGHES, SARAH MCKEN- treatment group A, exhibited significant increases in plasma level of TGF-β1 NEY, RONALD BRAZG, FRANCINE KAUFMAN, Northridge, CA, Renton, WA (26.18 ± 4.39 at 12 weeks vs. 3.68 ± 0.55 at baseline with P ≤ 0.001). Pa- Medtronic’s hybrid closed-loop system (HCL) requires that patients pro- tients of group A, had also exhibited significant increase in plasma levels vide an estimate of the carbohydrate content of upcoming meals; the system of IL-10 from baseline of (3.8535 ± 0.662) to (13.33 ± 1.516) at 12 weeks (P ≤ then calculates an appropriate meal bolus based on a pre-specified insulin: 0.009). Participants of the control group B did not show significant improve- carbohydrate ratio (CR). It was hypothesized that standardized and relatively ment in any of the previously mentioned parameters at any time point of the aggressive CRs could significantly improve the system’s performance by re- study period. Administration of (CF-CB-MSCs) microvesicles is safe and can ducing postprandial hyperglycemia without increasing the risk of hypoglyce- ameliorate autoimmunity and regenerate β cell mass in T1DM patients. Trial mia. Ten subjects (4 male, mean ages 50±15) wore Medtronic’s HCL system registration: ClinicalTrials.gov number NCT02138331. (composed of next generation insulin pump and sensor technologies) with the embedded HCL algorithm for 12 consecutive days in a monitored set- 103‑LB ting. The clinical trial consisted of three phases: 4 open-loop control days, 4 days with the HCL system using the subjects’ previous pump CRs, then 4 Withdrawn days in HCL with CRs determined using 300 divided by the total daily dose (300 Rule). Subjects consumed standardized meals on day 2 (open-loop), day 6 (closed-loop with previous pump CRs) and day 10 (closed-loop with CRs

using the 300 Rule). On days 2, 6, and 10, the average sensor glucose (SG) values were 162±16, 157±12 and 148±8 mg/dL, peak post-prandial SG values after the standardized meals were 210±44, 224±51 and 194±41 mg/dL, and the percentage of SG values between 70-180 mg/dL range were 66±16%, 73±12%, and 79±6%, respectively. The percentage SG values <70mg/dl in the three phases were: 1.6±1.8%, 0.4±0.45%, and 0.9±0.5%, respectively. POSTERS Therapeutics The average Insulin delivered in anticipation of a standard meal at day 6 Clinical Diabetes/ and 10 were 4.75±4.4, and 5.76±4.85 U and the average CRs were 13.1±4.9 and 10.2±4.4 U/g carbohydrate, respectively. The use of a standardized and relatively low CR resulted in higher pre-meal bolus doses and greater reduc- tions in postprandial hyperglycemia. This was achieved without increasing the risk of hypoglycemia in the Medtronic HCL system.

101‑LB Dose Safety Artificial Pancreas Controller Use in Ad Lib Living Studies RICHARD MAUSETH, DON MATHESON, ROBERT KIRCHER, Redmond, WA The Dose Safety artificial pancreas fuzzy logic dosing controller (FLC) is designed to reduce the high cognitive load on people with diabetes. In an at- tempt to better understand the dynamics of our FLC, we conducted sixteen 8 hour daytime ad lib living studies on five subjects in the CRC. Subjects were asked to perform their usual daily routine as much as possible, and were allowed to eat and exercise as they wished. Subjects had repeated studies. No pre meal boluses or meal or exercise notifications were given. Mean CHO intake was 110 gram range (33-190 grams). Mean exercise performed was 22 minutes range (0-84 minutes). In spite of this wide range of CHO intake and exercise periods, 36.9% of the time the subject’s glucose was within the 104‑LB 70-180mg/dL range. The average glucose was 183mg/dL during the hardest Liraglutide Causes Massive and Rapid Reduction of Cardiac Fat In‑ time of day to handle. For each meal we compared the FLC actual dosing dependent of Weight Loss in Type 2 Diabetes with what the subjects would have dosed. We found that the FLC delivered GIANLUCA IACOBELLIS, SUZY BIANCO, MAHSHID MOHSENI, Miami, FL 68% of the subject own dosing within the first hour and 102% in the first two Epicardial adipose tissue (EAT) is a unique visceral fat depot with peculiar hours post meal. The FLC was revised based on the subjects own dosing. anatomical, bio-molecular features and growing clinical applications. EAT Open loop regression tests of the revised controller using the clinical data can be measured using standard ultrasound and its thickness is an accurate showed that 87% of the subject’s usual dose in the first hour, again with no marker of visceral fat and an emerging therapeutic target. EAT is higher in pre meal bolus or meal notification. We believe this revision will significantly subjects with type 2 diabetes when compared to controls. Liraglutide, an improve the time in range and average blood glucose. analogue of glucagon-like peptide-1 (GLP-1RA) can improve glycemic control and cause weight loss in type 2 diabetic patients. Nevertheless, whether Liraglutide-related weight loss and improved metabolic profile can be at- Clinical Therapeutics/New Technology— tributed to a visceral fat loss is unknown and unexplored. We sought to test Non-Insulin Injectables the hypothesis that Liraglutide causes a rapid and significant reduction in EAT in well controlled overweight/obese type 2 diabetic patients. This was a 6-month interventional case-controlled study in type 2 diabetic subjects 102‑LB 2 Effect of Cell-Free Mesenchymal Stem Cells Microvesicles (MVs) with body mass index (BMI) > 27 kg/m andHemoglobin A1c (HbA1c) ≤ 8% on metformin monotherapy. Individuals were randomized in 2 groups to receive and Exosomes Therapy on β-Cell Mass in Type 1 Diabetes Mellitus (T1DM) additional Liraglutide up to 1.8 mg sc once daily or to remain on Metformin up WAEL F. NASSAR, Cairo, Egypt to 1 g twice daily. EAT thickness was measured at baseline, 3 and 6-month Type 1 diabetes (T1D) is an immunological mediated disease. The clini- follow up visits. Currently, 35 patients completed the 6-month study. In the cal applications of cord blood stem cells and their microvesicles have been Liraglutide group, EAT decreased from 10.2±2 to 6.9±1.9 and 5.8±1.9 mm (p< regarded as a crucial means of intercellular communication and their abil- 0.001) after 3 and 6 months, respectively, accounting for a -42% of reduction at 6 months, whereas there was no EAT reduction in the Metformin group; ity to ameliorate autoimmunity have increased enormously in recent years. 2 Twenty nine T1DM patients were enrolled into two groups; (group A) 20 pa- BMI decreased from 33±7 to 31.8±4 and 31.7±4 kg/m and HbA1c lowered tients, were treated with 2 doses of cell-free cord-blood mesenchymal stem from 6.6±0.8 to 5.7±0.7 and 5.4±0.8% in the Liraglutide group, reflecting -7% cells derived microvesicles and (group B) 9 patients, as matching placebo and -18% of reduction, respectively. Our preliminary results indicate that group. Participants in Group A exhibited improved HbA1c (6.67 ± 0.321 at 12 Liraglutide causes a massive and rapid cardiac fat loss in overweight/obese type 2 diabetic patients, independently of overall weight loss and improved

ADA-Funded Research For author disclosure information, see page LB98.

LB26 Clinical Therapeutics/New Technology—Non-Insulin Injectables glucose control. GLP-1RA effects may be therefore visceral fat specific. 106‑LB These data are of great novelty and immediate clinical application. Antibody LY2786890 Reduced Glucose Levels in Supported By: Novo Nordisk Type 2 Diabetes Mellitus Patients RONAN P. KELLY, PARAG GARHYAN, VINCENT L. REYNOLDS, JENNIFER A. MAR- 105‑LB TIN, CHENG CAI TANG, KWEE POO YEO, THOMAS A. HARDY, Singapore, Singa- Once-a-Month Treatment with HM11260C Improves Glycemic pore, Indianapolis, IN Control in Type 2 Diabetes (T2DM)—Interim Data from a 16-Week Glucagon levels are often elevated in type 2 diabetes mellitus (T2DM) Study and may contribute to hyperglycemia. LY2786890 (LY) is a humanized IgG4 STEFANO DEL PRATO, JAHOON KANG, SOOMIN CHOI, WOOHYUNG LEE, OAK- monoclonal glucagon receptor antibody that displays antagonistic activity PIL HAN, SIYOEN KIL, KYUHOON GEE, IN YOUNG CHOI, SE CHANG KWON, MI- against the human glucagon receptor. A Phase 1, randomized, double-blind, CHAEL TRAUTMANN, MARCUS HOMPESCH, Pisa, Italy, Seoul, Republic of Korea, placebo-controlled study examined the safety and efficacy of single doses Hwaseong, Republic of Korea, Hamburg, Germany, Chula Vista, CA of LY in healthy subjects (N=10, intravenous [IV] 0.05 mg/kg) and T2DM pa- tients (N=44; IV 0.05, 0.1, 0.3, 0.55 mg/kg; subcutaneous [SC] 0.1, 0.55 mg/ HM11260C (HM) is a novel ultra-long acting GLP-1R agonist with a T1/2 of ~ 158 hrs. This 16-week, randomized, placebo (PBO) controlled, double- kg; mean fasting blood glucose [FBG] 126 mg/dL; hemoglobin A1c 7.3%). LY blind parallel group study was designed to investigate efficacy, safety, and was safe and well tolerated. Hypoglycemia was infrequent and mild. Dose tolerability of a range of once monthly (QM) HM doses in subjects with dependent elevations in aminotransferase levels were seen in T2DM pa- T2DM. We report interim data from 86 patients (mean age 56 yrs, BMI 32.1 tients; levels returned to baseline during follow-up with no clinical signs kg/m2, T2DM duration 95.4 months) out of 209 patients with unsatisfactory of liver injury or significant elevations in bilirubin or alkaline . glycemic control while on a stable dose of metformin (≥ 3 months) before en- Pharmacokinetic and pharmacodynamic (PD) profiles of LY supported once weekly SC dosing. The half-life (4 to 26 days) and PD time-action were con- tering this study. Patients were randomized to one of three HM QM doses (8, 12 and 16 mg) or PBO, followed by a 4-week titration period. Overall, all HM centration dependent. Absolute bioavailability after SC administration was doses produced remarkable reductions in HbA1c, fasting plasma glucose, estimated to be 50%. In T2DM patients, LY significantly reduced FBG (Figure) and 7-point daily glucose (Table 1). Percentage of patients on HM achieving and increased plasma glucagon up to approximately 3-fold by day 2. As seen A1c Target < 7% was 73.3% (8 and 16 mg) and 64.3% (12 mg) vs. 22.2% on with oral glucagon receptor antagonists, these data demonstrate that block- PBO. With HM, the reduction in body weight ranged from 2.16% to 2.80% vs. ing glucagon action effectively lowers blood glucose in T2DM subjects.

1.24% on PBO. The most frequent AEs in HM-treated patients were mild or POSTERS moderate gastrointestinal events. No increase in heart rate was recorded. Therapeutics All QM doses of HM demonstrated clinically meaningful improvement in Clinical Diabetes/ blood glucose and body weight loss. The current results will have to be con- firmed upon completion of the trial and warrant further studies to evaluate the long-term efficacy and safety of a monthly regimen with HM in T2DM.

107‑LB Advancing Basal Insulin Glargine with Prandial QD vs. QD or TID in T2DM: The GetGoal-Duo2 Evidence- Based Trial (NCT01768559) JULIO ROSENSTOCK, MARKOLF HANEFELD, SANDRO GENTILE, RONNIE ARON- SON, FRANCISCO J. TINAHONES, BRUNO GUERCI, CHRISTINE ROY-DUVAL, ELIS- ABETH SOUHAMI, MAREK WARDECKI, JENNY YE, SIMON HELLER, ON BEHALF OF THE GETGOAL-DUO2 STUDY INVESTIGATORS, Dallas, TX, Dresden, Germany, Naples, Italy, Toronto, ON, Canada, Málaga, Spain, Vandœuvre-lès-Nancy, France, Paris, France, Warsaw, Poland, Bridgewater, NJ, Sheffield, United Kingdom To provide evidence on how to advance basal insulin (BI), we explored treatment options in poorly controlled, BI-treated (≥6 mo ± 1-3 OADs), pre- dominantly obese adults with T2DM randomized to lixisenatide 20 µg QD (LIXI), insulin glulisine QD (GLU-1), or GLU TID (GLU-3), all added to insulin glargine (IG) ± metformin, if HbA1c remained >7-9% after a 12-week IG optimization run-in period after stopping other OADs. Co-primary endpoints at 26 weeks were (1) non-inferiority (95% CI upper bound <0.4%) in HbA1c reduction with LIXI vs. GLU-1 and (2) for LIXI vs. GLU-3, either non-inferiority in HbA1c reduction (2a) OR superiority (one-sided α=0.025) in body weight change (2b). FPG, PPG, IG dose, AEs, and hypoglycemia were assessed. Each arm randomized 298 pts (T2DM duration 12 yrs, BI duration 3 yrs, weight 89 kg). All co-primary endpoints were met as LIXI was non-inferior to GLU-1 and GLU-3 for HbA1c reductions and sta- tistically superior to both for body weight loss (Table). Documented hypogly- cemia was numerically and significantly lower with LIXI than with GLU-1 and GLU-3, respectively. In conclusion, BI plus LIXI may become a preferred option to advance BI, attaining meaningful glycemic targets with less hypoglycemia and without negative impact on weight vs. prandial insulin as Basal Plus or Basal Bolus for uncontrolled, BI-treated T2DM.

ADA-Funded Research For author disclosure information, see page LB98.

LB27 Clinical Therapeutics/New Technology—Oral Agents

Clinical Therapeutics/New Technology— Oral Agents

109‑LB Withdrawn

POSTERS Therapeutics Clinical Diabetes/ 110‑LB Low Dose Pioglitazone on Glycemic Control and Insulin Resistance in Type 2 Diabetes: A Randomised, Double-Blind, Clinical Trial DEBASISH HOTA, SUJIT RAJAGOPALAN, AMITAVA CHAKRABARTI, PINAKI DUT- TA, ANIL BHANSALI, Bhubaneswar, India, Chandigarh, India Objective: To evaluate the antihyperglecemic and anti insulin sensitising effects of low dose pioglitazone (7.5 mg) along with characterisation of its adverse effect profile. 108‑LB Methods: This was a randomised, double blind, single centre study com- A Monoclonal Anti-aP2 Antibody Treats Diabetes and Ameliorates paring the effects of three doses (7.5 mg, 15 mg and 30 mg) of pioglitazone Fatty Liver Disease in Obese Mice over a period of 12 weeks. We recruited 90 patients who were allocated MEHMET FURKAN BURAK, KAREN INOUYE, ARIEL WHITE, CARL DOYLE, DAN to the three groups in (1:1:1) fashion. HbA1c, FPG, PPG, FPI, C-peptide, Adi- LIGHTWOOD, LOUISE HOWELLS, GEOFREY ODEDE, HANNA HAILU, SHAUNA ponectin, Leptin, Weight, Waist circumference, Body fat, haematological WEST, ALISON CLARGO, HELEN NEALE, RACHEL GARLISH, ADRIAN MOORE, and biochemical parameters were measured at baseline and at the end of GÖKHAN S. HOTAMISLIGIL, Boston, MA, Slough, United Kingdom 12th week. ITT analysis was done. The lipid chaperone aP2/FABP4 has been implicated in the pathology of Results: Significant reduction in HbA1c was seen with Pioglitazone 7.5 mg, many immunometabolic diseases, such as diabetes and atherosclerosis. 15 mg and 30 mg, with a mean reduction of -0.5 ± 0.1%, -0.6 ± 0.2 and -0.7 While multiple lines of evidence also supports its involvement in human ± 0.1 respectively. There was a significant reduction in FPG and PPG in all disease, targeting aP2 for therapeutic applications have not yet been ac- three groups. Pioglitazone 7.5 was also able to cause significant reduction complished. Recent studies in our laboratory have shown that aP2 is not in insulin, c-peptide and increase in adiponectin levels similar to its 15 mg simply an intracellular protein binding lipids but an active adipokine that and 30 mg doses. Moreover, there was significantly less weight gain and contributes to hyperglycemia by promoting hepatic gluconeogenesis and increase in body fat in the 7.5 mg group as compared to 30 mg group. There interfering with peripheral insulin action. Multiple groups have now dem- were no changes in hepatic or renal function. onstrated that serum aP2 levels are markedly elevated in mouse models of Conclusions: Pioglitazone 7.5 mg is as efficacious as higher doses of 15 mg obesity, and human serum aP2 levels strongly correlate with BMI, insulin re- and 30 mg and has lesser side effects. Hence it is better to start therapy at sistance, dyslipidemia, and cardiovascular risk. Importantly, blocking aP2 in a lower dose of pioglitazone in patients. preclinical models showed strong anti-diabetic activity. These observations raised an exciting new strategy for targeting serum aP2 to treat metabolic disease with a monoclonal anti-aP2 antibody. Here, we report the identifica- 111‑LB tion of a highly effective, anti-aP2 mAb, CA33, and the characterization of Cardiovascular Outcome Trial with Fasiglifam, a Novel Selective its effects in vivo. Treatment of mice with dietary or genetic obesity with GPR 40 Agonist CA33 lowered fasting blood glucose levels, improved glucose metabolism, VENU MENON, A. MICHAEL LINCOFF, STEPHEN NICHOLLS, PRABHAKAR VISWA- increased systemic insulin sensitivity and reduced fat mass and liver ste- NATHAN, DARREN K. MCGUIRE, THEODORE MAZZONE, BERNARD ZINMAN, atosis. In hyperinsulinemic-euglycemic clamp studies, we found that the ANTONIO CHACRA, JOHN BETTERIDGE, JULIO ROSENSTOCK, CYRUS MEHTA, anti-diabetic effect of CA33 was predominantly linked to the regulation of SUSAN JASPER, JOHN MARCINAK, CLAUDIA LOPEZ, STEVEN E. NISSEN, Cleve- hepatic glucose output and peripheral glucose utilization. We also examined land, OH, Adelaide, Australia, Deerfield, IL, Dallas, TX, Chicago, IL, Toronto, ON, the properties of this antibody by structural and biochemical studies, identi- Canada, São Paulo, Brazil, London, United Kingdom, Cambridge, MA Fasiglifam (FG) is a compound that potentiates glucose-stimulated insulin fied its target epitopes, and demonstrated its target specificity. We conclude secretion via selective agonism of the -coupled receptor 40. We that development of an anti-aP2 monoclonal antibody-mediated therapeutic designed a double blind, multicenter, international cardiovascular outcome is a feasible approach and would constitute a strong candidate for the treat- trial (CVOT). We planned to enroll approximately 5000 subjects with T2D ment of diabetes and fatty liver disease. (HbA1c 7-10.5%) with either “high risk” factors (prior MI, symptomatic PAD, Supported By: UCB Pharmaceuticals or stroke >2 but < 24 months of enrollment) or “intermediate risk” criteria. Trial subjects received either FG 50 mg or placebo once daily in addition to standard of care. Subjects with ALT/AST > 3x ULN, bili > 1x ULN, HIV, or active Hep B/C were excluded. The 10endpoint was time to first occur- rence of any component of the MACE composite of CV death, MI, stroke or hospitalization for unstable angina. The study was terminated early by

ADA-Funded Research For author disclosure information, see page LB98.

LB28 Clinical Therapeutics/New Technology—Oral Agents

DMC after enrollment of 3207 subjects with a mean exposure of 221±134 and 48% (P=0.06) respectively, but had no effect on tissue ceramide days for observed risks of hepatotoxicity that appeared to outweigh poten- content. Increased PKC-epsilon and PKC-theta activity play a major role tial benefits. The mean age was 63 ± 9 years, 65.5% of subjects were male, in promoting liver and muscle insulin resistance and consistent with the mean HbA1c was 8.3±0.9% and mean duration of T2D was 13±8 years. At 6 improvement in whole body insulin sensitivity. CRMP treatment reduced months, the median HbA1c on FG decreased 0.8% compared to 0.4% with PKC-epsilon in liver and PKC-theta activity in muscle by ~50% (P<0.05) and placebo (P <0.001). The number of subjects who had elevated ALT >3×ULN 70% (P<0.05) respectively. In conclusion these data support the potential during double blind treatment was higher in the FG than in the placebo group utility of CRMP for the treatment of NAFLD, NASH and T2D in the setting (32/1601 [2.0%] vs. 6/1603 [0.4%]), as were the number with elevated ALT of severe lipodystrophy. >5×ULN (17/1601 [1.1%] vs. 1/1603 [0.1%]) and with elevated ALT >10×ULN (5/1601 [0.3%] vs. 1/1603[0.1%]). There were no cases of Hy’s law but 1 sub- 114‑LB ject in FG arm had ALT >3xULN and total bili1.6xULN with no alternative in Diabetic Kidney Disease: Results from a Phase 2, Mul‑ 0 etiology. The 1 endpoint occurred in 40 subjects (2.5%) in each arm, RR for ticenter, Randomized, Double-Blind, Placebo-Controlled Study FG vs.placebo of 0.99 (95% CI: 0.641, 1.539), p=0.98. Whether the liver injury KATHERINE TUTTLE, FRANK C. BROSIUS III, SHARON G. ADLER, MATTHIAS represents a specific drug or class effect with this novel target remains un- KRETZLER, RAVINDRA L. MEHTA, JAMES A. TUMLIN, JIAJUN LIU, MARIA E. certain. Rates of CV endpoints were comparable for FG and placebo groups. SILK, TRACY E. CARDILLO, KEVIN L. DUFFIN, JOSEPH V. HAAS, WILLIAM L. MA- Long term CVOT in T2D contribute to understanding the overall safety profile CIAS, JONATHAN M. JANES, Spokane, WA, Ann Arbor, MI, Torrance, CA, San Di- of a compound. ego, CA, Chattanooga, TN, Indianapolis, IN Diabetic kidney disease (DKD) is the foremost cause of end-stage renal 112‑LB disease. New therapeutic strategies are needed as standard care fails to

TRPA1 Calcium Channel Activators as Novel GLP-1 Secretagogues prevent progressive DKD. Baricitinib (bari) is a small-molecule inhibitor of JIMMY WU, OLEG G. CHEPURNY, COLIN LEECH, HUI LI, XINPING HAN, GEORGE Janus kinases 1 and 2. This ph 2 study examined if bari treatment decreased G. HOLZ, Hanover, NH, Syracuse, NY, Dallas, TX levels of urine albumin in patients at high-risk for progressive DKD. Study Orally administrable blood glucose-lowering agents that exert their ef- participants (n=129) received standard care and were randomized (1:1:1:1:1) fects by stimulating GLP-1 release from intestinal L-cells may constitute to bari (0.75 mg QD, 0.75 mg BID, 1.5 mg QD, 4 mg QD) or placebo (PBO) for a new means by which to treat patients with diabetes mellitus. Here, we 6 months (mos) followed by a washout period of 4 weeks. Baseline 24 hr

report the synthesis, characterization, and target validation of JWU-A021, urine albumin-to-creatinine ratio (UACR) (median [interquartile range]) was POSTERS a small molecule cycloalka[b]indole that stimulates GLP-1 release and that 886 (488-1643) mg/g. Reductions in 24 hr UACR were observed at 3 and 6 Therapeutics is synthesized by means of a novel 3 component coupling reaction in which mos (Figure). Baseline estimated glomerular filtration rate (cystatin C based) Clinical Diabetes/ each component is independently varied (Han et al., ACIE, 2012). JWU-A021 was 49±23.2 ml/min/1.73 m2 (mean±SD) and did not change in any group. is orally bioavailable in mice, and it exerts a GLP-1 secretagogue action by Inflammatory markers, including urinary interferon gamma-induced protein virtue of its ability to activate TRPA1 calcium channels. Using intestinal STC- 10 and plasma soluble receptor 2, decreased in a dose- 1 cells that express TRPA1, we find that JWU-A021 activates voltage-inde- dependent manner suggesting an anti-inflammatory mechanism to reduce pendent calcium currents, an effect also measurable in HEK cells transfected albuminuria. At 6 mos, only the highest bari dose group had a decrease in he- with TRPA1. For both STC-1 and HEK cells, a dose-dependent, sustained, and moglobin compared to PBO (-1.0±0.35, g/dL) (difference in LSM±SE). Adverse reversible increase of calcium concentration is measured in response to events of anemia were also more frequent in bari 4 mg (8/25) vs. PBO (1/27). JWU-A021, and this effect is blocked by the TRPA1 antagonists HC-030031, These results encourage further study of bari as a new therapy for DKD. A-967079, and AP-18. Using HEK cells transfected with a mutant TRPA1, we find that JWU-A021 activates TRPA1 independently of covalent channel modification. The binding site for JWU-A021 on TRPA1 is enantiodiscrimina- tory since (+)-JWU-A021 elicits a more robust response than that of (-)-JWU- A021. Notably, JWU-A021 stimulates GLP-1 release from STC-1 cells (EC50 2 microM), as is also the case for the structurally related compounds JWU- A019 and JWU-A020 that activate TRPA1. The GLP-1 secretagogue action of JWU-A021 is measurable at both 5 and 25 mM extracellular glucose, and it is potentiated by cAMP-elevating agents (forskolin, IBMX). Since G protein- coupled receptors for fatty acid amides (GPR119) and bile acids (TGR5) are linked to cAMP production in L-cells that express TRPA1, these new find- ings suggest a drug treatment strategy in which cycloalka[b]indoles such as JWU-A021 are administered in combination with a GPR119 or TGR5 agonist so that L-cell GLP-1 secretion is fully stimulated. Supported By: National Institutes of Health (1R01GM111638-01)

113‑LB A Novel Extended-Release Mitochondrial Protonophore Reverses Diabetes in Lipoatrophic Mice ABUDUKADIER ABULIZI, RACHEL J. PERRY, NASIRI ALI, MICHAEL J. JURCZAK, GERALD I. SHULMAN, New Haven, CT Non-alcoholic fatty liver disease (NAFLD) is a major factor in the Supported By: Eli Lilly and Company pathogenesis of type 2 diabetes (T2D) and non alcoholic steatohepatitis (NASH). Recently, we showed that a controlled-release oral formulation 115‑LB of 2,4-dinitrophenol (CRMP) reversed insulin resistance, hyperglycemia as Comparative Effectiveness and Safety of Monotherapy and Add-on well as hepatic steatosis and liver inflammation in rat models of T2D and Therapy to Metformin in Type 2 Diabetes: An Updated Systematic NASH without adverse effects (Perry et al. Science 2015). We hypothesized Review and Meta-analysis that CRMP would also be effective in reversing insulin resistance and NA- NISA M. MARUTHUR, EVA TSENG, LISA WILSON, SUSAN HUTFLESS, EMAN- FLD/NASH in a transgenic (A-ZIP/F-1) mouse model of severe lipodystro- NUEL IYOHA, CATALINA SUAREZ-CUERVO, ZACK BERGER, JODI SEGAL, SHARI phy. Consistent with this hypothesis we found that CRMP treatment (2mg/ BOLEN, Baltimore, MD, Cleveland, OH kg/d x 3 wks) decreased plasma glucose and insulin concentrations in AZIP Given the recent approval of many new glucose-lowering drugs for type mice by 50-60% (P<0.01) during an intraperitoneal glucose tolerance test 2 diabetes, we updated the 2011 AHRQ-funded report about their compara- compared to controls. CRMP-induced improvement in glucose tolerance tive effectiveness. We searched the MEDLINE®, Embase™, and Cochrane and insulin sensitivity was associated with 50% reductions in liver trig- databases through July 2014 for articles evaluating the effects of monother- lyceride content and reduced liver inflammation as reflected by 30-45% apy (metformin [MET], thiazolidinediones [TZDs], sulfonylureas [SUs], GLP-1 reductions in plasma AST and ALT concentrations and occurred indepen- agonists, DPP-4 inhibitors, SGLT-2 inhibitors) and MET-based combinations dently of any changes in activity, food intake, energy expenditure or body (MET + any other class) on long-term, intermediate, or adverse outcomes. weight and was unassociated with any adverse effects. Furthermore, We included 115 new studies (total 229 studies). Cardiovascular (CV) mortal- CRMP reduced liver and muscle diacylglycerol content by 36% (P<0.001) ity was 37-50% lower for MET compared to SUs; CV morbidity was also

ADA-Funded Research For author disclosure information, see page LB98.

LB29 Clinical Therapeutics/New Technology—Oral Agents

lower for this comparison. Most monotherapy medications decreased HbA1c 2. Episodes of Hypoglycemia/pt/24 hours in CGM at start and end of therapy similarly except DPP-4 inhibitors which had a lesser effect. MET-based com- Overall hypoglycemia (< 70 mg/dl) 0.28 + 0.9 0.31 + 0.6 0.05 binations lowered HbA1c by 0.7-1% vs. MET alone. MET, GLP-1 agonists, Overall Severe hypoglycemia (< 50 mg/dl) and SGLT-2 inhibitors caused weight loss vs. SUs and TZDs which caused Nocturnal Hypoglycemia 0.05 + 0.2 0.07 + 0.2 NS weight gain. SGLT-2 inhibitors reduced systolic blood pressure by 3-5 mm (< 70 mg/dl, 12 midnight-6 am) 0.06 + 0.2 0.09 + 0.1 NS Hg and increased the risk of genital mycotic infections vs. other drugs. SUs Nocturnal Severe hypoglycemia increased the risk of hypoglycemia vs. other drugs; SGLT-2 inhibitors caused (< 50 mg/dl) 0.02 + 0.0 0.03 + 0.1 NS less hypoglycemia than MET. MET caused more gastrointestinal side effects 3. Duration of Hypoglycemia in Minutes/ 24 hrs in CGM start and end of vs. other drugs except GLP-1 agonists which increased vomiting vs. MET. therapy Evidence on microvascular and other adverse outcomes was sparse. While A: Overall hypoglycemia the comparative long-term benefits and harms of most diabetes medications remain unclear, the evidence suggests that MET is associated with lower All Hypoglycemia < 70 mg/dl 18.8 + 70.0 21.3 + 51.3 NS Mild Hypoglycemia 50-69 mg/dl 8.9 + 29.2 12.1 + 25.9 0.04 CV mortality and morbidity compared to SUs. Given the similar short-term Severe Hypoglycemia < 50 mg /dl 9.8 + 44.8 9.2 + 36.7 NS glycemic effects and differential effects on other outcomes of interest (e.g., weight, hypoglycemia, GI side effects, and infections) by drug class, B: Nocturnal Hypoglycemia (12 midnight-6 am) our updated synthesis should help clinicians and patients choose diabetes All Hypoglycemia < 70 mg/ 8.1 + 31.7 9.2 + 31.7 NS medications collaboratively and prioritize patient concerns related to spe- Mild Nocturnal Hypoglycemia 2.6 + 10.7 4.2 + 12.4 NS cific benefits and harms. 50-69 mg/dl Severe Nocturnal Hypoglycemia 5.5 + 23.7 5.0 + 29.1 NS Supported By: HHSA290201200007I < 50 mg /dl

4. Area Over the Curve (AOC) of Hypoglycemia in CGM start and end of 116‑LB therapy (mg/dl.min) Hypoglycemia (Hypo) during Therapy (Rx) of New Onset Type 2 Dia‑ A: Overall hypoglycemia AOC betes (DM2) Patients (Pts) Presenting with Severe Hyperglycemia: Comparison of 2 Protocols All Hypoglycemia < 70 mg/dl AOC 74.5 + 317.7 71.7 + 233.8 NS AMBIKA AMBLEE, DANIEL LIOUS, ZACHARIAH SHEBANI, LEON FOGELFELD, Mild Hypoglycemia 50-69 mg/dl AOC 57.6 + 243.7 56.3 + 171.3 NS Severe Hypoglycemia < 50 mg /dl 16.9 + 75.1 15.4 + 64.3 NS

POSTERS Chicago, IL Therapeutics To test hypo occurrence with Continuous Glucose Monitoring (CGM) in 2 B: Nocturnal Hypoglycemia (12 midnight-6 am) AOC Clinical Diabetes/ simple oral Rx in newly diagnosed DM2 pts presenting with severe hyperg- All Hypoglycemia < 70 mg/dl AOC 37.4 + 156.1 35.6 + 173.7 NS lycemia. Open label, RCT of 100 adult DM2 pts with blood glucose (BG) levels Mild Nocturnal Hypoglycemia 27.9 + 115.8 26.5 + 119.9 NS of 300-450 mg/dl at a public hospital. Pts were randomized to Glipizide XL (G 50-69 mg/dl AOC group {gp}) versus (vs.) Kombiglyze XR, the saxagliptin/metformin fixed-dose Severe Nocturnal Hypoglycemia 9.5 + 41.7 9.1 + 54.4 NS combination (K gp). Three -5 day CGM was performed at start (1st week of < 50 mg /dl Rx) and at the end of study (12 weeks). Data are available for 77 pts at start *CGM are expressed either as combination of start and follow up data or and 53 pts at the end of the study. Baseline characteristics and glycemic separately. control (A1c) at the end of the study were similar, K gp 10.8 to 6.8%; G gp Supported By: AstraZeneca/Bristol-Myers Squibb 11.0 to 6.9%. Hypoglycemia incidence and episodes (epi) in patients by self- monitored BG were lower in the K gp, (8.9% vs. 25%; 4 vs. 27). The CGM data 117‑LB (Table) indicate that overall incidence of hypos, the episodes of hypo/pt/24 MARCH Sub-analysis: Influential Factors for Efficacy of Acarbose hours and the duration of mild hypos were lower in K gp. There were hypos and Metformin as Initial Therapy in Chinese Patients with Newly at start of Rx in both gps including nocturnal and severe hypos. Glipizide XL Diagnosed Type 2 Diabetes and Kombiglyze XR Rx improved severe hyperglycemia in newly diagnosed WENYING YANG, JINPING ZHANG, Beijing, China DM2 patients. Hypoglycemia, including nocturnal and severe, was present MARCH trial demonstrated that as initial therapy for Chinese newly diag- within the 1st week of therapy in both gps. The Kombiglyze XR gp had less nosed T2DM patients, acarbose and metformin has similar efficacy in HbA1c hypoglycemia at the end of the study. Hypoglycemia can occur early after Rx reduction and there was no difference in the proportion of patients with HbA1c initiation in newly diagnosed pts with severe hyperglycemia. ≤ 7% between those two treatment. We aimed to investigate whether specif- Table. *CGM Hypoglycemia Data (adjusted for 24 hours). ic characteristics were associated with treatment efficacy for either drug. All K Group G Group P-value patients (n=657) randomly assigned to acarbose or metformin treatment were 1. Incidence of Hypoglycemia (% of Patients) divided into two groups based on HbA1c levels at the end of 48 weeks follow- up: HbA1c <7% and HbA1c ≥7%. Univariate, multivariate, and stepwise linear A: Overall hypoglycemia (< 70 mg/dl) regression analysis were applied to identify factors associated with treat- Hypoglycemia 9/44 (20.4%) 18/43 (41.8%) 0.03 ment efficacy. Univariate analysis revealed that the efficacy of acarbose and (CGM at start and end of study) metformin were influenced by baseline glucose level and the change of BMI —Hypoglycemia (CGM start of therapy) 4/40 (10%) 5/37 (13.5%) NS (P≤0.006). And the efficacy of acarbose was also associated with age, gender —Hypoglycemia (CGM end of therapy) 5/25 (20%) 13/28 (46.5%) 0.04 and AUC of insulin, while for metformin treatment, the efficacy was also as- B: Nocturnal Hypoglycemia (< 70 mg/dl from 12 midnight-6 am) sociated with baseline diastolic blood pressure, HDL-C and β cell function (HO- Nocturnal hypoglycemia 5/44 (11.3%) 9/43 (20.9%) NS MA-B). Multivariate and stepwise regression model analyses revealed that (CGM at start and end of study) lower baseline 2hPPG and more change of BMI are protect factors for efficacy —Nocturnal Hypoglycemia 3/40 (7.5%) 3/37 (8.1%) NS in both treatment group (P≤0.05). And the efficacy of acarbose treatment was (CGM start of therapy) also increased with baseline AUC of serum insulin, while for metformin treat- —Nocturnal Hypoglycemia 2/25 (8%) 6/28 (21%) NS ment, the efficacy was also increased with baseline diastolic blood pressure (CGM end of therapy) and HDL-C (P≤0.05). Stepwise regression model analysis demonstrated that, C: Severe hypoglycemia (< 50 mg/dl) except for baseline 2hPPG and the change of BMI, lower baseline HOMA-IR Severe hypoglycemia 3/44 (6.8%) 5/43 (11.6%) NS and higher AUC of serum insulin are also protect factors for HbA1c normaliza- (CGM at start and end of study) tion for all patients (P≤0.001). Newly diagnosed T2DM patients with lower —Severe Hypoglycemia 2/40 (5%) 2/37 (5.4%) NS 2hPPG and HOMA-IR, higher insulin level are more likely to achieve glucose (CGM start of therapy) control. And the change of BMI or body weight after acarbose or metformin —Severe Hypoglycemia 1/25 (4%) 3/28 (10.7%) NS treatment is also an influential factor for treatment efficacy. (CGM end of therapy) D: Severe Nocturnal hypoglycemia (< 50 mg/dl) Nocturnal Severe hypoglycemia 3/44 (6.8%) 3/43 (6.9%) NS (CGM at start and end of study) — Nocturnal Severe Hypoglycemia 2/40 (5%) 2/37(5.4%) NS (CGM start of therapy) — Nocturnal Severe Hypoglycemia 1/25(4%) 1/28(3.5%) NS (CGM end of therapy)

ADA-Funded Research For author disclosure information, see page LB98.

LB30 Clinical Therapeutics/New Technology—Oral Agents

118‑LB Table. Influence of Baseline HbA1c, BMI, β-cell Function, and Insulin Sen‑ sitivity on the Treatment Response of (EMPA) in Pa‑ tients with Type 2 Diabetes (T2DM) MARTIN RIDDERSTRALE, ULRICH ELSASSER, CORDULA ZELLER, STEFAN HAN- TEL, AFSHIN SALSALI, ULI BROEDL, Gentofte, Denmark, Ingelheim, Germany, Bib- erach, Germany, Ridgefield, CT EMPA, a potent, selective sodium glucose cotransporter 2 inhibitor, inhib- its renal glucose reabsorption, leading to glucosuria and improved fasting and postprandial glucose. Due to its renal mechanism of action (MOA), we hypothesized that glucose lowering with EMPA is independent of β-cell func- tion and insulin resistance. Using pooled data from three 24-week trials that investigated EMPA 10 mg (n=632) and EMPA 25 mg (n=626) vs. placebo (PBO; n=622) as monotherapy or add-on to metformin (MET) or MET+sulfonylurea, we investigated the influence of baseline HbA1c, body mass index (BMI), HOMA-B and HOMA-IR on change from baseline in HbA1c using 2-way in- teraction models. EMPA significantly reduced HbA1c from baseline vs. PBO at week 24; in a model without interaction, mean HbA1c reductions vs. PBO Supported By: Boehringer Ingelheim/Eli Lilly and Company were -0.65% with EMPA 10 mg and -0.70% with EMPA 25 mg. Baseline HbA1c had a significant influence on the treatment effect (p<0.001 for in- 120‑LB teraction). There were no interactions between treatment and baseline BMI CNX-013-B2 Provides Long-Term Glycemic Control and Has Poten‑ (p=0.606), HOMA-B (p=0.384) or HOMA-IR (p=0.199). Predicted reductions in tial to Reduce Diabetic Complications—Studies in mZDF Rats HbA1c based on a model including baseline HbA1c by treatment interaction MADANAHALLI R. JAGANNATH, MARIKUNTE V. VENKATARANGANNA, BAG- are presented in the Table. In summary, treatment effects of EMPA on HbA1c GAVALLI P. SOMESH, MAMMEN O. ANUP, THARAPPEL M. ANIL, MAHESH KU- reductions appear to be driven by baseline HbA1c and to be independent of MAR VERMA, KRISHNAREDDY HARSHA, RAJ GOWTHAM, PATIL A. HANSRAJ, baseline -cell function, insulin sensitivity and BMI. β MUDIGERE N. LAKSHMI, PUTTREVANA M. PALLAVI, SIVAKUMARAN YOGESH- POSTERS Therapeutics Table. WARI, ARALAKUPPE S. GOPALA, Bangalore, India We have previously reported that CNX-013-B2, an orally administered het- Clinical Diabetes/ erodimer selective rexinoid, controlled multiple risk factors of the metabolic syndrome in obese rodent models of disease. CNX-013-B2 did not cause edema or fluid accumulation or hepatomegaly nor did it increase body weight in ro- dents. We now report the effect of long term treatment of male Zucker Diabetic Fatty (mZDF) rats with CNX-013-B2 (10 mg/kg qd, n=10) on control of diabetes and certain aspects of diabetic complications. CNX-013-B2 treatment provided significant glycemic control all through the study period reaching a decrease of 67% fed (115 vs. 348 mg/dl) and 69% fasting (110 vs. 355 mg/dl) glucose com- pared to mZDF control animals (22nd week). This robust glycemic control trans- lated to a steep reduction in HbA1c (4.54% vs. 14.56%) compared to control animals. In OGTT (10th week), treatment reduced glucose AUC by 16% (32552 vs. 38524; p<0.05) and insulin AUC by 39% (769.48 vs. 1270.17; p<0.001) indicat- ing significant improvement in insulin sensitivity. After 18 weeks treatment a Supported By: Boehringer Ingelheim/Eli Lilly and Company significant reduction in serum levels of oxidized LDL (45%), leptin (36%) and an increase in adiponectin (31%) was observed even in absence of any change in 119‑LB body weight. At end of study significant reduction in fasting triglyceride (TG - Initial Combinations of Empagliflozin and Metformin (EMPA+MET) 25%), total cholesterol (10%), liver TG (34%) and muscle TG (40%) was observed. in Patients with Type 2 Diabetes (T2DM) A significant 29 mg/dl reduction in Blood Urea Nitrogen, an increase in nerve SAMY HADJADJ, ANTE JELASKA, SHU ZHANG, THOMAS MEINICKE, HANS J. conductance velocity and decrease in serum levels of known cardiovascular WOERLE, ULI C. BROEDL, Poitiers, France, Ridgefield, CT, Biberach, Germany, Ingel­ risk factors were observed indicating control over progression of diabetic com- heim, Germany plications. Treatment has shown a significant improvement in genes those are MET is the recommended first-line therapy for patients with T2DM, but involved in glucose and fat oxidation, energy expenditure and cellular stress. initial combination therapy may provide more robust glucose-lowering efficacy. In a Phase III study, 1364 drug-naïve patients with T2DM were 121‑LB randomized to EMPA 12.5mg bid+MET 1000mg bid (n=170), EMPA 12.5mg Effects of Dextromethorphan (DXM) Alone and as Add-on to Sita‑ bid+MET 500mg bid (n=170), EMPA 5mg bid+MET 1000mg bid (n=172), EMPA gliptin (SITA) on Blood Glucose (BG) and Serum Insulin (INS) Con‑ 5mg bid+MET 500mg bid (n=170), EMPA 25mg qd (n=168), EMPA 10mg qd centrations in Patients with Type 2 Diabetes Mellitus (T2DM) after (n=172), MET 1000mg bid (n=171) or MET 500mg bid (n=171). The primary an Oral Glucose Tolerance Test (OGTT) endpoint was change from baseline in HbA1c at week 24. Key secondary JAN MARQUARD, ALIN STIRBAN, FREIMUT SCHLIESS, FELIX SIEVERS, ALENA endpoints were changes from baseline in fasting plasma glucose (FPG) and WELTERS, SILKE OTTER, ANNELIE FISCHER, STEPHAN WNENDT, THOMAS weight. EMPA+MET bid led to statistically superior and clinically meaningful MEISSNER, TIM HEISE, ECKHARD LAMMERT, Düsseldorf, Germany, Neuss, Ger- reductions in HbA1c vs. EMPA qd and MET bid doses (Table). EMPA+MET bid many, Mönchengladbach, Germany led to significant reductions in FPG vs. EMPA qd and MET bid and in weight Recently we showed that the NMDA DXM enhances vs. MET bid (Table). Adverse events (AEs) were reported in 56.7-66.3% of postprandial INS and oral BG tolerance in T2DM and improves islet insu- patients across groups. Percentage of patients with confirmed hypoglycemic lin content, islet cell mass and BG control in db/db mice (Nature Medicine, AEs (glucose ≤70mg/dL and/or requiring assistance) was low in all groups April 2015, DOI 10.1038/nm.3822). In this double-blind, placebo-controlled, (0-1.8%); none required assistance. EMPA+MET bid significantly reduced cross-over study we investigated the BG-lowering effect of 60 mg DXM and HbA1c vs. EMPA qd and MET bid and was well tolerated. 100 mg SITA alone and the combination of DXM + SITA with an OGTT in 20 patients with T2DM. DXM 60 mg significantly reduced blood glucose excur- sions and increased insulin secretion versus placebo (data combined from two clinical studies, not shown). The effects on BG were similar to those seen with SITA alone, whereas the combination of DXM and SITA improved both maximum blood glucose levels and early phase insulin secretion sig- nificantly better than SITA and DXM alone (Figure). All study drugs were well tolerated without relevant adverse events. These findings confirm the therapeutic potential of DXM alone and, in particular, in combination with

ADA-Funded Research For author disclosure information, see page LB98.

LB31 Clinical Therapeutics/New Technology—Oral Agents

DPP-IV inhibitors in patients with T2DM. This potential warrants further in- carried out for 16 weeks in 18 patients with gliclazide (60-120 mg/day) and vestigation in long-term clinical trials. 16 with vildagliptin (100 mg/day). Fasting and postprandial plasma glucose, HbA1c, insulin, glucagon, soluble markers of cell adhesion (VCAM, ICAM and E-selectin), inflammatory markers (PAI-1, TNF-alpha and IL-6) and of oxida- tive stress (TBAR and TAOS) were measured at the beginning and at the end of the study. The two drugs showed significant improvement in glycemic control There was no intergroup statistical difference in soluble markers of cell adhesion and PAI-1. TNF-α showed a significant improvement in the vildagliptin group compared with gliclazide (3.0±1.5 and 3.5±1, 1 pg/ml, re- spectively, ajusted p=0.001) and IL-6 (2 4±1.1 and 2.8±1, 1 pg/ml, respective- ly, ajusted p=0.005). There was also significant improvement in TBAR and TAOS in the vildagliptin group compared with gliclazide (8.0±0.7 and 8.4±0, 9 nmol/MDA/ml, respectively, ajusted p<0.001 and 266.5±49, 4 and 264.3±34, 0μM Trolox Equivalents respectively ajusted p=0.001). Both drugs improved glycemic control. Vildagliptin provided significant improvement in inflamma- tory markers TNF and IL-6 and oxidative stress markers TBAR TAOS.

124‑LB Adverse Effects of Incretin-based Therapies on Major Cardiovascu‑

lar and Arrhythmia Events: Meta-analysis of Randomized Trials FEI WANG, TIANSHENG WANG, JUNWEN ZHOU, HUILIN TANG, TRINH NHAN, SHARON GIOVENALE, Storrs, CT, Beijing, China The long-term cardiovascular safety outcome of incretin therapies remains controversial. A meta-analysis of RCTs was conducted to quantitatively evaluate CV safety (all cause death, CV death, myocardial infarction, stroke,

POSTERS heart failure, unstable angina, and arrhythmia) of incretin therapies: sitaglip- Therapeutics 122‑LB tin (SIT), vildagliptin (VIL), saxagliptin (SAX), (LIN), (EXE), Clinical Diabetes/ LEZ763, a Novel GPR119 Agonist, Increases GLP-1, GIP, PYY, and liraglutide (LIR), (ALB), (DUL), and lixisenatide (LIX). A Glucagon, but Has Minimal Effects on Glucose in Patients with Type systematic search of EMBASE, MEDLINE, Cochrane Database of System- 2 Diabetes atic Reviews, and ClinicalTrials.gov was conducted through November 2014. YANLING HE, LORI DAVIS, PRAFULLA BHAD, AHMED AMER, LAURENCE COLIN, From relevant reports, 99 randomized clinical trials were included. Results JING-HE YAN, STUART HARRIS, ANN TAYLOR, Cambridge, MA, Burlington, ON, were pooled via Peto methods and meta-regressions. Of 85231 participants Canada, East Hanover, NJ, Miami, FL from 99 trial reports including 102 trial populations (26 SIT, 9 VIL, 11 SAX, Agonists of GPR119 have been tested in patients with T2DM, although the 13 LIN, 8 ALO, 13 EXE, 8 LIR, 6 ALB, 3 DUL, and 5 LIX), there were a total effects on glucose have been disappointing. The objective of this study was to of 1280 all cause death events and 3455 CV events (805 CV death, 1101 assess the effects of LEZ763, a potent and selective GPR119 agonist, on glu- myocardial infarction, 515 stroke, 626 heart failure, 253 unstable angina, 155 cose and biomarkers including glucagon, insulin, C-peptide, and gut arrhythmias). There was a statistically significant increase in heart failure (total and active GLP-1, total GIP and PYY) in T2DM patients. A total of 96 outcomes associated with SAX (OR 1.23; 95% CI, 1.03-1.46). Compared with patients were enrolled and 92 completed the study. Patients were randomized controls, EXE was associated with increased risk of arrhythmia (OR 2.83; to one of the six treatments: 25,100, 300 and 600 mg qd LEZ763, placebo, or 95% CI, 1.06-7.57). SIT was associated with a significantly decreased risk sitagliptin 100 mg qd for 4 weeks. At baseline and after 4 weeks of treatment, of all cause death compared to active controls (OR 0.39, 95% CI 0.18-0.82). a standardized mixed test meal was given whereafter serial blood samples Other agents were not significantly associated with risk. Time-cumulative were collected up to 4-hour post dose for biomarkers measurement. LEZ763 analyses indicated that for EXE the risk for arrhythmia was evident by the treatment modestly decreased postprandial glucose (AUC0-4h; 3-8%), although end of 2014; the evidence for heart failure risk of SAX became apparent this was not statistically significant. Sitagliptin reduced postprandial glucose by 2013. Our meta-analysis indicates that EXE might be associated with in- by 14% (p<0.05). LEZ763 treatment was associated with a non-significant in- creased risk of arrhythmia; and that SIT was associated with a reduced risk crease in insulin (6-15%) and C-peptide (4-9%). LEZ763 treatment increased of all cause death compared with other anti-diabetic agents. These results glucagon (22~41%; p<0.05), total GLP-1 (29-35%; p<0.01), active GLP-1 (29- need confirmation in long-term CV outcome trials. 50%; p<0.05), total GIP (21-36%; p<0.05) and PYY (39-76%; p<0.05). Although LEZ763 significantly increased glucagon, GLP-1, GIP and PYY, it did not signifi- 125‑LB cantly decrease postprandial glucose. The lack of translation of the preclinical Maintenance of Normokalemia with Sodium Zirconium Cyclosili‑ glycemic control of a GPR119 agonist may be, at least partially, attributed to cate (ZS-9) in Diabetic Patients on RAASi from the Phase 3 Random‑ the increased levels of glucagon in patients with T2DM. The counter-regula- ized, Placebo-Controlled HARMONIZE Study tion effects of glucagon in humans may be more efficient than animal models STEVEN N. FISHBANE, MOHAMED EL-SHAHAWY, HENRIK S. RASMUSSEN, in the context of increased levels of gut hormones and insulin. To our knowl- PHILIP T. LAVIN, BHUPINDER SINGH, ALEX YANG, WAJEH QUNIBI, Manhasset, edge, this is the first report with well characterized glucagon data in T2DM NY, Los Angeles, CA, Coppell, TX, Framingham, MA, San Antonio, TX following treatment with a GPR119 agonist. GPR119 agonists may not be an Hyperkalemia (HK) is higher in pts with diabetes mellitus (DM), limits use effective glucose-lowering treatment in T2DM. of RAAS inhibitors (RAASi), and is associated with morbidity and/or mortal- ity. Current HK treatments such as polymer resins have questionable effi- 123‑LB cacy and are limited by potentially fatal GI side effects (eg, colonic necrosis). Comparative Study of 16 Weeks of the Effect of Vildagliptin and Sodium zirconium cyclosilicate (ZS-9) is a first in class, highly specific, non- Gliclazide on Markers of Inflammation and Oxidative Stress in Dm2 absorbed cation exchanger designed to trap K+ in the gut. Here we present Inadequately Controlled with Metformin a subgroup analysis of DM pts on RAASi from a Phase 3 study. HARMONIZE LILIAN L.A. CAVALCANTE, MARCELO R.N. HISSA, SERGIO B. GUIMARAES, HER- was a multicenter, randomized, double-blind, PBO-controlled trial in 258 HK MANO A.L. ROCHA, MIGUEL N. HISSA, Fortaleza, Brazil pts. All pts received open label 10g ZS-9 TID for 48h (acute). Pts achieving Diabetes mellitus has a latent baseline inflammatory status and a high normokalemia (NK; 3.5-5.0 mEq/L) were randomized to 5, 10, or 15g ZS-9 QD oxidative stress that are intrinsically related to complications of the dis- or PBO for 28d (maintenance). RAASi dose was maintained. Of 258 enrolled ease. Atherosclerosis is also an inflammatory disease and represents a pts, 121 (47%) had DM and were on RAASi. Median time to K+ normalization major cause of morbimortality associated with diabetes. Recent studies was 2.1h. Mean K+ declined from 5.6 mEq/L at baseline to 4.6 mEq/L at 48h, have shown anti-inflammatory actions and reducing oxidative stress, in ad- with 97% of pts achieving NK at 48h. Mean K+ was maintained (28d) at 4.9, dition to improved glycemia, using incretin based therapy. To evaluate the 4.5, and 4.4 mEq/L with the 5, 10, and 15g doses, respectively, vs. 5.2 mEq/L response from the gliclazide, second-generation sulfonylurea, and from with PBO (P<0.0001 all). In DM pts on RAASi, ZS-9 rapidly and safely normal- vildagliptin, DPP-4 inhibitor, in the inflammatory markers and in the oxidative ized K+ within hours, maintained NK for 28d and was well tolerated with GI stress in DM2, we performed a prospective study, randomized, open-label side effects similar to PBO, suggesting that ZS-9 acts quickly and may enable in 34 patients inadequately controlled with metformin. The monitoring was continued RAASi use in DM pts with HK.

ADA-Funded Research For author disclosure information, see page LB98.

LB32 Clinical Therapeutics/New Technology—Oral Agents

lowed by a 40-week, double blind active-controlled extension phase (pla- cebo switched to linagliptin). This 12-week randomized trial investigated the efficacy and safety of gemigliptin in type 2 diabetic patients with moder- ate to severe renal impairment. It was also evaluated whether gemigliptin has renoprotective effects in these patients. A total of 132 patients were randomized to gemigliptin (n=66) or placebo (n=66). Primary endpoint was HbA1c change from baseline at Week 12. Baseline demographics were similar between treatment groups (mean HbA1c 8.4%; age 62.0 years; BMI 26.2 kg/m2, duration of T2DM 16.3 years; eGFR 33.3 mL/min/1.73 m2). The predominant background therapy was insulin (63.1%). At Week 12, adjusted mean ± SE change HbA1c with gemigliptin was -0.83 ± 0.14% (change with placebo 0.38 ± 0.14%; difference -1.21, 95% CI -1.54 to -0.89; p<0.0001). A similar profile was also observed in other glycemic control parameters (FPG, glycated albumin, and fructosamine). After 12 weeks of gemigliptin treat- ment, albuminuria (measured by urinary albumin creatinine ratio [UACR]) significantly decreased in the patients with micro- and macro-albuminuria. 126‑LB Furthermore, urinary nephrin and type IV in the gemigliptin were Saroglitazar in Diabetic Dyslipidemia: 1-Year Data also significantly reduced compared to placebo. Drug-related AEs including SHASHANK R. JOSHI, SUJOY GHOSH, PARAG SHAH, ASHOK D. JAISWAL, hypoglycemia for gemigliptin was similar to placebo (15.2% and 12.1%, re- spectively). There was no meaningful change from baseline in body weight

PANKAJ PATEL, Mumbai, India, Kolkata, India, Ahmedabad, India Saroglitazar is the world’s first commercially available dual PPAR α and γ (gemigliptin, -0.3 kg; placebo -0.2 kg). Gemigliptin improved glycemic control agonist which was launched in September 2013 in India. The objective of this and provided additional renoprotection in T2DM patients with moderate to post-marketing surveillance study was to evaluate the safety and efficacy severe renal impairment. There was no additional risk of hypoglycemia and of saroglitazar for 1 year follow up in clinical practice. It was a multicenter, no weight gain. phase 4 study conducted all over India. Total 236 patients with diabetic Supported By: LG Life

dyslipidemia who were prescribed saroglitazar 4mg daily were evaluated POSTERS for lipid and glycemic parameters at baseline, 3 month, 6 month, 9 month 128‑LB Therapeutics and 12 month follow up. Baseline patient demographics were: age 52 ± 10 Organ-specific Uptake and Elimination of Metformin Can Be Deter‑ Clinical Diabetes/ year (mean ± SD), average duration of diabetes 5.91 year, and BMI 28.8 ± mined In Vivo in Mice and Humans by PET-imaging Using a Novel 3.99 kg/m2 (mean ± SD). At baseline, 89% and 38.6% patients were reported 11C-metformin Tracer to be on antidiabetic and statin therapy respectively. Metformin was the JONAS B. JENSEN, LARS C. GORMSEN, ELIAS SUNDELIN, STEEN JAKOBSEN, most commonly reported in 72% patients followed by sulfonylureas (66.9%), OLE L. MUNK, MIKKEL H. VENDELBO, METTE M.H. CHRISTENSEN, KIM BROSEN, gliptins (16.1%), insulin (20.8%) and pioglitazone (4.7%). One year treatment JØRGEN FROKIAER, NIELS JESSEN, Aarhus, Denmark, Odense, Denmark with saroglitazar resulted into significant improvement in glycemic and lipid Metformin is the most commonly prescribed oral anti-diabetic drug. parameters (results are shown in Table). There were no serious adverse However, despite being in clinical use for almost 60 years the underlying events reported. Saroglitazar was found to be safe, well tolerated and was mechanisms for action remain elusive. We have therefore applied a novel not associated with edema or weight gain. This is the first data of one year PET-tracer, 11C-metformin, to determine uptake and elimination in liver in vi- safety and efficacy of saroglitazar in a real world setting which clearly dem- vo. To test the role of organic cation transporters, we used OCT1/2 knock out onstrated the dual action of glucose and lipid lowering. mice and pharmacological inhibitors. In a second series of experiments we 11 Table. Effect of Saroglitazar 4 mg Once Daily on Glycemic and Lipid have determined organ specific uptake of C-metformin in healthy humans. Parameters at 1 Year Follow-up; All val. Our results demonstrate that in mice, OCT1/2 expressions are essential for normal uptake while MATE1 is necessary for elimination of metformin from Absolute P % 11 Laboratory 3 month 6 month 1 year change value change the liver. There is no detectable secretion of C-metformin to the bile after parameter Baseline follow up follow up follow up at 1 year % at 1 year iv-injection, but metformin is transported into duodenal enterocytes from blood. In humans (Fig. 1) there is visible uptake in liver, kidney and salivary HbA1C (%) 8.5± 7.9± 7.5± 6.9± -1.6± <0.0001 — 1.06 0.87 0.78 0.76 1.12 glands, but no detectable uptake in brain, muscle or fat. Effective dose was 0.0095 mSv/MBq. The therapeutic effects of metformin vary considerably Fasting Plasma 179.4± 144.1± 132.6± 115.5± -63.9± <0.0001 -32.7± from patient to patient. Determination of tissue specific uptake of metformin Glucose (mg/dL) 54.67 40.29 37.81 28.90 44.20 15.20 can be an important tool to investigate the underlying causes and optimizing Post-prandial 252.6± 192.0± 168.8± 146.5± -106.1± <0.0001 -38.7± treatment. In addition, precise determination of metformin action in specific Plasma Glucose 64.17 38.81 31.34 22.11 63.56 16.24 tissues could help clarify the mechanisms of action of metformin outside its (mg/dL) present indications. Triglycerides 316.0± 222.1± 194.9± 153.9± -162.1± <0.0001 -47.3± (mg/dL) 139.02 70.63 66.36 50.06 136.73 16.91 LDL-C (mg/dL) 131.8± 114.8± 108.1± 96.7± -35.1± <0.0001 -24.1± 43.78 35.55 31.9 30.13 34.2 21.72 HDL-C (mg/dL) 42.5± 43.6± 45.0± 44.8± 2.3± 0.0044 9.2± 8.74 7.18 8.20 9.11 12.09 29.59 Non HDL-C 194.0± 160.6± 147.3± 127.0± -67.1± <0.0001 -33.4± (mg/dL) 48.48 37.75 35.92 35.04 45.54 16.49

127‑LB Efficacy and Safety of Gemigliptin in Type 2 Diabetes Patients with Moderate to Severe Renal Impairment SUN AE YOON, BYOUNG GEUN HAN, SUNG GYUN KIM, SANG YOUB HAN, YOUNG-IL JO, KYUNG HWAN JEONG, KOOK-HWAN OH, HYOUNGCHUN PARK, Supported By: Novo Nordisk Foundation SUN-HEE PARK, SHIN-WOOK KANG, KI-RYANG NA, NAM-HO KIM, DAE RYONG CHA, GUARD STUDY, Uijeongbu, Republic of Korea, Wonju, Republic of Korea, 129‑LB Anyang, Republic of Korea, Goyang, Republic of Korea, Seoul, Republic of Korea, Activation of the cAMP-PKA Pathway Antagonizes Metformin Sup‑ Daegu, Republic of Korea, Daejeon, Republic of Korea, Gwangju, Republic of Korea, pression of Hepatic Glucose Production Ansan, Republic of Korea LING HE, EVAN CHANG, JINGHUA PENG, SALLY RADOVICK, FREDRIC E. WOND- Gemigliptin, a potent and selective DPP-4 inhibitor, can be used without ISFORD, Baltimore, MD dose reduction in renal impairment. This randomized, double blind, parallel Metformin is a widely prescribed anti-diabetic agent, which is taken by group Phase 3b study comprised a 12-week, placebo-controlled phase fol- more than 150 million people worldwide. Treatment guidelines for type 2

ADA-Funded Research For author disclosure information, see page LB98.

LB33 Clinical Therapeutics/New Technology—Oral Agents

diabetes mellitus (T2D) recommend metformin as the initial drug. Surpris- AE rates were 41.8%, 44.3%, 37.1%, 39.9%, and 37.6% with CANA 100 mg/ ingly, about 35% of diabetic patients either lack or have a delayed response MET XR, CANA 300 mg/MET XR, CANA 100 and 300 mg, and MET XR with to metformin treatment, and many patients become less responsive to met- low rates of serious AEs. Incidences of genital mycotic infections and osmot- formin over time. It remains unknown how metformin resistance or insensi- ic diuresis, volume depletion, and renal-related AEs and hypoglycemia were tivity occurs. Recently, we find that therapeutic metformin concentrations low, but higher in all CANA arms vs. MET XR with overall low discontinuation suppress glucose production in primary hepatocytes through the activation rates across groups. In conclusion, initial combination therapy with CANA/ of AMPK; and activation of the cAMP-PKA pathway negatively regulates MET XR is efficacious and well tolerated in drug-naïve T2DM. AMPK activity by phosphorylating the AMPKα subunit at S485, which in turn reduces net phosphorylation at T172 and AMPK activity. Indeed, met- formin failed to suppress cAMP-stimulated glucose production in primary hepatocytes with constitutive PKA activation and to improve hyperglyce- mia in mice with hyperglucagonemia. of a PKA phosphorylation site on AMPKα1 (S485A) increased both AMPKα1 phosphorylation at T172 and suppression of glucose production in primary hepatocytes treated with metformin. Intriguingly, salicylate/aspirin prevents the phosphorylation of AMPKα S485, blocks this cAMP-PKA negative regulation of AMPK, and im- proves metformin resistance. We propose that salicylate/aspirin may aug- ment metformin’s hepatic action to suppress glucose production. Supported By: National Institutes of Health

130‑LB The Combination of Insulin, Liraglutide, and Dapagliflozin as Triple Therapy for Type 1 Diabetes NITESH D. KUHADIYA, ADITYA MEHTA, HUSAM GHANIM, JEANNE HEJNA, ANTOINE MAKDISSI, AJAY CHAUDHURI, MANAV BATRA, PARESH DANDONA,

POSTERS Buffalo, NY Therapeutics We have recently demonstrated that the addition of liraglutide to insulin Clinical Diabetes/ significantly improves the glycemic control in patients with type 1 diabetes (T1D). We have now investigated whether the addition of dapagliflozin, a SGLT-2 inhibitor, which induces glycosuria, to insulin and liraglutide would improve glycemia further. We conducted a retrospective analysis of 10 pa- tients on continuous glucose monitoring system (CGMS) treated with this combination. They were under treatment with insulin and had received liraglutide for 11±2 months (baseline HbA1c: 8.01±0.22%; mean age: 56±4 years; mean age of diabetes diagnosis: 29±5 years; mean BMI: 29±1 Kg/m2; mean body weight: 86.4±4.5 kg; mean BP: 125/75±3 mm Hg). In all patients, dapagliflozin was started at a dose of 5 mg daily and was increased to 10 mg daily 7±1 days later. At the end of 12±1 weeks of dapagliflozin therapy, mean HbA1c fell by 0.66±0.22% (p=0.0004); mean glucose fell by 28±2mg/ dl from a baseline of 172±9 mg/dl (p=0.016,); the daily carbohydrate intake increased from 166±3g to 196±4g (p= 0.04); mean body weight and BMI fell from 87±5 Kg to 85±5 Kg and 29±1 to 28±1Kg/m2, respectively (p=0.02). Total insulin dose remained unchanged at 0.7±0.1 u/Kg daily. Percent time spent in glycemic range of 70-160 mg/dl increased by 11±2% while that greater Supported By: Janssen Research and Development, LLC. than 160 mg/dl decreased by 13±3% (p<0.05 for both). There was no ad- ditional hypoglycemia (<70 mg/dl). One patient developed diabetic ketoaci- 132‑LB dosis (DKA) in spite of normal blood glucose concentrations within 48 hours Exogenous GLP-1 Is Not Fully Protected by Acute DPP-4 Inhibition of increasing the dose of dapagliflozin to 10 mg. The dose of insulin in this EMILIE S. ANDERSEN, ASGER LUND, CAMILLA ANDREASEN, JONATAN I. BAG- patient had declined from 0.45 to 0.39 u/kg (total dose: 32.9 to 28.5 units). GER, CAROLYN DEACON, BOLETTE HARTMANN, JENS JUUL HOLST, FILIP K. Carbohydrate intake had increased from 50 to 95g daily. We conclude that KNOP, TINA VILSBØLL, Hellerup, Denmark, Copenhagen, Denmark the addition of dapagliflozin to insulin and liraglutide in patients with T1D Dipeptidyl peptidase-4 (DPP-4) inhibitors limit glucagon-like peptide-1 results in a significant improvement in glycemia. However, care would have (GLP-1) degradation, and are used to treat type 2 diabetes (T2D). DPP-4 exists to be exercised in terms of the reduction in insulin dose and thus the occur- in soluble and membrane-bound forms. It is unclear if plasma DPP-4 activity rence of euglycemic DKA. levels reflect the full extent of DPP-4 inhibition in all compartments. We used the selective inhibitor sitagliptin to explore the relationship between DPP- 131‑LB 4 activity and protection of GLP-1. On 4 separate days, subjects with T2D Initial Combination Therapy with Canagliflozin (CANA) plus Met‑ (BMI: 28.8±1.4 kg/m2 [mean±SEM]; HbA1c: 43.1±2.4 mmol/mol) and matched formin Extended-Release (MET XR) in Drug-Naïve Type 2 Diabetes healthy controls (BMI: 28.1±1.2 kg/m2; HbA1c: 34.4±1.2 mmol/mol) received Mellitus (T2DM) continuous iv GLP-1 (1.0 pmol/kg/min) and oral sitagliptin (0 [placebo], 25, JULIO ROSENSTOCK, LEONARD CHUCK, MANUEL GONZÁLEZ-ORTIZ, KATE MER- 100 or 200 mg; double-blind randomized order). Plasma DPP-4 activity was TON, JAGRITI CRAIG, GEORGE CAPUANO, RONG QIU, Dallas, TX, Walnut Creek, measured by chromogenic assay, and the degree of protection of GLP-1 (as- CA, Guadalajara, Mexico, Raritan, NJ sessed with specific RIAs) was used as a surrogate index of inhibition of This study assessed the efficacy and safety of initial combination therapy “total” DPP-4 activity. At steady-state, within the time period 180-360 min- with CANA, an SGLT2 inhibitor, and MET XR in drug-naïve T2DM (A1C 7.5%- utes, plasma DPP-4 activity decreased dose-dependently (Table), but with 12.0%; N = 1186; mean age, 54.9 y; A1C, 8.8%; BMI, 32.5 kg/m2; eGFR, 88 differences between DPP-4 compartments and groups, the latter possibly mL/min/1.73 m2; T2DM duration, 3.3 y) randomized to CANA 100 mg/MET due to differences in gastric emptying. Despite relatively high inhibition of XR, CANA 300 mg/MET XR, CANA 100 or 300 mg, or MET XR (titrated up plasma DPP-4 activity, intact GLP-1 levels remained lower than total GLP-1 to 2000 mg/d; median dose = 2000 mg/d) for 26 weeks. Both CANA/MET levels. This could suggest that membrane-bound DPP-4 was not fully inhib- XR doses provided statistically superior A1C reductions vs. their respective ited. Furthermore, other , not inhibitable by sitagliptin, may also monotherapies (Fig. A). CANA 100 mg/MET XR and CANA 300 mg/MET XR have been responsible. provided larger A1C reductions vs. CANA 100 and 300 mg or MET XR in pa- tients with baseline A1C ≥9.0% (-2.4%, -2.4%, -1.9%, -2.0%, -1.8%). More attainment of A1C <7.0% (Fig. B) and significant weight loss were seen with both CANA/MET XR doses vs. MET XR. CANA 100 and 300 mg showed non- inferiority in A1C lowering and greater body weight loss vs. MET XR. Overall

ADA-Funded Research For author disclosure information, see page LB98.

LB34 Clinical Therapeutics/New Technology— Health Care Delivery— Pharmacologic Treatment of Complications

Table. Table. Results. Parameters Group-1 Group-1 Change Group-2 Group-2 Change p VALUE Baseline Week 24 Group 1 Baseline Week 24 Group 2 (changes (Exenatide Only) (Exenatide+Saroglitazar) between groups) HbA1c (%) 7.9 +/- 0.54 7.09 +/- 0.29 - 0.81 8.1 +/- 1.01 6.94 +/- 0.40 - 1.16 0.09 (NS) HDL-C (mg/dL) 35.8 +/- 9.8 38.1 +/- 8.9 + 6.4 % 31.6 +/- 10.5 38.4 +/- 10.3 + 21.5 % 0.003 Triglycerides 362.9 +/- 167.2 233.8 +/- 60.8 - 35.6 % 390.4 +/- 96.6 180.3 +/- 51.6 - 53.8 % 0.01 (mg/dL) Liver Fat Content 319.3 +/- 31.4 248.3 +/- 30.5 - 22.2 % 330.7 +/- 36.1 202.8 +/- 28.3 - 38.7 % <0.001 133‑LB (dB/m) Triple Therapy with Dapagliflozin (DAPA) Add-on to Saxagliptin We conclude that the Exenatide-Saroglitazar combination leads to sig- (SAXA) plus Metformin (MET): Characterization of the Open-Label nificant reductions in Liver fat content and serum triglycerides. It also raises SAXA+MET Lead-in Period of a Phase 3 Trial HDL-C significantly in these patients. This combination maybe effective at CHANTAL MATHIEU, AURELIAN EMIL RANETTI, LARS HANSEN, HUNTGA CHEN, retarding the progression of hepatic steatosis and longitudinal studies are RICARDO GARCIA-SANCHEZ, ALEX J. CHIN, NAYYAR IQBAL, Leuven, Belgium, required to look at the long term effects of this combination. Bucharest, Romania, Princeton, NJ, Gaithersburg, MD The 24-week efficacy and safety of DAPA versus placebo (PBO) as add-on 135‑LB to SAXA+ MET in adults with type 2 diabetes (T2DM) was demonstrated Treatment, Adherence, and Change in A1c in Type 2 Diabetes (T2DM) in a randomized, double-blind, phase 3 trial (NCT01646320). The 8-16 week with High (>10%) HbA1c open-label (OL) lead-in period of this study was designed to generate a set S. CARLS, CHRISTIAN FROIS, EDWARD TUTTLE, MICHELLE A. BARON, of uniform patients on SAXA+MET that could be randomized for double-blind Menlo Park, CA, Boston, MA treatment. Patients on stable MET (stratum A; A1C 8.0%-11.5%, N=349) or The prevalence of T2DM patients (pts) in the U.S. with A1C > 10% has MET+DPP-4 inhibitor (stratum B; A1C 7.5%-10.5%, N=134) for ≥8 weeks re- increased and is associated with a high healthcare burden. A recent trial POSTERS ceived OL SAXA 5 mg/d+MET for 16 (stratum A) or 8 weeks (stratum B, any of ITCA 650 (continuous subcutaneous exenatide) in pts with high baseline Therapeutics

DPP-4 inhibitor replaced with SAXA). Patients with inadequate glycemic A1C (mean 10.9%) resulted in a 3.4% reduction in A1c at 39 weeks with 26% Clinical Diabetes/ control (A1C 7%–10.5%) at week –2 before randomization were randomized of pts achieving the goal of A1C <7%. Little is known about the patterns of to PBO or DAPA 10 mg/d plus OL SAXA+MET. This analysis was focused on treatment, adherence and change in A1C among real-world (RW) pts after patients in stratum A (baseline A1C 8.0%-11.5% and poorly controlled on an extremely high A1C has been identified. Linked Optum-Humedica claims MET alone). At entry to the OL period (baseline), mean age was 54 years and and electronic medical records (1/2007-3/2014) were used to identify a RW 58% were women. Most patients (81.9%) completed the OL period. The most sample with T2DM, high baseline A1C and characteristics similar to pts in common reason for not completing the OL period was not meeting study the ITCA 650 study. Pts had 10 %< A1c≤12% (index date), and an A1C mea- criteria (12.3%). At OL baseline, mean (SD) A1C was 9.38% (0.91), and fol- surement 12 months later (± 3 months). Demographics, change in A1C, diabe- lowing the addition of SAXA, decreased to 8.06% (1.02) at week -2 (mean tes drug classes filled, and adherence (percent of days covered ≥80%) were change [95% CI] from baseline A1C, –1.32% [–1.46, –1.17]). At week –2, 61 measured in the year before (baseline) and after index date (study period). patients (17.5%) achieved a therapeutic response (defined as A1C <7%), most 1,248 pts met study criteria. They had a mean age of 58 years, BMI of 35 kg/ patients (234; 67.0%) had A1C 7.0%−10.5%, and 12 patients (3.4%) had A1C m2, and A1C of 10.8%; 59% were male. At baseline, 46% of pts were adher- >10.5%; an additional 42 patients (12%) had no −2 week data. During the ent to diabetes drugs. 77% filled Rx for diabetes drugs at baseline: 11% met- OL period, no hypoglycemic events were reported; 113 (32.4%) patients re- formin only, 34% other oral regimens, 28% insulin, and 6% GLP-1s. Pts taking ported adverse events (AEs), and 5 reported serious AEs (none considered any diabetes drugs increased 13% points (P<0.01) from baseline and 50% of related to treatment). The results show that 17.5% of patients with poorly all patients added a new drug class in the study period. Adherence increased controlled T2DM and high baseline A1C of 8.0%-11.5% despite MET treat- to 58% in the study period (P<0.01). Mean A1C declined 1.8% points from ment achieved A1C <7% with the addition of SAXA. However, most patients index to 2nd A1C (mean 364 days) (P<0.01) with 16% of pts achieving A1C would require additional therapy in an effort to achieve a desired glycemic goal <7. Sensitivity analyses that matched RW and trial pts yielded similar goal of A1C <7%. results. While Rx fills increased in this RW study, non-adherence remained Supported By: AstraZeneca high and reduction in A1C was modest with few pts achieving goal after a year. New treatments that achieve greater reductions in A1C and improve adherence at the same time are needed to more effectively treat T2DM pts Clinical Therapeutics/New Technology— with high A1C who carry both a higher risk of complications and a higher cost Pharmacologic Treatment of Complications burden to the healthcare system.

134‑LB Efficacy of Exenatide-Saroglitazar Combination in Treatment of NA‑ Health Care Delivery—Economics FLD in Type 2 Diabetes KIRAN PAL SINGH, MOHINISH CHHABRA, AVINAINDER SINGH, JYOTIKA MAN- 136‑LB AN, SHAKUN DABRA, Ajitgarh, India Access to High-Acuity Care among Diabetes Patients in High De‑ Non Alcoholic Fatty Liver Disease (NAFLD) is commonly associated with ductible Insurance: A NEXT-D Study T2DM. Current treatment is aimed at lifestyle modifications only. Recently, JAMES F. WHARAM, FANG ZHANG, EMMA B. MORTON-EGGLESTON, CHRIS- we studied the efficacy of a novel dual PPAR agonist - Saroglitazar in revers- TINE LU, STEPHEN SOUMERAI, DENNIS ROSS-DEGNAN, Boston, MA ing the biochemical manifestations of MetS. Recent evidence also suggests The Affordable Care Act (ACA) will soon make high deductible health plans a role of Incretin based therapies for the management of NAFLD in diabetics. (HDHP) the predominant private insurance benefit in the U.S. No studies have We set out to combine these two approaches for the management of NAFLD examined the impact of HDHPs on high-acuity care among diabetes (DM) in diabetics. We studied the effects of Exenatide in combination with Saro- patients. We studied privately insured members of a large national health glitazar on hepatic fat content and other biochemical parameters in obese plan. We followed DM patients from 2004-2012 and included 11,490 with diabetics with NAFLD. 40 patients on dietary, Metformin and statin therapy 1 baseline year in traditional (≤$500 deductible) coverage whose employ- received treatment with exenatide alone (10 mcg BD) (n=20) or exenatide ers then mandated transition to HDHP (≥$1000) coverage for 2 continuously and saroglitazar (4mg PO) (n=20) for 24 weeks. Age, BMI, Diabetes dura- enrolled years. We performed employer- and member-level 1:1 propensity tion and abnormal transaminase levels were comparable between the two score matching based on multiple baseline characteristics to contemporane- groups. Hepatic steatosis was measured by Transient Elastography (Fibro- ous DM patients continuously enrolled for 3 years whose employers offered scan). Other parameters including BMI, FPG, PPPG, HbA1c, lipid profile, RFT only traditional coverage. We assessed annual rates of emergency depart- and LFT were measured. ment (ED) visits and hospitalizations for 1 year before and 2 years after the mandated switch from traditional to HDHPs, vs. controls. We stratified by income and sex. We used annual difference-in-differences negative bino-

ADA-Funded Research For author disclosure information, see page LB98.

LB35 Health Care Delivery—Economics

mial regression with generalized estimating equations to calculate adjusted Criteria 2 Pre-DM: 92.78% SN, 20.22% SP, 43.04% PPV, and 81.18% NPV. pre-to-post changes in the HDHP group vs. controls. In follow-up years 1 Criteria 1 DM: 97.83% SN, 13.63% SP, 14.15% PPV and 97.74% NPV. Criteria and 2, the overall HDHP group experienced no relative changes in ED vis- 2 DM: 96.83% SN, 16.84% SP, 14.49% PPV and 97.33% NPV. This data sug- its (3.2% [-5.2, 11.7] and 0.0% [-8.2, -8.1], respectively) and findings were gests that BMI and age may be sufficient to identify eligible patients for A1C similar across income and sex stratifications. The overall HDHP group also testing, as further addition of RF added little to the sensitivity of eligibility demonstrated no detectable follow-up changes in hospitalizations (-2.5% criteria. More importantly, a negative test (normal A1C) in an eligible patient [-14.4, 9.4] and -4.7% [-16.0, 6.5], respectively). However, by follow-up year should not give a false sense of security and follow up should address modi- 2, low income and male HDHP members experienced pronounced relative fiable risk factors. reductions in hospitalizations (-34.5%, [-60.5, -8.5] and (-18.9% [-32.9, -4.8], Supported By: Centers for Disease Control and Prevention (U58DP002717) respectively). Low income and male HDHP members with DM experienced major reductions in access to hospital care. Male DM patients in HDHPs are 139‑LB a previously overlooked vulnerable subgroup. As HDHPs expand under the CMS Competitive Bidding Program Disrupted Access to Diabetes ACA, policy makers and researchers should focus on chronically ill male and Supplies with Resultant Increased Mortality low income HDHP members. GARY A. PUCKREIN, FARHAD ZANGENEH, GAIL NUNLEE-BLAND, LIOU XU, Supported By: Natural Experiments in Diabetes Translation (NEXT-D) Initiative CHRISTOPHER G. PARKIN, JAIME A. DAVIDSON, Washington, DC, Boulder City, (5U58DP002719) NV, Dallas, TX The Centers for Medicare and Medicaid (CMS) implemented a trial of the 137‑LB Competitive Bidding Program (CBP) for diabetes supplies in 9 test sites on Use of Digital Tracking Devices in the Management of Diabetes January 2011. In 2012, CMS reported the program was a success, noting

Mellitus: A Systemic Review and Meta-analysis that beneficiary access to supplies was not compromised. We used CMS BARBARA J. GROHMANN-IZAY, MICHAEL FORISCH, Vienna, Austria data from 2009-2012 to assess the impact of CBP on acquisition of self- A systemic literature search was conducted in October 2014 to identify monitoring of blood glucose (SMBG) supplies by Medicare beneficiaries who randomized, controlled clinical trials investigating the effect of a digital acquired insulin >80% of days covered (n=529,627). The 2009 records were tracking device in diabetes mellitus type 1 (DM1) and type 2 (DM2), including separated into two cohorts; inclusion in the test sites (TEST; n=43,939) vs. adults, adolescents and the special population of pregnant women (GDM) all other non-test sites (NON-TEST; n=485,688) In 2011, the percentage of

POSTERS compared to a conventional, usual-care approach. Included trials were TEST beneficiaries with reduced SMBG acquisition, increased 23.0% vs. Therapeutics evaluated regarding outcome of clinical parameters, quality of life (QoL) and 1.7% in NON-TEST beneficiaries. The percentage of TEST vs. NON-TEST Clinical Diabetes/ socio-economical parameters. A meta-analysis was performed on pooled beneficiaries with no SMBG record increased (16.7% vs. 1.2%). Migration HbA1c change from baseline reported in the trials identified during the sys- from full to reduced acquisition or no SMBG was associated with increased temic review. In this review, a total of 31 studies fulfilled the search crite- mortality in both cohorts; however, a significantly higher percentage of TEST ria and were included in the final evaluation. Twelve (12) studies assessed vs. NON-TEST beneficiaries made this migration (p<0.0001) (Table) Acquisi- DM1, 11 DM2, 5 included both indications (DM1/DM2), and additional 3 tion of SMBG supplies was somehow disrupted in the TEST population, with trials evaluated GDM. Most of the trials (93.5%) compared digital tracking resultant increased mortality; a finding not supported by the CMS report on devices with controls (conventional/usual care without digital tracking/tele- adverse outcomes associated with the CBP. These data suggest that the CBP medicine). Twenty-four (24) studies (77.4%) used a telecare approach and may have had unanticipated, deleterious consequences, and argue for more 2 of the included studies (6.5%) used gamification. Several studies (51.9%) careful monitoring of CBP impact by CMS. have shown that usage of a digital tracking device in diabetes management Table. Mortality Associated with Migration from Full SMBG* to Reduced or is significantly improving metabolic control (measured by HbA1c); additional No SMBG. positive effects on the lipid profile, blood pressure, QoL (including self-ef- Full Mortality Reduced/ Mortality ficacy and adherence behaviour) and cost of care were observed. Some of Acquisition 2011 No Record 2011 the studies failed to show significant differences between the two groups n (%) n, (%) n, (%) n, (%) (digital tracking device vs. controls), but it has to be noted that none of the Full Cohort studies found that the use of a digital tracking device was inferior to the conservative approach. Meta-analysis of 19 trials in the adult population TEST: Full SMBG acquisition (n=7,123) found a -0.38% difference [95% CI -0.40 to -0.37] in HbA1c between usage migrating to Full or Reduced/No Record: 4,014 (56.4%) 279 (7.0%) 2,306 (32.4%) 218 (9.5%) of digital tracking devices and controls. Therefore, we conclude that the use NON-TEST: Full SMBG acquisition (n=68,742) of digital tracking devices in diabetes management is effective, safe and migrating to Full or Reduced/No Record: 47,898 (69.7%) 3,080 (6.4%) 12,618 (18.3%) 1,209 (9.6%) well accepted for different patient populations with DM. Propensity Score Matched TEST: Full SMBG acquisition (n=4,205) 138‑LB migrating to Full or Reduced/No Record: 2,112 (50.2%) 133 (6.3%) 1,163 (27.7%) 102 (8.8%) Testing for Type 2 Diabetes (DM) or Prediabetes (Pre-DM) in Asymp‑ NON-TEST: Full SMBG acquisition (n=4,311) tomatic Adults: Sensitivity and Specificity of American Diabetes migrating to Full or Reduced/No Record: 2,495 (57.9%) 143 (5.7%) 605 (14.0%) 60 (9.9%) Association (ADA) Eligibility Criteria Extracted from the Electronic * >80% of proportion of days covered, based on 3 test strips per day. Health Record (EHR) YELENA ZUBATOV, PINDAN HAO, EDWIN YOUNG, NANCY SOHLER, JEANINE 140‑LB ALBU, New York, NY Do Financial Incentives Improve Participation in a Workplace Dia‑ Since 2010 the ADA has published evidence-based demographic and betes Management Program? Yes, but Not by Much clinical risk factors (RF) for development of DM, used to optimize eligibility ZACHARY PREDMORE, EMILY HOCH, JOHN CALOYERAS, HANGSHENG LIU, Bos- for blood glucose testing (fasting glucose, OGTT or A1C) to identify previ- ton, MA, Santa Monica, CA ously undiagnosed DM or Pre-DM. In clinical practice, testing eligibility is Financial incentives have become increasingly popular to improve diabe- determined by the physician’s knowledge, which is often influenced by the tes management, but its impact in the workplace remains largely unknown. availability of RF data in the EHR. We identified 4,715 patients (ages 18-100, This study used disease program eligibility and participation data from a 61% female) who, between Jan 1 2012-Dec 31 2014, had a complete set Fortune 500 employer for 2003 to 2011. The data set contains 3,343 diabetes of RF documented in the EHR and subsequent A1C testing. We calculated patients who were eligible for a diabetes management program, with a total the sensitivity and specificity of A1C testing eligibility criteria to diagnose of 8,519 patient-years. In 2009, the employer imposed a $600 penalty on eli- the presence of DM or Pre-DM. We used Criteria 1 which defined testing gible employees who did not participate in the program. We performed a lo- eligible as age >45 years OR age <45 AND BMI >25 and Criteria 2 which, in gistic regression to see whether the penalty was associated with employee addition, incorporated the other ADA RF. The data was obtained from avail- participation. The eligible employees were 81.5% male, 68.5% Caucasian, able structured fields in the EHR (BMI, age, race/ethnicity, HTN, CVD, dyslipi- average age of 48.3 years, and had an average Charlson Comorbidity Index demia, PCOS) and a RF Questionnaire (RFQ) filled in during the patient’s visit (CCI) of 0.98. The unadjusted participation rate rose from 25.9% before the with the PCP (family history, GDM, physical inactivity). Highest A1C value introduction of the penalty to 30.9% after. Women (31.2% vs. 27.1%, p<0.01), documented in the EHR after the RFQ was used to identify Pre-DM and DM those over the age of 55 (32.8% vs. 26.2%, p<0.01), and Caucasians (37.7% (5.7-6.4% Pre-DM, >6.5% DM). vs. 28.3%, p<0.01) were most likely to participate. Additionally, participants Results: Criteria 1 Pre-DM 94.18% SN (sensitivity), 16.31% SP (specific- had higher CCI (1.16 vs. 0.91, p<0.01). After adjusting for gender, age, region, ity), 42.24% PPV (positive predictive value) and 81.18% NPV (negative PV).

ADA-Funded Research For author disclosure information, see page LB98.

LB36 —Obesity and Type 2 Diabetes pay type, union status, zip code median income, and CCI, the introduction that std measures have misclassified non-adherent multidrug pts and conse- of a penalty was associated with an increase in the participation rate from quently underestimated the burden of non-adherence. Estimates of medica- 25.5% (95% CI: 24.3% - 26.7%) to 30.8% (95% CI: 29.2% - 32.5%). Several tion adherence in T2DM should be based on the pt’s regimen and not simply covariates had a significant effect on participation in the program, includ- any diabetes medication on hand. ing sex, age, region, CCI, ethnicity, and blood pressure. These findings sug- gest that financial penalties can increase participation in a diabetes disease management program, but the effect size is relatively small given penalty Pediatrics—Obesity and Type 2 Diabetes size, which is about 10% of typical individual insurance premium. Employers should not expect to see large increases in participation simply by increasing 143‑LB the size of financial incentives. Making programs attractive to employees or Glycemic Variability Is Associated with Vascular Stress Markers in framing incentives in a way that is acceptable to employees might be a more Adolescents With and Without Type 2 Diabetes effective means of increasing employee participation. PAUL S. DASARI, BEN S. GANDOMANI, APRIL M. TEAGUE, AMEYA PITALE, MI- CHAEL OTTO, KEVIN R. SHORT, Oklahoma City, OK, Norman, OK 141‑LB Previous studies showed that variable glucose concentration results in Barriers to Diabetic Retinal Screening: Patient Perspective Is Dif‑ greater stress in endothelial cells than hyperglycemia per se. It was also ferent from Providers and Staff reported that the magnitude of glycemic excursions (MAGE) was positively YANG LU, LILIAN SERPAS, PAULINE GENTER, DAVID CAMPA, ELI IPP, Torrance, CA related to a urinary marker of oxidative stress in adults with type 2 diabetes Screening for diabetic retinopathy (DR) is an efficient and cost-effective tool (T2D). Our purpose was to determine for the first time if MAGE is associated to prevent visual impairment in people with diabetes. Yet relatively low rates with oxidative and vascular stress in adolescents without overt cardiovas-

of DR screening are common, especially in delivery systems. To cular disease. Boys and girls 13-21 y old classified as normal weight (NW), improve DR screening rates in a single, large safety net health center that obese (Ob), or with T2D (N=10-12 per group) wore a continuous glucose moni- serves predominantly low-income minority patients in South Los Angeles, we tor for 5 days to determine MAGE under free-living conditions. The T2D group undertook a survey of providers (P; n=18), staff (S; n=26), and patients (Pa; was not using insulin. The Ob group had normal glucose tolerance but had n=101) to identify barriers to DR screening. Pa were surveyed at scheduled hyperinsulinemia. All participants had low habitual physical activity (6,551 clinic visits. Questionnaires were tested for basic language and cultural com- ± 401 steps per day measured with accelerometry) and low aerobic fitness. petency prior to use. The survey revealed a low DR screening rate among Pa; MAGE was higher (p<0.01) in the T2D group (82 ± 10 mg/dl) than either the POSTERS Therapeutics only 51% were screened in the previous year, despite 78% reporting a physi- NW (30 ± 3) or Ob (33 ± 3) groups. Several markers of oxidative and vascular Clinical Diabetes/ cian recommendation. We examined potential barriers that might explain this. stress were also increased in the T2D group. Oxidized LDL (NW: 48.4 ± 2.0; Pa acknowledged the presence of 2 or more barriers in 44%; 1 barrier in 26%, Ob: 58.1 ± 3.8, T2D: 70.3 ± 5.0 U/l), an atherogenic particle elevated in T2D, and none in 30%. Most common barriers were depression (22% of Pa) and was strongly correlated with MAGE (r = 0.77, p<0.01). Likewise, the vascular financial problems (26%); 14% reported both. Other barriers identified by Pa stress markers E-selectin (NW: 43.5 ± 4.9; Ob: 51.8 ± 8.8, T2D: 72.8 ± 7.5 ng/ were language issues, lack of transportation, and time pressure (all by 15% of ml) and ICAM-1 (NW: 181 ± 9; Ob: 195 ± 17, T2D: 231 ± 19 ng/ml) were high- Pa). Women (59%) were more likely to report barriers (p<0.01). Pa who could est in the T2D group and positively correlated with MAGE (r = 0.50 and 0.35, not adequately explain the need for DR screening also reported more barri- respectively, p<0.01). The glycemic control marker, sRAGE (NW: 655 ± 54; ers (p<0.01). Pa consisted of 27% African American and 71% Latino; though Ob: 356 ± 48, T2D: 344 ± 44 pg/ml) was lowest in the T2D group and inversely no difference was observed in the number of barriers between these groups, correlated with MAGE (r = -0.38, p<0.01). These results demonstrate that African American were less likely to be screened (p<0.01). We also compared vascular stress is present adolescents and related to MAGE. Interventions Pa survey results with P and S combined (n=44), revealing markedly divergent that reduce glycemic variability in youth may reduce vascular stress and the perceptions of the importance of 9 barriers (all p<0.01). In summary, many bar- risk for future cardiovascular disease. riers acknowledged by Pa were anticipated, but the striking divergence be- Supported By: University of Oklahoma Health Sciences Center tween Pa and P/S perception of their importance was not. We conclude that preconceived ideas of barriers to DR screening do not match actual patient 144‑LB perception. To increase DR screening rates, patient communities should be Longitudinal Trends in Children with Severe Early Onset Obesity engaged to find key elements for intervention. VIDHU THAKER, MOLLY MCDONALD, MICHAELA BANKS, ADRIANNE LAGE, Supported By: California Community Foundation STAVROULA OSGANIAN, Boston, MA Background: The prevalence of severe childhood obesity continues to in- 142‑LB crease. There is a significant risk of cardiovascular disease (CVD) mortality A Regimen-based Measure of Adherence and Costs Associated in adults with greater body mass index (BMI) velocity at ages 8-13 years. with Nonadherence to Type 2 Diabetes (T2DM) Medications There is little information about the longitudinal trends of BMI in children RUO-DING TAN, GINGER S. CARLS, CHRISTIAN FROIS, EDWARD TUTTLE, Menlo with severe early onset obesity, who likely will be at higher risk of CVD or Park, CA, Boston, MA metabolic morbidity and mortality. In order to achieve recommended A1c targets, many patients (pts) require Methods: We used a validated electronic algorithm with structured and multidrug regimens, but these regimens present increased hurdles to patient unstructured data to identify children with severe early onset obesity (BMI adherence. Current methods of measuring patient adherence to multidrug >120% of 95th percentile at an age < 6 years) visiting the clinics at Boston regimens may overestimate adherence. This study compares a common Children’s Hospital. We extracted longitudinal growth and BMI data for at measure of adherence, proportion of days covered (PDC) by any diabetes least > 3 points/child over minimum 6 months with at least one value under medication, with a regimen-based refinement. Linked Optum-Humedica 6 years of age using EHR data and WebPlot digitizer software for scanned data (1/2007-3/2014) that included claims, electronic medical records and records. We excluded outlier data points using 3 methods. The longitudinal A1c were extracted for adult T2DM patients with at least one diabetes drug trends of BMI and BMI velocity were analyzed using multivariate mixed ef- fill. PDC and healthcare (medical and drug) patient costs were assessed over fects adaptive spline model (SAS software) and superimposition by transla- the most recent continuously enrolled 1 year period. We compare PDC by tion and rotation model (SITAR, R software). any diabetes medication ≥80%, a standard measure of adherence (std), Results: A total of 630 children were identified for the study - primary care with regimen-based PDC≥80%. Regimen-based PDC accounts for initiation, (76.3%) and weight management (57.5%) clinic. The gender distribution was switching, discontinuation, and stockpiling at the class level. ADA guidelines even (51% girls, 49% boys) with predominantly underrepresented minori- provide rules for determining whether a switch or discontinuation reflects ties (39% African American, 48.2% Hispanic/Latino). The median age at visit standard of care or non-adherence. 26,076 patients met study criteria hav- was 89 months with an average 33 observations/child. Trend analysis was ing a mean age of 61 years, 52% male, and a mean A1c of 7.3%. 53% of performed on 551 children, excluding outliers and inadequate data. The BMI patients had A1c <7% and mean healthcare costs of $18,041. 52% of all velocity is higher than predicted by CDC curves, boys 1.33kg/m2/yr (SE 0.03) pts filled multiple drug classes. The fraction of multidrug pts classified as and girls 1.44kg/m2/yr (SE 0.04), p < 0.05. The velocity is highest between non-adherent increased to 57% (regimen-based) from 36% (std). The excess 11-14 years of age, girls later than boys. healthcare cost of non-adherent multidrug pts was $3,374 (regimen-based) Conclusion: Children with early onset obesity are at a high risk of CVD vs. $1,758 (std) (P<0.0001). Excess healthcare cost for all non-adherent pts based on BMI velocity. The highest velocity is reached in later childhood was $3,091 (19% above adherent pts) with the regimen-based measure vs. calling for early identification and intervention, especially when obesity is $2,405 (14% above adherent pts) with the std measure (P<0.001). A measure established prior to 6 years of age. of PDC which more closely approximates T2DM medication regimen shows Supported By: T32DK007699, P30DK040561

ADA-Funded Research For author disclosure information, see page LB98.

LB37 Pediatrics—Type 1 Diabetes

Pediatrics—Type 1 Diabetes tionship with gender, age, HbA1c, IAA at diagnosis and HLA-DQ genotypes. The study included 636 patients with T1D aged from 0.2 to 28.3 years at 145‑LB diagnosis, with a follow-up of 1.4 to 25.3 years. Among the 636 patients, 5.4% were negative for all autoantibodies at diagnosis, 11.8% were positive HOMA2 Is Predictive of the Development of Type 1 Diabetes in Tri‑ β for 1 autoantibody, 22.5% for 2 autoantibodies, 31.8% for 3 autoantibod- alNet Pathway to Prevention Participants ies and 28.6% were positive for the 4 autoantibodies. A nearly total disap- FARAH MEAH, PING XU, LINDA A. DIMEGLIO, JAY M. SOSENKO, SUSAN GEYER, pearance of ICA was observed after 5 years, of GADA after 7 years and of CARMELLA EVANS-MOLINA, TYPE I DIABETES TRIALNET GROUP, Indianapolis, IA-2A after 8 years. The susceptible genotype 0301-0302/0501-0201 was IN, Tampa, FL, Miami, FL more prevalent in patients with multiple autoantibodies and at a younger Decreases in cell function as measured by changes in the first phase in- β age at diagnosis. The most frequent autoantibody among the patients was sulin response and cell glucose sensitivity are useful predictors of progres- β ICA. IAA and ICA were more frequent in younger patients at diagnosis and sion towards type 1 diabetes (T1D) but require the performance of provocative GADA in older patients. Male gender, younger age, higher HbA1c and the procedures such as intravenous and oral glucose tolerance tests (OGTT). The presence of autoantibodies (especially of ICA) at diagnosis were related to homeostasis model assessment (HOMA2) online calculator is a validated lower C-peptide levels. Male gender, older age, and positivity of IAA at diag- mathematical tool commonly used in type 2 diabetes research that assesses β nosis were correlated with longer persistence of ICA. Male gender was also cell function (HOMA2 ) and insulin sensitivity (HOMA2s) using fasting glucose β correlated with longer persistence of GADA. Older age, lower HbA1c and and insulin measurements. However, the utility of HOMA2 in predicting T1D β positivity of IAA at diagnosis, as well as 0301-0302/0301-0302 genotype, progression has not been previously tested. To this end, the HOMA2 calculator were associated with longer persistence of IA-2A. During the long follow-up was used to estimate HOMA2 in non-diabetic first-degree (age 1-45 yrs) and β of this study (25 years), there was an association between the evolution of second or third-degree (age 1-20 yrs) relatives of individuals with T1D who the autoantibodies and age, gender, HbA1c, C-peptide, positivity of IAA at were positive for one or more cell autoantibodies (aab) and followed longitu- β diagnosis and HLA-DQ genotype (only for IA-2A). In conclusion, the evolution dinally in the TrialNet Pathway to Prevention (PTP) Cohort. A Cox proportional of C-peptide was influenced by the presence of autoantibodies at diagnosis, hazards model was used to determine associations between HOMA2 at β age, gender and HbA1c at diagnosis. study entry and time to progression to T1D with adjustment for age, HOMA2s, and peak C-peptide on OGTT. 2,700 aab+ PTP participants entered the protocol (mean age 19.6 ± 13.7 yrs, HOMA2β 92.8 ± 43.5, HOMA2s 143.3 ± 99.6, peak 148‑LB

POSTERS C-peptide from OGTT 8.1 ± 3.7 ng/mL); 543 participants developed T1D during Prepubertal Children Need More Bolus Insulin than Derived from Therapeutics the 500-Rule

Clinical Diabetes/ the monitoring period. In multivariate analysis, likelihood of T1D moderately but significantly increased with decreasing HOMA2β among all aab+ subjects RAGNAR HANAS, KRISTIN LUNDQVIST, ANNIKA SJÖSTRAND, Uddevalla, Sweden (HR 0.987; 95% CI 0.983-0.992; p<0.0001) and in subjects with multiple (≥2) Objectives: The “500-rule” has been used extensively to find the insulin: aabs (n = 475, HR 0.989; 95% CI 0.984-0.994; p<0.001). Furthermore, HOMA2β carbohydrate (IC) ratio when carbohydrate counting is practiced, both in was positively correlated with peak C-peptide (r=0.54; p<0.0001). Our results adults and children. Data is lacking on validating this in young children. suggest that decrements in HOMA2β may have utility in predicting progres- Methods: We initiated carbohydrate counting by finding the individual IC sion to T1D in individuals with established autoimmunity. Future analyses will for each child by dividing the carbohydrate content in grams by the insulin focus on combining HOMA2β with additional metabolic and immunologic end- dose (breakfast and other meals separately). Insulin correction factor (ISF) points to improve T1D risk assessment. was defined by the “100-rule” (100 divided by total daily insulin dose (TDD). IC and ISF were adjusted at each visit. Data was taken from pump down- 146‑LB loads. IC and ISF were recalculated to “rules” (IC/ISF multiplied by TDD). Results: 21 prepubertal children aged 7.0±2.3 (±SD) (range 2-10) years with Early Identification of Cardiac Autonomic Neuropathy Using Com‑ diabetes duration 3.0±1.9 (0.5-7.7) years used the pump bolus guide for car- plexity Analysis bohydrate counting (CC) and correction boluses. 15 had started with a pump PENELOPE KANE, PETER LARSEN, ESKO WILTSHIRE, Wellington, New Zealand from the onset of diabetes. Their HbA1c was 53±6 mmol/mol (7.0±0.5%), and Abnormal heart rate variability (HRV), a marker of cardiac autonomic neu- none had experienced severe hypoglycemia with unconsciousness or sei- ropathy (CAN), contributes to mortality in adults with diabetes. Traditional HRV zures since diabetes diagnosis. Their total daily dose was 0.7±0.1 U/kg/24h measures do not consistently detect abnormalities in youth with type 1 diabetes (range 0.5-1.0), and their percentage basal insulin was 38±11%. The medi- (T1D). We aimed to assess whether complexity analysis of HRV would identify an breakfast rule was 211 (Q, quartiles 137; 285), and for other meals 434 CAN earlier than traditional methods, in youth with T1D. We studied 17 youth (Q 336; 532). The median ISF rule was 113 (Q99; 127) in the morning, and 122 with T1D [age 12.8±1.8 years, duration 4.5±2.6 years, HbA1c 7.9±1%] and 15 con- (Q 107; 137) during the rest of the day. There was a significant correlation trols (age 12.9±1.6), with 12 lead EKGs (sampling frequency 1000Hz) recorded between the total daily insulin dose (U/24h) and both IC and ISF. continuously for 10 mins. Recordings were analysed using Labview software and Conclusions: Prepubertal children seem to need more bolus insulin for an algorithm for complexity analysis (sample entropy and detrended fluctuation meals than calculated from the 500 rule, especially at breakfast, but less analysis), with standard methods for time-domain and spectral analysis. Clini- insulin for corrections than calculated from the 100 rule. When adjusting the cal (auxology, BP, insulin dose) and laboratory (lipids, HbA1c, electrolytes) data, bolus wizard according to the downloaded data and parent’s experience of as well as heart rate (HR) and BP responses to standing were obtained. Data insulin effect, a good metabolic control can be achieved with a low rate of were analysed using chi-squared, student’s t or Mann Whitney-U tests and Pear- severe hypoglycemia. son’s or Spearman’s correlation. Youth with T1D had significantly higher sample Supported By: Fyrbodal Research Institute entropy (0.149±0.011 vs. 0.136±0.014, p=0.015) than controls suggesting in- creased complexity in HRV, but similar detrended fluctuation analysis (0.67±0.12, 0.65±0.13, p=0.68). They had increased % high frequency (62±14% vs. 46±16%, 149‑LB p=0.017) and reduced mid-frequency (18±7.5% vs. 26±1.5%, p=0.019) power on Antibiotic Use in Early Childhood and the Development of Type 1 spectral analysis, but no differences in HR or BP responses to standing or time- Diabetes Autoimmunity: The TEDDY Study domain analysis of HRV. In T1D, sample entropy correlated strongly with trig- KAISA M. KEMPPAINEN, KENDRA VEHIK, RONALD J. CANEPA, ALEXANDRIA N. lycerides (TGs) (r=0.76, p=0.001) and detrended fluctuation analysis correlated ARDISSONE, AUSTIN G. DAVIS-RICHARDSON, OLLI G. SIMELL, JORMA TOPPARI, strongly with serum potassium (K+) (r= -0.86, p<0.001). Complexity analysis of ANETTE-GABRIELE ZIEGLER, MARIAN REWERS, ÅKE LERNMARK, WILLIAM A. HRV may detect CAN earlier than traditional measures. Our data suggest serum HAGOPIAN, JIN-XIONG SHE, BEENA AKOLKAR, DESMOND SCHATZ, MARK A. potassium and TGs may contribute to abnormal HRV. It is conceivable an inter- ATKINSON, MARTIN J. BLASER, JEFFREY P. KRISCHER, ERIC W. TRIPLETT, TEDDY action between abnormal HRV and serum K+ contributes to the “dead-in-bed” STUDY GROUP, Gainesville, FL, Tampa, FL, Turku, Finland, Munich, Germany, Aurora, syndrome in youth with T1D, which would be worth further investigation. CO, Malmö, Sweden, Seattle, WA, Augusta, GA, Bethesda, MD, New York, NY Antibiotic treatment can have profound effects on gut microbiota. Recent 147‑LB studies have described a link between the gut microbial community and risk of type 1 diabetes (T1D). Here the association between the appearance of Evolution of Diabetes-associated Autoantibodies and of C-Peptide islet autoantibodies (IA) and the use of antibiotics during the first 4 years of Since the Onset of Type 1 Diabetes life in children genetically at risk for T1D is assessed. In the TEDDY study, HARRY R. DORCHY, ANDRIANA ASIMAKOPOULOU, Brussels, Belgium 8495 children with T1D-associated HLA genotypes from Sweden, Finland, The objective is to investigate the immunological markers (ICA, GADA, Germany, and the U.S. were enrolled at 3 months of age and tested for IA IA-2A) and the residual insulin secretion (as measured by the C-peptide (mIAA, IA2A, GADA) every 3 months up to 48 months. Persistent autoimmu- levels) from the onset of diabetes, their evolution over time and their rela- nity was defined as an IA present on≥ 2 consecutive visits and was confirmed

ADA-Funded Research For author disclosure information, see page LB98.

LB38 —Basic Science Pregnancy—Clinical in 476 subjects (5.6%) at a median age of 21.6 months. Antibiotic use (oral ment could affect cellular function and development in F1 and F2 embryos. or parenteral) was reported every 3 months. Cox models assessed associa- To test this hypothesis, ICR mice (F0) were bred and assigned to control (C) tions between the use of common antibiotics (penicillins, cephalosporins, or undernutrition (UN) - 50% caloric restriction, ED 11.5 to 13.5; embryos and macrolides) and the instantaneous risk of developing persistent IA. were collected at E13.5 for isolation of mouse embryonic fibroblasts (F1-C Amoxicillin use, but not other antibiotics, 3-6 months prior to seroconver- and UN MEFs) for ex vivo culture. Using FACS-based analysis, we observed sion increased the risk of multiple IAs (HR=1.27, 95% CI=1.01-1.59, p=0.04). a 25% reduction in the ratio of cells in G0-G1 to G2-M phase in F1-UN-MEFs. However, cumulative use of penicillin-based antibiotics over time (HR=0.98), In parallel, we observed a 17-42% reduction (P<0.05) in expression of cell in the first year (HR=1.02), in the first two years (HR=0.99), and within a year cycle regulatory genes, including cyclins and aurora kinases, and upregula- before seroconversion (HR=1.02); or use of other antibiotics, were not signifi- tion (4-9 fold) of the cell cycle regulators and , the insulin and IGF-1 cantly associated with risk of any or multiple IAs. All analyses were adjusted receptors. Interestingly, the MEFs isolated from F2 embryo offspring of F1- for HLA, first degree relative status, gender, breastfeeding, probiotic use, UN males also displayed a 40% lower proliferation rate compared to F1-C, mode of delivery, maternal antibiotic use during pregnancy, country, and despite no change in cell cycle phase. In summary, in utero undernutrition season of birth. These findings suggest that amoxicillin use is associated reduces proliferation and cell cycle progression of MEFs cultured ex vivo, with the risk of developing IA in high-risk children. Further research assess- and also has a striking impact to reduce proliferation in second-generation ing causal relationships between antibiotic use, gut microbiota, and mucosal MEFs. Together, these data indicate that intergenerational inheritance of immunity is needed for better understanding the mechanisms involved in metabolic disease may be linked to epigenetic mechanisms perturbing tran- T1D development. scriptional control of cellular proliferation and cell cycle regulation. Supported By: National Institutes of Health; National Institute of Diabetes Supported By: CAPES; Ajinomoto Pharmaceuticals Co., Ltd. and Digestive and Kidney Diseases; National Institute of Allergy and Infectious Diseases; Eunice Kennedy Shriver National Institute of Child Health and Human

152‑LB Development; National Institute of Sciences; JDRF; Centers Translocator Protein (TSPO): An Early Marker of Placental Mito‑ for Disease Control and Prevention chondrial Dysfunction in Pregnancy Affected by Obesity JOANNA ZHOU, LUCIANA LASSANCE GOMES, MARICELA HAGHIAC, JUDI MINI- 150‑LB UM, PATRICK M. CATALANO, SYLVIE HAUGUEL-DE MOUZON, Cleveland, OH Stress Trajectories in Newly Diagnosed Youth with Type 1 Diabetes Obesity in pregnancy is associated with decreased maternal and

and Their Caregivers: The Moderating Role of Resilience progesterone concentrations combined with global mitochondrial dysfunc- POSTERS JOYCE P. YI-FRAZIER, KATIE COCHRANE, KATHRYN B. WHITLOCK, MICHAEL tion and lower cholesterol content in placenta. The aim of this study was Therapeutics Clinical Diabetes/ PASCUAL, NATALIE BEAUREGARD, CONNOR MITROVICH, NEIL PANLASIGUI, to investigate mechanisms for impaired placental mitochondrial function in CATE PIHOKER, Seattle, WA early pregnancy. Maternal blood and placenta tissue were collected at vol- It is well-known that stress is associated with poor outcomes for youth untary termination of pregnancy (9-11 weeks of gestation) from 55 women with diabetes. Less is known about the trajectory of stress over time and the with BMI ranging from 21.3-54.3 and no metabolic disease. Maternal total potential moderators of that stress. Resilience is a construct describing an plasma cholesterol and progesterone were assayed by ELISA. Placental ATP individual’s capacity to maintain psychological and/or physical well-being in and mitochondrial cholesterol were measured via fluorometric assays. Ex- the face of stress, and it has been shown to buffer the negative effects of pression of the mitochondrial cholesterol transporters, MLN64 and TSPO stress in adults with diabetes. Our study proposed to explore the impact of were quantified by Western blot. Mitochondrial DNA copy number and resilience on the trajectory of stress over the first year of diagnosis for ado- VDAC protein were assessed as markers of mitochondrial density. Plasma lescent youth with type 1 diabetes (ages 10-17) and a primary caregiver. We progesterone was lower in obese (BMI>30) compared to normal weight assessed resilience (Connor-Davidson Resilience Scale) and stress (overall (BMI <25) women (27.9±7.0 vs. 43.3±18.9 ng/mL, p=0.001). Expression of stress rating) at time of new onset and every 3 months over the first year. the outer mitochondrial membrane cholesterol transporter TSPO was 60% Stress trajectories were identified using semiparametric group-based tra- lower (p=0.03) in obese compared to lean women, whereas the endosomal jectory modeling with backward model selection strategy and final model cholesterol transporter, MLN64, was unchanged. Placental mitochondrial selection based on minimizing Bayesian Information Criterion. Resilience cholesterol concentration was 20% lower in obese vs. lean (p<0.0003). Pla- scores across time were stable for both patient and parent groups. For pa- cental ATP content did not vary as a function of BMI. Placental mtDNA and tients, 3 patterns of stress were identified: 1) stable low stress (n=33), 2) VDAC expression were unchanged, suggesting similar mitochondrial number stable moderate stress (n=22), and 3) stable high stress (n=5); no patterns in lean and obese women. In conclusion, maternal obesity impairs placen- indicated significant change across time. Compared to the low stress group, tal mitochondrial cholesterol transport and progesterone synthesis early in the moderate and high stress groups had lower baseline resilience (p’s = pregnancy. TSPO protein may serve as an early marker of defects in placen- .04, .03 respectively). For parents, 4 patterns of stress were identified: 1) tal mitochondrial function in pregnancy affected by obesity. The resulting initial high stress quickly decreasing to stable low stress (n=4) , 2) initial high impairment in intrauterine progesterone balance, may yield adverse conse- stress, briefly decreasing to moderate stress but returning to high stress, quences for maintenance of pregnancy and fetal development. (n=7), 3) stable moderate stress (n=18), and 4) initial high stress decreasing Supported By: National Institutes of Health (R01HD22965) gradually to moderate stress (n=31). Parent resilience was not associated with the parent stress trajectories. In sum, trajectories of parents’ stress seemed much more variable over the first year than youth. However, resil- Pregnancy—Clinical ience was only found to moderate stress trajectories in youth. Supported By: Seattle Children’s Center for Clinical and Translational Research 153‑LB The UPBEAT RCT: A Complex Intervention of Diet and Physical Ac‑ tivity in 1,555 Obese Pregnant Women Pregnancy—Basic Science LUCILLA POSTON, RUTH BELL, HELEN CROKER, KEITH M. GODFREY, C. FLYNN, LOUISE HAYES, NINA KHAZAEZADEH, SCOTT M. NELSON, EUGENE 151‑LB OTENG-NTIM, NASHITA PATEL, STEPHEN C. ROBSON, JANE SANDALL, THOM- In Utero Caloric Restriction Induces Intergenerational Cell Cycle AS A.B. SANDERS, PAUL T. SEED, NAVEED SATTAR, JANE WARDLE, MELISSA K. Dysregulation WHITWORTH, ANNETTE L. BRILEY, THE UPBEAT TRIAL CONSORTIUM, London, VICENCIA M. SALES, YUSUKE ADACHI, ELIZABETH J. RADFORD, ANNE FERGU- United Kingdom, Newcastle, United Kingdom, Southampton, United Kingdom, Glas- SON-SMITH, MARY-ELIZABETH PATTI, Boston, MA, Cambridge, United Kingdom gow, United Kingdom, Manchester, United Kingdom Nutrition during intrauterine development is critical for normal fetal de- The risk of gestational diabetes (GDM) increases with obesity. Numerous velopment and metabolic health during later life and in subsequent genera- interventions in obese women have focused on limiting gestational weight tions. We have previously demonstrated that transient exposure to caloric gain (GWG). The UPBEAT intervention was designed to prevent GDM. 1555 restriction during intrauterine life causes low birth weight, impaired glucose obese pregnant women (mean BMI 36.3 kg/m2; 63% White, 26% Black; 78% tolerance and obesity in not only offspring mice (F1), but also in F2 offspring 4th or 5th quintiles of deprivation) were randomized (15+0 to 18+6 weeks’ ges- of F1 males, despite no further nutritional insult. Transmission of phenotypes tation) to standard antenatal care or a health trainer delivered intervention via the male lineage implicates alterations in sperm. Consistent with this (weekly, 8 weeks) of dietary advice (focus, low glycemic index) and physical hypothesis, we have recently demonstrated altered sperm methylation of F1 activity. All women had an OGTT (27+0-28+6 weeks’ gestation). Compared to male mice and perturbed gene expression at differentially methylated loci in standard care, the intervention (mean 7 sessions/woman) reduced dietary F2 mouse embryos. We therefore hypothesized that the intrauterine environ- glycemic load by 26.3 units (95% CI -31.6 to -20.9) (19% lower), saturated fat ADA-Funded Research For author disclosure information, see page LB98.

LB39 Pregnancy—Clinical

intake (% energy) by 1.03% (-1.35 to -0.70) (8% lower) and total energy intake 155‑LB by 1.08MJ (-1.36 to -0.80) (14% lower). Protein intake increased (p<0.001) Differential Expression of MicroRNA in Human Umbilical Vein En‑ and total carbohydrate intake (p=0.02) fell. Physical activity improved by 295 dothelial Cells from Infants of Diabetic Mothers (112.1 to 477.6) metabolic equivalents min/wk (21.3% higher). Maternal GWG JEANIE B. TRYGGESTAD, APRIL M. TEAGUE, ANU VISHWANATH, DAVID M. was reduced by 0.55 kg (-1.1 to 0.0), from 7.76 to 7.19kg and the sum of skin- THOMPSON, YUSUKE TAKAHASHI, JIAN-XING MA, STEVEN D. CHERNAUSEK, fold thicknesses decreased (p=0.010). Despite achieving significant changes Oklahoma City, OK, Bangalore, India in dietary and physical activity behaviors, reducing GWG and improving Perinatal conditions such as diabetes mellitus (DM) have been shown to body composition, the intervention did not reduce GDM (IADPSG; control “program” offspring for certain metabolic phenotypes later in life. The mecha- 26.6% vs. intervention 25.5%, -1.1% (-6.0 to 3.9)). Large for gestational age nisms underpinning this sequence are not well understood, but epigenetic (LGA) deliveries (>90th customized centile, primary neonatal outcome) were modification has come to the forefront as a potential mediator of the associa- similar (control 8.3%; intervention 9.3%) as were LGA by population centiles tion of perinatal conditions and future cardiometabolic disease. One possible (11.1%,12.6%), SGA and preterm birth. BMI, ethnicity and age were similar mechanism for epigenetic modification involves micro-RNAs (miRNAs), small, in participants and women who declined. UPBEAT, the largest complex in- non-coding RNAs that bind to complementary sequences within 3’UTR of tervention study to date in obese pregnant women provides a safe strategy messenger RNAs (mRNAs) and modulate gene expression, typically repress- to improve diet, physical activity, GWG and body fat. However, in ethnically ing translation of targeted mRNAs. The purpose of the current study was to diverse obese women of mostly low socioeconomic status, we conclude that identify miRNAs that are differentially expressed in the human umbilical vein GDM is not preventable by an intense lifestyle intervention in pregnancy. endothelial cells (HUVEC) in infants of mothers with diabetes compared with Supported By: UK National Institute for Health Research (RP-PG-0407-10452); infants born to mothers with euglycemia. Total RNA including miRNAs was extracted from freshly isolated HUVEC cells from the umbilical cords of in- GSTT/KCL Biomedical Research Centre; Chief Scientists Office, Scotland; Guys and fants born to mothers with gestational diabetes as defined by the American St. Thomas’ Charity; Tommy’s Charity Diabetes Association and infants born to mothers with normal glycemia. A mi- croarray of 2,019 miRNA species probed for differentially expressed miRNAs. 154‑LB Twenty-seven miRNA species were selected for validation by RT-PCR from the Gestational Diabetes Mellitus microarray based on a significant difference between the groups or evidence MUSTAFA DEMIRPENCE, NUR DEMIRPENCE, ALIYE P. TÜTÜNCÜOGLU, GUZIDE from literature. Exact permutation tests found 5 of these 27 miRNA species to GONCA ORUK, NESIL ATALAY, AHMET GORGEL, BANU ARSLAN, HAMIYET YIL- be differentially expressed (miR-126, P=0.0004; miR-30c-5p, P=0.0015; miR- ·

POSTERS MAZ, MITAT BAHCECI, Izmir, Turkey, Diyarbakir, Turkey 452-5p, P=0.0172; miR-let-7a, P=0.0004; miR-let-7g, P=0.0004). Predicted tar- Therapeutics Recent observations suggest that a defective glucose stimulated insulin gets of these differentially expressed miRNAs include IRS1 and vascular cell Clinical Diabetes/ secretion by glucagon-like peptide-1 (GLP- 1) plays a role in the pathogenesis adhesion molecule 1 (VCAM1). In conclusion, we have identified 5 miRNA spe- of type 2 diabetes (T2D). Whether such a defect is impaired in Gestational cies that are differentially expressed in HUVECs from diabetic . diabetes mellitus (GDM) remains to be ascertained. The aims of this study Future work will focus on validating the targets of these miRNA and further were to evaluate how change GLP-1 levels among highly risky pregnancy elucidating their impact on cardiometabolic health in the offspring. with GDM. We investigated fasting and after 75-g oral glucose tolerance Supported By: Oklahoma Shared Clinical and Translational Resources test (OGTT) GLP-1 responses in pregnant women with and without GDM. 75-g-2h OGTT was performed in 20 GDM at 25.1±7.1 weeks and 11 with- 156‑LB out GDM women 26.8±4.8 weeks of gestation, for determination of plasma The Impact of Group Compared with Individual Prenatal Care on GLP-1, glucose, insulin, C-peptide levels. All of them were evaluated among Gestational Diabetes Mellitus: The South Carolina Centering Preg‑ fasting blood sample. Besides glucose, insulin, c-peptide, GLP-1 levels were nancy Expansion Project also performed among both 60. and 120. minutes blood samples of OGTT. LIWEI CHEN, EMILY HEBERLEIN, SARAH COVINGTON-KOLB, AMY PICKLESIMER, Data analysis was performed by SPSS 15.0 package programmer. Continu- Clemson, SC, Greenville, SC ous variables were presented with mean and standard deviation (SD) values. Centering Pregnancy group prenatal care (CPNC), a patient-centered model Man Whitney U tests was performed to evaluate the statistical significance of integrating medical checkups with social support and education in a group between two different medians. p < 0.05 was accepted as statistically sig- setting, has shown promise in reducing preterm birth. However, the impact of nificant. All results were summarized (Table). Women with GDM were found CPNC on gestational diabetes mellitus (GDM) has not been investigated. This to have lower fasting GLP-1 levels than women without GDM (p=0.028). retrospective cohort study included pregnant women who received prenatal Although it was not significant, GLP-1 levels of 60. and 120. minutes were care from 7 obstetric practices participated in the South Carolina (SC) Center- also lower among women with GDM. GLP-1 levels also may have a part as ing Pregnancy Expansion Project. Using SC birth certificate data linked with decreasing in the etiopathogenesis of GDM like T2D. Medicaid claims, we compared the incidence of GDM in women who chose CPNC and had a live birth between August, 2013 and September, 2014 to Table. Evaluation of All Results of Women With and Without Gestational women from the same practices receiving standard individual prenatal care Diabetes Mellitus. (IPNC). We applied multivariate regressions to estimate the ORs and 95% CI GDM + (n=20) GDM - (n=11) p value with controlling for demographic and clinical risk factors. The crude rate of Mean±SD Mean±SD GDM was 6.42% in IPNC (N=6,807) and 4.14% in CPNC (N=604) (P=0.03). Com- Age (year) 31.4±5.4 27.8±3.8 0.046 pared to women in IPNC, women in CPNC were less likely to develop GDM A1c (%) 5.7±0.3 5.4±0.4 0.039 (OR=0.53; 95% CI: 0.34-0.81; P=0.003) after adjusted for age, race, education, GLUCOSE (mg/dl) marital status, parity, time of entering and adequacy of prenatal care. The OR Fasting 88.6± 11.4 80.5±7.3 0.051 only slightly changed and remained significant (OR=0.58; 95% CI: 0.38-0.89; 60.min 177.5 ±33.3 147.8±23.8 0.002 P=0.012) after additional controlling for pre-pregnancy BMI category, gesta- 120.min 147.0±36.5 113.3±21.4 0.017 tional weight gain, and gestational age. In conclusion, approximately 40% lower risk of GDM was observed in pregnant women who received CPNC as C-PEPTIDE (ng/mL) Fasting 2.3±0.8 1.8±1.6 0.091 compared with women receiving IPNC, suggesting that Centering Pregnancy 60.min 10.9±4.0 8.6±2.9 0.076 has clinically significant benefits on reducing the occurrence of GDM. 120.min 11.7±4.1 8.1±2.3 0.016 Supported By: South Carolina Department of Health and INSULIN (mU/ml) Fasting 14.8 ±4.9 10.5±3.7 0.024 157‑LB 60.min 122.4 ±62.1 87.1±48.0 0.151 Sex of Offspring Influences DNA Methylation Patterns in Placentae 120.min 105.4±65.4 66.8±29.1 0.237 from Native American and Hispanic Women with Diabetes during GLP-1 Pregnancy Fasting 5.5±1.8 16.0±18.3 0.028 SARA E. PINNEY, APRIL TEAGUE, JULIE DOBKIN, RUIZ, STEVEN CHER- 60.min 5.9±1.9 11.5±13.9 0.237 NAUSEK, REBECCA A. SIMMONS, Philadelphia, PA, Oklahoma City, OK 120.min 7.7±9.8 10.1±9.8 0.434 Offspring of mothers with diabetes during pregnancy (DDP) are at increased risk for obesity and type 2 diabetes, which may be influenced by off‑spring sex. The mechanisms responsible for the phenomenon are unknown. We hypothesize that that DDP alters genome-wide DNA methylation resulting in differentially methylated loci of genes critical to glucose homeostasis resulting in diabetes and metabolic syndrome in the offspring. To test this hypothesis we mapped genome-wide DNA methylation with the Infinium 450K Human Methylation Ar-

ADA-Funded Research For author disclosure information, see page LB98.

LB40 —Aging ray using a nested case-control design from a cohort of Native American and development. Most of previous studies were case-control which could not Hispanic women with DDP. Term fetal placentae were collected and matched 1:1 give a cut-off value for practice. This study was to investigate whether sex with controls based on maternal age, race/ethnicity, and offspring sex. Methyla- hormone-binding globulin (SHGB) was a biomarker associated with GDM de- tion status at each probe site was determined by calculating = M/(M+U=100) velopment in later pregnancy. This prospective cohort study was conducted (M= methylated signal; U= unmethylated signal). Differential methylation (dm) in four hospitals. A total of 713 pregnant women who visited these centers was calculated as Δ per pair and averaged across all samples. during the first trimester (<12 weeks of gestation) between May 2013 and Table. May 2014 were enrolled. SHGB level were measured at 4-12 weeks of ges- tation. Among the 443 participants included in the final analysis, 41 (9.3%) All Male offspring Female offspring developed GDM. Participants were divided into 4 quartiles, according to Pairs 18 8 10 SHBG levels (Q1: <70.84 nmol/L, n=111; Q2: 70.84-116.35 nmol/L, n=110); Maternal age: mean (range) 28.4 (21-39) 29.2 (21-39) 27.9 (23-33) Q3: 116.35-158.49 nmol/L, n=111; Q4: >158.49 nmol/L, n=111). Among them, 15.3%,17.2%, 6.3%, and 2.7% developed GDM, respectively, in Q1, Q2, Q3, # Probes with p< 0.001 277 465 247 and Q4. No differences were found between Q1 and Q2, and Q3 and Q4, Genes with > 1 probe with dm 5 15 4 with the Q1/Q2 group showing higher rates. Finally, at SHBG >116.35 nmol/L, (p<0.001) GDM rates were significantly decreased. Decreased SHBG concentrations Probes with dm > or =+/- 10% 7 (-10.5 % +11.9%) 56 (-28% - +23%) 21 (-28.7% - +16.9%) during the first trimester may predict GDM development. (range) Supported By: Science and Information Technology of Guangzhou, China Probes with dm > or = +/- 15% 0 25 5 (12C22021649) Probes assigned to 5’ UTR (%) 1 (13) 14 (19) 0 Probes assigned to 3’UTR (%) 0 1 (1) 1 (5) 160‑LB Blood Levels of Glycated CD59 (GCD59) as a Novel Biomarker for st Probes assigned to 1 exon (%) 1 (13) 12 (16) 0 Screening and Diagnosis of Gestational Diabetes Probes assigned to TSS (%) 2 (25) 21 (29) 3 (15) PAMELA GHOSH, MIGUEL A. LUQUE-FERNANDEZ, ANAND VAIDYA, MICHAEL Probes assigned to gene 4 (50) 24 (33) 17 (80) CHOREV, CHLOE ZERA, THOMAS F. MCELRTAH, MICHELLE WILLIAMS, ELLEN W. body (%) SEELY, JOSE HALPERIN, Boston, MA DAVID gene function glycoproteins, cadherins, cell adhesion, glycoprotein, CD59 is a membrane-anchored complement regulatory protein that inhibits enrichment plasma membrane, plasma membrane, metal ion transport, formation of the membrane attack complex (MAC). A soluble form of CD59, neuronal development binding, cation binding, transcription regulation, shed off cell membranes, is present in human blood. We recently reported glucose metabolism, metal binding, that plasma levels of glycated CD59 (GCD59) served as a sensitive and specific transcription regulation cation binding biomarker for acute and chronic glucose handling in non-pregnant individuals In summary, DDP alters placental DNA methylation at metabolically- (JCEM. 2014;99:999). We therefore hypothesized that plasma levels of GCD59 relevant loci in a sex specific manner, with more probes affected in males. may represent a sensitive method to screen for impaired glucose tolerance and This finding may begin to explain the long-term metabolic effects of DDP gestational diabetes (GDM) in pregnant women. We conducted a prospective on offspring as the placenta functions to regulate the environment of the study of plasma GCD59 levels in 1114 consecutive pregnant women undergoing

two-step screening for GDM at Brigham and Women’s Hospital. Normal glucose G enetics

developing fetus. Future studies will correlate site-specific methylation with POSTERS mRNA expression via RNA-Sequencing. tolerance (NGT) was defined as a 50gr glucose load test (GLT) value <140 mg/dL, Epidemiology/ Supported By: American Diabetes Association (1-10-CT-09 to S.C.); National impaired glucose tolerance (IGT) as a GLT value >140 mg/dL followed by 0 or 1 Institutes of Health (R01DK089034-03) abnormal value on a 100gr/3hr glucose tolerance test (OGTT), and GDM by OGTT Carpenter-Coustan criteria. GCD59 was measured in plasma samples using a 158‑LB recently reported ELISA (AJH. 2013;88-670). We used ROC curves to assess the The Effect of Maternal Nutritional Intake during Pregnancy in Obese sensitivity and specificity of GCD59 to classify women with NGT, IGT or GDM. Women on Infant Body Composition Infant birth weight z-scores were calculated using population based growth PRANEETA CHODAVARAPU, SHARON GROH-WARGO, DENNIS SUPER, PATRICK norms. Mean plasma levels of GCD59 at 24-26 weeks gestation were 0.09±0.04 M. CATALANO, Cleveland, OH units in women with NGT (n=698) and 2.9±0.1 units in women with GDM (n=126; The purpose of this study was to determine the relationship of maternal nutri- p< 0.0001). Plasma values of GCD59 classified with high sensitivity and speci- tion in obese women on infant body composition. Healthy, obese (Body Mass In- ficity women with GDM (ROC curve AUC = 0.93), as well as women with IGT dex; BMI > 25 kg/m2), pregnant women between the ages of 18 and 40 years and and NGT (ROC AUC 0.79). Importantly, higher concentrations of maternal GCD59 8 to 16 weeks of gestational age (GA) were recruited in the antenatal clinic of were associated with higher incidence of large for gestational age newborns (z- MetroHealth Medical Center. Exclusion criteria were any maternal (i.e., diabetes) score >2). As most pregnant women are screened for GDM using a cumbersome or infant (i.e. respiratory distress) illnesses. During the first and third trimesters testing methodology, we conclude that a one time measurement of GCD59 in the (GA 14.4 + 1.7 and 35.2 + 0.8 weeks), all mothers underwent a detailed nutritional late second trimester represents a promising new biomarker for screening and assessment (Harvard Food Frequency Questionnaire, 2007, Harvard University, diagnosis of impaired glucose tolerance and GDM. Cambridge, MA), body composition by air displacement plethysmography using Supported By: National Institutes of Health-National Institute of Diabetes and the Bod Pod (COSMED, Rome, Italy) and BMI (weight on a calibrated scale and Digestive and Kidney Diseases (DK095429) height using stadiometer). Infants had their body composition measured during the first week of life by the Pea Pod (COSMED). Of the 38 mothers enrolled, the following first trimester maternal characteristics were associated with their in- Epidemiology—Aging fant’s percent body fat (% BF): carbohydrate intake (Pearson r = + 0.346, p = 0.034 two-tail); linoleic acid (r = + 0.334, p = 0.040); maternal BMI (r = + 0.284, p = 0.084); omega 3:6 ratio (r = - 0.280, p = 0.090) and physical activity (r = - 0.329, p = 0.044). 161‑LB Follicle-stimulating Hormone Associates with Prediabetes and In a stepwise multiple regression analysis, carbohydrate intake, Omega 3:6 ratio and physical activity in early pregnancy were independently associated with the Diabetes in Postmenopausal Women infant’s % BF (adjusted r squared 0.245, P = 0.006). None of the above variables NINGJIAN WANG, LIN KUANG, QIN LI, BING HAN, YI CHEN, CHUNFANG ZHU, obtained in the third trimester were associated with infant’s % BF. In summary, YINGCHAO CHEN, FANGZHEN XIA, ZHEN CANG, CHAOXIA ZHU, MENG LU, YING increased maternal carbohydrate intake, decreased omega 3:6 ratio and de- MENG, HUI GUO, CHI CHEN, DONGPING LIN, YINGLI LU, Shanghai, China, Hang- creased physical activity during early but not in late pregnancy are significantly zhou, China associated with higher infant % BF. Objective: Follicle-stimulating hormone (FSH) was reported to be associ- ated with obesity in pre- and post-menopausal women. Few studies concern 159‑LB the association between FSH and glucose metabolism. We aim to investi- SHBG Concentrations during the First Trimester May Predict GDM gate whether the variation of FSH is associated with prediabetes and diabe- Development tes in postmenopausal women. TONG ZHANG, WANGEN LI, SHAOJUAN YANG, WEIQIANG LIANG, YING LIU, Methods: Our data was from population-based Survey on Prevalence in YIMEI CHEN, JIANMIN NIU, FANG WANG, ZIHAO LI, Guangzhou, China, Phila- East China for Metabolic Diseases and Risk Factors (SPECT-China) (ChiCTR- delphia, PA ECS-14005052, www.chictr.org) in 2014. 1642 women ages 55-89 that were Gestational diabetes mellitus (GDM) is one of most common complica- postmenopausal and were not using hormone replacement therapy were tions of pregnancy. No well-known early pregnancy biomarker predict GDM selected. Newly diagnosed diabetes was defined as fasting plasma glucose

ADA-Funded Research For author disclosure information, see page LB98.

LB41 Epidemiology—Cardiovascular Disease

≥7.0mmol/L and/or HbA1c ≥6.5%. Prediabetes was defined as impaired fast- Blood glucose and HbA1c levels were documented to characterize hyperg- ing glucose (fasting plasma glucose 5.6-6.9mmol/L) or HbA1c between 5.7% lycemia. We report a significant increase in end diastolic volume (p<0.02), and 6.4%, or both. FSH, luteinizing hormone, total testosterone and estradiol end systolic volume (p<0.03), stroke volume (p<0.04), circumferential strain were measured by chemiluminescence in one central laboratory certified by (p<0.03) and the CURE index (p<0.03) in the diabetic rats when compared the College of American Pathologists. Multinomial logistic analyses were to age matched control rats. We have characterized the functional changes used to measure the association of FSH with prediabetes and diabetes. in the diabetic heart induced by chronic hyperglycemia in-vivo; exemplify- Results: Among the participants, 801 (48.8%) had prediabetes and 127 ing the utility of advanced CINE/tagging protocols to characterize disease (7.6%) had newly-diagnosed diabetes. Increased quartiles of FSH were associ- pathology and the need for early therapeutic intervention. ated with significantly decreased odds ratios of prediabetes and diabetes (P for trend <0.01). This association was attenuated by waist circumference and HOMA-IR but persisted in fully adjusted model (P for trend <0.01) in which for the lowest compared with the highest quartile of FSH, the odds ratios of prediabetes and diabetes were 2.07 (95% CI 1.32-3.24) and 3.56 (95% CI 1.34- 9.46). Conclusion: Low FSH was associated with higher prevalence of prediabe- tes and diabetes in postmenopausal women, which was partially explained by adiposity and insulin resistance. FSH may be a protective biomarker of glucose metabolism in postmenopausal women. Supported By: National Natural Science Foundation of China (81270885, 81070677); Clinical Potential Subject Construction of Shanghai Jiaotong Uni- versity School of Medicine (2014); Ministry of Science and Technology in China (2012CB524906); Science and Technology Commission of Shanghai Municipality 164‑LB (14495810700); Fund for Outstanding Academic Leaders in Shanghai (12XD1403100) Risk of Hospitalization for Heart Failure with Dipeptidyl Peptidase-4 Inhibitors vs. Sulfonylureas and with Saxagliptin vs. Sitagliptin in a U.S. Claims Database Epidemiology—Cardiovascular Disease ALEX Z. FU, STEPHEN JOHNSTON, JOHN SHEEHAN, AMEEN GHANNAM, KATH- ERINE TSAI, KATHERINE CAPPELL, ROBERT FOWLER, IFTEKHAR KALSEKAR, 162‑LB Washington, DC, Bethesda, MD, Fort Washington, PA, Gaithersburg, MD Aboriginal Australians with Type 2 Diabetes Have a Substantially In the SAVOR trial, the risk of hospitalization for heart failure (hHF), a com-

Increased Risk of Recurrent Cardiovascular Events: The Fremantle ponent of the secondary endpoint, was increased with saxagliptin compared Diabetes Study to placebo. This observational cohort study used a U.S. insurance claims WENDY A. DAVIS, TIMOTHY M.E. DAVIS, Fremantle, Australia database to compare the risk of hHF between patients with type 2 diabetes Patients with type 2 diabetes (T2D) and a history of coronary artery dis- mellitus (T2DM) treated with dipeptidyl peptidase-4 inhibitors (DPP-4i) vs. ease are at increased risk of further cardiovascular disease (CVD) events. We sulfonylureas (SU) and between those treated with saxagliptin vs. sitaglip- G enetics

POSTERS compared the risk of recurrent CVD events in community-based Aboriginal vs. tin. Methods followed the FDA’s Mini-Sentinel protocol for active surveillance Epidemiology/ non-Aboriginal T2D patients after hospitalization for acute coronary syndrome of antidiabetic agents. Patients initiated treatment between 8/1/2010 and (ACS). Of 1296 patients with T2D in the longitudinal observational Fremantle 8/30/2013 and had no use of the comparator treatments in the prior 12 months Diabetes Study recruited in 1993-1996 (mean age 64 yrs, 49% males), 422 (33%) (baseline). Each comparison consisted of patients matched 1:1 on a propensity had a first (index) ACS hospitalization during mean±SD 14±6 years’ follow-up score (nearest neighbor; caliper=0.01). Analyses were stratified by presence of from 2 years before entry to census (last contact/death/end 2012). The mean baseline cardiovascular disease (CVD). Time to hHF was compared between age at index event was 71 yrs; 3% were Aboriginal. Subsequent CVD episodes matched groups using Cox models. The Table shows the study results. Among (non-fatal acute myocardial infarction (AMI)/stroke, CVD death) were identified patients with no baseline CVD, those treated with DPP-4i had significantly through validated data linkage. Nearly three-quarters of Aboriginals (73%) vs. (P=0.013) lower hazards of hHF compared to those treated with SU; other com- 57% of non-Aboriginals suffered a recurrent CVD event (P=0.37). The recurrent parisons were statistically insignificant. In this analysis of patients with T2DM CVD event was an AMI in 44%, stroke in 17%, and CVD death in 39%, with no in a real world setting, there was no evidence of increased risk of hHF for DPP- difference by Aboriginal status (P=0.79). Aboriginals were younger at the time of 4i relative to SU or for saxagliptin relative to sitagliptin. the recurrent event (63±13 vs. 77±9 years, P<0.001). In Cox proportional hazards Table. Study Results* for Propensity Score Matched Cohorts**. modelling with age as the time-scale and after adjusting for sex, Aboriginals DPP-4i vs. SU Saxa vs. Sita were nearly four times more likely to have a recurrent CVD event (hazard ratio (95% CI): 3.77 (1.85-7.69)). During further follow-up starting from the recurrent No Baseline CVD Baseline CVD No Baseline CVD Baseline CVD CVD event until end-2012, 87.5% of Aboriginals vs. 88.1% non-Aboriginals died DPP-4i SU*** DPP-4i SU*** Saxa Sita*** Saxa Sita*** (P=1.00), a median [IQR] 0 [0-0.4] vs. 0 [0-1.2] years, respectively, later (P=0.78). N of patients**** 82,019 82,019 27,259 27,259 43,402 43,402 13,042 13,042 The incidence of recurrent CVD events after ACS hospitalization and the as- Mean follow-up***** 171 164 187 177 181 187 206 206 sociated early mortality are high in community-based Australians with T2D. Aboriginals are especially at risk, suggesting an urgent need for targeted and N of hHF events 35 58 200 202 23 24 82 87 culturally-sensitive strategies for prevention and management of CVD. IR per 100 PY 0.091 0.157 1.434 1.527 0.107 0.108 1.116 1.180 Supported By: Takeda Pharmaceuticals International, Inc. HR (95% CI), P 0.585 (0.384-0.892), 0.946 (0.778-1.151), 0.990 (0.560-1.749), 0.945 (0.699-1.278), P=0.013 P=0.58 P=0.972 P=0.712 163‑LB *Sensitivity analyses of hHF risk factor subgroups and using alternative follow- In Vivo MR Imaging in Investigating the Effect of Hyperglycemia in up assumptions produced consistent results (not shown) **The propensity a Rodent Heart score match achieved balance on all patient characteristics included in the SANKAR SERAMANI, SAKTHIVEL SEKAR, KISHORE KUMAR BHAKOO, Singapore, propensity score model (not shown). ***Reference category for HR; HR<1 Singapore indicates lower risk for DPP-4i or saxagliptin. ****Patients were matched 1:1 on a propensity score based on demographics, general clinical characteristics, Hyperglycemia is associated with higher cardiovascular risk. The impact and hHF risk factors from the 1-year baseline. *****In days; patients were of cardiac function due to hyperglycemia and/or diabetes are poorly under- followed from treatment initiation until hHF or censoring at cessation of stood in preclinical models due to difficulty in measuring the heart function the initiated treatment, use of the alternative comparator treatment, loss to non-invasively. Advances in ultra-high field (7 Tesla) MRI allow us to observe follow-up, or 8/31/2013. CI=confidence interval; CVD=cardiovascular disease; functional changes in a rodent heart with and without hyperglycemia. This DPP-4i=dipeptidyl peptidase 4 inhibitors; hHF=hospitalization for heart study aims to identify the cardiovascular risk associated with hyperglyce- failure; HR=hazard ratio; IR=incidence rate; PY=person-years of follow-up; mia with structural imaging (cine MRI) and strain assessment (MR tagging Saxa=saxagliptin; Sita=sitagliptin; SU=sulfonylurea. technique). Hyperglycemia was induced in a cohort of male Wistar rats (350- Supported By: AstraZeneca 450g, n=6) with STZ (60 mg/kg, IV) at week 7. MRI data were collected at week 40. Data were acquired with Bruker 7Tesla MRI scanner; GRE based cine imaging and tagged image data was acquired on the rat heart with the dedicated phased array cardiac coil [TR/TE: 5ms/1.7ms with 25 phases]. ADA-Funded Research For author disclosure information, see page LB98.

LB42 Epidemiology—Clinical—Diagnosis and Screening Epidemiology—Diabetes Complications

Epidemiology—Clinical—Diagnosis spectively examined the associations between the number of nevi and risk of and Screening T2DM among 23,748 men (1986-2010) from the Health Professionals Follow-up Study (HPFS) and 67,050 women (1989-2010) from the Nurses’ Health Study 165‑LB (NHS). Information on the numbers of melanocytic nevi on arms and the inci- Prevalence of Diabetes and Metabolic Syndrome in Jinuo Chinese dence of T2DM was collected by validated questionnaires. During 1,831,118 Adults person-years of follow-up, we documented 8748 incident cases of T2DM. Af- JIANG FUSONG, HOU XUHONG, WEIPING JIA, Shanghai, China ter adjustment for age, BMI, and other diabetes risk factors, the number of Background: To investigate the prevalence of diabetes and metabolic syn- nevi was significantly associated with increased risk of T2DM. Multivariable- drome in Jinuo Chinese adults, the last established ethnic minority popula- adjusted HRs (95% CIs) for <1, 1-5, 6-14, and ≥15 nevi were 1.00 (reference), tion in Yunnan, China. 1.02 (0.92, 1.14), 1.10 (0.87, 1.38), and 1.70 (1.22, 2.36), respectively, for men (P Methods: Between January and May 2012, we conducted a cross-sectional trend = 0.03) and 1.00 (reference), 1.15 (1.09, 1.21), 1.25 (1.11, 1.40), and 1.70 survey. A representative sample of 5,633 adults, aged ≥18 years, from the (1.38, 2.09), respectively, for women (P trend = 0.019). In the subgroup analyses Jinuo minority of Yunnan province participated in this study. After an overnight in the NHS, the positive relationship between nevi count and T2DM remained fast, blood samples were drawn to measure fasting plasma glucose levels and significant in postmenopausal women but not in premenopausal women. Mole 2 hours after an oral glucose-tolerance test in participants without history of count may represent a novel marker for development of T2DM in men and diabetes. Physical examination and laboratory tests were also performed. postmenopausal women, indicating a possible role of levels or functions of en- Results: The age-standardized prevalence of diabetes was 7.2% in the dogenous sex hormones in the pathogenesis of T2DM. Further studies population (men: 10.2%; women: 4.4%). Among 297 patients with newly are warranted to clarify the relationship and underlying mechanisms. diagnosed diabetes, 38.4% had raised fasting plasma glucose levels (≥7.0 mmol/L) only, 39.7% had raised 2-hour plasma glucose levels (≥11.1 mmol/L) only, and both parameters were raised in 21.9%. The age-standardized Epidemiology—Diabetes Complications prevalence of prediabetes was 19.0% (men: 21.2%; women: 17.0%). Among 1070 patients with prediabetes, 42.5%, 44.0%, and 13.5% had isolated im- 168‑LB paired fasting glucose, isolated impaired glucose tolerance and combined Point-of-Care Hba1c Testing in a Clinical Setting: Performance impaired fasting glucose and impaired glucose tolerance, respectively. The Analysis age-standardized prevalences of central obesity, general obesity, hyper- ELENA MATTEUCCI, CRISTINA CONSANI, LUCA ROSSI, LUCA DELLA BARTOLA, tension, dyslipidemia, and metabolic syndrome were 8.9%, 20.4%, 20.9%, OTTAVIO GIAMPIETRO, Pisa, Italy 20.4%, and 33.5%, respectively. HbA1c test reflects glycemic control over past three months, predicts dia- Conclusion: Jinuo male adults have a higher prevalence of diabetes and betic complications and can be used for diabetes diagnosis and screening; pre-diabetes and are prone to elevated fasting glucose levels. changes of 0.5-1.0% are clinically significant. Although POCT HbA1c assays may Supported By: Asahi Kasei Corporation be NGSP-certified the ADA doesn’t recommend them for diagnostic purposes. PTS Diagnostics (Indianapolis, USA) has recently introduced POCT HbA1c moni- 166‑LB toring system (A1cNow), NGSP and IFCC-certified, CLIA-waived, that provides Impact of Diabetes Screening in Asian Americans Based on the Re‑ results in 5 minutes and requires a 5µl blood sample. We investigated A1cNow G enetics vised ADA Standards of Medical Care in Diabetes 2015 performance in out clinic diabetic patients. HbA1c levels of 101 diabetic sub- POSTERS DANIEL S. HSIA, SANDRA LARRIVEE, WILLIAM T. CEFALU, WILLIAM D. JOHN- jects were measured with A1cNow devices, using capillary blood samples, and Epidemiology/ SON, Baton Rouge, LA laboratory Tosoh G8 HPLC Analyzer (CV% from external quality assessment The BMI cut point for screening overweight or obese Asian Americans for of low and high HbA1c levels: 2.1 and 2.6%, respectively) using EDTA venous prediabetes and type 2 diabetes was changed recently from 25 kg/m2 to 23 kg/ blood samples. A1cNow precision was evaluated by the CV of ten replicates m2 to reflect the evidence that this population is at increased risk for diabetes in two consecutive days using low (5.4%) and high (10.0%) NOD HbA1c control at lower BMI levels relative to the general population. The purpose of this cross solutions (Nova-One Diagnostics, Woodland Hills, USA). Diabetic patients To- sectional study was to examine screening rates using the new lower BMI cutoff soh results were 7.6±1.2% (range 5.3-11.0) vs. A1cNow 7.4±1.2 (5.1-10.5). The compared to the previous BMI cutoff of 25 kg/m2 in Asians participating in the A1cNow results correlated with laboratory results (r= 0.95, p<0.001), but mean National Health and Nutrition Examination Survey (NHANES) from 2011-2012 difference between A1cNow results minus Tosoh results was -0.24±0.39 (from when there was an oversampling of Non-Hispanic Asians. We hypothesized -1.6 to 1.1, p<0.001); the 95% confidence intervals (CIs) of mean difference were that including Non-Hispanic Asians ≥ 45 years old at a BMI cutoff of 23 kg/m2 -0.16 and -0.32. The relative error (bias/reference x 100) was 3.1±5.1% and would significantly increase the prevalence of prediabetes and diabetes in this showed a non-normal distribution: skewness 0.57 and kurtosis 3.84 (p<0.0001). population compared to a BMI of 25 kg/m2. NHANES 2011-2012 consisted of The within- and between-run CVs were well <4% for both levels of control solu- 9756 participants of which 13.1% (1282) were identified as Non-Hispanic Asian. tions. Thus, although the majority of A1cNow measurements were accurate in From this demographic group, 341 participants were identified as ≥ 45 years comparison with results of the reference method, a small percentage (5%) of old with available BMI, HbA1c, and fasting glucose data. In this subset, 45% mismatched results could lead to inappropriate medical decision. Research is in (155) had a BMI ≥ 25 kg/m2 compared to 69% (236) with a BMI ≥ 23 kg/m2. progress to determine system factors contributing to error. A high quality POCT Using the lower BMI cutoff, the prevalence of prediabetes and diabetes was could have a big impact on diabetes screening promotion as well as on diabetes 48.4% compared to 32.8% when using the previous BMI cutoff of ≥ 25 kg/m2. care at home, in the hospital or office setting. Moreover, lowering the screening BMI increased the sensitivity of screening for prediabetes and diabetes from 49.3% to 72.7% (p<0.0001) but decreased the 169‑LB specificity from 62.3% to 37.7% (p=0.0003). Overall, the combined prevalence Bladder Cancer Risk in Relation to Exposure to Pioglitazone among of prediabetes and diabetes was 66.6% (227 of 341) in this cohort. Although this Patients with T2DM in the Pan European Multi-Database Bladder will add additional healthcare costs due to more widespread screening, early Cancer Risk Characterisation Study identification of these conditions may be beneficial for primary and secondary PASI KORHONEN, EDITH M. HEINTJES, RACHAEL WILLIAMS, FABIAN HOTI, SOL- prevention in this unique population. More research is indicated to determine OMON CHRISTOPHER, MAILA MAJAK, LEANNE HOUWELING, HELEN STRONG- if this lower cutoff should apply to younger populations and to more specific MAN, MARIE LINDER, PAUL DOLIN, SHAHRAM BAHMANYAR, Espoo, Finland, ethnic groups within the Non-Hispanic Asian demographic. Utrecht, Netherlands, London, United Kingdom, Stockholm, Sweden Supported By: National Institute of General Medical Sciences (1U54GM104940) This observational cohort study was conducted in Finland, Netherlands, Sweden and United Kingdom at the request of the European 167‑LB Agency. The objective was to evaluate bladder cancer risk in T2DM patients Associations between Benign Cutaneous Nevi and Risk of Type 2 in relation to exposure to pioglitazone. A common study protocol and pooled Diabetes Mellitus in Men and Women: Results from Two Prospec‑ analysis plan was used across countries. Linked prescription, hospital, gen- tive Cohort Studies eral practitioner, cancer and death registration records were used to build the HONGJI DAI, QI SUN, XI ZHANG, JOANN E. MANSON, FRANK B. HU, YIQING study database from the country specific datasets. To limit channelling bias, SONG, Indianapolis, IN, Boston, MA pioglitazone exposed (n=56,337) and non-exposed were matched based on Previous studies suggest that the number of cutaneous nevi and type 2 treatment history and propensity scores accounting for variables affecting pi- diabetes mellitus (T2DM) are both associated with endogenous sex hormone oglitazone initiation. The hazard ratios (HR) with 95% confidence intervals (CIs) levels. However, no prospective studies have specifically examined the rela- were estimated using Cox’s model with adjustments for relevant confounders. tionship between the number of benign cutaneous nevi and T2DM. We pro- Follow-up was from cohort entry until first incident bladder cancer, secondary ADA-Funded Research For author disclosure information, see page LB98.

LB43 Epidemiology—Nutrition

malignant of bladder, death, start of other TZDs, leaving the data- p-yrs, RR=3.29 (2.27-4.77). The risk of falls in youth with T1D diabetes was base, end of database coverage or 30 June 2011 whichever occurred first. A less pronounced - RR 1.62 (1.05-2.48). total of 283 bladder cancer cases occurred: 130 in the exposed group and 153 Conclusions: Youth with T1D is more likely to suffer injury, particularly in in the non-exposed group during a mean follow-up time of 2.9 years and 2.8 older teenage years. Increased incidence of MVA-related injuries in youth years, respectively. The pooled adjusted HR (exposed vs. non-exposed) was with T1D requires further evaluation. 0.99 (95% CI: 0.75-1.30). The dataset specific HRs varied from 0.56 (95% CI: 0.31-1.00) for Finland to 4.27 (95% CI: 1.26-14.46) for Sweden. We did not ob- serve a trend with regard to cumulative exposure to pioglitazone. The adjusted Epidemiology—Nutrition HRs varied from 1.10 (95% CI: 0.82-1.48) to 0.86 (95% CI: 0.44-1.66) for <18 months and >48 months of exposure and from 1.05 (95% CI: 0.77-1.42) to 0.65 172‑LB (95% CI: 0.33-1.26) for 1-14,000 mg and >40,000 mg of exposure, respectively Pinitol-enriched Beverage Improves Mitochondrial and Endothelial when compared with the never exposed group. In conclusion, exposure to pio- Function in Type 2 Diabetic Patients glitazone did not increase bladder cancer risk. Further analyses are needed to ANTONIO HERNÁNDEZ, CELIA BAÑULS, SUSANA ROVIRA-LLOPIS, OLALLA explore the observed heterogeneity between datasets. Rubio-Puchol, Victor M. Victor, Milagros Rocha, Valencia, Spain Background: A limited amount of research suggests that inositol derivates 170‑LB have a positive influence on glucose tolerance in type 2 diabetic patients, Effects of Depression on Mortality Risk in Subjects With or With‑ but little is known about their effects on endothelial function. out Diabetes: The National Health Insurance Service—National Objective: To assess the anti-diabetic properties of an inositol-enriched Sample Cohort (2002-2010) in Korea beverage (IEB) on glycaemic control and its influence on the endothelial func- JI A. SEO, TAE JOON KIM, JI HYE SEO, JI HEE YU, HYE JIN YOO, SIN GON KIM, tion and/or redox status in type 2 diabetic subjects. KYUNG MOOK CHOI, SEI HYUN BAIK, DONG SEOP CHOI, YOUSUNG PARK, NAN Design: This was a 12-week, double-blind randomized trial employing HEE KIM, Ansan, Republic of Korea, Seoul, Republic of Korea nineteen diabetic subjects that receiving an IEB, containing mainly of pinitol, The aim of this study was to evaluate the effect of depression on all- 4.0 g/day. Anthropometric and biochemical measurements, postprandial and cause, cardiovascular and suicidal mortality among Koreans with or without fasting nocturnal glycemia, endothelial and inflammatory parameters, and diabetes. We evaluated the mortality risk in Korean adults using the large oxidative stress markers were analyzed at baseline and after intervention. prospective cohort data provided by the National Health Insurance Service, Results: Subjects consuming IEB exhibited a significant decrease in trig- which consisted of more than one million subjects. A total of 749,051 adults lyceride (8.82%) and HbA1c (4.53%) levels. Continuous glucose monitoring over 20 years of age at baseline of 2003 and 2004 were classified into 4 system revealed a significant reduction of -9.15% and -4.24% in glucose dur- groups by the presence/absence of diabetes and depression and were fol- ing postprandial breakfast and dinner, respectively and of 4.52% overnight

lowed-up until 2010. The prevalence of depression in 2003~2004 in subjects fasting periods. It also improved endothelial function by reducing P-selectin with or without diabetes was 5.83% and 1.58%. Over 7 years, 39,603 deaths levels (p<0.05) and leukocyte-endothelium interactions, as there was an in- were documented, including 6,999 deaths from cardiovascular disease and crease in rolling velocity and a reduction in polymorphonuclear leukocyte 1,906 from suicide. Compared with the reference group (no diabetes and no adhesion (p<0.05 for both). This response was mediated by a significant depression), mortality risk was highest in those with both diabetes and de- diminution in the generation of ROS determined by DFCH-DA (p<0.01). G enetics

POSTERS pression [HR 2.09 (95% CI 1.94-2.26)]. Subjects with only depression or dia- Conclusions: The present results show that IEB supplementation induces Epidemiology/ betes had modestly increased risk for death [depression only, 1.38 (95% CI a significant improvement in glycemic control in diabetic subjects by improv- 1.30-1.47); diabetes only 1.43 (1.39-1.47)]. Cardiovascular mortality showed ing endothelial function and intracellular redox status, which could, in turn, a similar pattern in these four groups [depression only, 1.32 (1.14 -1.53); reduce cardiovascular events. diabetes only, 1.47 (1.38 -1.57); both diabetes and depression, 2.28 (1.93- Supported By: Fund for Health Research (PI12/01984, PI13/1025, PI13/0073) 2.70)] compared to the reference group]. However, suicidal mortality was increased in subjects with depression regardless of the presence/absence 173‑LB of diabetes [depression only, 3.90 (3.18-4.77); both diabetes and depression Food Craving, Self-Control of Eating, and Appetite Score Were Pre‑ 3.65 (2.57-5.20)]. Depression is more prevalent in those with diabetes than dictors for Weight Loss in the POUNDS Lost Trial without. The coexistence of diabetes and depression increased the risk for JENNY TONG, DENNIS HANSEMAN, CATHERINE M. CHAMPAGNE, GEORGE A. all-cause and cardiovascular mortality. BRAY, LU QI, DONALD A. WILLIAMSON, STEPHEN D. ANTON, FRANK M. SACKS, Durham, NC, Cincinnati, OH, Baton Rouge, LA, Boston, MA, Gainesville, FL 171‑LB Eating habits and food craving are strong correlates of obesity but how Higher Incidence of Injuries in Children and Adolescents with psychological and behavioral factors may influence successful weight loss is Type 1 Diabetes not well understood. We aimed to identify predictors for successful weight ARLETA REWERS, MOLLY NOWLAN, DANA DABELEA, GREGORY TUNG, JUSTIN loss over a six months time period in the Preventing Overweight Using Novel CURIE, DAWN COMSTOCK, Aurora, CO Dietary Strategies (POUNDS Lost) trial. A total of 811 overweight and obese Background: Hypoglycemia or hyperglycemia may increase the risk of in- participants (age 51 ± 9 y [mean ± SD], 64% female, BMI 33 ± 4 kg/m2) were jury in patients with type 1 diabetes (T1D); however little is known concern- randomly assigned to one of the four diets with targeted percent energy ing the incidence of injuries in diabetic youth. The goal of this study was to from fat, protein and carbohydrates as 20-15-65, 20-25-55, 40-15-45, and determine whether the risk of injury in youth with T1D differs from that in 40-25-35 for 2 years. Multivariable linear regression analyses as well as the general population. partial correlation analyses were performed. Mean weight loss achieved Material and Methods: The study population included all Colorado resi- across all dietary conditions at 6 months was 5.8 ± 5.7 kg. There was no dif- dents aged <20 years followed for 14 332 638 person-years, during 2000- ference in weight loss according to dietary assignment. Greater craving for 2010. Annual intercensal population estimates were obtained from the state. carbohydrates and higher dietary restraint scores at baseline predicted less Cases of injury resulting in death, hospitalization or ER visit (N=34 761) were weight loss, while greater craving for high fat foods and high appetite score ascertained using the population-based Colorado Trauma Registry. Injury was at baseline predicted greater weight loss at 6 months. Both greater carbo- classified using the ICD-9 codes. Children and adolescents with T1D among hydrate and fat craving were correlated with higher intake of carbohydrates, injury cases (N=84) were identified based on a comorbidity variable. The protein and fat as well as total calories estimated at 0 and 6 months, but only population of youth with T1D who were at risk for injury in 2000-2010 was craving of high fat foods at baseline was associated with decreased fat and estimated based on SEARCH Colorado diabetes prevalence data. total calorie intake over the first 6 months. Higher dietary restraint at base- Results: The incidence of injury in youth with T1D was significantly high- line was associated with less food intake at baseline independent of BMI er - 5.4/1000 p-yrs than that in the underlying population - 2.4 /1000 p-yrs, but was associated with increased calorie intake from 0 to 6 months. Ap- RR=2.25 (95% C 1.81-2.78). Most injuries (67%) occurred in males, regardless petite score was negatively correlated with dietary restraint. Interestingly, of diabetes status. Age-group 15-19 yrs accounted for 67% of injuries in higher appetite score was associated with decreased calorie intake over the patients with T1D and 42% in the general population. T1D patients in this first 6 months. We conclude that while varying macronutrients in the diet did age group experienced the greatest increase in injuries, compared to the not lead to difference in weight loss, craving for specific macronutrients and general population. Motor vehicle accidents (MVA) were the primary cause levels of dietary restraint both predict short-term weight loss. of injuries in T1D patients and responsible for half of the injuries among 15- Supported By: National Institutes of Health-National Institute of Diabetes and 19 yr olds. The incidence of MVA injuries in T1D patients - 1.8/1000 p-yrs Digestive and Kidney Diseases was significantly increased, compared to the general population - 0.6/1000

ADA-Funded Research For author disclosure information, see page LB98.

LB44 Epidemiology—Nutrition

174‑LB 176‑LB Genetic Predisposition to Central Obesity, Dietary Fat, and Changes Randomized Trial of Multivitamin Use and Risk of Type 2 Diabetes in Appetite: Preventing Overweight Using Novel Dietary Strategies Mellitus in Men Trial (POUNDS Lost) YIQING SONG, LU WANG, JOANN E. MANSON, ROBERT J. GLYNN, JULIE E. BUR- CHRISTINA-ALEXANDRA SCHULZ, TAO HUANG, YAN ZHENG, TIANGE WANG, ING, J. MICHAEL GAZIANO, HOWARD D. SESSO, Indianapolis, IN, Boston, MA FRANK M. SACKS, GEROGE A. BRAY, QI LU, Malmö, Sweden, Boston, MA, Baton Objective: Multivitamin supplements are the most commonly used dietary Rouge, LA supplements in the U.S. and have been suggested as a means to prevent Central obesity is a major risk factor for diabetes and is determined by both type 2 diabetes. However, observational studies have shown an inconsis- genetic and environmental factors. Energy homeostasis plays a central role tent association and multivitamin supplement use and type 2 diabetes. In in influencing body fat distribution and risk of central obesity. However, little addition, there are no long-term randomized trials of multivitamin use that is known about whether genetic variants related to central obesity affect en- examined its effect on diabetes risk. ergy intake. In the 2-y Preventing Overweight Using Novel Dietary Strategies Research Design and Methods: In a secondary analysis of the Physicians’ Trial, we examined the relation between a genetics risk score (GRS) for central Health Study II (PHS II), a randomized, double-blind, placebo-controlled trial obesity and changes in appetite related behaviors, and particularly assessed of a multivitamin among 14,641 U.S. male physicians aged >=50 years, we interactions between the GRS and diet interventions. The GRS was created examined whether randomized multivitamin supplementation decreases the based on 13 central obesity-associated SNPs in 742 participants. The appetite- risk of type 2 diabetes. related traits included food craving, fullness, hunger and prospective consump- Results: Among 13,621 men free of diabetes at baseline, 1,074 incident tion. We found a significant interaction between the central obesity GRS and cases of type 2 diabetes were identified during a median follow-up of 11 dietary fat intake in relation to 2-y changes in appetite (P-interaction=0.0009). years. Overall, there was no significant difference in diabetes risk between Individuals with high GRS had increased appetite, while those with low GRS those randomized to take a daily multivitamin and those taking a placebo had decreased appetite (P=0.005) in the low-fat diet group. In subjects with (log-rank P=0.38). There were 551 incident diabetes cases in the multivita- high-fat diet, there was no significant genetic effect on appetite (P=0.381). In min supplement group and 523 in the placebo group (hazard ratio [HR], 0.98; addition, we found that the central obesity GRS score significantly modified 95% CI, 0.78-1.22; P = .83). Similarly, there was no effect of multivitamin the effect of dietary fat intake on 2-y changes in prospective consumption use on diabetes risk according to follow-up time (>0 to <5 and >=5 years of (P-interaction=0.0005). Participants with high GRS had a greater reduction in follow-up). Stratification by known diabetes risk factors, history of coronary prospective consumption when their fat intake was high (P=0.015); but tended heart disease, and other randomized treatments showed no significant in- to have less reduction in prospective consumption when their fat intake was teractions. low (P=0.111). Our data suggest that participants with a high genetic risk for Conclusions: In this large, long-term randomized trial of a daily multivita- central obesity might obtain more benefits in appetite and prospective con- min among male physicians, a common multivitamin had no effect on the risk

sumption by choosing a hypocaloric higher-fat weight-loss-diet. This trial was of developing type 2 diabetes among initially healthy men. registered at clinicaltrials.gov as NCT00072995. Supported By: Indiana University School of Medicine (to Y.S.)

175‑LB 177‑LB Effects of Substituting Brown Rice for White Rice on Diabetes Risk Dietary Lipophilic Index and Lipophilic Load and Risk of Type 2 Dia‑ G enetics

Factors in India: A Randomized Controlled Trial betes in the Women’s Health Study: Importance of Both Fat Quality POSTERS VASANTI S. MALIK, SUDHA VASUDEVAN, NICOLE M. WEDICK, RAMYA BAI, and Quantity Epidemiology/ VIJAYALAKSMI PARTHASARATHY, LAKSHMIPRIYA NAGARAJAN, KOKILA ARU- ERIC L. DING, KATERINA M. DE VITO, QI SUN, HONGYU WU, HANNIA CAMPOS, MUGAM, BILING HONG, RUIFENG LI, KAMALA KRISHNASWAMY, RANJIT M. EILIS J. O’REILLY, VASANTI S. MALIK, JULIE E. BURING, JOANN E. MANSON, ANJANA, DONNA SPIEGELMAN, WALTER C. WILLETT, FRANK B. HU, VISWANA- Cambridge, MA, Boston, MA THAN MOHAN, Boston, MA, Chennai, India Background: Fatty acid fluidity may influence insulin resistance and in- India has the second largest number of people with type 2 diabetes (T2D) flammation. Traditional broad fat classification may not sufficiently describe in the world following China. Epidemiological evidence indicates that con- differing risks of fatty acids. Therefore, we investigated the association sumption of white rice is associated with increased risk for T2D, while intake between two novel lipid indexes of fatty acid fluidity, the Dietary Lipophilic of brown rice decreases T2D risk. However, data from trials are sparse. We Index (DLI) and the Dietary Lipophilic Load (DLL), and risk of incident T2D: the determined the effect of substituting brown rice for white rice on T2D risk DLI reflects average fatty acid fluidity independent of quantity, while the factors among adults in urban South India. Following a 1-week run-in phase, DLL reflects both fat intake quantity and fluidity. We also tested an a priori 166 overweight (BMI ≥23kg/m2) volunteers aged 25-65 years who consume hypothesis of interaction with C-reactive protein (CRP). ≥200 g of rice/day were enrolled in a randomized cross-over trial conducted Methods: Study included 19,388 women in the Women’s Health Study, at the study center. The intervention consisted of a brown rice and white who were free of major chronic diseases and metabolic conditions (diabetes, rice regimen each providing 2 ad libitum meals/day, 6 days/week for 3 dyslipidemia, and hypertension) at baseline. DLL was calculated by summing months with a 2-week -out period. Fasting measurements of glucose across the products of each fatty acid (g/day) and its Celcius . metabolism, dyslipidemia and inflammation were assessed at baseline and DLI was calculated by dividing DLL by total fatty acid intake (g/day). We end of follow-up. During the intervention, no significant between-group dif- calculated hazard ratios (HR) for T2D using Cox regression adjusted for es- ferences were observed for markers of glycemic control or lipids. There was tablished risk factors and explored interaction with CRP. less increase in high-sensitivity C-reactive protein in the brown rice (0.03 Results: There were 442 cases of incident T2D in 238,690 person-years (2.12) mg/L) compared to white rice group (0.63 (2.35) mg/L) (p=0.04). Among of follow-up. In multivariate models, DLL, but not DLI, was positively as- participants who thought brown rice was healthy, the brown rice group sociated with an increased risk of T2D. The HR for T2D comparing extreme gained more weight than the white rice group, while among participants quintiles of DLL was 2.55 (95% CI: 1.13-5.74), while HR for T2D comparing who did not think brown rice was healthy there was no difference in weight extreme quintiles of DLI was 1.13 (0.50-2.55). The DLL positive association between groups (p-for-heterogeneity=0.002). Changes in HbA1c were more persisted after further adjustment for polyunsaturated:saturated fat ratio favorable in the brown rice group among those who did not think brown rice (HR=2.55, 1.13-5.74). Analyses by CRP levels (>1 vs. <=1 mg/L) suggested po- was healthy while there was no difference among those who thought brown tential CRP effect modification of both DLI and DLL (P interaction=0.042 and rice was healthy (p-for-heterogeneity=0.01). In this 3-month trial, substitut- 0.047, respectively), where DLL and T2D risk was stronger among high CRP. ing brown rice for white rice did not appreciably improve glycemic or lipid Conclusions: The Dietary Lipophilic Load, but not Dietary Lipophilic Index, parameters but had a favorable effect on inflammation. Changes in body is associated with higher risk of T2D, indicating the synergistic importance weight and glycemia differed by perception about brown rice. Larger stud- of both fatty acid fluidity and quantity. ies of longer duration are needed to examine the role of brown rice in T2D Supported By: American Diabetes Association (1-12-JF-13 to E.L.D.); American prevention in India. Heart Association Supported By: Fogarty International Center; National Institutes of Health (R03TW008726)

ADA-Funded Research For author disclosure information, see page LB98.

LB45 Epidemiology—Other

Epidemiology—Other 180‑LB Reduction in Diabetes Incidence Differs by Prediabetes Type in a 178‑LB Randomized Translational Trial of Prevention An Interleukin-6 Polymorphism May Modify Air Pollutants and Dia‑ MARY BETH WEBER, HARISH RANJANI, LISA R. STAIMEZ, RANJIT M. ANJANA, betes Association MOHAMMED K. ALI, K.M. VENKAT NARAYAN, VISWANATHAN MOHAN, Atlanta, IKENNA C. EZE, MEDEA IMBODEN, ASHISH KUMAR, ARNOLD VON ECKARD­ GA, Chennai, India STEIN, DAIANA STOLZ, MARGARET GERBASE, NINO KÜNZLI, THIERRY ROCHAT, Based on the success of trials in people with impaired glucose tolerance CHRISTIAN SCHINDLER, FLORIAN KRONENBERG, NICOLE PROBST-HENSCH, Ba- (IGT), the ADA and others issued prevention guidelines; however, real-life ef- sel, Switzerland, Zurich, Switzerland, Geneva, Switzerland, Innsbruck, Austria fectiveness of these guidelines for all prediabetes (isolated impaired fasting Air (AP) has been linked to type 2 diabetes (T2D) and hypoth- glucose, iIFG, iIGT, and IFG+IGT) remains unknown. The Diabetes Community esized to act through inflammatory pathways. AP has been linked to induc- Lifestyle Improvement Program (D-CLIP) in Chennai, India randomized adults tion of interleukin-6 gene (IL6 ) in the airway epithelium, and IL6 may impact with iIFG, iIGT, or IFG+IGT to control (N=293) or a low-resource lifestyle modi- on glucose homeostasis. A recent meta-analysis showed the common poly- fication program (N=283) based on the Diabetes Prevention Program (DPP) morphism, IL6 -572G>C (rs1800795) to be associated with T2D. IL6 -572G>C plus metformin for individuals remaining at highest risk (IFG+IGT or IFG + ele- has also been shown to influence circulatory IL-6 levels. We hypothesize that vated HbA1c at four months or later). Participants were 63.2% men; mean age polymorphisms on IL6 may modify the association between AP and T2D. We of 44.4 ± 9.3 years; mean BMI of 27.9 ± 3.7 kg/m2; and 30.2% had iIFG, 29.7% cross-sectionally studied 4410 follow-up participants of the Swiss Cohort had iIGT, and 40.1% had IFG+IGT. Mean follow-up was 2.54 ± 0.91 years, loss Study on and Lung and Heart Diseases (SAPALDIA), aged 29 to to follow-up 9.5%, and 71.5% in the lifestyle arm needed metformin. In inten- 73 years, with complete data on IL6 -572G>C genotype and covariates. We tion to treat analyses, the overall reduction in diabetes incidence was 32% defined diabetes as self-reported, physician-diagnosed, or diabetes medi- (Table), but intervention was less effective among iIFG compared to iIGT or cation use or non-fasting glucose >11.1mmol/L or HbA1c>0.065. Genotyp- IFG+IGT. Incidence reduction was greatest among obese (-49%), male (-37%; ing was done using 5'-nuclease Taqman assay. AP exposures were 10-year -24% in women) and older participants (-47% ages >50; -34% ages ≤35; -21% means of particulate matter <10um in diameter (PM ) and Nitrogen dioxide ages 36-50). A DPP-like intervention plus metformin when needed reduces 10 diabetes incidence by a third among all people with prediabetes; however (NO2). We derived interaction terms between AP and genotype and applied mixed logistic models to explore effect modification by IL6 -572G>C. There additional prevention tools may be needed in iIFG or BMI <27.5 kg/m2. were 252 diabetes cases. Minor allele frequency was 7%. IL6 -572G>C Table. Diabetes Incidence in the D-CLIP Study. was not associated with diabetes in our study. We observed a positive Diabetes Incidence Diabetes Incidence Relative association between AP and diabetes among homozygous carriers of the Rate Control Rate Intervention Reduction in Number proinflammatory major G-allele [ORPM10: 1.53 (1.22, 1.92; Pinteraction (additive): (cases/100 (cases/100 Incidence % Needed

0.031); ORNO2: 1.32 (1.15, 1.53); P: 0.042]. There was indication that the N person-years) person-years) (95% CI) to Treat C-allele mitigated the effect of PM10 and NO2. Sensitivity analyses showed Overall 550 14.2 9.8 32 (7, 50) 9.8 this effect modification to be consistent across various diabetes pheno- BMI (kg/m2) 23-<27.5 246 10.5 8.7 14 (-43, 48) 46.3 types when limiting case definition to each diagnostic criterion. We found a modifying effect of IL6 -572G>C on the association between AP and dia- ≥27.5 273 19.1 10.5 49 (23, 66) 6.8 G enetics

POSTERS betes in the SAPALDIA cohort. Our results are consistent with hypothesis Glycemic Status iIFG 166 7.2 6.5 12 (-80, 57) 15.5 Epidemiology/ that AP impacts on T2D through inflammatory pathways. Further studies iIGT 162 10.7 7.4 31 (-31, 64) 11.0 are needed to determine the public health impact of these findings. IFG+IGT 222 22.2 14.5 36 (3, 57) 12.3 179‑LB Supported By: International Diabetes Federation Modification of Air Pollution and Diabetes Association by Genetic Risk Score of Type 2 Diabetes Variants 181‑LB IKENNA C. EZE, MEDEA IMBODEN, ASHISH KUMAR, ARNOLD VON ECKARD- STEIN, DAIANA STOLZ, MARGARET W. GERBASE, NINO KÜNZLI, THIERRY Withdrawn ROCHAT, FLORIAN KRONENBERG, CHRISTIAN SCHINDLER, NICOLE PROBST- HENSCH, Basel, Switzerland, Zurich, Switzerland, Geneva, Switzerland, Innsbruck, Austria Exposure to ambient air pollution has been associated with risk of type 2 diabetes (T2D). Genetic factors may influence susceptibility to environmen- tal stressors in the aetiology of T2D. The effect of T2D genetic risk vari- ants on susceptibility to air pollution has not been studied. Compared to single variants, joint genetic variants contribute substantially to disease risk. Therefore, we did cross-sectional analyses of the modifying effect of genetic risk scores (GRS) of 46 European T2D risk variants on the associa- tion between air pollution and diabetes in 2825 participants of the Swiss Cohort Study on Air Pollution and Lung and Heart Diseases in Adults, aged 29-73 years, with complete genetic data. T2D risk variants were identified from genome-wide meta-analyses. Air pollution exposures were the 10-year means of particulate matter <10µm in diameter (PM10) and Nitrogen dioxide (NO2). Genotyping of 46 European T2D risk variants was done using Illumina Human Omni Express Exome chip. We computed two risk scores, count-GRS and weighted-GRS, and applied pollutant-specific interaction term with each risk score in mixed logistic models, including subgroup analyses. Diabetes prevalence was 5.9%. There was an increase in the association between PM10 and diabetes across tertiles (t) of count-GRS [ORt1:1.32 (0.86, 2.01); ORt2:1.66 (1.06, 2.61); ORt3:1.99 (1.06, 3.73); Pinteraction=0.275). We observed a positive interaction between PM10 and count-GRS (βint=0.27; P=0.003) among participants with chronic obstructive pulmonary disease (COPD). Al- though there was no evidence for effect modification of the GRS in the entire sample, two T2D risk variants (rs1531343 near gene HMG2A and rs8043680 near PRC1) showed significant interactions with PM10 (P<0.05). We observed similar results with weighted-GRS as well as with NO2. In conclusion, our results suggest that genetic risk for diabetes may modify susceptibility to air pollution. The results need follow-up in diabetes cohort consortia.

ADA-Funded Research For author disclosure information, see page LB98.

LB46 Epidemiology—Other

182‑LB diabetic subjects (DS) in comparison with a group of non diabetic subjects Life-Course Evolution of Prediabetes in Young Rural Indians (NDS). During the first outbreak of CKF in Haiti in 2014, the first 46 consecu- CHITTARANJAN YAJNIK, CHARUDATTA JOGLEKAR, DATTATREYA BHAT, HI- tive adult patients with preexisting diabetes and the first 53 consecutive MANGI LUBREE, PALLAVI YAJNIK, CAROLINE FALL, Pune, India, Southampton, non diabetic adult patients, diagnosed with CKF in a FHADIMAC (Fondation United Kingdom Haïtienne de Diabète et de Maladies Cardio-vasculaires) affiliated clinic in The Pune Maternal Nutrition Study was set up in 1993 to study the effect Port-au-Prince, were enrolled. Clinical history, capillary fasting glycemia and of maternal nutrition on fetal growth and programming of diabetes and car- HbA1c (DCA Vantage) were used to rule out diabetes in controls. All patients diovascular disease. We studied mothers from before and during pregnancy, with signs/symptoms suggestive of CKF underwent whole blood immuno- and children from birth onwards with serial anthropometric and metabolic- chromatographic tests for CKF (IgM Antibodies), dengue fever (IgG and IgM endocrine measurements. Fathers were also studied. At 18 years of age, Antibodies) and plasmodium falciparum malaria (Antigen). Mean age was we followed 663 (94%) of possible 709 children for their glucose tolerance, 53.2 and 47.4 years, 56.5% and 56.6% were women, 23.9% and 20.7% were body size and composition, and other risk factors for diabetes and CVD. Av- obese among DS and NDS respectively (NS). Mean duration of diabetes was erage BMI was 19.1 kg/m2, and there was one girl with diabetes (possibly 7.1 years; 4.3% of DS (2/46) were treated with lifestyle modifications (LM) monogenic). Twenty five percent had prediabetes (37% in boys and 18% in only, 82.6% (38/46) were on oral antidiabetic agents (OAA) and 13.0% (6/46) girls) by ADA criteria (23% IFG, 10% IGT, and 5% both). At 18 years, pre- on insulin. No patient with CKF had concomitant malaria or dengue fever. diabetic children had higher waist circumference (72.5 cm vs. 69.0), higher Arthralgia (100 and 98.1%), fever (86.9 and 90.5%), and myalgia (80.4 and subscutaneous abdominal fat area ( 96.9 cm2 vs. 92.9) but similar visceral 50.9%, p<0.01) were the most frequent clinical findings in DS and NDS, re- fat area when compared to NGT. They also had higher HOMA-IR (1.8 vs. 0.4), spectively. Improvement of arthralgia was reported after 8 days versus 3.5 lower insulinogenic index (1.4 vs. 1.7) and lower disposition index (63 vs. 82). days among DS and NDS respectively (p<0.01). In DS mean fasting glyce- Prediabetic children had higher fasting glucose and lower disposition index mia, based on glucose self-monitoring over 1 week, was 29.2% higher post at 12 and 6 years of age, had similar but lower gestation compared to pre CKF symptoms onset (p<0.01). This increase of glycemic (271 days vs. 273) at birth, and their mothers had lower plasma triglyceride values was 1.6 times more in 32.6% of DS (15/46). Anti-diabetic medication concentrations (128 mg% vs. 137) in pregnancy. In this world’s first lifecourse was titrated up in 41.3% of DS (19/46): 74.7% more for OAA, 35.5% more analysis of glucose intolerance in a high risk “undernourished” population, for insulin, addition of OAA for both DS on LM. Our study shows a signifi- we highlight importance of early life beta cell impairment and programming cant negative impact of CFK on glycemic control among diabetic patients. effect of intrauterine undernutrition and minimal prematurity. Our findings It also suggests greater morbidity related to CKF among diabetic patients suggest that type 2 diabetes in developing countries may have a “malnutri- compared with non diabetic subjects. tion related” beta-cell pathology. Current ideas of prevention of diabetes by lifestyle interventions in adults should be revised to include the role of 185‑LB intergenerational programming. Hepatitis C and New Onset Diabetes Mellitus in Liver Transplant Supported By: UK Wellcome Trust; Government of India Patients UZMA MOHAMMAD SIDDIQUI, MICHAEL THOMPSON, Worcester, MA 183‑LB Several risk factors have been cited for the development of NODM (New Life-Course Associations of Body Fat Patterns with Diabetes and onset Diabetes Mellitus) in Liver transplant patients. Hepatitis C has been G enetics

Cardiovascular Risk Factors identified as an independent risk factor for the development of NODM. We POSTERS CHITTARANJAN YAJNIK, ROHINI KELKAR, SUYOG JOSHI, CHARUDATTA performed a study looking for a correlation between viral loads, viral geno- Epidemiology/ JOGLEKAR, MANOJ CHINCHWADKAR, CAROLINE FALL, Pune, India, Southamp- types and treatment for Hepatitis C with the development and persistence ton, United Kingdom of Post transplant diabetes mellitus. This was a retrospective chart-review, The Pune Maternal Nutrition Study was set up in 1993 to study inter- which looked at patients who underwent a Liver transplant at University generational determinants and lifecourse evolution of diabetes (DM) and of Massachusetts (UMass) Medical Center from 6/2/2012-7/9/2014 (N=113). cardiovascular (CVD) risk. Serial anthropometric and DXA measurements are The patients were followed for up to 12 months post transplant. The data available, and at 18 years of age we used MRI (mean of 3 sections 1mm apart was collected from the Transplant Registry at UMass and from support- at L4-5 level) to study abdominal fat distribution (n=633, 95.5% of possible). ing medical records. Of the 113 patients, 6 underwent Living donor trans- The participants had an average BMI of 19.1 kg/m2 (48.2% underweight, plants (5.3%), while the rest underwent deceased donor. Indications for the 5.7% overweight and obese) and DXA fat percent 21.3 (men 15.5, women transplant included Alcohol abuse (47%), Hepatitis C (34.5%) and Hepatitis 28.0). The abdominal subcutaneous fat area (SFA) was higher than the vis- B (0.8%), amongst other reasons. Of the total patients, 29% were diabetic ceral (VFA) (94.1 vs. 57.7 cm2), and the two were inversely related (curvilinear pre-transplant and hence were excluded from follow up. 7 patients died prior r2 =0.534, p<0.001). Men had higher VFA and women higher SFA. SFA was to completion of the 12 month follow up. Of the 39 patients with Hepatitis directly related to socio-economic status, to parental BMI, and maternal fo- C, 12 patients had Pre-transplant diabetes. Of the remaining Hepatitis C pa- late , and inversely to maternal Vit D and B12 concentrations and physical tients, 14 (51.8%) developed NODM at 3 months post transplant, and most activity in pregnancy (p<0.05 for all, adjusted for age and sex). It was also of them remained diabetic a year out of transplant. Most of the patients that directly related to weight, length, and head circumference at birth, and fat developed NODM had a Hepatitis C genotype of 1a/1b. The post transplant percent at 6, 12 and 18y. VFA had opposite relationships (p<0.05 for all). SFA immunosuppressants, viral loads and treatment for Hepatitis C for these pa- was directly and VFA inversely related to current weight, waist circumfer- tients were also followed. The presence of NODM has been implicated in ence and fat percent, but not to height. SFA was directly related to 120 min poor outcomes in terms of graft survival and increased patient mortality. Our glucose (OGTT), HOMA-IR, cholesterol, triglycerides and TLC, but inversely ongoing study may help in identifying Liver transplant patients who are at to disposition index. VFA was inversely related. Hyperglycemics (IFG + IGT, increased risk for Post transplant NODM and may therefore provide indica- ADA criteria) had higher SFA compared to the normoglycemic (96.9 cm2 vs. tion for closer observation, or even preemptive management. 92.9 cm2, p<0.05) but similar VFA. In this world’s first description, we found that parental BMI, maternal micronutrient nutrition and physical activity 186‑LB during pregnancy were associated with subcutaneous and abdominal adi- Association between Type 2 Diabetes and Prognosis in Colorectal posity in adult offspring. SFA had a predisposing while VFA a protective as- Cancer sociation with glycemic and cardiovascular risk. Our results shed new light JUHONG YANG, Boston, MA on early life determinants of components of abdominal adiposity, and sup- Purpose: Type 2 diabetes is associated with an increased risk of colorectal port observations that subcutaneous abdominal adiposity increases risk of cancer (CRC) but controversial exists in its association with prognosis, as DM and CVD in SA Indians. most studies did not account for various potential confounders, such as can- Supported By: UK Wellcome Trust; Government of India cer stage, physical activity and body mass index (BMI) in their analyses. Patients and Methods: We analyzed survival by diabetes status among 184‑LB 1,303 patients diagnosed from 1986 to 2010 from two prospective cohort Effects of Chikungunya Fever on Diabetes studies: the Nurses’ Health Study (NHS) and Health Professionals Follow-Up EDDY JEAN-BAPTISTE, FREDERICA RAPHAEL, NANCY C. LARCO, PHILIPPE LAR- Study (HPFS). We used Cox proportional hazards models to calculate the CO, JULIA VON OETTINGEN, RENE CHARLES, Port-au-Prince, Haiti, Boston, MA hazard ratios (HRs) for colorectal cancer specific mortality (CM) and overall Very few data exist regarding the effects of chikungunya fever (CKF) mortality (OM), after adjustment for cancer stage, tumor grade and location, on diabetic patients. This study aimed to determine the impact of CKF on postdiagnosis smoking, aspirin usage, BMI, and physical activity. Survival time was calculated from CRC diagnosis to death or last follow-up.

ADA-Funded Research For author disclosure information, see page LB98.

LB47 Epidemiology—Type 1 Diabetes Genetics—Type 1 Diabetes

Results: In 1,303 CRC patients, 107 (8.21%) were complicated with type 2 diabetes. There was no difference in cancer stage, differentiation, loca- tion, family history and gender between diabetes and non-diabetic patients. Diabetic patients had a higher BMI and less physical activity. Comparing diabetic patients to non-diabetic patients, the HRs for death were 0.944 (95% CI, 0.582 to 1.531, P>0.05) for CM and 1.492 (95% CI, 1.135 to 1.961, P=0.004) for OM. Compared to those without diabetes, the HRs for OM was 1.072 (95% CI, 0.667 to 1.721, P>0.05) for patients with short-term diabetes (<5 years), and 1.804 (95% CI, 1.305 to 2.492, P=0.003) for patients with long-term diabetes (>5 years). Conclusion: Diabetes especially long-term diabetes is associated with decreased overall survival but not cancer specific survival among patients with colorectal cancer. Supported By: R01CA151993, K07CA190673

Epidemiology—Type 1 Diabetes

187‑LB Who Is Not Returning? Retention of Recruited Subjects in the Type 1 Diabetes TrialNet Pathway to Prevention 189‑LB EMILY K. SIMS, DAVID BOULWARE, CARMELLA EVANS-MOLINA, CARLA J. GREEN­ Noninvasive Measurement of Beta Cell Function in Adult Subjects BAUM, HENRY RODRIGUEZ, JEFFREY P. KRISCHER, LINDA A. DIMEGLIO, TYPE 1 with New Onset Type 1 Diabetes DIABETES TRIALNET STUDY GROUP, Indianapolis, IN, Tampa, FL, Seattle, WA DAVID A. BAIDAL, JASON L. GAGLIA, Boston, MA The TrialNet Pathway to Prevention (PTP) screens first and second-degree Serum C-peptide (CP) measures during mixed meal tolerance test (MMTT) family members of persons with type 1 diabetes (T1D) to identify subjects at are often used to assess beta-cell function in type 1 diabetes (T1D) clini- high T1D risk, and enrolls eligible persons into natural history and prevention cal trials. As a noninvasive alternative, we evaluated whether urinary C- studies. As of January 2015, PTP screened 144,476 individuals worldwide peptide/creatinine ratio (UCPCR) correlated with CP during MMTT in newly at both clinical centers and affiliate sites. To determine which antibody- diagnosed (< 6 months) T1D subjects and healthy controls. Nineteen T1D

positive (Ab+) subjects were either successfully recruited into monitoring subjects (age 25±6 years, male 13/19) and 20 healthy controls (age 26±4 studies or lost to follow-up, we performed multivariate logistic regressions years, male 16/20) were enrolled. Subjects underwent standardized 2hr of PTP data. Only variables with a p value <0.05 were interpreted as having MMTT. A subset of 6 T1D patients had serial MMTT over 1 year. UCPCR a significant effect. First, we defined characteristics of single Ab+ subjects was calculated from 2nd fasting and post-MMTT urine samples. We found on initial screen (n=4228) who failed to return for confirmatory Ab testing no significant correlation between UCPCR and fasting or MMTT CP values in G enetics controls. By contrast, in T1D subjects fasting UCPCR correlated with fasting POSTERS (n=1191, 28.2% of recruited subjects). Older subjects, parents and children Epidemiology/ of probands with T1D, persons recruited by affiliate sites (vs. clinical cen- CP (r=0.61, p<0.01), and post-MMTT UCPCR correlated with both 90min CP ters), racial minorities (Blacks, Native Americans, Pacific Islanders), and (r=0.64, p<0.01) and CP AUC (r=0.69, p<0.01). Serial MMTT showed persis- Hispanics/Latinos were less likely to follow-up. We also examined which tent correlations between fasting UCPCR and fasting CP (r=0.63, p=0.003), subjects eligible for monitoring (n=4726) were not currently participating in and between post-MMTT UCPCR and 90min CP (r=0.78, p<0.001) and CP TN PTP monitoring visits (n=1542, 32.6% of Ab+ subjects). Again parents of AUC (r=0.81, p<0.001) (Fig. 1). In T1D patients UCPCR strongly correlated with probands, racial minorities, and subjects recruited by affiliates were less fasting CP, 90min CP, and CP AUC with correlations persisting over time, sup- likely to continue with monitoring. Interestingly, age and ethnicity were not porting use of this simple test for monitoring beta-cell function in new onset predictive at this stage. Those who were 4Ab+ were most likely to return. T1D clinical trials. A nonlinear association at higher CP values may explain These data confirm clear differences between successfully recruited popu- the lack of significant correlations seen in controls. lations and those lost to follow-up. Future work is needed to improve reten- tion of Ab+ participants in order to facilitate rapid enrollment and reduce selection biases in T1D natural history and prevention studies. Supported By: K08DK103983 (to E.K.S.)

188‑LB Are There Gender Differences in the Management among Our Pa‑ tients with Type 1 Diabetes? NOEMI GONZALEZ, LUCRECIA HERRANZ, ROSALIA SANCHEZ, NATALIA HILL­ MAN, BEATRIZ BARQUIEL, FELIPE PALLARDO, Madrid, Spain Sex differences in achievement of lipid and glycemic control have been related to worse cardiovascular outcomes in women with type 1 diabetes (DM1). We examined if quality of care varied by gender in our Diabetes Unit in patients without coronary heart disease. A1c, lipid profile (LDLcol, HDLcol, total col, triglycerides) and clinical data from patients seen during 2013 were collected from lab and clinical reports. Target Glycemic Control (TGC) was defined as A1c <7%. Target Lipid Control (TLC) as LDLcol <100 mg/dL, HDLcol Genetics—Type 1 Diabetes >40 (men) or >50 (women) mg/dL and TG <150 mg/dL; Target Cardiovascular Index (TCVI) as total chol/HDL <4 (women) or <4.5 (men). Univariate analysis 190‑LB was used to compare women and men with DM1. 828 patients were in- A RAGE Gene SNP Is Associated with Type 1 Diabetes cluded. Clinical characteristics, biochemical parameters and glycemic/ lipid JUNNOSUKE MIURA, MANABU KAWAMOTO, YASUSHI KAWAGUCHI, SARI targets are shown in Table 1. Less than 40% of the patients achieved gly- HOSHINA, HIROKO TAKAIKE, MARI OSAWA, HISASHI YAMANAKA, YASUKO cemic or lipid target, with no sex differences (TGC 39.3% vs. 37.7%; TLC UCHIGATA, Tokyo, Japan 35.4 vs. 40.3; p=ns). 93.1% (women) and 92.8% (men) (p=0.854) had targeted Receptor for advanced glycation endproducts (RAGE) is related to not only CV Index. Despite longer duration of diabetes, and less lipid lowering drugs vascular damage but also immune disturbance. Therefore, we tested the as- in women, no gender differences with regard to Target Glycemic, Lipid and sociation between RAGE gene SNPs and type 1 diabetes (T1D). The subjects Cardiovascular Index Control were found. These results reflect an adequate were 817 patients with T1D (305 men, 698 of acute onset, onset age: 19±13 awareness about female cardiovascular risk, but an effort to improve guide- years old, 119 of slowly progressive with GAD Ab+, onset age: 34±16 yrs line-based clinical practice is still needed independent of sex. old). Gene polymorphisms were determined by Taqman SNP assay of known SNPs of RAGE gene, G82S (G/A), -429T/C and -374T/A. A sixty-three bp dele-

ADA-Funded Research For author disclosure information, see page LB98.

LB48 Genetics—Type 2 Diabetes tion polymorphism between -429T/C and -374T/A was determined by PCR. detectable type 1 diabetes (T1D) antibodies or b) diagnosed with T1D but These allele frequencies were compared to that of 887 healthy controls (HC) with evidence of persistent C-peptide production >5 years after diagnosis. (525 men, 39±11 yrs old). The Linkage disequilibrium (LD) analysis was done Those with cystic fibrosis or a BMI >35 kg/m2 were excluded. We identified among polymorphisms of RAGE genes. All SNPs in T1D and HC were satisfied 38 cases for genetic testing; DNA of sufficient quality for analysis was avail- with Hardy-Weinberg Equilibrium. The allele frequencies (%) of T1D were able for 35 cases. DNA was isolated and samples were analyzed using an G82S G/A: 86.9/13.1, -429T/C T/C: 79.4/20.6, -374T/A A/T:76.2/23.8, and in-house next-generation sequencing (NGS) panel including 41 genes associ- 63bp wild/del:96.7/3.3 while those of HC were G/A: 86.0/14.0, T/C: 92.1/7.9, ated with monogenic diabetes and lipodystrophy. 24 donors were negative A/T:76.0/24.0, and 63bp wild/del: 98.0/2.0, respectively. There was signifi- for variants of significance while 11 of 35 donors had variants identified with- cant difference in -429T/C SNP between T1D and HC (p = 1.75 x 10-24), and the in targeted genes (8 most significant shown in Table 1). Case 6176 represents odds ratio was 2.82 (95% CI: 2.29-3.46). The allele frequencies of acute onset the first report of histopathology for MODY3/HNF1A (known causal variant). and slowly progressive T1D were -429T/C T/C: 79.5/20.5 and 80.5/19.5 (not 6033, 6249, 6264 and 6166 require further study regarding unexpected but significant). There was significant difference in -429T/C frequency of each plausible causes related to chronic insulin resistance/overproduction. We T1D subclass compared with HC (p=1.39 x 10-23 and 3.9 x10-8). The -429T/C demonstrate that variants within monogenic diabetes and lipodystrophy allele frequencies in male and female T1D were T/C: 77.3/22.7 and 80.8/19.2 genes are common and deleterious may go unrecognized. (not significant). There was significant difference in -429T/C SNP between Table 1. Example of Variants Found. T1D and HC in male (p=9.28x10-23), and in female (p=6.05 x10-19), and these odds ratio were 3.41 (95% CI: 2.64-4.41) and 2.77 (2.20-3.30). Pairwise LD nPOD Gene, AA PolyPhen Minor Allele Cause of Death Histopathology ID Variant Change Score Frequency analyses revealed the presence of complete disequilibrium among the four RAGE polymorphisms. There were no differences in frequencies of other 6033 KCNJ11, Val290Met 1.000 0.00001648 Cerebrovascular Ins-/Gluc+ islets. Moderate Ki67+ 3 polymorphisms between 2 subclasses of T1D. This study indicated that c.868G>A acinar cells. Acinar atrophy with increased fibrosis RAGE gene -429 T/C SNP was strongly associated with T1D in Japanese. 6037 MNX1, Pro356Ser 0.915 0.00006834 Cerebrovascular Ins-/Gluc+ islets, reduced size and c.1066C>T numbers. Mild infiltrate, Low Ki67 191‑LB acinar cells. Minimal vascular Two Novel Loci in the GCKR Gene Contribute to Develop Monogenic disease. Diabetes 6166 LMNA, Asp300Asn 0.955 0 Anoxia Ins+ (highly)/Gluc+ islets, numerous. PIOTR GNYS, KAROLINA ANTOSIK, WOJCIECH MLYNARSKI, MACIEJ BOROW- c.898G>A Mild fatty infiltrate. Multifocal, mild IEC, Ł ó d ’z , Poland ductular dysplasia. CVD- moderate. GCKR gene encodes GKRP (Glucokinase Regulatory Protein) that is a 6173 UCP2, Met287Thr 0.990 0.00002713 Anoxia Ins-/Gluc+ islets, reduced density. hepatocyte-specific protein acting as a modulator of glucokinase. We per- c.860T>C Acinar atrophy moderate to severe formed Sanger’s sequencing of GCKR gene among 15 patients of Polish with prominent nerve fibers and descent with clinical features of diabetes (Table 1). Beside already known diffuse chronic pancreatitis (CD3+ single polymorphisms (rs1260320, 2293571, 1260326, 8179236, infiltrates). 183738110) we have found 2 novel genetic alteration. First GCKR variant - 6176 HNF1A, Thr10Met 0.965 0.00003463 Anoxia Ins+ (weak)/Gluc+ islets, numerous c.5592G>T, was found in a patient who was initially screened for mutations c.29C>T but small sized. Mild acinar atrophy. G enetics in the GCK gene. Second - c.26521A>G, was found in a patient who was ana- 6243 GLIS3, His621Gln 0.999 0 Cerebrovascular Ins+/Gluc+ islets (reduced numbers POSTERS lyzed throughout KCNJ11, INS and GCK gene. In both cases Sanger sequenc- c.1863C>G but present throughout), glucagon+ Epidemiology/ ing and MLPA technique were performed and none mutations beside those only islets (pseudoatrophic). Insulitis among GCKR gene were identified. Intronic variant c.5592G>T is located present particularly PanTail. Low inside the sequence assigned as Long Interspersed Nuclear Elements (LINE), normal Ki67 islets and acinar cells. which may have influence on epigenetic regulation. The second identified in- Hydropic degeneration in scattered tronic change - c.26521A>G is a part of the sequence that binds transcription islets within most regions. factor CTCF. CTCF is known for being responsible for transcriptional regula- 6249 INSR, N/A N/A N/A Cerebrovascular Ins+/Gluc+ islets. Moderate exocrine tion by binding to chromatin insulators and preventing interaction between Multi- atrophy. Global robust amyloidosis. promoter and nearby enhancers and silencers. Taking into account these in- exonic Multifocal, mild chronic pancreatitis. formations we may consider potential role and association of these changes Mild to moderate atherosclerosis with infrequent focal calcification with patients clinical outcome. These cases brings new ways of thinking within arterial walls. about the role of GKRP in regulating glucose homeostasis. 6264 INSR, Val1012Met 0.992 0.00000824 DKA Ins+ (very rare)/Gluc+ islets present. c.3034G>A Numerous scattered single alpha cells or in very small islets (clusters). Insulitis in PanBody 03 observed. Peri-ductular, lobular fibrosis mild. Very mild acinar atrophy. Supported By: JDRF (nPOD)

Genetics—Type 2 Diabetes

193‑LB High-Density Imputation and Trans-ethnic Association Analysis Reveals a Novel Locus for Type 2 Diabetes Susceptibility ANDREW P. MORRIS, Liverpool, United Kingdom Supported By: 2013/09/N/NZ4/01775, TEAM-2009-3/7 The Resource for Genetic Epidemiology Research on Adult Health and Aging (GERA) is a large multi-ethnic population-based cohort, created for 192‑LB investigating the genetic and environmental basis of common age-related The Histopathology of Monogenic Diabetes diseases, including type 2 diabetes (T2D). Participants were genotyped using DAVID CARMODY, DANIELA DEL GAUDIO, KELLY ARNDT, YING YING HU, FRAN- one of four custom arrays, designed to maximise coverage of common and CES KOBIERNICKI, GORKA ALKORTA-ARANBURU, MARK A. ATKINSON, IRINA low-frequency variants in non-Hispanic white, East Asian, African-American KUSMARTSEVA, SIRI ATMA W. GREELEY, Chicago, IL, Gainesville, FL and Latino ethnicities. With these data, this study aimed to discover loci for Single gene mutations cause 1-2% of all diabetes but because diagnosis T2D susceptibility through high-density imputation and trans-ethnic asso- relies on clinical suspicion many are unrecognized. We utilized the Network ciation analysis and to evaluate the evidence for heterogeneity in allelic ef- for Pancreatic Organ Donors with Diabetes (nPOD) to allow histopathological fects on the disease between ancestry groups. After quality control, 71,604 correlation to genetic results in cases with potential monogenic causes of unrelated participants, including 9,747 T2D cases, were retained for analysis diabetes. 310 nPOD cases were considered for genetic testing if they met and imputed up to the multi-ethnic reference panel (Phase 3, October 2014 either of the following: a) diabetes diagnosed under 35 years of age without release) from the 1000 Genomes Project Consortium. High-quality imputed

ADA-Funded Research For author disclosure information, see page LB98.

LB49 Genetics—Type 2 Diabetes

variants were tested for association with T2D in a logistic regression model, acid IR index (FFA-IRI; P=1.3x10-4). The TGD rate represents mainly skeletal after adjustment for sex and eigenvectors from principal components analy- muscle IR; hGP indicates hepatic IR and FFA IR indicates adipose IR. ADH1B sis to account for trans-ethnic and ancestry-specific population structure. protein was decreased with high BMI (P<0.05, N=12). In summary, decreased Common lead SNPs at ten loci attained genome-wide significant evidence adipose ADH1B expression was associated with increased obesity, whole (p<5x10-8) of association with T2D, including a novel signal mapping to body IR, IR in liver, skeletal muscle and adipose tissue, and with declining TOMM40 (p=2.8x10-9). This gene has been previously implicated in Wolfram β-cell function. Interestingly, serum levels of circulating endogenous etha- Syndrome, a neurodegenerative disorder characterised by diabetes mellitus. nol, a substrate for ADH1B, decreased with increasing OB/IR (P=0.019 with Across lead SNPs for the ten loci, nominal evidence of heterogeneity in al- a 7-fold increase in FPI). lelic effects between ethnicities was observed only at TCF7L2 (pHET=0.012), Supported By: National Institutes of Health; U.S. Department of Veterans Affairs where the risk allele had the lowest T2D odds-ratio for participants of East Asian ancestry. This study provides further evidence for the homogeneity of 196‑LB allelic effects of common T2D risk variants across diverse populations, and PCSK2 Variant rs200711626 R430W Is Associated with Type 2 Dia‑ highlights the benefits of trans-ethnic analysis for discovery of novel loci betes in the Amish associated with the disease. ALEXANDRA H. WINTERS, LAURA YERGES-ARMSTRONG, TONI I. POLLIN, IRIS Supported By: UK Wellcome Trust (WT098017) LINDBERG, Baltimore, MD Prohormone convertase 2 (PC2), encoded by PCSK2, is one of two en- 194‑LB zymes that cleave and is the sole that cleaves mature TCF7L2 Overexpression and Type 2 Diabetes: Dissecting the Func‑ glucagon. In humans, noncoding variants near PCSK2 have been previously tion of TCF7L2 as a Regulator of Glucose Metabolism associated with risk for and age of onset of type 2 diabetes and with varia- KATHLEEN A. BAILEY, MATTHEW PIRON, JONATHAN KAHN, RONALD COHEN, tion in glucagon levels. However, coding variants in PCSK2 are rare and no GRAEME I. BELL, MATTHEW J. BRADY, MARCELO A. NOBREGA, Chicago, IL missense variants with a minor allele frequency (MAF) greater than 0.001 Intronic variation within TCF7L2 is the most strongly associated genetic are present in 1000 Genomes (phase 3). The Old Order Amish (OOA) are a determinant of T2D risk in humans. Although the majority of studies have genetically well-defined founder population of European descent that im- concentrated on the roles of TCF7L2 in pancreatic beta cells, the T2D associ- migrated to the U.S. from Western . The Amish Family Diabetes Study ated interval drives TCF7L2 expression throughout a variety of peripheral was a study designed to identify genes associated with type 2 diabetes by tissues with known roles in glucose metabolism. We interrogated the role recruiting OOA individuals with type 2 diabetes and their first- and second- of TCF7L2 in mouse adipocytes to elucidate the peripheral contribution of degree relatives. We hypothesized that coding variants in PCSK2 would be TCF7L2 signaling and identify how perturbation of this pathway could lead associated with type 2 diabetes and diabetes-related traits. There is one to T2D risk. Utilizing a glucose intolerant humanized mouse model globally coding variant found in PCSK2 in the OOA, R430W (rs200711626), with ap-

overexpressing TCF7L2, we specifically restored endogenous expression proximately 4% MAF in the OOA. This variant is greatly enriched in the OOA in adipocytes while maintaining overexpression elsewhere. We found that as compared to other populations with 2 copies (0.04%) in 1000 genomes restoration of TCF7L2 expression in adipocytes alone was sufficient to res- and 1 copy in the NHLBI Exome Sequencing Project (0.008%). R430W is cue whole-body glucose and insulin intolerance. Furthermore, we identified twice as common among Amish individuals with diabetes (8.4% MAF in 137 restored adipocyte insulin sensitivity, proper triglyceride storage, reduced individuals) as compared to those with normal glucose tolerance (3.7% in G enetics

POSTERS adipocyte hypertrophy, and the prevention of ectopic lipid accumulation, 578 individuals) (p=0.04). R430W also has a trend towards carriers having Epidemiology/ indicating that restoration of endogenous TCF7L2 expression in adipocytes increased insulin at 30 minutes of the OGTT (p=0.07) and increased HbA1c markedly improved glucose metabolism and storage, even in face of the (p=0.07). PC2 R430W shows greater enzyme activity as measured by in vitro persistent overexpression of TCF7L2 elsewhere. These data demonstrate in cleavage of a fluorogenic substrate. We hypothesize that R430W carriers’ that the restoration of TCF7L2 expression in adipocytes restores glucose increased PC2 activity compared to wildtype causes increased cleavage of tolerance and metabolic health, indicating that overexpression of TCF7L2 in proglucagon to glucagon particularly at the time of inappropriate glucagon adipocytes significantly contributes to the T2D state. Our study highlights secretion postprandially, necessitating the higher insulin levels at 30 min- the complexities of a multi-system phenotype such as glucose metabolism utes of the OGTT. This increased glucagon may be leading to the increased and supports a distinct and relevant role of TCF7L2 expression in adipocytes. risk of type 2 diabetes. Further elucidation of the signaling mechanism of TCF7L2 action in adipo- cytes may lead to new therapeutic targets for T2D treatment. 197‑LB Single Nucleotide Polymorphisms Associated with Clinical Out‑ 195‑LB comes of High-Dose Insulin Intensification in Type 2 Diabetes Transcriptomic Identification of ADH1B as a Candidate Gene for P. ANTHONY AKKARI, SUMAN DUVVURU, SREEKUMAR G. PILLAI, SUDHA S. Obesity and Insulin Resistance in Human Adipose Tissue in Mexi‑ SHANKAR, MARK A. DEEG, R. MARTIN, JENNAL L. JOHNSON, STEPHEN can Americans from the Veterans Administration Genetic Epidemi‑ O’RAHILLY, JEFFREY A. JACKSON, Chapel Hill, NC, Indianapolis, IN, Cambridge, ology Study (VAGES) United Kingdom CHRISTOPHER P. JENKINSON, DEVJIT T. TRIPATHY, DOUGLAS T. CROMACK, This study sought to characterize relationships between gene variants JOANNE E. CURRAN, SATISH KUMAR, MELANIE CARLESS, MUHAMMAD and various clinical outcomes in severely insulin-resistant patients with ABDUL-GHANI, SOBHA PUPPALA, RECTOR ARYA, THOMAS D. DYER, DONNA type 2 diabetes after treatment intensification with high-dose human regu- M. LEHMAN, SHIRLEY L. HU, MARCEL FOURCAUDOT, LUKE NORTON, VIDYA S. lar U-500 insulin. DNA samples were obtained from patients enrolled in a FAROOK, JOHN BLANGERO, HARALD H. GÖRING, RALPH A. DEFRONZO, RAVIN- 24-week, multicenter, open-label, randomized trial in the United States. As- DRANATH DUGGIRALA, Edinburg, TX, San Antonio, TX, Harlingen, TX sociation of clinical outcomes of 660 single nucleotide polymorphisms (SNPs) Type 2 diabetes is a complex disease that is highly prevalent in Mexican in genes involved in metabolism and type 2 diabetes risk were tested in 211 Americans, and is strongly associated with obesity and insulin resistance Caucasian individuals. These outcomes included glycemic efficacy, risk of (OB/IR). The aim of this study was to measure genome-wide gene expression hypoglycemia, change in body mass index, insulin dose requirements, lipid in adipose tissue to detect gene regulation associated with OB/IR in 75 un- levels, and liver and renal function. Several SNPs with P value (raw) thresh- related Mexican Americans. Fasting RNA was extracted from adipose biop- old of ≤0.01 were observed in genotype-phenotype associations (Table). The sies, and gene expression data generated using Illumina Bead Arrays (47,324 IGF-1 SNP, rs1520220, demonstrated significant associations with change in probes). Gene sets analysis identified one gene, alcohol dehydrogenase 1B aspartate and alanine aminotransferase levels (P <0.0001). These data show (ADH1B) with significantly enriched expression (P<10-60) as a candidate for for the first time that phenotypic responses to high-dose insulin therapy for involvement in multiple relevant metabolic pathways. Adipocyte ADH1B was type 2 diabetes are linked to select genetic markers. Further validation of highly and specifically expressed in adipose tissue at levels greater than in these findings in prospective trials is warranted. all other tissues examined. ADH1B expression was inversely correlated with all OB/IR variables at the tissue and whole body levels: waist circumfer- ence (P=2.8x10-9), BMI (P<0.0001), fasting plasma insulin (P<0.001), HOMA- IR (P<0.01), Matsuda Index (P<0.01), β-cell function (oral disposition index across 120 minutes of the oral glucose tolerance test (ODI1-120; OGTT) (P=8.6x10-4), pre-T2D (impaired glucose tolerance and fasting glucose dur- ing the OGTT (P=8.6x10-5); and from the insulin clamp: total glucose dis- posal (P=8.6x10-10), hepatic glucose production (hGP, P=8.6x10-4) free fatty

ADA-Funded Research For author disclosure information, see page LB98.

LB50 Genetics—Type 2 Diabetes

Table. on genome and transcriptome variability available through GTEx, in which whole genome sequencing has been conducted in a set of individuals (>450) in which RNAseq has been completed on up to >30 tissues. We applied penalized regression procedures to develop SNP-based predictors of gene expression. We can apply these predictors in a method we term “PrediXcan” (predicted expression scan) to any data with at least GWAS level interroga- tion of the genome, and test the association of genetically predicted gene expression for a specific tissue with disease phenotypes. Thus, we conduct a gene-based test that is mechanistic by design, robust to reverse-causality issues, and provides an easy-to-interpret direction of effect. We applied PrediXcan using models for 15 tissues from the GTEx project to GWAS data from the WTCCC and Starr County (Mexican American) cohorts. Associ- ated genes in the WTCCC analysis include TRIM66 (p = 1.7e-5, adipose), ID4 (p = 1.0e-6, small intestine), and MTMR10 (p = 3.3e-6, whole blood). In the Starr County analysis, TOMM7 showed the most significant association in multiple tissues (p = 1.2e-6, 6.4e-7, 1.0e-6 in skeletal muscle, adipose, and cerebellum, respectively). Overall, we found enrichment of previously impli- cated T2D genes among SC and WTCCC results across several tissues as 198‑LB well as significant overlap of top genes between the two studies. These Genetic Risk to Fasting Glucose Modulates Changes in Glycemic results show that more can be gleaned from the union of GWAS with Traits in Response to 2-Year Weight-Loss Diet Intervention: The functional data and suggest that PrediXcan can provide new opportunities POUNDS Lost Trial for researchers to characterize the genetic basis of T2D. TIANGE WANG, TAO HUANG, YAN ZHENG, GEORGE A. BRAY, FRANK M. SACKS, Supported By: National Institute of Diabetes and Digestive and Kidney Diseases LU QI, Boston, MA, Baton Rouge, LA We examined whether a genetic risk score (GRS) for fasting glucose modi- 200‑LB fies the long-term changes in glycemic traits in response to weight-loss diets Exome-Wide Association Study Revealed Seven Novel Variants As‑ in the Preventing Overweight Using Novel Dietary Strategies (POUNDS Lost) sociated with Liver Enzymes trial. A GRS was calculated based on 15 fasting glucose-associated SNPs in YOUNG JIN KIM, YUN KYOUNG KIM, TAE-JOON PARK, SANGHOON MOON, 733 adults. The changes in fasting glucose, insulin, homeostasis model assess- BONG-JO KIM, Cheongju, Republic of Korea ment of insulin resistance (HOMA-IR) and insulin sensitivity (HOMA-S) were Liver enzymes have been reported to be an index of liver injury and a marker assessed by GRS and diet interventions. At 6 months, in the lowest tertile of of fatty liver and oxidative stress. Also elevated liver enzymes have been GRS, participants assigned to low-fat diet group had less reduction in fasting known to be related with type 2 diabetes, body mass index, metabolic control glucose, insulin, and HOMA-IR, and less increase in HOMA-S, compared with and the presence of the metabolic syndrome. Therefore, finding genetic fac- those assigned to high-fat diet group. Opposite relations between dietary fat tors influencing liver enzyme levels is very important to understand individual G enetics

and changes in glycemic traits were found in the highest tertile of GRS (Fig- difference and also underlying mechanism of liver related diseases and meta- POSTERS ure). The GRS-dietary fat interactions were significant on changes in glucose, bolic iseases. In the last decade, numerous common variants (MAF >= 5%) Epidemiology/ HOMA-IR and HOMA-S (P≤0.047) after adjustment for age, sex, ethnicity, and responsible for liver enzymes have been discovered by the advent of genome- baseline values for respective outcomes. After further adjustment for weight wide association studies (GWAS). However, rare exonic variants (MAF < 5%) loss, the GRS-dietary fat interaction on change in glucose remained significant have not yet been studied for potential association with liver enzymes. In this (P=0.013). The interactions became attenuated at 2 years due to the rebound study, we conducted an exome-wide association study to identify rare variants of glycemic traits. Individuals with higher genetic predisposition to fasting glu- associated with liver enzymes. First, we constructed 848 samples of whole cose may benefit more in glycemic improvement by choosing a low-fat diet. exome reference panel using GWAS chip, exome array, and exome sequencing data. Using whole-exome reference panel, imputation analysis was performed on 8,529 samples of combined data consists of GWAS chip and exome array. For imputation analysis, we used generally used pre-phasing based imputation process using shapeit and minimac software. Subsequent association analysis was performed on about half million imputed and genotyped variants. No new associations were discovered at the genome-wide significance level (P < 5e-8). At the suggestive significance level (P < 5e-6), we discovered 7 novel vari- ants including two missense variants. Among them, six variants were located at exonic regions of genes including LHCGR, A1CF, OBSCN, RET, COL4A1, and KIAA1456. One novel variant was discovered at intergenic region of 10q21.1.

201‑LB High Resolution Maps Identify Novel T2D Genes and Regulatory Hot Spots in African Americans and Europeans NIKOLAS MANIATIS, WINSTON LAU, FILIPPO TAMANINI, TOBY ANDREW, Lon- don, United Kingdom High-resolution genetic maps provide refined information about the struc- ture of linkage disequilibrium (LD) in the . This information is essential in genome-wide association studies (GWAS) and for determining genetic differences between populations. Despite the known importance of LD in gene mapping, most GWAS studies ignore LD when testing for asso- ciation or treat it as a nuisance factor. Our GWAS method improves power 199‑LB to locate genes by using genetic map distance for this task. Here we identify “Imputing” the Genetics of Type 2 Diabetes: Testing the Association new loci by 1) analysing two different ethnic populations of African-American of Genetically Imputed Gene Expression with Type 2 Diabetes and Northern-European descent; 2) utilising genetic map distances that are JASON M. TORRES, HEATHER E. WHEELER, NICHOLAS W. KNOBLAUCH, KAAN- specific to each of these two populations; 3) integrating data from European AN SHAH, JENNIFER E. BELOW, CRAIG L. HANIS, NANCY J. COX, HAE KYUNG GWAS and adipose tissue expression profiling with the aim to co-locate loci IM, Chicago, IL, Houston, TX, Nashville, TN on these genetic maps. Two population-specific genetic maps in LD units (LDU Recent studies have shown that a substantial part (up to 80%) of the maps) for African-Americans and Europeans were constructed using HapMap heritability for common diseases is attributable to DNA variation in DNAse I data. The two European T2D GWAS data were provided from the WTCCC1 hypersensitivity sites (Gusev et al. 2014. AJHG), suggesting that regulation and WTCCC2 and African-American from the NIDDK. Independent genomic at the level of transcription may drive much of the common variant signal ob- and adipose expression data for healthy Europeans were obtained from dbGaP served for common disease. Moreover, there is now a wealth of information and EBI respectively. Our whole genome analysis using map distances in LDU

ADA-Funded Research For author disclosure information, see page LB98.

LB51 Genetics—Type 2 Diabetes

identified 93 novel genome-wide significant gene regions that are common to 204‑LB both Europeans and African-Americans. More than 60% of these trans-ethnic Exome Chip Meta-analysis Identifies Low-Frequency Variants Con‑ signals reside within <50kb of one another, demonstrating the high resolution tributing to Body Fat Distribution of our findings. Using the adipose expression data, two-thirds of the 93 loci CECILIA M. LINDGREN, ANNE E. JUSTICE, HEATHER M. HIGHLAND, KRISTIN L. also appeared to regulate gene expression. Such location estimates are instru- YOUNG, MISA GRAFF, TUGCE KARADERI, NANCY L. HEARD-COSTA, DOROTA mental for designed targeted resequencing, which in turn has the potential to PASKO, VALERIE TURCOT, YONGKE LU, LORRAINE SOUTHAM, L. ADRIENNE CUP- bring us closer to personalised medicine and understanding what screening PLES, CHING-TI LIU, CAROLINE S. FOX, THOMAS W. WINKLER, NIELS GRARUP, can be applied to T2D patients from different ethnic backgrounds. ROBERT A. SCOTT, MARK I. MCCARTHY, KAREN L. MOHLKE, RUTH J.F. LOOS, Supported By: UK Medical Research Council (G0901017) INGRID BORECKI, KARI E. NORTH, THE BBMRI CONSORTIUM, THE GOT2D CON- SORTIUM, THE CHARGE CONSORTIUM, THE GIANT CONSORTIUM, Cambridge, 202‑LB MA, Chapel Hill, NC, Houston, TX, Oxford, United Kingdom, Boston, MA, Exeter, Obtaining More from Genome-Wide Analysis: Localisation of Novel United Kingdom, Montreal, QC, Canada, New York, NY, Cambridge, United Kingdom, European-specific Genes for Type 2 Diabetes Farmingham, MA, Regensburg, Germany, Copenhagen, Denmark, St. Louis, MO WINSTON LAU, FILIPPO TAMANINI, TOBY ANDREW, NIKOLAS MANIATIS, Lon- Fat distribution, a heritable trait measured as waist to hip ratio adjusted don, United Kingdom for BMI (WHR), is correlated with visceral adiposity (r=0.56). Aggregation of Although 80 loci increasing risk of type 2 diabetes (T2D) have been iden- visceral fat and unfavourable fat distribution is a predictor of increased type tified by genome-wide association studies (GWAS) in European popula- 2 diabetes (T2D) risk. Here, we set out to identify coding and low-frequency tions, additional fine mapping is required since 1) many loci remain to be variants (LFVs) (minor allele frequency, MAF<5%) associated with fat dis- identified given the polygenic nature of T2D; 2) the most significant genetic tribution across the human exome using array data from 136,404 European markers (SNPs) associated with disease will often not be proximal to the ancestry (EA) and an additional 26,697 participants of other ancestries. We causal variant(s) location; and 3) the implicated genes and variant function meta-analyzed study specific additive models for both single variant and are often still ambivalent. We aimed to identify novel loci by using a map- gene-based results with WHR in men and women combined. Gene-based ping approach that utilises information from multiple markers within an ana- models were defined by non-synonymous variants of MAF<5% and analyzed lytical interval rather than assessing one SNP at a time. The markers in the using the sequence kernel association test (SKAT) method. Analyses includ- analysis are located on a genetic rather than physical map and hence the ed up to 201,126 variants with MAF<5% and 15,000 genes with >1 variant method provides a location estimate for the causal variant. This is achieved at MAF<5%. We identified three variants in novel loci: one with MAF>5% by exploiting high-resolution linkage disequilibrium (LD) maps in LD Units (intergenic) and two non-synonymous variants with MAF<5% (in KIAA0408 (LDU maps) derived using the population-specific and publicly available SNPs and RAPGEF3). The non-synonymous variant within RAPGEF3 exhibited a provided by the HapMap Project. All genome-wide significant locations for much greater effect on WHR compared to common variants (beta > 0.1 ver- sus 0.062). Our gene-based analyses also identifiedRAPGEF3 as significantly T2D were tested for evidence that they confer risk of disease by regulating gene expression, using fine map genomic and adipose expression data for associated with WHR (p<2.5e-06) after correction for multiple testing. healthy European samples (EBI, E-TABM-1140). Using Wellcome Trust Case RAPGEF3 has been reported to be involved in the regulation of insulin secre- Control Consortium (WTCCC) data for T2D, our whole genome analysis has tion. Ongoing analyses include an expansion of the sample (>300,000) and identified 17 novel gene regions specific to Europeans with genome-wide functional follow-up. These observations highlight the importance of large-

G enetics scale genomic studies for identifying fat distribution susceptibility variants

POSTERS significance. None of these signals were identified in African-Americans. Epidemiology/ These locations were replicated using independent European Metabochip and provide insights into the etiology of fat distribution, and may highlight data (WTCCC2). The majority of the 17 novel loci showed strong evidence of population-specific variants that pose increased susceptibility among indi- being cis-eQTLs, with 11/17 co-locating to within <50kb of variant locations viduals at greater risk. that regulate neighbouring gene expression in adipose tissue. We conclude that the integrative multi-marker analysis of GWAS data on T2D with data 205‑LB on adipose expression profiling has great potential to provide refined loca- TCF7L2 in Hypothalamic Neurogenesis in Mice and Men tion and functional information relating to T2D disease susceptibility. DONNA M. LEHMAN, LI YAO, YUANHANG LIU, IRISCILLA AYALA, SWETHA MA- HESULA, YIDONG CHEN, ERZSEBET KOKOVAY, San Antonio, TX 203‑LB Growing evidence indicates that adult hypothalamic neurogenesis is nec- RASGRF1 and IGF2BP2 Confer Pleiotropic Risk of Susceptibility to essary for energy homeostasis and is affected by environmental conditions. Both Type 2 Diabetes and Common Myopia in Europeans Therapeutic interventions upon this process may be beneficial for metabolic TOBY ANDREW, KRISTAL SHEHATA, WINSTON LAU, NIKOLAS MANIATIS, Lon- disorders. We are investigating involvement of TCF7L2 isoforms using human don, United Kingdom neurons and murine neural stem cells. During murine embryonic develop- Diabetic individuals are at increased risk of myopia. However, in the gen- ment TCF7L2 isoforms expressed in thalamus are 34kD (dominant-negative), eral population the relationship between myopia and subtle dysregulation in 58kD and 75kD (weak). Postnatally, the 34kD form is not expressed. We have glucose metabolism is unknown. It has been suggested for example, that the generated human iPS-derived hypothalamic NPY/AgRP neurons, analyzed rapid increased incidence of myopia observed in SE Asia - which is correlated longitudinal patterns of normalized gene expression profiles across 6 time with many aspects of rapid urbanisation - is in part due to the widespread points during development of our human neurons (Days 35-115, embryonic- adoption of a more Westernised, high-glycaemic index diet. We investigated adult) and used cluster analysis to identify potential coordinated expression RASGRF1 (an established gene for myopia) and 3q26-29 (a ge- patterns. Similar to mouse, we see 34kD, 58kD and weak 75kD TCF7L2 iso- nomic region with co-incident replicated linkage for myopia and type 2 diabe- forms early and until Day 75. From Day 75-115 (presumed postnatal to adult), tes) for evidence of pleiotropic association with common myopia and T2D. We only 58kD and weak 75kD are expressed. A cluster of 268 genes whose ex- used population-specific, fine-scale genetic maps derived from high-resolution pression sharply peaks at Day 75 and then rapidly declines is enriched for HapMap data on Northern-Europeans and phenotype data for 1) type 2 dia- the key GO terms “synapse” and “transmission of nerve impulse” (p=1.1E-7). betes (T2D) cases and controls from the Wellcome Trust Case Control Con- Conversely, a cluster of genes whose expression sharply increases from Day sortium, WTCCC1 (Affymetrix 500K SNPs) and WTCCC2 (Illumina MetaboChip 75-95 is enriched for GO terms “actin-myosin filament sliding” (p=4.3E-09) 200K targeted SNP array) and 2) TwinsUK/dbGaP myopia samples (accession and “extracellular matrix” (p= 7.6E-07). Several genes in both clusters have phs000142.v1.p1 Illumina Human 610). We found 1) strong evidence of pleio- canonical TCF7L2 binding sites. We next conducted siRNA knockdown of TC- tropic association at RASGRF1 (4e-06) and IGF2BP2 (2e-24). RASGRF1 has been F7L2 adult isoforms in the human neurons at Day 55 resulting in expression shown to be associated with retinal photoreceptor function and glucose me- of only the 34kD form. GO analysis indicated up-regulation of genes involved tabolism. In addition to IGF2BP2 on chromosome 3q26-29, ABCC5, IQCJ and in synaptogenesis and release, and down-regulation of genes TBL1XR1 also show evidence of pleiotropy at this locus; 2) there is a statisti- involved in myosin networks which in turn affect neuronal migration and cally significant (p=0.00003), but small phenotypic correlation between myo- plasticity. Additionally, we isolated adult neural stem cells from the murine pia and circulating plasma insulin levels in the UK population with evidence hypothalamus and found very weak expression of the 34kD- but high levels from the twin data that most (approximately 75%) of the covariance between of the 58kD- and 75kD isoforms of TCF7L2, suggesting that these isoforms these two traits is due to shared genetic factors. We conclude that shared are important in adult hypothalamic neurogenesis as well. genetic risk factors may contribute common myopia and T2D and that IGFBP2 Supported By: National Institutes of Health (DK047482) and RASGRF1 contribute to the (patho)physiology of both conditions with the potential to provide new aetiological insights. Supported By: UK Medical Research Council (G0901017)

ADA-Funded Research For author disclosure information, see page LB98.

LB52 Immunology

206‑LB 208‑LB Diverse Molecular ProfilingM aps of Skeletal Muscle Reveal Mech‑ Integrated 3-D Epigenomic and Transcriptomic Analysis of EndoC- anistic Insights about Type 2 Diabetes betaH1 Human Beta Cells STEPHEN PARKER, JEROEN HUYGHE, MICHAEL ERDOS, HEIKKI KOISTENEN, PE- MICHAEL L. STITZEL, STEPHEN C.J. PARKER, BROOKE N. WOLFORD, XINGWANG TER CHINES, RYAN WELCH, LAURA SCOTT, D. LELAND TAYLOR, BROOKE WOL- LI, EMALY PIECUCH, ASA THIBODEAU, ELADIO MARQUEZ, OSCAR LUO, MI- FORD, HEATHER STRINGHAM, ANNE JACKSON, ANDREW BECK, HUI JIANG, CHAEL ERDOS, DUYGU UCAR, YIJUN RUAN, FRANCIS S. COLLINS, Farmington, XIAOQUAN WEN, NARISU NARISU, TIMO LAKKA, RICHARD M. WATANABE, CT, Ann Arbor, MI, Bethesda, MD KAREN L. MOHLKE, JAAKKO TOUMILEHTO, MICHAEL BOEHNKE, FRANCIS S. Genome-wide association studies (GWAS) and functional (epi)genomic COLLINS, Ann Arbor, MI, Bethesda, MD, Helsinki, Finland, Kuopio, Finland, Los An- analyses of human pancreatic islets converged to implicate DNA sequence geles, CA, Chapel Hill, NC variation in islet enhancers in islet dysfunction and type 2 diabetes (T2D). The Type 2 diabetes (T2D) results from environmental and genetic factors in- target gene(s), direction of effect, and molecular mechanism are unknown teracting across time and multiple tissues. More than 90% of >100 variants for many T2D and metabolic trait (MT) GWAS SNPs. Integrated genomic, associated with T2D and related traits through genome wide association epigenomic, and transcriptomic approaches offer an opportunity to answer studies (GWAS) occur in non-coding regions, suggesting a strong regula- these questions. EndoC is the first human cell line exhibiting functional beta tory component to disease susceptibility. To understand the full spectrum cell properties. As such, it is an attractive model to study the molecular ge- of genetic variation and regulatory element usage in T2D-relevant tissue netics and functional (epi)genomics of beta cell physiology and dysfunction. and across disease progression, the FUSION Study obtained skeletal muscle Here, we combine deep mRNA-seq, epigenomic (ChIP-seq, ATAC-seq) and biopsies from 278 well-phenotyped Finns with normal or impaired glucose 3D epigenome (ChIA-PET) analyses with karyotyping and dense genotyping tolerance or T2D. We performed dense genotyping and imputation and con- to understand both general and allele-specific transcriptional regulation in structed strand-specific mRNA-seq libraries and sequenced a total of 25.3B EndoC-betaH1. Karyotyping indicates that EndoC is a heterogeneous popu- fragments (mean 91.3M per sample). We identified >13k genes with expres- lation of cells, with subsets harboring specific translocations. Comparison sion and/or splicing quantitative trait loci (e/sQTL) (5% FDR). We produced of ChIP-seq chromatin states from multiple cell types reveals a striking reference chromatin state maps across 30 cell types and reference tran- similarity between EndoC and human pancreatic islets. In particular, we find scriptome maps across 16 tissue types. Integrative analyses show that the that T2D/MT GWAS SNPs overlap EndoC enhancers. We identify general genetic regulatory architecture of skeletal muscle specific gene expression (e.g.CTCF) and specific (e.g. PDX1) transcription factor motifs by footprinting is encoded in skeletal muscle stretch enhancers and not typical enhancers or analysis of EndoC ATAC-seq profiles. RNA Pol2 ChIA-PET confirms published, stretch enhancers from unrelated tissues. Our eQTL analyses identify target targeted interactions between ISL1 and multiple enhancers and identifies genes and direction of effect of GWAS-identified T2D and related trait risk ~10,000 promoter-promoter, enhancer-enhancer, and enhancer-promoter alleles. Some of these genes are significantly differentially expressed, impli- interactions genome-wide. Integration of genotyping and -omics datasets cating them as key targets for therapeutic development. These rich data en- allows us to link allelic biases in enhancers (ChIP-seq, ATAC-seq) and target able identification of diverse molecular processes involved in muscle based gene expression (mRNA-seq) at several sites in the genome, including sev- insulin resistance, changes in transcription with progression towards T2D, eral identified as T2D/MT risk SNPs and expression quantitative trait loci and reveal mechanistic insights about disease predisposition. (eQTL) SNPs in islets. Together, these data define the transcriptional archi- Supported By: American Diabetes Association (1-14-INI-07 to S.P.); National tecture of EndoC and provide insights into beta cell transcription. Institute of Diabetes and Digestive and Kidney Diseases Supported By: American Diabetes Association (1-14-INI-07 to S.C.J.P.); 4R00DK09225103, Z01HG000024, K99DK099240 207‑LB Type 2 Diabetes Susceptibility Loci in the Singapore Chinese Health

Study Immunology MYRON GROSS, MARK A. PEREIRA, CHI-YUAN HSU, RENWEI WANG, MARK SEIELSTAD, KOH WOON PUAY, TEO YIK YING, TAI E. SHYONG, LIU JIANJUN, 209‑LB HENG KHAI KOON, JIAN-MIN YUAN, REVATI KORATKAR, KENNETH BECKMAN, NATHAN PANKRATZ, DANIEL O. STRAM, Minneapolis, MN, San Francisco, CA, Withdrawn POSTERS

Pittsburgh, PA, Singapore, Singapore, Los Angeles, CA I mmunology/

To explore novel genetic contributions toward susceptibility for type 2 dia- Transplantation betes (T2D), we performed a 2-stage GWAS in the Singapore Chinese Health Study. In stage I, we genotyped 507,509 SNPs in 4678 participants including 2338 incident cases with diagnosed T2D and 2340 matching controls with HbA1c <6.0% on the Affymetrix ASI SNP array platform. Imputation using the 1000 genomes project was conducted for replication of known T2D SNPs and fine-mapping. 73 of 98 known T2D SNPs (p<10-5) from the NHGRI GWAS Catalog were associated with T2D, 24 were statistically significant (p0.80. Combining the risk alleles into an unweighted score, we estimated a per allele of 1.025 (p=7.5×10-10). In stage II of the GWAS, approximately 3000 SNPs, based on the stage I analysis and next generation sequencing of +/- 50kb, 39 known T2D sites were genotyped in prevalent cases and match- ing controls (n=4571) from the Singapore Study. These analyses confirmed known SNPs and identified potentially new SNPs. Pooled over two stages we found 12 SNPs of interest after adjustment for age, sex, dialect and BMI. 6 of these were tested for replication in the AGEN consortium of 8 Asian studies. Two SNPs replicated (p<0.05) and were specific to Asians. One SNP, located near the PAX4 gene on , remained an independent novel signal for T2D in Asians (p=0.0003). PAX4 has a critical role in fetal development and is involved in pancreatic islet development including dif- ferentiation of beta cells. In conclusion, we have confirmed numerous known diabetes-related SNPs in the Singapore Chinese Health Study, and identified at least one new Asian-specific T2D SNP. Supported By: Singapore Chinese Health Study

ADA-Funded Research For author disclosure information, see page LB98.

LB53 Immunology

210‑LB 212‑LB HCELL Expression on Murine MSC Licenses Pancreatotropism and Anti-paralemmin 2 Antibody as a Novel Antibody for Latent Autoim‑ Confers Durable Reversal of Autoimmune Diabetes in NOD Mice mune Diabetes in Adults REZA ABDI, ROBERT SACKSTEIN, ROBERT MOORE, SHINOBU SAKAI, CONOR MASAHIDE HMAGUCHI, KANAE MATSUSHITA, MASAHIRO YAMAZAKI, TAKUYA BRIAN DONNELLY, MARWAN MOUNAYAR, Boston, MA FUKUDA, MICHIAKI FUKUI, NAOTO NAKAMURA, Kyoto, Japan Type 1 diabetes (T1D) is an immune-mediated disease resulting in destruc- Background: The phenotype of latent autoimmune diabetes in adults tion of insulin-producing pancreatic beta cells. Mesenchymal stem cells (LADA) at early stage is similar to that of type 2 diabetes mellitus in clini- (MSCs) possess potent immunomodulatory properties, garnering increasing cal practice. However, it is thought that the ability of insulin secretion from attention as cellular therapy for T1D and other immunologic diseases. How- pancreatic β cells of LADA decreases gradually in months to years. The de- ever, MSCs generally lack homing molecules, hindering their colonization at crease of β cell might be prevented by the induction of insulin therapy in inflammatory sites following intravenous (IV) administration. Here we ana- LADA. Therefore, it is further necessary to diagnose and treat LADA at an lyzed whether enforced E-selectin ligand expression on murine MSCs could early stage. Nowadays, islet specific autoantibodies such as anti-glutamic impact their effect in reversing hyperglycemia in non-obese diabetic (NOD) acid decarboxylase antibody and anti-tyrosine phosphatase-like insulinoma- mice. Though murine MSCs natively do not express the E-selectin binding associated protein 2 antibody have been used for the diagnosis of LADA. determinant sialyl Lewisx (sLex), we found that fucosyltransferase-mediated However, there are diabetic patients, in whom autoimmune reaction for β α (1,3)-exofucosylation of murine MSCs resulted in sLex display uniquely on cell might be exist, but current available islet autoantibodies were not de- cell surface CD44 thereby creating HCELL, the E-selectin-binding glycoform tected. The aim of the study was to detect a novel autoantibody for diagnos- of CD44. Following IV infusion into diabetic NOD mice, allogeneic HCELL+ ing LADA. MSCs showed 3-fold greater peri-islet infiltrates compared to buffer-treated Method: We used an unbiased whole autoantibody array to identify novel (i.e., HCELL-) MSCs, with distribution in proximity to E-selectin-expressing islet autoantibodies. We developed the quantitive measurement method for microvessels. Exofucosylation had no effect on MSC immunosuppressive the identified antibody in sera. We evaluated the diagnostic value of the capacity in in vitro assays, however, though engraftment was temporary for novel antibody for diagnosing LADA in the cohort consisted with 152 pa- both HCELL+ and HCELL- MSCs, administration of HCELL+ MSCs resulted tients with diabetes mellitus. in durable reversal of hyperglycemia, whereas only transient reversal was Results: Anti-paralemmin2 (PALM2) antibody was identified as a specific observed following administration of HCELL- MSCs. Notably, exofucosyla- autoantibody for LADA. AUC, the sensitivity, the specificity of anti-PALM2 tion of MSCs generated from CD44-/- mice induced prominent membrane antibody for diagnosing LADA were 0.644, 70.8%, and 100%, respectively. expression of sLex, but IV administration of these MSCs into hyperglycemic The association of the level of anti-PALM2 antibody and the change of se- NOD mice showed no enhanced pancreatotropism or reversal of hypergly- rum C-peptide immunoreactivity per year (ng/ml/year) was -0.389 (P<0.001), cemia. These findings provide evidence that glycan engineering to enforce although there was no significant association between the change of serum HCELL expression boosts trafficking of infused MSCs to pancreatic islets of C-peptide immunoreactivity per year and titer of anti-GAD antibody, anti- NOD mice and substantially improves their efficacy in reversing autoimmune IA-2 antibody, or anti-ZnT8 antibody. diabetes. Conclusion: Anti-PALM2 antibody could be a novel antibody for LADA. Supported By: American Diabetes Association (1-14-BS-001 to R.A.) Moreover, the level of anti-PALM2 antibody could predict the decrease of insulin secretion. 211‑LB Supported By: AS262Z02103P Circulating Antibodies against Glycated Serum Albumin in Diabetic Patients 213‑LB MEYAD A. ALKARNI, Riyadh, Saudi Arabia Identification of Tetraspanin-7 as a Major Target of Autoimmunity

The enhanced glycation status of albumin under hyperglycemic conditions in Type 1 Diabetes leads to the occurrence of a protein that has reduced beneficial activities KERRY A. MCLAUGHLIN, CAROLYN C. RICHARDSON, AARTHI RAVISHANKAR, and that exerts new detrimental actions. Glycated albumin (GA) appears to RICHARD FELTBOWER, DIANA MORGAN, MICHAEL R. CHRISTIE, London, United be an underestimated potential index to fill the gap between self-monitoring Kingdom, Leeds, United Kingdom of blood glucose and HbA1c testing in diabetes management. Presence of The presence of antibodies to multiple autoantigens confers high risk for

POSTERS development of type 1 diabetes. Four major autoantigens are established I mmunology/ circulating antibodie (Abs) against GA will help achieve a better understand-

Transplantation ing of the impact of albumin glycation in pathological progression. The aim (insulin, GAD, IA-2 and ZnT8), but the molecular identity of a fifth, bound of this study was to check the presence of Abs against GA in diabetic pa- by antibodies in 50% of diabetic children and shown only to be a 38 kDa tients. If yes, to light upon its consequences. Spectrophotometry was used membrane glycoprotein (GLIMA), is unknown. Antibodies to GLIMA are de- to measure the changes in the spectral reading of prepared GA and the con- tectable only by from extracts of radiolabelled islet or trol albumin every 12 hrs. The significant hypochromicity occurred with the neuronal cells followed by SDS-PAGE and autoradiography. The aim of this albumin and glucose concentration of 400mg/100ml after 60hrs of incuba- study was to identify GLIMA to enable efficient assay of the autoantibodies. tion at 37Cº; which means maximum glycation of glucose with albumin had Sera from recent onset type 1 diabetic patients were screened for GLIMA occurred and this was confirmed by fluorometry which showed significant antibodies using radiolabelled neuronal cells to identify samples with high quenching after 60hrs. Indirect binding ELISA was done for 120 patient’s se- GLIMA immunoreactivity. Competition studies with extracts of normal rum samples and 40 control samples with the prepared antigen (GA) and the mouse tissues detected high levels of GLIMA only in islets, brain, pituitary overall results show significant difference among the patient groups where and lung. Membrane glycoproteins from extracts of mouse brain and lung the (p-value < 0.05), which mean effective binding of patients sera Abs and were purified by lectin affinity chromatography and separated by SDS-PAGE. the antigen (GA) was observed almost in all patients as compared to normal Brain extracts were also immunoprecipitated with sera from GLIMA positive samples. Formation of immune complex between GA and anti-GA Abs in and negative subjects before SDS-PAGE. Regions of gels equivalent to 38 sera of patients was also confirmed by gel retardation assay and polyacryl- kDa for each sample were excised and treated with trypsin. Eluted amide gel electrophoresis. Results showed high binding between the Abs were subjected to LC-MS/MS and mass data used for protein identification. in diabetic serum and GA. This further reiterate our contention that protein Only 3 proteins returned in database searches were detected in samples modification may render it immunogenic. The binding patterns of diabetic from the brain and lung extracts, in the GLIMA antibody positive immuno- sera obtained from different patients were remarkably similar in each group, precipitate, but not the GLIMA antibody negative immunoprecipitate: actin, indicating the recognition of altered confirmation of the modified protein by G(i) subunit alpha-2 and tetraspanin-7. Whereas actin and G(i) are widely ex- circulating antibodies in diabetic patients. Thus, circulating Abs against GA pressed, tetraspanin-7 is a multipass transmembrane protein with restricted in diabetic patients were detected. neuronal and islet expression, similar to GLIMA. GLIMA identity was es- Supported By: King Saud University tablished by demonstrating binding of tetraspanin-7 to antibodies in GLIMA positive type 1 diabetic patients’ sera. We identify tetraspanin-7 as a major target of autoimmunity in diabetes, allowing its exploitation for diabetes prediction and immunotherapy. Supported By: Diabetes UK (11/0004297)

ADA-Funded Research For author disclosure information, see page LB98.

LB54 Immunology

214‑LB (DPP-4) is a cell surface serine protease expressed in a variety of tissue. Toll-like Receptors 2 and 4 in Type 2 Diabetes Inhibitors of DPP-4 are widely used in treatment of type 2 diabetes mellitus. EMANUELA ZAHARIEVA, ZDRAVKO KAMENOV, ELENA VIKENTIEVA, DORA Accumulating data suggests that DPP-4 inhibition yields further beneficial POPOVA, Sofia, Bulgaria pleiotropic effects, but the exact mechanisms remain poorly elucidated. We Toll-like receptors (TLR) activate Nuclear Factor κB pathway, implicated to investigated whether the DPP-4 inhibitor sitagliptin affects complement ac- contribute to insulin resistance. This study aimed to determine expression of tivation by altering the functional activity of the lectin pathway in vitro and TLR 4 and 2 in patients with type 2 diabetes mellitus (DM2), correlate it with in vivo. The effect of sitagliptin on the mannan-binding lectin (MBL) medi- glycemia, body mass index (BMI) and waist circumference, and establish an ated activation of the complement system was analysed in vitro by quan- association with chronic complications of the disease. We included 28 pa- tifying complement protein C4b deposition onto a surface of mannan in a tients with DM2 and 7 control persons. Multicoloured immunofluorescence time-resolved immunofluorometric assay. The effect in vivo was analysed in analysis with fluorochrome-conjugated monoclonal antibodies was used to plasma samples from 71 patients with acute coronary syndrome and glucose evaluate the TLR4 and TLR2 expression by classical, intermediate and non- disturbances in the BEGAMI trial, randomly assigned to sitagliptin 100 mg classical monocytes (Mo). TLR4 expression in diabetic patients is lower, com- (n=34) or placebo (n=37) for 12 weeks. Plasma concentrations of MBL and pared to controls (classical - Md=1.6% vs. Md=8.7%; nonclassical - Md=0.6%, levels of C4b deposition were measured at baseline and after 12 weeks of vs. Md=4.0%; intermediate Mo: Md=2.9% vs. Md=16.2%, p<0,05) and TLR2 treatment. In vitro, sitagliptin was found to inhibit the lectin pathway of expression is higher (nonclassical- Md=33.1% vs. Md=12.0%; intermediate the complement system in a dose-dependent manner. 50% reduction in C4b Mo - Md=92.8% vs. Md=29.3%, p<0,05). In men with diabetes (n=10) we found levels was observed with a concentration of 1 mM sitagliptin as compared a positive correlation between TLR4 expression on classical Mo and fasting to 0.25 mM Pefabloc (a known inhibitor of the complement system). In vivo, plasma glucose, Spearman’s correlation coefficient (Sp.CC) = 0,65, p=0.042 and MBL and C4b declined significantly during 12 weeks of follow-up in both also between TLR4 expression on intermediate Mo and HbA1c, Sp.CC =0.693; groups (p < 0.002). The changes in C4b appeared to be driven by changes in p=0.026. TLR2 was not associated with glycemia (p>0,05). Both did not cor- MBL with no significant additional effect of sitagliptin. In conclusion, sita- relate with BMI or waist circumference (p>0,05). TLR4 expression by interme- gliptin resulted in reduced functional activity of the lectin pathway in vitro. diate Mo decreases with rise of creatinine level in patients with DM2, Sp.CC The mechanisms behind a potential complement inhibitory effect of sita- rho = -0.38; p = 0.048, and with lowering of estimated glomerular filtration gliptin in vivo could not be demonstrated in the present material but merits rate (eGFR) - Sp.CC rho = 0.36; p=0.049. TLR2 expression also decreases with further investigations. renal function decline (classical Mo: creatinine - Sp.CC rho = -0.64; p = 0.044; Supported By: Aarhus University eGFR - Sp.CC rho=0.79, p=0.007; intermediate Mo - eGFR - Sp.CC rho = 0.64, p = 0.047). Patients with DM2 have lower expression of TLR4 although it tends 217‑LB to rise with worsening of glycemia. Expression of TLR2 is higher in diabetic Methyldopa Blocks HLA-DQ8 Antigen Presentation in Recent Onset patients but does not correlate with current or recent glycemia. Both tend to Patients with Type 1 Diabetes (T1D) decrease with progress of diabetic nephropathy, which questions the role of AARON W. MICHELS, VIRAL SHAH, SARIT POLSKY, KRISTEN MCDANIEL, AIMON innate immunity in its early stages. ALKANANI, SATISH K. GARG, PETER A. GOTTLIEB, Aurora, CO Supported By: Medical University-Sofia (83/2013) Human leukocyte antigen (HLA) alleles confer significant genetic risk for T1D with recent studies implicating DQ8 in its pathogenesis, making it an im- 215‑LB portant target. DQ8 antigen presentation can be inhibited in animal models with methyldopa. In this pilot study, we evaluated methyldopa treatment in Withdrawn 10 DQ8 positive T1D subjects, ages 18-46 years (mean 27) with < 2 years of diabetes duration (mean 3 months). This was an open label phase 1b dose es-

calation study. All subjects tolerated low (500mg BID) and moderate (500mg TID) dosages of methyldopa, while 9/10 tolerated the high dose (2-3g/day). There was a dose dependent reduction in DQ8 stimulated IL-2 response at 1 (-32%) and 3 weeks (-39%), which returned to normal 6 weeks after stopping therapy (Fig. 1a). The response was specific as DR4 T cell responses

were minimally effected (Fig. 1b). Patients had good glycemic control and 2 POSTERS I mmunology/

hour AUC for C-peptide following a mixed meal tolerance test at 12 weeks Transplantation was similar to baseline levels. No serious adverse events (, DKA, or hypoglycemia) were reported throughout the study. We conclude that methyldopa inhibits DQ8 antigen presentation in T1D. Long-term ran- domized double-blinded placebo controlled trials are needed to evaluate the exact role of methyldopa in potentially preventing and/or delaying T1D onset and preserving residual beta cell function in new-onset T1D.

216‑LB Effect of Dipeptidyl Peptidase-4 Inhibition on Complement Activa‑ Supported By: JDRF; 2-SAR-2014-142-C-R tion in Diabetes INGEBORG T. HOFFMANN-PETERSEN, JAKOB A. ØSTERGAARD, CHARLOTTE B. HOLT, CAMILLA HAGE, KERSTIN BRISMAR, LARS RYDÉN, LINDA G. MELLBIN, STEFFEN THIEL, TROELS K. HANSEN, Aarhus, Denmark, Stockholm, Sweden Diabetic nephropathy remains the most common cause of end-stage renal failure. Increasing evidence indicates that adverse activation of the comple- ment system may damage the kidneys in diabetes. Dipeptidyl peptidase-4

ADA-Funded Research For author disclosure information, see page LB98.

LB55 Transplantation Insulin Action—Adipocyte Biology

218‑LB tivirus, to overexpress human pancreatic and duodenal 1 (PDX1), Nasal Administration of Novel Insulin Degrading neurogenin 3 (NGN3) and/or forkhead box A2 (FOXA2). These genes are in- Ameliorates Autoimmunity in Diabetic Animal Model volved in the development of β-cells and might enhance the reprogramming DAN FRENKEL, Tel Aviv, Israel of ADSCs into pancreatic endodermal progenitors. Thereafter, multi-step Islet reactive T cells are found in many diabetes patients and in first degree induction protocols were applied to the cells. Induction of Ins1 expression relatives with a high risk to develop overt diabetes. It was also found that mice was indicated by fluorescence. RNA was isolated from fluorescent cells to with a high diabetes risk, non-obese diabetic (NOD) mice, routinely target clas- access the expression of pancreatic hormones and other genes essential for sical islet. Clonally expanded T cells from the site of autoinflammatory in long- β-cell function by qPCR. We developed several protocols that can induce term type 1 diabetics, indicates that insulin may be the target antigen causing fluorescence in up to 20% of the transduced ADSCs. Besides, cells become autoimmune diabetes. Insulin-degrading enzyme (IDE) is a large -binding cuboidal in morphology and tend to form cell clumps in the protocols us- protease plays an important role in degrading insulin. Since its discovery, IDE ing 3-D culture. The positive protocols are able to induce the expression is considered as an important therapeutic target in diabetes reasoned that of pancreatic hormones (insulin and glucagon) in ADSCs that overexpress inhibitors of IDE would be an ideal anti-diabetic therapy, as they would slow PDX1. Co-expressions of FOXA2 and/or NGN3 with PDX1 do not significantly the degradation of insulin. It was report suggest that IDE is a cellular receptor increase the expression levels. However, their overexpression leads to the mediating varicella-zoster virus (VZV) infection and cell-to-cell spreading. Us- expression of glucokinase (GCK), which is crucial for glucose sensing. Thus ing computational analysis we have developed an IDE inhibitor, ADT, based on overexpression of PDX1 alone is sufficient to induce the expression of pan- the interaction between IDE to VZV. We discovered that ADT inhibits IDE in a creatic hormones, including insulin, in ADSCs treated with reprograming dose dependent manner (IC50≈80 nM). We aim to investigate the effect of IDE protocols. Cell morphology and structure can also be used as a gauge of inhibitor on the development of autoimmunity in diabetes. We found that nasal reprogramming efficiency. While FOXA2 and NGN3 co-expression does not ADT21 can ameliorate diabetes in NOD mice and increase blood insulin levels, increase the efficacy of reprogramming, they induce the expression of GCK thus allowing physiological regulation of blood glucose and insulin levels. Th17 potentially enhancing other β-cell functions. and Th1 population are involved in the pathogenesis of autoimmune diabe- Supported By: National Medical Research Council of Singapore tes. We discovered a marked reduction in the levels of IL-17 and IFN-gamma in spleenocytes from ADT treated mice vs. control NOD mice. Furthermore, 221‑LB ADT21 reduce pro-inflammatory and increase anti-inflammatory response of B Ten-Year Outcomes after Islet Transplantation with the Edmonton chain peptide positive CD4+ T-cells. Our results suggest that ADT may be use Immunosuppression Protocol in Patients with Type 1 Diabetes as therapeutic approach to ameliorate autoimmunity in diabetes. MARIE CHRISTINE VANTYGHEM, JULIE KERR-CONTE, FRANÇOIS PATTOU, Lille, Supported By: ISF France Remarkable short term outcome has been often reported after intraportal islet transplantation (IT). Here we analyzed the influence of primary graft func- Transplantation tion (PGF) on 10 years metabolic outcome of IT with the Edmonton protocole in patients with brittle type 1 diabetes (ITA) or a previous kidney graft (IAK). 219‑LB Methods: Thirty-three consecutive patients (19 ITA, 14 IAK) received 2 (n=10) or 3 (n=23) infusions of allogenic islets, within a median (IQR) period PI3Kα and STAT1 Regulate Human Mesenchymal Stem Cell Immune Polarization of 80 (47-145) days, Immunosuppression was induced with anti IL2rc ab, and EIRINI KEFALOYIANNI, MARWAN MOUNAYAR, BRIAN SMITH, ZHABIZ SOLH- maintained with and . PGF was defined as the value of JOU, OMAR H. MAAROUF, JAMIL AZZI, LOLA CHABTINI, PAOLO FIORINA, MO- the Beta score (0 to 8) at 30 days after the last islet infusion, and consid- REY KRAUS, ROBERT BRIDDELL, WILLIAM FODOR, ANDREAS HERRLICH, REZA ered as optimal when ≥7 or suboptimal when ≤6. Patients were regularly ABDI, Boston, MA, Cambridge, MA, Hebron, KY, Madison, CT followed up, at least every 6 months, up to 10 years. The proportions of Due to their potent immunomodulatory function, MSC have become the patients with graft function (fasting c-peptide ≥0.3 ng/L) and insulin inde- focus of attention as a promising cell therapy for the treatment of various pendence were estimated with Kaplan-Meier method and compared with refractory immune-mediated diseases, including type 1 diabetes. MSC re- Logrank Mantel-Cox test. sponse to specific inflammatory cues allows them to switch between a pro- Results: Insulin independence was achieved after IT in 31 patients (94%), inflammatory (MSC1) or anti-inflammatory (MSC2) phenotype. Regulatory 23 (11-46) days after the last infusion. PGF was optimal in 19 patients (56%). mechanisms controlling this switch remain to be defined. One characteristic At the time of this report (median follow-up 8.3 years), 7 patients (21%) had feature of MSC2 is their ability to respond to IFNγ with induction of Indoleam- lost graft function, while 11 patients (33%) remained insulin independent for ine 2, 3-dioxygenase (IDO), representing the key immunoregulatory molecule up to 10 years, with a HbA1c of 5.8% (5.6%-6.4%) at last visit. Overall, the released by human MSC. Here we show that STAT1 and PI3Kα pathways proportions of patients with graft function and insulin independence were interplay regulates IFNγ-induced IDO production in MSC. Chemical PI3K pan- 0.82 [0.63; 0.91, 95% CI] and 0.48 [0.29; 0.64] at 5 years, and 0.76 [0.56; 0.88] inhibition, PI3Kα-specific inhibition or shRNA knockdown diminished IFNγ- and 0.22 [0.08; 0.41] at 10 years, respectively. These outcomes were simi- induced IDO production. This effect involved PI3Kα-mediated upregulation of lar between ITA and IAK patients, but were significantly better in patients STAT1 protein levels and phosphorylation at Ser727. Overexpression of STAT1 with optimal vs. suboptimal PGF: 10 years graft function 0.93 [0.59; 0.99] vs.

POSTERS or of a constitutively active PI3Kα mutant failed to induce basal IDO produc- 0.57 [0.28; 0.78] (p<0001); insulin independence 0.34 [0.12; 0.58] vs. 0 [0; 0] I nsulin Action/ tion, but shifted MSC into an MSC2-like phenotype by strongly enhancing IDO (p<0001). Conclusion: Our results suggest that the long term outcome of IT depends

M olecular etabolism production in response to IFNγ as compared to controls. STAT1 overexpres- sion strongly enhanced MSC-mediated T-cell suppression. The same effect in the first place on initial graft function. could be induced using short-term pre-treatment of MSC with a chemical in- Supported By: ARD hibitor of the counter player of PI3K, Phosphatase and tensin homolog (PTEN). Finally, downregulation of STAT1 abrogated the immunosuppressive capacity of MSC. Our results for the first time identify critical upstream signals for the Insulin Action—Adipocyte Biology induced production of IDO in MSCs that could be manipulated therapeutically to enhance their immunosuppressive phenotype. 222‑LB Sucrose Non-fermenting Related Kinase Is an Important Regulator 220‑LB of Adipose Energy Homeostasis Role of Transcription Factors in Reprogramming Adipose-derived BIN FENG, YAOHUI NIE, PING JIAO, QIN HE, ARTHUR SALOMON, KIRSTEN SIG- Mesenchymal Stem Cells into Insulin-Producing Cells RIST, HAIYAN XU, Providence, RI GUODONG LI, CHUI SUN YAP, JONATHAN CALEB QUEK, SHU MENG, THUAN KAI Obesity has become an epidemic disease and a major risk factor for the JELVIN SIM, SAI KIANG LIM, YONG MONG BEE, Singapore, Singapore development of insulin resistance and type 2 diabetes. Two types of adipose Generation of surrogate islet β-cells for transplantation may cure insulin- tissues exist in humans and rodents. White adipose tissue (WAT) is essential dependent diabetes. This study examined the efficacy of overexpressing for maintaining whole body energy homeostasis by storing excessive energy transcription factors, involved in pancreatic β-cell development, in the re- when nutrients are in surplus and releasing free fatty acids as fuels during programming of adipose-derived stem cells (ADSCs) into insulin-producing energy shortage. Pathological expansion of WAT is the basis for obesity de- cells. ADSCs isolated from the MIP-GFP mice that harbour a transgene of velopment. WAT derived inflammatory events characterized by macrophage GFP under control of insulin 1 (Ins1) promoter were transduced, using len- infiltration in obese state are considered as a causal factor for the develop- ment of obesity-related insulin resistance. In contrast, brown adipose tissue ADA-Funded Research For author disclosure information, see page LB98.

LB56 Insulin Action—Adipocyte Biology

(BAT) is a thermogenic organ and can dissipate energy as heat and enhanced ers. These findings suggest that 1) exerts adiponectin-independent BAT function is desired for treating obesity. We recently identified SNRK as effects on macrophage recruitment, but not macrophage number, and 2) the a potential suppressor of WAT inflammation in response to over-nutrition absence of adiponectin alters the effect of niacin on markers of macrophage as well as a critical factor for adaptive thermogenesis. Our studies demon- polarity, suggesting underlying adiponectin-dependent mechanisms. strate that SNRK is most abundantly expressed in WAT and BAT, and the expression levels as well as activities are significantly decreased in both 225‑LB tissues in obese mice. Global SNRK deficiency is perinatal lethal and pups can only survive for 1 day. Reduction of SNRK expression induces inflamma- Withdrawn tion in cultured white adipocytes, in WAT of global SNRK heterozygous mice and in WAT of adipose specific SNRK knockout mice. In BAT, SNRK deficiency significantly reduces expression of UCP1, decreases mitochondria density, and significantly reduces oxygen consumption. Furthermore, adipose spe- cific SNRK knockout mice are obese and resistant toβ 3- agonist-induced weight loss. These results indicate that SNRK is a critical regulator to integrate nutrient input and metabolism, and SNRK deficiency leads to WAT inflammation and impaired BAT thermogenesis.

223‑LB A Novel Lipocalin, LCN14, Ameliorates Hyperglycemia in Diet-in‑ duced Obese Mice via Reducing Glycerol Efflux from Adipose Tis‑ sue JIMMY TSZ-HANG LEE, ZHE HUANG, KEWU PAN, KAREN S.L. LAM, AIMIN XU, CHI-MING WONG, Hong Kong, Hong Kong Adipose tissue is an active endocrine organ that plays important roles in regulating energy metabolism in various organs, and dysreguation of adipose tissue-derived hormones may contribute to the pathogenesis of dia- betic complications. In this study, we identified a novel adipokine, lipocalin 14 (LCN14), whose circulating level and expression in white adipose tissues are severely reduced in both diet-induced and genetically diabetic mice. This study aims to investigate whether over-expression of LCN14 could alleviate hyperglycemia, glucose intolerance and insulin resistance in obese mice. Mice (C57/BL6N) were fed with either chow diet (STC) or high-fat diet (HFD) 226‑LB for 10 weeks, followed by infection with recombinant adeno-associated vi- Oncostatin M: Metabolic Friend or Foe? rus (rAAV) encoding LCN14, or eGFP as a control. Our findings suggest that CARRIE M. ELKS, RANDALL L. MYNATT, PENG ZHAO, JACQUELINE M. STE- over-expressing LCN14 could lead to elevate circulating level of LCN14, PHENS, Baton Rouge, LA which increase in insulin sensitivity in major metabolic tissues, including IL-6 and CNTF are gp130 cytokines that are well-studied in the context of liver, muscle and adipose tissues. Interestingly, over-expressing LCN14 can metabolic disease states. Another gp130 cytokine, oncostatin M (OSM), has also lower serum glycerol level by reducing the glycerol efflux from adipose recently been shown to have some anti-diabetic properties in mice. Pub- tissue, which limited the availability of glycerol for hepatic gluconeogenesis, lished studies from our lab demonstrate that OSM is produced by adipose and hence reversing hyperglycemia. Collectively, our results provided the tissue (AT) immune cells and is highly induced in murine and human obesity first evidence that LCN14 is a novel adipokine involved in glucose metabo- and type 2 diabetes. Our current studies demonstrate that OSM significantly lism. The deficiency of LCN14 in diet-induced obese mice may contribute to decreases insulin action in adipocytes in vitro. Acute and chronic OSM the development of hyperglycemia and insulin resistance. LCN14, therefore, treatment also induces pro-inflammatory and pro-fibrotic gene expression represents a promising molecular target for the development of new tools in adipocytes. Knockdown of the OSM-specific receptor (OSMRβ) in vitro for blood-glucose-lowering therapy. confirms that OSMRβ mediates the biological effects of OSM in adipocytes. These observations suggest that OSM has pro-diabetic effects. We hypoth- 224‑LB esized that loss of OSM signaling in fat cells may prevent the development High-Fat Diet-Induced Adipose Tissue Inflammation Is Attenuated of high-fat diet-induced obesity. To address this hypothesis, we generated by Niacin in Both an Adiponectin-Dependent and Independent Man‑ adipocyte-specific OSMRβ knockout mice (OSMRβFKO). To our surprise, the ner OSMRβFKO mice are insulin-resistant, which is likely due to an observed EMILY C. GRAFF, HAN FANG, DESIREE WANDERS, ROBERT L. JUDD, Auburn, AL, increase in AT OSM that promotes metabolic dysfunction in non-adipocyte Baton Rouge, LA cells in AT. In conclusion, our in vitro and in vivo studies in adipocytes sug-

Chronic obesity induces adipose tissue inflammation characterized by in- gest that OSM is a metabolic foe. POSTERS creased adipose tissue macrophages (ATM) and dysregulation of adipocyte Supported By: R01DK052968-15 I nsulin Action/

function. Studies demonstrate that chronic niacin administration attenuates M olecular etabolism obesity-induced adipose tissue inflammation and suggest that niacin alters 227‑LB ATM polarity away from the classic (M1) phenotype. In addition, niacin ad- NF-KappaB Inducing Kinase-mediated Adipose Tissue Inflamma‑ ministration increases tissue and serum adiponectin, an adipokine that pro- tion in Obesity and Type 2 Diabetes motes an alternative (M2) phenotype. Therefore, the objectives of this study MANDEEP BAJAJ, JONGOH KIM, ABSALON GUTIERREZ, PADMA SATHYANARA­ were to 1) determine if the anti-inflammatory effects of niacin are associ- YANA, LAWRENCE C.B. CHAN, SEAN M. HARTIG, Houston, TX ated with increased adiponectin concentrations and 2) evaluate the effects Adipose tissue inflammation plays a key role in insulin resistance in obe- of niacin on markers of adipose tissue inflammation in the absence of adi- sity and type 2 diabetes. Enhanced levels of nuclear factor (NF)-kappaB- ponectin. Male C57BL/6 mice (wild-type, WT) and adiponectin null mice (Ad- inducing kinase (NIK), an upstream kinase in the NF-kappaB pathway, have ipoq-/-) were maintained on a control (10% kcal as fat) or high fat diet (HFD; been implicated in the pathogenesis of chronic inflammation in diabetes. 60% kcal as fat). After 6 weeks, half of the mice from each group received NF-kappaB-inducing kinase is a member of the MAPK family that plays a either vehicle (water) or niacin (360 mg/kg/day) in their drinking water for 5 critical role in noncanonical NF-kappaB pathway activation and can act as weeks. Niacin treatment resulted in increased serum adiponectin in chow- a proximal inducer of IKK complex. We have previously shown that prior fed mice only. In adipose tissue of WT and Adipoq-/- mice fed a HFD, there treatment of NIK-transfected myotubes with adiponectin completely attenu- was increased gene expression of MCP-1 and CD68. In WT and Adipoq-/- ated NIK-induced increases in NF-kappaB binding and insulin resistance in mice, niacin treatment attenuated HFD-induced increases in MCP-1 but had vitro. Furthermore, NIK could amplify the inflammatory signal by regulating no effect on CD68. HFD fed mice had increased gene expression of both M1 Toll-like Receptor 4 (TLR4) expression. We investigated the role of NF-kap- and M2 macrophage markers. Treatment with niacin decreased expression paB-inducing kinase in adipose tissue inflammation and insulin resistance of M2 markers and showed a trend towards decreased M1 markers in the induced by obesity and type 2 diabetes (T2DM). We studied lean nondiabetic adipose tissue of WT mice fed a HFD. Interestingly, in HFD fed Adipoq-/- subjects (BMI 23.9±0.5, n=3), obese subjects (BMI 38.2±1.5, n=8), and type mice, niacin significantly increased expression of both M1 and M2 mark-

ADA-Funded Research For author disclosure information, see page LB98.

LB57 Insulin Action—Adipocyte Biology

2 diabetic subjects (BMI 38.5 ± 2.5, n=5), who underwent subcutaneous adi- 230‑LB pose tissue biopsies from the lateral thigh. Adipose tissue NIK expression Functional Roles of c-Jun in KLF15-mediated White Adipocyte Dif‑ was increased in obese subjects and type 2 diabetics (p<0.05) compared ferentiation with lean subjects. The increase in NIK was associated with an increase KYOUNG-JIN OH, ANNA PARK, Daejeon, Republic of Korea in adipose tissue TLR4 expression in obese and type 2 diabetic subjects Hyperplasia in adipose tissue plays a critical role in the development of compared to lean subjects (p<0.10) as well as a decrease in adipose tis- metabolic disorders such as obesity. Therefore, understanding the process sue adiponectin expression (p<0.05). Plasma adiponectin was decreased in of adipocyte differentiation and its regulatory mechanisms is critical to obese (6.4±0.4 µg/ml, p<0.01) and type 2 diabetic subjects (4.4±0.4 µg/ml, improve several pathological problems caused by excessive fat deposition p<0.05) compared to lean controls (12.4±4.0 µg/ml). These results suggest and insulin resistance. In this study, we investigated the novel role of c-Jun that adipose tissue NIK may play a key role in adipose tissue inflammation in white adipocyte differentiation. Firstly, we generated stable 3T3-L1 cell in insulin resistant obese and type 2 diabetic subjects in association with lines expressing retroviral control vector or c-Jun. Especially, differentiation hypoadiponectinemia. of 3T3-L1 preadipocyte cell line stably expressing c-Jun was significantly Supported By: American Diabetes Association (7-13-TS-04 to M.B.) inhibited as shown in the measurement of lipid accumulation using Oil-red O staining and quantification of mRNA levels of adipocyte-specific markers. To 228‑LB determine the relationship between c-Jun and markers of adipocyte differ- Adipocyte Hypertrophy Induces Insulin Resistance Independent of entiation, we compared c-Jun and their expression pattern during adipocyte Inflammation differentiation. The expression level of c-Jun was peaked at early stage of JAE BUM KIM, Seoul, Republic of Korea white adipocyte differentiation to induce the proliferation of preadipocytes In obesity, adipocyte hypertrophy and pro-inflammatory responses are and was rapidly repressed. Notably, the expression level of KLF15 was in- closely associated with the development of insulin resistance in adipose tis- creased when there was a decrease in the expression level of c-Jun. Fur- sue. However, it is largely unknown whether adipocyte hypertrophy in the ther, c-Jun-expressing 3T3-L1 cell line showed the decreased KLF15 mRNA absence of inflammation is sufficient to induce insulin resistance. Here, we level with remarkably reduced mRNA levels of its downstream genes, such developed an in vitro model of adipocyte hypertrophy by treating adipocytes as C/EBPα and PPARγ. In addition, c-Jun inhibited basal and glucocorticoid with long-chain fatty acids. Treatment with saturated or monounsaturated receptor(GR)-induced promoter activities of KLF15. Consequentially, these fatty acids resulted in adipocyte hypertrophy, but a pro-inflammatory re- results strongly suggest that c-Jun inhibits KLF15 at the transcriptional level sponse was only observed in adipocytes treated with saturated fatty acids. to suppress adipocyte differentiation. This study proposes a novel mecha- Regardless of inflammation, hypertrophic adipocytes with unilocular lipid nism for regulating adipocyte differentiation, and eventually would provide droplets exhibited impaired insulin-dependent glucose uptake with a defect clues for treatment of obesity. in GLUT4 trafficking to the plasma membrane. Moreover, Toll-like receptor 4 mutant mice (C3H/HeJ) with diet-induced obesity were not protected 231‑LB against insulin resistance, although they were resistant to adipose tissue Insulin and Nutrients Suppress ATGL-mediated Lipolysis in Adipo‑ inflammation. Together, our in vitro and in vivo data suggest that adipocyte cytes via mTORC1, Transcription Factor Egr1, and A Lipid Droplet hypertrophy alone would be sufficient to cause insulin resistance in early Protein FSP27 obesity. MANEET SINGH, PURI, KONSTANTIN V. KANDROR, Boston, MA One of the key physiological functions of insulin is to restrain lipolysis in 229‑LB adipocytes in the post-prandial state. Failure of insulin to suppress lipolysis Downregulation of Lipid Synthesis Occurring Early in the Process of has been long considered as a very serious metabolic defect and one of the Insulin Resistance in Adipose Tissue most important if not the most important causative factor of insulin resis- XIANCHAO XIAO, YUJIA LIU, SUYAN TIAN, XIAOKUN GANG, CHENGLIN SUN, tance and diabetes mellitus. We have found that insulin controls lipolysis via GUIXIA WANG, Changchun, China mTORC1 that represents the central energy and nutrient sensor in the cell. Insulin resistance associates closely with obesity, type 2 diabetes mel- mTORC1 decreases expression of the rate-limiting lipolytic enzyme, adipose litus and cardiovascular disease, occurring in liver, muscle and adipose tis- triglyceride lipase, or ATGL. Importantly, regulation of ATGL expression by sue. Till now, mechanisms underlying insulin resistance are still not exactly mTORC1 is conserved in evolution from yeast through Drosophila to mam- known. Besides, metabolic alteration of lipid and glucose are obscure. Pur- mals and thus should be essential for the metabolic control. However, the pose of this study was to distinguish gene biomarkers of insulin resistance in mechanism of this regulation remained completely unknown. Using a ge- adipose tissue from vast numbers of Gene Expression Omnibus (GEO) profiles netic screen in S.cerevisiae, we have determined that the effect of mTORC1 and figure out probable metabolic modification of lipid and glucose. The gene on the expression of ATGL is mediated by the primary early growth response expression datasets GSE20950 (39 samples) and GSE26637 (10 samples) transcription factor Egr1. With the help of 35S-labeling, we have found that were downloaded from GEO. In the preprocess, frozen robust multiarray mTORC1 activates Egr1 expression at the level of translation via the 4E-BP- analysis (fRMA) were used for background adjustment, normalization and mediated axis. Knock out of 4E-BP1/2 dramatically increases levels of the summarization, then converting CEL raw expression data to gene expression Egr1 protein, suppresses ATGL gene expression, and causes a marked ac- values. ComBat algorithm was used to combine these two datasets, and cumulation of triglycerides in the cell. On the contrary, knock down of Egr1 in

POSTERS then abandoned probes with expression level standard deviation<0.1. Sig- in 4E-BP1/2-null cells increases ATGL expression and decreases fat storage. I nsulin Action/ nificance analysis of microarrays applied to identify differentially expressed Unexpectedly, it turns out that the repressor activity of Egr1 toward ATGL transcription is enhanced by the lipid droplet protein FSP27 (a.k.a. CIDEC) M olecular etabolism genes (DEGs), with false discovery rate (FDR) <0.05. As a result, 386 DEGs were in insulin resistant group recognized compared to insulin sensitive that interacts with Egr1 and increases its binding to the ATGL promoter. The group, 56 of which were at lower expression level and 330 of which were analysis of the intracellular localization of FSP27 in human adipocytes re- at higher expression level respectively. Bio-information and function in vari- veals that it is localized not only on lipid droplets but is also present in the ous signaling pathway of each DEG was confirmed in Genecards Database. . We hypothesize that FSP27 plays a dual role in fat metabolism The most prominent down-regulated DEGs in insulin resistant adipose tis- as a LD protein and a nuclear regulator of ATGL transcription. sue were SLC27A2, AGPAT9 and ACACB, proteins expressed by which were Supported By: R01DK052057 playing important roles in fatty acid transporting into adipocyte, triglyceride synthesis and . On the contrary, genes related to glucose 232‑LB metabolism didn’t show any significance. In conclusion, down-regulation of FGF-mediated Regulation of Cellular Bioenergetics lipid synthesis is a primary metabolic transformation in non-diabetic insulin FARNAZ SHAMSI, RUIDAN XUE, TIAN LIAN HUANG, MATTEW D. LYNES, C. RON- resistant adipose tissue. ALD KAHN, YU-HUA TSENG, Boston, MA Supported By: Chinese Society of ; National Clinical Research Brown adipose tissue (BAT) plays a central role in regulation of energy Center for Metabolic Diseases expenditure in response to environmental changes, such as cold and diet. Uncoupling protein 1 (UCP1) is the key mediator of adaptive thermogenesis through uncoupling oxidative phosphorylation from ATP production and re- leasing energy as heat. Increasing amount and thermogenic activity of brown adipose tissue hold great promise for treatment of obesity-related disorders. To discover protein(s) that can improve energy expenditure through induction of UCP1 expression, we performed a proprietary high-throughput screen us-

ADA-Funded Research For author disclosure information, see page LB98.

LB58 Insulin Action—Cellular and Molecular Metabolism ing a protein library containing more than 5,000 mammalian secreted pro- sistance (IR) and glucose intolerance, in part, by cross-talk between innate teins in an immortalized murine brown preadipocyte cell line. The screen immune signaling and metabolic insulin signaling. We previously showed identified a number of hits that can induce UCP1 mRNA expression in the that IRAK-1, downstream from IL-1R/TLRs, phosphorylates IRS-1 at Ser24 committed brown preadipocytes. Among those, we confirmed that an para- to cause IR. Thus, we hypothesize that absence of IRAK-1 opposes IR. In- crine/autocrine fibroblast growth factor (FGF) could induce UCP1 expres- deed, C57Bl/6J IRAK-1 k/o mice (20 wk) on normal chow had substantially sion in a time- and dose-dependent manner. In vivo analysis revealed that improved insulin sensitivity (glucose clamp) and glucose tolerance (IPGTT) this factor was expressed in both brown and white adipose tissue, and its when compared with littermate controls (WT mice). When WT mice with expression in BAT, subcutaneous WAT (sqWAT) and epididymal WAT (epi- diet-induced obesity (DIO) from high fat diet (HFD; 60% kcal fat; D12492 WAT) was upregulated by cold exposure. Additionally, FGF treatment led to Research Diets, Inc.) were treated with Metformin (6 wk HFD, then 6 wk marked increase in mitochondrial activity and uncoupled respiration. Inter- HFD + Metformin (200 mg/kg/d)), we observed comparable body weight estingly, FGF-dependent induction of UCP1 is not accompanied by enhanced when compared with HFD alone (12 wk) 41 ± 1 vs. 43 ± 1 g; p < 0.2; n = 6). adipogenic differentiation and lipid accumulation. In conclusion, these data Interestingly, when treated with metformin, body weight for IRAK-1 k/o mice have introduced a previously unknown paradigm for regulation of energy was significantly higher than that of WT (45 ± 2 vs. 41 ± 1; p < 0.05) suggesting expenditure, in which UCP1 expression and mitochondrial activity are dis- that well known effects of metformin to cause weight loss in diabetes was sociated from adipocyte differentiation and lipid accumulation. absent in IRAK-1 k/o mice. As expected, metformin treatment substantially increased insulin sensitivity in WT mice (QUICKI = 0.227 ± 0.006 vs. 0.254 ± 233‑LB 0.005; p < 0.005; n = 5) and glucose tolerance (IPGTT AUCg = 16700 ± 3400 vs. IL-6 Signaling as a Critical Mediator of Healthy Adipose Tissue Ex‑ 22900 ± 2400 (mg/dl)·min, ANOVA for multiple comparison, p < 0.03, n = 5). pansion Importantly, these anti-diabetic actions of metformin were absent in met- THOMAS S. MORLEY, F. THOMAS WUNDERLICH, JENS C. BRÜNING, PHILIPP E. formin-treated IRAK-1 k/o mice (QUICKI = 0.234 ± 0.015 vs. 0.239 ± 0.012, SCHERER, Dallas, TX, Cologne, Germany p < 0.4; IPGTT AUCg = 20800 ± 3000 vs. 25000 ± 4500 (mg/dl)·min, ANOVA Obesity and the concomitant insulin resistant segment of the population for multiple comparison: p < 0.34). Thus, we conclude that IRAK-1 is required is still on the rise. Plasma profiling of these individuals has demonstrated to mediate beneficial metabolic actions of metformin. In future studies we elevated inflammatory cytokines and acute phase reactants. Specifically, will elucidate mechanism for IRAK-1 to mediate metabolic actions of met- circulating IL-6 levels (an with a plethora of known formin. Our results may lead to novel therapeutic drug targets for treatment activities), is elevated in the obese insulin-resistant population and is re- of T2DM. flecting dysfunctional adipose tissue. A systemic elevation of inflamma- Supported By: American Diabetes Association (1-13-BS-150 to M.J.Q.) tory factors can induce insulin resistance. Recently however, TNF-alpha and other inflammatory cytokines have been demonstrated to be of pivotal 236‑LB importance in the healthy expansion of adipose tissue under high fat diet The Role of Adipose Tissue mTORC2 in Regulating Hepatic Insulin (HFD) exposure. To this end, we wished to determine the in vivo role of IL-6 Sensitivity signaling in adipose tissue specifically with respect to the adipose tissue YUEFENG TANG, DAVID A. GUERTIN, Worcester, MA homeostasis during expansion. Using a doxycycline-inducible system, we Insulin resistance (IR) plays an important role in the pathogenesis of obe- eliminated the IL-6 receptor from adipocytes exclusively in the adult mouse sity and type 2 diabetes (T2D); however, the cellular and molecular mecha- and subsequently challenged the mice with a high fat diet. HFD feeding nisms are still poorly understood. White adipose tissues (WAT) are the major leads to glucose intolerance and additional metabolic dysregulation. These energy storage site and endocrine organs that regulate insulin sensitivity results substantiate the essential contributions of inflammation in the mi- via the release of adipokines. In obesity, the failure of insulin to suppress croenvironment of the adipocyte that allow appropriate remodeling of the lipolysis in adipose tissue is thought to be a major driver of IR by increasing tissue during HFD-induced tissue expansion. the flux of FFAs to liver and skeletal muscle. Recent studies revealed the Supported By: National Institutes of Health (R01DK55758, 1P01DK088761 to important role of de novo lipogenesis-derived bioactive lipids in systemic P.E.S.); National Institutes of Health (T32-GM083831 to T.S.M.) insulin sensitivity. However, the importance of each mechanism in the pro- cess of T2D, and the molecular basis of AT dysfunction in obesity remains 234‑LB unclear. The mechanistic target of rapamycin complex 2 (mTORC2) phospho- The ER-associated Degradation Adaptor Protein SEL1L Regulates rylates AKT at S473 and this event is thought to be required for full AKT Body Weight and Glucose Homeostasis in Age-induced Obesity activity to all of its substrates. However, we recently found that mTORC2 HAIBO SHA, LING QI, Ithaca, NY promotes de novo lipogenesis in brown AT via the independence of the clas- SEL1L is an essential adaptor protein for the E3 ligase HRD1 in the en- sic downstream AKT substrates. To investigate the role of mTORC2 in WAT, doplasmic reticulum (ER)-associated degradation (ERAD), a universal qual- we knocked out rictor (an essential subunit of mTORC2) using adiponectin- ity-control system in the cell. Previously we have shown that mice with Cre mice (adipo; rictor). Ap2-Cre-mediated rictor gene deletion (AP2; rictor) adipocyte-specific SEL1L deficiency (AKO) exhibit postprandial hypertriglyc- had no effect on fat mass, but increased lean tissue mass, suggesting that eridemia. Further analyses reveal that SEL1L is indispensable for the secretion mTORC2 in fat controls whole body growth. However, recent studies have of lipoprotein lipase (LPL), independent of its role in HRD1-mediated ERAD highlighted several caveats associated with using Ap2-Cre. While we find and ER homeostasis. Here we further characterize AKO mice in chronic age- some partially overlapping phenotypes with the Ap2; rictor mice, the adipo; POSTERS induced obesity. Aged AKO mice are resistant to obesity and demonstrate rictor mice exhibited many markedly different phenotypes. Adipo; rictor mice I nsulin Action/ transiently decreases fat mass, but has no significant effect on lean tissue improved glucose tolerance. Gene expression analyses showed increased M olecular etabolism unfolded protein response and autophagy in the white adipose tissue (WAT) mass. Rictor loss has no effect muscle insulin sensitivity or glucose toler- of AKO mice, likely in compensation for the loss of SEL1L-HRD1 arm of ERAD. ance, but dramatically impairs insulin’s ability to suppress hepatic glucose The underlying mechanisms and potential roles of SEL1L in energy metabo- production suggesting an early defect in fat-liver crosstalk. However, with lism and brown adipose tissue are currently under investigation. age the KO mice become glucose intolerant. Thus, adipose mTORC2 plays a Supported By: American Diabetes Association (07-08-JF-47, 1-12-CD-04 to L.Q); pivotal role in T2D. Cornell University Supported By: American Diabetes Association (1-13-BS-066 to D.A.G.); National Institutes of Health-National Institute of Diabetes and Digestive and Kidney Dis- eases (R01DK094004) Insulin Action—Cellular and Molecular Metabolism 237‑LB Partial Recovery of Insulin Secretion in Type 1 Diabetes? ANDRZEJ S. JANUSZEWSKI, YOON HI CHO, YIK WEN LOH, DAVID O’NEAL, MA- 235‑LB RIA CRAIG, KIM C. DONAGHUE, ALICIA JENKINS, Camperdown, Australia, West- Actions of Metformin to Ameliorate Insulin Resistance and Glucose mead, Australia, Fitzroy, Australia, Sydney, Australia, Oklahoma City, OK Intolerance in Obese Mice Requires IL-1 Receptor Associated Ki‑ Type 1 diabetes (T1D) can be associated with low residual insulin pro- nase-1 (IRAK-1) duction. T1D patients (F/M=198/167), aged 10-80 y, (mean±SD) 30±16 y, T1D XIAO JIAN SUN, SOOHYUN PARK KIM, DONGMING ZHANG, LIWU LI, MICHAEL duration 16±12 y and 249 healthy controls (CON) were evaluated in a cross- J. QUON, Baltimore, MD, Blacksburg, VA sectional study. HbA1c was 8.4±1.6% and 5.1±0.4% in T1D and CON respec- Metformin is first-line therapy for T2DM. Chronic inflammation mediated tively (p<0.00001). Plasma C-peptide levels were measured by ultra-sensitive by pro-inflammatory cytokines and free fatty acids contributes to insulin re- ELISA (Mercodia, Sweden), with a low detection limit of 1.25 pmol/L (0.0038

ADA-Funded Research For author disclosure information, see page LB98.

LB59 Insulin Action—Cellular and Molecular Metabolism

ng/mL). Undetectable C-peptide levels were expressed as ¼ of the concen- als not treated with lipid lowering medications were studied. Overweight/ tration of the assay’s lowest calibrator as per manufacturer’s instructions obese individuals (BMI>25 kg/m2, n=28) were stratified based on median (Technical Note 34-0144). C-peptide in CON and T1D were 547.1±1.2 pmol/L glucose infusion rate (GIR) during a hyperinsulinemic-euglycemic clamp, into and 3.6±1.2 pmol/L respectively; p<0.0001. Subjects were divided into co- insulin-sensitive and insulin-resistant groups (top vs. bottom, OIS and OIR horts by T1D diagnosis age (≤10, 10 to ≤20 and >20 y) and T1D duration (≤10, respectively). Lean insulin-sensitive individuals (n=23) served as a reference 10 to ≤20 and >20 y). C-peptide levels are shown in the Table. Young age di- group. Vastus lateralis muscle biopsies and plasma samples were collected. agnosis (≤10 y.o.) was associated with higher rates of undetectable C-peptide, Lipidomics analysis was performed by liquid chromatography, electrospray p<0.0001 vs. combined age T1D diagnosis 10 to ≤20y.o. and >20y.o. ionization-tandem mass spectrometry. Pathway analysis of gene array Table. C-peptide Levels (Geometrical Mean±SEM, Age, and Gender Adjusted). in muscle was performed in a subset (13 lean, 11 OIR, 11 OIS). Lipidomics analyses of skeletal muscle and plasma revealed distinct of ex- Age T1D n T1D duration % with undetectable C-peptide cess weight and insulin resistance. Specifically, in muscle insulin resistance diagnosis (yrs) (yrs) C-peptide (pmol/L) was characterized by increases in C18:0 , including ceramide, ≤10 62 ≤10 82 2.2±1.2 dihexosylceramide (DHC) and trihexosylceramide (THC), while in plasma in- ≤10 61 10 to ≤20 67 3.5±1.2 creases in diacylglycerol (DAG), triacylglycerol (TAG) and cholesterol ester ≤10 34 >20 56 5.1±1.2 ‡ (CE) and decreases in lysophosphatidylcholine (LPC) and lysoalkylphosphati- dylcholine (LPC(O)) indicated insulin resistance independent of body weight. 10 to 20 50 10 44 2.5±1.2 ≤ ≤ An overweight/obesity lipidomic was only apparent in plasma and 10 to ≤20 26 10 to ≤20 23 5.2±1.2 ‡ was predominated by increased TAG and decreased plasmalogen species. 10 to ≤20 38 >20 21 3.1±1.2 Biological pathways associated with metabolism were up regu- >20 39 ≤10 10 7.2±1.2 lated in muscle in OIR vs. OIS. These findings suggest that insulin resistance and excess body weight exhibit discrete footprints in plasma and may serve >20 17 10 to 20 29 2.2±1.2 ‡ ≤ as a useful marker of insulin resistance independent of obesity per se. >20 26 >20 31 2.5±1.2 ‡ Supported By: Diabetes Australia; Victorian Government ‡ p<0.05 vs. duration ≤10 in respective age of diagnosis group. Conclusions In T1D subjects diagnosed in childhood C-peptide levels are 240‑LB higher with intermediate or long T1D duration. In those diagnosed >20 yrs C- GPS2 at the Crossroad of Lipid Metabolism and Inflammation in peptide levels fall with longer T1D duration. Results are supportive of more Mouse Adipose Tissue complete beta cell loss in younger onset T1D, and potential beta cell regen- CARLY T. CEDERQUIST, MARIA D. CARDAMONE, CLAUDIA LENTUCCI, VALEN- eration. Longitudinal studies are merited. TINA PERISSI, Boston, MA Supported By: Diabetes Australia Obesity-associated inflammation is widely recognized as a critical factor in the development of insulin resistance leading to T2D. However, recent 238‑LB studies suggest that local recruitment of immune cells to the adipose tissue may have some unexpected beneficial effects, such as facilitating local tis- Effect of on TLR4/IKKβ/NF-κB Signaling Pathways in Skeletal Muscle of Obese Rats with Insulin Resistance sue remodeling and contributing to the disposal of excess lipids. Thus, the YIYI ZHANG, LIQIONG HOU, TIEYUN ZHAO, Chengdu, China critical question of whether inhibiting inflammation is a good approach in the Recently it has been found that Berberine can play a role in blood-glucose attempt of treating insulin resistance remains unanswered. G-protein path- lowering and improving insulin resistance. The mechanism by which ber- way suppressor 2 (GPS2) is an inhibitor of non-proteolytic signaling berine improve insulin resistance is still not fully understood. We investigat- recently emerged as an important regulator of homeostasis and inflamma- tory responses in metabolic organs. Previous work from our lab and others ed the effect of berberine on the TLR4-IKKβ/NF-κB signaling pathway and insulin sensitivity in skeletal muscle. Forty Wistar rats were divided into nor- indicates that GPS2 complementary functions in the and the nucleus mal-diet control group (NC, n=10) and high fat diet-caused obese group (HF, cooperate to inhibit the expression of the pro-inflammatory gene program n=30). After the obese rats model was established successfully (28 weeks), under control of JNK and the TNFα signaling pathway, while promoting the the NC group (n=10) and the obese group (HF1, n=10) were sacrificed. The activation of key mediators of the lipolysis pathway. Here, we present the rest of obese rats were divided randomly into two groups: untreated group characterization of GPS2 adipo-specific knockout (GPS2 AKO) and transgenic (HF2, n=10) and 200 mg.kg-1.d-1 berberine-intervened group (BBR, n=10). (Ap2-GPS2) mouse models confirming the critical role played by GPS2 in Two groups were sacrificed after intervening eight weeks. The expression regulating obesity-induced inflammation and lipid metabolism in vivo. Be- of Toll-like receptor-4 (TLR-4) mRNA in skeletal muscle were detected by cause of increased adipose tissue lipid storage capacity, GPS2 AKO mice placed under HFD are more obese but metabolically healthier than their wild real time quantitative PCR. The expression of TLR-4, IκB kinaseβ (IKKβ), type littermates despite the substantial increase in immune cell infiltration phospho-IKKβ, Nuclear factor-κB (NF-κB), insulin receptor (IR), insulin re- ceptor substrate-1 (IRS-1), phospho-IRS-1 and the tyrosine phosphorylation and expression of pro-inflammatory cytokines. Conversely, systemic insulin of IR and IRS-1 protein in skeletal muscle were detected by Western blotting. sensitivity is not improved in the obese Ap2-GPS2 mice despite inflamma- The results showed: 1. The mRNA and protein expression of TLR-4, phospho- tion being inhibited in both adipocytes and macrophages. These results indi-

POSTERS cate that insulin resistance and inflammation are uncoupled in GPS2 mouse IKKβ (Ser181), NF-κB increased significantly and the protein expression of I nsulin Action/ IRS-1, phospho-IRS-1 and the tyrosine phosphorylation of IR and IRS-1 pro- models and suggest that a better understanding of the casual relationship between obesity, inflammation, and insulin resistance is required for the de-

M olecular etabolism tein of skeletal muscle decreased significantly in HF1 group compared with those in NC group (all P<0.05). 2. The mRNA and protein expression of TLR- sign of effective therapeutic approaches against T2D. Supported By: Boston Nutrition Obesity Research Center; National Institutes of 4, phospho- IKKβ (Ser181), NF-κB decreased significantly and the protein expression of IRS-1, phospho-IRS-1 and the tyrosine phosphorylation of IR Health (R01DK100422) and IRS-1 protein of skeletal muscle increased significantly in BBR group compared with those in HF2 group (all P<0.05). Our study revealed that ber- 241‑LB berine can improve insulin resistance of skeletal muscle through inhibiting High-Resolution Plasma Metabolomics during Treatment of Dia‑ the active of the TLR4/IKKβ/NF-κB signaling pathway. betic Ketoacidosis FRANCISCO J. PASQUEL, KARAN UPPAL, J. SONYA HAW, PRIYATHAMA VEL­LANKI, 239‑LB THOMAS R. ZIEGLER, DEAN P. JONES, GUILLERMO E. UMPIERREZ, Atlanta, GA Skeletal Muscle and Plasma Lipidomics Reveal Distinct Signatures Diabetic ketoacidosis (DKA) is a disorder affecting carbohydrate, fat, and of Overweight/Obesity and Insulin Resistance in Humans protein metabolism. High-resolution metabolomics (HRM), a new approach DORIT SAMOCHA-BONET, KATHERINE TONKS, ADELLE C.F. COSTER, MICHAEL to characterize metabolism with advanced liquid chromatography-mass J. CHRISTOPHER, AIMIN XU, DON J. CHISHOLM, RIMA CHAUDHURI, DAVID E. spectrometry (LC-MS) and data extraction methods, provides information JAMES, PETER J. MEIKLE, JERRY R. GREENFIELD, Sydney, Australia, Melbourne, on thousands of known, as well as uncharacterized metabolites in human Australia, Hong Kong, Hong Kong plasma. In the present study, more than 8,000 metabolites were evaluated Alterations in lipid species in muscle and plasma have been documented in in 29 adult patients with DKA. Plasma samples collected at baseline, 4 hours insulin-resistant obese individuals and are suggested to contribute to insulin after insulin infusion, and at resolution of acid-base disorder were analyzed resistance. Whether these lipid alterations are a reflection of insulin resis- by HRM. Patient characteristics were as follows: 40±12 years, 62% male, tance or obesity per se remains unclear. Non-diabetic sedentary individu- BMI 29±9 kg/m2, HbA1c 12.0±2.5%; at baseline, BG was 510±123 mg/dL, pH 7.1 ±0.2, beta-hydroxybutyrate 7.9±3.1 mg/dL, HCO3 12.8±4.6; at DKA

ADA-Funded Research For author disclosure information, see page LB98.

LB60 Insulin Action—Glucose Transport and Insulin Resistance In Vitro resolution: BG 161±60mg/dL, pH 7.33±0.03, HCO3 19.8±3.2. A total of 369 receptor-dependent mechanism and insulin sensitivity through a separate metabolites significantly differed from baseline values over time, p<0.05. mechanism. Thus, PAHSAs exert beneficial effects through multiple path- Pathway enrichment analysis showed significant changes in ways. Restoring the low PAHSA levels in people with type 2 diabetes is metabolism (, valine, and isoleucine, tyrosine, and selenom- likely to improve insulin and GLP1 secretion, insulin sensitivity and blood ethionine), B vitamin (cobalamine and pyridoxine), nucleotide ( and glucose control. ), and lipid (leukotriene, sterol, ) metabolism. Abundance of Apelin-13, an adipokine involved in energy metabolism, decreased signifi- 244‑LB cantly during treatment. These results show complex metabolic responses Torin1 Initiates Autophagy in Cardiomyocytes in an mTOR-indepen‑ to insulin during DKA treatment. Future studies will require determination dent Manner of specific metabolites of most interest and additional investigation of the QUANJIANG ZHANG, E. DALE ABEL, Iowa City, IA clinical/metabolic importance of the changes in specific metabolic pathways Phosphorylation of ULK1 by mTOR inhibits autophagy, a lysosomal-de- and their association with DKA treatment and it’s resolution. pendent process. Torin1 a potent mTOR inhibitor may induce autophagy in concert with reduced phosphorylation of ULK1. This study initially sought to 242‑LB confirm that Torin1 may initiate autophagy by inhibiting mTOR in H9C2 cells. IRF6 Controls Macrophage Alternative Activation H9C2 cells were treated with Torin1 for 2 hrs under either nutrient replete TYLER J. BREHM, WEI YING, BEIYAN ZHOU, JING XU, College Station, TX (NR, DMEM+10% FBS) or nutrient deplete (ND, glucose-free HBSS+0.5 mM Under obese stress, adipose tissue macrophages (ATMs) undergo a phe- pyruvate). Torin1 dose-dependently deactivated mTOR and Akt signaling notypic switch from anti-inflammatory status (M2) to proinflammatory (M1) as shown by dephosphorylation of mTOR at S2448, P70S6K at T389, Akt status, a major contributor to the development of chronic tissue inflammation at S473 and T308, and GSK3β at S9 (P<0.05, n≥8), without any effects on and insulin resistance which are causal factors for type 2 diabetes. However, ERK1/2 phosphorylation (P>0.05, n≥8). Torin1 increased ULK1 expression by the mechanisms underlying the control of macrophage activation statuses >3 fold, dephosphorylated ULK1 at both S757 and S555 (P<0.05, n≥8), and in- have not been fully elucidated. In this study, we demonstrate that interferon duced autophagy as shown by increased LC3-II content in NR (P<0.05, n≥8). regulatory factor 6 (IRF6) exerts a profound impact on macrophage polariza- Torin1 did not significantly augment ND-induced autophagy as determined tion. Interestingly, we observed that the expression of IRF6 was dramatically by LC3-II content and degradation of p62 and NBR1 (P>0.05, n≥8). Insulin at suppressed in M2 macrophages upon IL4 stimulation, but not in LPS-activat- 100 nM increased phosphorylated Akt and mTOR, and inhibited autophagy ed M1 macrophages, as compared to naive (M0) macrophages. In addition, in ND media (P<0.05, n≥10), which was blocked by Torin1 (P<0.05, n≥10). To IRF6 expression differs distinctly between lean and obese ATMs. We further test whether Torin1-induced autophagy requires mTOR signaling, mTOR was investigated the role of IRF6 using gain and loss of function strategies in a silenced by ~80%. Silencing mTOR neither initiated autophagy in NR condi- well-defined in vitro system. Knockdown of IRF6 with a gene-specific shRNA tion, nor augmented ND-induced autophagy. Unexpectedly, Torin1 still in- successfully suppressed IRF6 expression level in macrophages. Interest- duced autophagy in the absence of mTOR as shown by increased LC3-II level ingly, significantly enhanced M2 responses were demonstrated by elevated and degradation of p62 (P<0.05, n≥8), in concert with reduced phosphoryla- levels of the activation-related cell surface markers CD69 and CD86 and tion of Akt. These data show that Torin1 may increase autophagic flux in a the expression of M2-related genes including IRF4, PPARγ, Arginase1, and mTOR-independent manner, and supports our earlier observations that mTOR IL10. Conversely, bone marrow derived macrophages (BMDMs) with ectopic might be dispensable in ND-induced autophagy in cardiomyocytes. expression of IRF6 displayed blunted M2 responses in the presence of IL4, Supported By: National Institutes of Health compared to the M2 BMDMs transfected with an empty vector. In addition, the gain or loss of IRF6 expression did not significantly affect M1 responses of BMDMs upon LPS stimulation, suggesting the regulatory effect of IRF6 Insulin Action—Glucose Transport and primarily acts on enhancing macrophage alternative activation. In summary, Insulin Resistance In Vitro our findings identified a novel transcription factor, IRF6, in mediating mac- rophage alternative activation program. Further analysis of IRF6 will provide crucial information to understand the ATM action and their contribution to 245‑LB adipose tissue function and subsequent obesity-induced chronic inflamma- Independent and Combined Effects of Calorie Restriction and Exer‑ tion and insulin resistance. cise on Insulin-stimulated Glucose Uptake and Insulin Signaling in the Soleus of Old, Insulin-Resistant Rats Supported By: American Diabetes Association (1-13-JF-59 to B.Z.) HAIYAN WANG, NAVEEN SHARMA, EDWARD B. ARIAS, GREG CARTEE, Ann Ar- bor, MI, Mount Pleasant, MI 243‑LB Exercise and calorie restriction (CR) are widely used with the goal of im-

A Novel Lipid Class Improves Glucose Homeostasis through GLP-1 proving insulin sensitivity in older, insulin resistant individuals, but the ben- Receptor-Dependent and Independent Mechanisms efits of combining these treatments on muscle insulin signaling and action ISMAIL SYED, JENNIFER LEE, ALEXANDRA SONTHEIMER, PRATIK ARYAL, MARK remain poorly understood. Accordingly, we assessed the independent and M. YORE, ODILE D. PERONI, MATTHEW J. KOLAR, ALAN SAGHATELIAN, BAR- combined effects of acute exercise (3-4 hours after an exercise protocol pre- BARA B. KAHN, Boston, MA, La Jolla, CA viously demonstrated to increase insulin-stimulated glucose uptake, ISGU, in Increased adipose tissue (AT) lipogenesis is associated with enhanced POSTERS

24 mo-old rats) and chronic CR (65% of ad libitum, AL, intake beginning at 14 I nsulin Action/ insulin sensitivity but the mechanisms are unknown. Recently we discov- wk-old) on insulin signaling and ISGU in soleus of 30 mo-old rats. Soleus mus- ered a novel class of endogenous anti-diabetic and anti-inflammatory lipids, cle strips, after ex vivo incubation with [3H]-2-D-deoxyglucose (2-DG) ±0.6 M olecular etabolism branched Fatty Acid Esters of Hydroxy Fatty Acids (FAHFAs). One FAHFA nM insulin, were analyzed for [3H]-2-DG accumulation (by scintillation count- family member, Palmitic Acid Hydroxy Stearic Acid (PAHSA), is present in ing) and abundance and phosphorylation of key proteins (by immunoblotting). serum and nearly all tissues with highest expression in AT. PAHSAs are regu- CR alone versus AL sedentary controls induced greater ISGU concomitant lated by fasting-refeeding and high fat diet-induced obesity. PAHSAs are with diet-related (CR > AL) elevations in insulin-stimulated phosphorylation reduced ~70% in AT of insulin-resistant vs. insulin-sensitive people and cor- of AktSer473, AktThr308 and Akt substrate of 160 kDa (AS160) Ser588. CR relate highly with insulin sensitivity measured by euglycemic clamp. PAHSAs alone did not increase GLUT4 abundance or insulin-stimulated phosphoryla- improve glucose tolerance but effects on insulin sensitivity are unknown. tion of the insulin receptor Tyr1146 and AS160 Thr642. Exercise alone did not Aim: to determine whether PAHSA treatment improves insulin sensitivity alter ISGU, GLUT4 abundance or insulin-stimulated phosphorylation of the and if so, by what mechanism. There are multiple PAHSA isomers defined by insulin receptor, Akt or AS160. Although CR combined with exercise versus the position of the ester bond. Administration of 5- and 9-PAHSA by osmotic CR or exercise alone increased GLUT4 abundance and insulin-stimulated Ak- pump in chow-fed mice for 7-8 weeks elevated serum levels of these lipids tSer473 and AktThr308 phosphorylation, it did not induce further elevation 2-3 fold. This improved insulin sensitivity (insulin tolerance test area above of ISGU or insulin-stimulated insulin receptor and AS160 phosphorylation curve: vehicle 4482 ± 961 vs. PAHSA 7106 ± 488) with no change in body versus CR alone. These results revealed that although the soleus muscles of weight or food intake. PAHSA administration also improved glucose toler- old rats were highly responsive to a CR-induced enhancement of insulin sig- ance and augmented secretion of both insulin (vehicle 1.2 ± 0.3 vs. PAHSA naling and action, an exercise protocol previously demonstrated to enhance 3.4 ± 0.6 ng/ml) and total GLP-1 (vehicle 17.07 ± 1.1 vs. PAHSA 24.52 ± 1.7 pM) ISGU in younger rats was ineffective for increasing ISGU, either alone or during GTT. The GLP-1 receptor antagonist, Exendin-(9-39) (5µg/mouse daily when combined with CR. X 14 days) reversed the PAHSA effects on insulin and total GLP-1 secretion Supported By: National Institutes of Health (AG-010026) and glucose tolerance but not on insulin sensitivity. In summary, chronic ad- ministration of 5- and 9-PAHSA improves glucose tolerance through a GLP-1

ADA-Funded Research For author disclosure information, see page LB98.

LB61 Insulin Action—Signal Transduction, Insulin, and Other Hormones

Insulin Action—Signal Transduction, 248‑LB Insulin, and Other Hormones SORCS1 and SORCS3 Cooperate in Regulation of Glucose Homeo‑ stasis 246‑LB AYGUL SUBKHANGULOVA, THOMAS WILLNOW, Berlin, Germany SORCS1 and SORCS3 are members of the VPS10P-domain receptor family, Effect of the Long-Acting Insulin Analogs Glargine and Degludec on a group of endocytic and sorting receptors genetically implicated in Alzheim- Cardiac Cell Signaling and Function er’s disease (Reitz et al., 2013). SORCS1 is also genetically associated with THORSTEN HARTMANN, NINA WRONKOWITZ, SABRINA GREULICH, MARGRIET diabetes in humans and mouse models, and was recently shown to have a OUWENS, PAULUS WOHLFART, NORBERT TENNAGELS, JUERGEN ECKEL, Düs- function in insulin granule replenishment (Kebede et al., 2014). Based on the seldorf, Germany, Frankfurt, Germany One important aspect for the long-term use of insulin analogs is cardio- close structural similarity of SORCS1 and SORCS3, we investigated possible vascular safety data. Insulin glargine has proven to be safe in the cardiovas- redundant functions of both proteins in control of glucose metabolism in a cular outcome ORIGIN trial, while for (IDeg) the outcome novel mouse model with combined deficiency for Sorcs1 and Sorcs3. Our ini- trial DEVOTE is ongoing. The aim of this study was to investigate insulin tial analysis documented an aggravation of phenotypes in the double mutant glargine (IGla), its active metabolite M1 (IGlaM1) and IDeg on signaling and line as compared to the Sorcs1 or Sorcs3 single mutant lines with glucose intolerance in young mice (10 weeks of age), even when fed a normal chow. contractility in three preclinical cardiovascular cellular models. In mouse -/- HL-1 cardiomyocytes, IDeg stimulation results in a lower Akt (Ser473) phos- In addition, Sorcs1/3 females showed an overall reduction in body weight, albeit at an increased fat mass. Circulating levels of hormones (insulin, C- phorylation compared with insulin IGla and IGlaM1 after 5- and 10-min in- -/- cubation. After 60-min treatment the phosphorylation was comparable to peptide, leptin, glucagon) were not different between Sorcs1/3 mice and insulin and IGlaM1. In freshly isolated adult rat ventricular cardiomyocytes their wild-type littermates. Since the brain is the main site of co-expression (ARVM), we observed similar increases in Akt (Ser473) phosphorylation with of SORCS1 and 3, we currently explore a function for both proteins in central insulin, IGlaM1 and IDeg after a single time point (10 min). Incubation of elec- control of energy homeostasis. trically paced ARVM with the different analogs resulted for all insulins in a significantly increased sarcomere shortening and similarly increased con- 249‑LB tractility and relaxation velocities. The positive inotropic effect of all insulins Insulin Increases Cerebral Blood Flow in Regions Involved in Hu‑ could be abrogated by the specific Akt inhibitor triciribine. In iPS-derived man Feeding and Executive Function human Cor.4U cardiomyocytes, cell viability and beating rate was monitored LISA PARIKH, RENATA BELFORT DE AGUIAR, CHERYL LACADIE, DONGJU SEO, with an impedance- based device up to 24 h. All insulins displayed no obvi- SARITA NAIK, JANICE J. HWANG, RAJITA SINHA, R. TODD CONSTABLE, ROBERT ous cardio-toxicity and slightly increased the rate of spontaneous beating S. SHERWIN, New Haven, CT 1.1-1.2-fold. In conclusion, we characterized for the first time the efficacy Insulin’s effect on human brain activity as measured by cerebral blood and safety of IGla, its metabolite M1 and IDeg, and demonstrated similar flow (CBF) remains unclear. Previous animal studies have shown an increase efficacy under steady-state-conditions compared with regular insulin. In HL- in CBF with insulin administration. Human studies using positron emission 1 cardiomyocytes, IDeg exhibited a slower on-set of action on Akt (Ser473) tomography detected no change in CBF after intravenous (IV) insulin infu- phosphorylation. Investigation may be needed to determine whether the ob- sion, while intranasal insulin increased insular cortex blood flow. To further served kinetic difference plays a role in more complex tissue models. evaluate the effect of IV insulin on CBF, we used functional MRI (fMRI) with Supported By: Sanofi-Aventis Deutschland GmbH pulsed arterial spin labeling to identify region-specific changes in CBF in humans. Sixteen healthy participants (INS group: age 29+/- 8 years, BMI 247‑LB 24 +/- 2 kg/m2, HbA1c 5.4 +/- 0.3, weight 68 +/- 10 kg) underwent a hyper- insulinemic-euglycemic clamp during an fMRI scan. They were compared to Identification of PP1 as an S/T-Phosphatase that Regulates AS160 α a control group of 16 subjects (CON group: age 28 +/- 8 years, BMI 22 +/- 2 Dephosphorylation in Skeletal Muscle kg/m2, HbA1c 5.1 +/- 0.3, weight 64 +/- 8 kg) that received an IV saline infu- PRAGYA SHARMA, GREG CARTEE, Ann Arbor, MI Akt substrate of 160 kDa (AS160; also known as TBC1D4) is a Rab GTPase sion during an fMRI scan. Cerebral blood flow was measured approximately activating protein and a key regulator of insulin-stimulated GLUT4 translo- 40 minutes after the infusion onset. Plasma glucose, insulin, and counter- cation and glucose transport in skeletal muscle. Akt’s phosphorylation of regulatory hormones were measured throughout both studies. At the time AS160 on T642 and S588 is essential for insulin’s full effect on glucose of CBF measurement, plasma insulin significantly differed between both transport. However, phosphorylation status of proteins depends on the bal- groups (INS group: 152 +/- 40 microunits/mL and the CON group: 13 +/- 10 ance of actions by kinases and , and the specific S/T-protein microunits/mL). There was a greater decline in glucagon in the INS vs. CON group (p=0.05). Other counterregulatory hormones did not differ. CBF was

phosphatase(s) controlling AS160 dephosphorylation is (are) unknown. Ac- cordingly, we assessed possible roles of highly expressed skeletal muscle greater in the anterior cingulate gyrus, left and right putamen, and medial S/T-phosphatases (PP1, PP2A, PP2B and PP2C) on AS160 dephosphorylation. frontal cortex in the INS group compared to CON group. This study shows Preliminary screening of the candidate phosphatases used an AS160 de- that elevations in circulating insulin increase CBF in a variety of brain regions phosphorylation assay: lysates from insulin-stimulated rat skeletal muscle that are involved in reward, learning, executive functioning, and eating be- underwent a time-course incubation with several chemical phosphatase havior. Thus, blood flow may serve as a potential biomarker of insulin’s effect

POSTERS on brain activity.

I nsulin Action/ inhibitors, followed by S588 and T642 dephosphorylation rates determined with AS160 phosphosite-specific antibodies. PP2B and PP2C inhibitors had

M olecular etabolism no effect on either site, but okadaic acid (which at low doses inhibits PP2A, 250‑LB and at high doses inhibits PP1) had dose-dependent effects (high > low dose) CD36 Mediates the Effects of Saturated and Unsaturated Fatty Ac‑ on both sites. Immunoprecipitation (IP) with anti-AS160 followed by im- ids on Insulin Sensitivity by Direct Interaction with Insulin Receptor munoblotting with antibodies against PP1 isoforms (α, β and γ) and PP2A Signaling Complex revealed only PP1α co-immunoprecipitated with AS160. We next performed DMITRI SAMOVSKI, SINJU SUNDARESAN, MEGHAN LAM, XIONG SU, NADA a dephosphorylation assay using recombinant inhibitor 2 protein (a selective ABUMRAD, St. Louis, MO PP1 inhibitor) and found delayed dephosphorylation on both sites. Subse- Elevated concentrations of saturated fatty acids (SFA) in plasma are as- quently, using L6 myocytes we performed co-IP analysis, and found specific sociated with insulin resistance in skeletal muscle and the development of AS160-association with PP1α, but not PP1β, PP1γ or PP2A. Finally, we used type 2 diabetes, while the increase in circulating polyunsaturated fatty acids siRNA to selectively deplete each PP1 isoform and found that knockdown (PUFA) is thought to improve insulin sensitivity and metabolic function. While of PP1α, but not PP1β and PP1γ, caused greater AS160 phosphorylation in several mechanisms were proposed to explain the role of SFA in the impair- insulin-stimulated L6 cells. In summary, the current study provided multiple ment of insulin signal transduction, the underlying molecular mechanisms lines of novel evidence that PP1α regulates AS160 dephosphorylation in that allow the discrimination between the SFA and PUFA and directly link skeletal muscle. them to regulation of insulin sensitivity have not been elucidated. Our recent Supported By: National Institutes of Health (DK071771) findings identify CD36 as a key regulator of signal transduction by fatty acids (FA). We show by co-immunoprecipitation experiments in cultured myotubes that CD36 is directly involved in formation of complexes consisting of CD36, insulin receptor, Fyn kinase, c-Cbl and PI3 kinase. Binding of saturated FA to CD36 resulted in acute (within 15 min) dissociation of the CD36/Fyn/c-Cbl/PI3K signaling complexes and suppressed insulin-induced

ADA-Funded Research For author disclosure information, see page LB98.

LB62 Integrated Physiology—Insulin Secretion In Vivo

Akt activation. Conversely, binding of PUFA to CD36 augmented the forma- 253‑LB tion of the signaling complexes and enhanced insulin-induced Akt activation. Outpatient Beta Cell Function (BCF) Testing Yields Comparable The effects of both SFA and PUFA were abolished in CD36-defeicent cells, Within-Subject Variability to Inpatient BCF Testing suggesting the direct role of CD36 in regulation of PI3K signaling pathway. DOUGLAS S. LEE, MARIA T. VASSILEVA, MYRLENE STATEN, SUDHA S. SHAN­ Insulin-induced activation of PI3K/Akt signaling was increased in skeletal KAR, R. PAUL ROBERTSON, RALPH RAYMOND, ROBERTO A. CALLE, DAVID A. muscle of CD36 -/- mice, suggesting that CD36 is involved in regulation of FRYBURG, FOR THE FOUNDATION FOR NIH BETA CELL PROJECT TEAM, Cam- insulin signal transduction in-vivo. Together, our findings document a novel bridge, MA, Bethesda, MD, Indianapolis, IN, Seattle, WA, Skillman, NJ, East Lyme, role for CD36 as an FA receptor that accounts for the different effects of SFA CT and PUFA on insulin signal transduction. We postulate that the persistent Prevailing practice to minimize variability in BCF testing is to admit sub- elevation in circulating SFA would suppress insulin signaling through CD36, jects as inpatients (IP) to ensure subjects have fasted and rested overnight while the increase in PUFA binding to CD36 would negate the negative ef- prior to study. However, this is a burden on subjects, requires housing, and fects of SFA and enhance insulin sensitivity. adds cost. Previous results from this group reported the repeatability (in- dexed by within subject coefficient of variation (WSCV)) of a mixed meal tolerance test (MMTT) and arginine stimulation test (AST) in IP subjects with Integrated Physiology—Insulin Secretion T2DM. We performed the present study to assess outpatient (OP) WSCV In Vivo and compare with earlier IP results. To do so, we assessed MMTT and AST WSCV in a different cohort of 20 OP, overnight fasted, T2DM subjects who 251‑LB had 2 MMTTs and 2 ASTs. We then compared WSCV of BCF tests in OP vs. Characterization of GPR40 Knockout Rats Generated by IP. For AST, acute insulin response to arg (AIRarg) was determined in first 5 Nucleases min post Arg (5 gm IV) followed by a 60 min infusion of glucose and repeat JIN SHANG, MYUNG SHIN, YUE FENG, SHENG-PING WANG, XIAODONG YANG, injection of Arg (AIRargMAX). Insulin secretory reserve (ISR)=AIRargMAX- JULIE LAO, NINA LI, JOHN MUDGETT, LIANGSU WANG, ANDREW HOWARD, AIRarg. For MMTT, a standardized 470kCal meal was used. MMTT param- Kenilworth, NJ eters include insulin sensitivity (Si); insulin release (Φtot); and disposition GPR40, a fatty acid sensing G protein coupled receptor, has emerged as a index (DItot (=Si* Φtot)). Table shows OP (and IP for comparison) parameter promising target for type 2 diabetes. Using the zinc finger nuclease technolo- geometric mean and CV values. OP WSCV, the key measure, was similar to gy, we created a Wistar-Hans rat model lacking GPR40 protein. The knockout IP WSCV for each parameter. rat carries a small deletion and insertion with a stop codon, resulting in the Conclusion: These BCF measures can be used for repeat testing as OP and premature truncation of the GPR40 protein at the region of TM2. To confirm not require IP admission. that the knockout rat is devoid of GPR40 activity, IPGTT was performed with Table. a GPR40 selective agonist. Significant reduction in glucose excursion was observed in wild-type littermate rats but not in the homozygous knockout rats. We further examined pancreatic islets isolated from both knockout and wild-type rats. The effect on enhancing glucose-dependent insulin secretion by a GPR40 selective agonist was seen in the islets isolated from wild-type but not from the GPR40 knockout rats. Gene expression analysis confirmed that the targeted deletion region of GPR40 was not expressed in islets. Further, the mRNA expression levels of insulin, GLP-1R or GPR120 were not altered in the islets of GPR40 knockout rats. The Glucose, lipid and energy homeostasis in homozygous GPR40 null rats was characterized in com- parison with wild type littermate controls with either chow or high-fat diet feeding. Taken together, our studies demonstrate that the ZFN-generated GPR40-/- rat will be a valuable tool for investigating GPR40 biology, and for determining whether beneficial effects as well as safety liability mediated by GPR40 agonists are mechanism-based. Supported By: Foundation for the National Institutes of Health Biomarkers 252‑LB Consortium Long-Term Regulation of Glycemia in Rhesus Monkeys on Caloric Restriction or Eating Ad Libitum 254‑LB JOSEPH W. KEMNITZ, HELENA M. DZIADOWICZ, SHEILA GHANIAN, ROZALYN A New Model-Based Method for Estimating Hepatic and Peripheral M. ANDERSON, RICHARD WEINDRUCH, RICKI J. COLMAN, Madison, WI Insulin Clearance from Intravenous Glucose Tolerance Test Data For the past 25 years we have been assessing glycemic regulation in co- DAVID POLIDORI, RICHARD N. BERGMAN, ANNE SUMNER, San Diego, CA, Los horts of male and female rhesus monkeys to evaluate the effects of moder- Angeles, CA, Bethesda, MD ate caloric restriction (CR) on healthspan and lifespan. Beginning ~10 yr of Insulin clearance is an important factor in the regulation of plasma insulin age (median lifespan ~26 yr) all subjects were fed a purified diet containing concentrations and insulin action. Common methods for estimating clearance 15% protein (lactalbumin), 10% fat (corn oil) and ~65% carbohydrate (su- involve measuring plasma insulin during hyperinsulinemic clamps or insulin- crose, starch and dextrin), supplemented daily with fresh fruit or vegetables. modified frequently sampled intravenous glucose tolerance tests (FSIGT) and

Control monkeys (C, n=38 initially, 3 currently surviving) were fed amounts of then using the insulin infusion rate to calculate clearance. These methods do purified diet to allow unlimited access for ~8 hr/day. Restricted monkeys (R, not provide information on the relative contributions of hepatic or peripheral n=38, 10 currently surviving) were fed 20-30% of their individualized base- clearance or an estimate of clearance for endogenous insulin secretion. We line level of intake, subsequently adjusted for changes in intake by C except developed a mathematical model that utilized both C-peptide and insulin to maintain health as indicated. Fasting glucose (Gb) and insulin (Ib) concen- measurements during FSIGT to estimate endogenous insulin secretion and I ntegrated trations were measured semi-annually and additional parameters by FSIGT both hepatic and peripheral insulin clearance. Data from 101 black subjects POSTERS (mean (SD) BMI = 28 (4) kg/m2, age = 38 (10) yr, fasting insulin = 42 (60) and minimal modeling at 6-mo (0-10 yr), annually (11-15 yr) and bi-annually Physiology/Obesity -4 -1 -1 (16 yr - present). Mean values of survivors over time (decreasing n’s) for Gb pM, SI = 3.9 (2.4) ∙ 10 (µU/ml) min ) were analyzed. The model provided an and Ib were consistently higher for C than R (p<0.02). Insulin sensitivity (SI) excellent fit to the observed data (Figure; mean r2 = 0.88 for individual fits). and disposition index (DI) steadily declined with advancing age for both Model-estimated clearance for IV- (1.7 (0.7) L/min) and portally-delivered groups, but were greater for R (p<0.05), and glucose tolerance (KG) tended (2.5 (1.1) L/min) insulin were 80-170% higher than IV clearance estimated to be improved for R (p=0.1). Insulin response to glucose (AIRG) did not differ from previous FSIGT method (0.9 (0.5) L/min). Clearance for both IV and between groups. During the course of study, 14 C exhibited persistent Ib portal insulin delivery were correlated with insulin sensitivity (Figure). The greater than 90th percentile of baseline average and 5 developed fasting method provides a promising new approach for estimating insulin clearance hyperglycemia; only 5 and 2 of R showed these impairments, respectively. in clinical studies. Glycemic regulation was enhanced and preserved throughout adulthood by moderate restriction of a relatively high sugar diet.

ADA-Funded Research For author disclosure information, see page LB98.

LB63 Integrated Physiology—Liver

257‑LB Orphan Estrogen-related Receptor gamma Medi‑ ates Homocysteine-induced 11β-hydroxysteroid Dehydrogenase1 Expression in Liver KWI-HYUN BAE, AE-KYUNG MIN, JAE-HAN JEON, SUNG-WOO KIM, DONG- WOOK KIM, IN-KYU LEE, KEUN-GYU PARK, Daegu, Republic of Korea 11β-Hydroxysteroid dehydrogenase1 (11β-HSD1), an enzyme converting inactive cortisone to active cortisol, is one of the most promising target for the treatment of metabolic syndrome including diabetes, obesity and fatty liver. Hyperhomocysteinemia is associated with diabetes and dia- betic complications, considering as an independent risk factor for cardio- vascular diseases. Although homocysteine-induced endoplasmic reticulum (ER) stress has been proposed to explain the pathological changes in di- Integrated Physiology—Liver verse disease models, the precise mechanisms are still largely unknown. In the present study, we investigated whether homocysteine-induced ER 255‑LB stress leads to transcriptional activation of the estrogen-related receptor The RNA Binding Protein Tristetraprolin Regulates Hepatic Metab‑ γ (ERRγ) and 11β-HSD1. We found that homocysteine induced ER stress olism and the Development of Diabetes response related markers, ERRγ and 11β-HSD1expression in H4IIE cells. KONRAD T. SAWICKI, MARINA BAYEVA, HSIANG-CHUN CHANG, ADAM DEJE- Tunicamycin and thapsigargin known as ER stress inducers increased he- SUS, ANTHONY LEONARDI, HOSSEIN ARDEHALI, Chicago, IL patic ERRγ and 11β-HSD1 expression in cultured hepatocytes. To exam- Diabetes is associated with extensive metabolic dysfunction, particularly ine the potential role of ERRγ in hepatic 11β-HSD1 expression, ERRγ was in glucose and fatty acid metabolism. Tristetraprolin (TTP) is a zinc finger over-expressed or knock-downed by adenovirus expressing ERRγ or siRNA protein that binds to AU-rich elements in the 3’-untranslated region (UTR) against ERRγ, respectively. Overexpression of ERRγ significantly increased of target mRNAs, resulting in their degradation. The yeast homologs of 11β-HSD1 expression, whereas knockdown of ERRγ expression attenuated TTP were recently shown to regulate the mRNAs of metabolic enzymes, homocysteine-mediated induction of 11β-HSD1 expression. Moreover, an and clinical studies have linked TTP expression to metabolic syndrome in inverse agonist of ERRγ, GSK5182, ameliorated homocysteine-mediated human patients. We hypothesized that TTP protects against the develop- 11β-HSD1 induction. In conclusion, this study shows that ERRγ mediates ment of diabetes by promoting glucose oxidation through downregulation of homocysteine-induced hepatic 11β-HSD1 expression, and suggests a novel pyruvate dehydrogenase kinase 4 (PDK4) and reducing FA oxidation through mechanism by which hepatic 11β-HSD1 transcription is mediated under hy- downregulation of peroxisome proliferator activated receptor (PPAR)-α in perhomocysteinemia. The present study suggests that ERRγ inhibitors such the liver. TTP protein and mRNA levels were significantly reduced in the liv- as GSK5182 has potential metabolic benefits by ameliorating homocysteine ers of db/db and high-fat diet fed mice compared to controls, suggesting induced hepatic 11β-HSD1 expression. that the mRNA targets of TTP may be stabilized in diabetes. Primary hepa- tocytes from TTP KO mice demonstrated increased PPARα mRNA, a major 258‑LB regulator of lipid metabolism compared to control mice. Consistent with Pemt Deficiency Promotes Steatohepatitis through Sustained increased PPARα, rates of lipid uptake and β-oxidation were increased in Apoptosis via Clathrin Heavy Chain- Mediated Transcriptional primary hepatocytes isolated from TTP KO compared to control mice. PPARα Mechanisms mRNA was also significantly stabilized in TTP KO compared to control cells, ATSUKO NAKATSUKA, KAZUTOSHI MURAKAMI, NUNOUE TOMOKAZU, SATOSHI suggestive of post-transcriptional regulation by TTP. Primary hepatocytes YAMAGUCHI, JUN EGUCHI, DAISUKE OGAWA, JUN WADA, Okayama, Japan from TTP KO mice also demonstrated increased PDK4 mRNA, a key regulator N-methyltransferase (pemt) catalyzes the of glucose utilization. Consistent with increased PDK4, lactate content was conversion of phosphathidylethanolamine to phosphatidylcholine, which is increased in primary hepatocytes from TTP KO compared to control mice. In critical pathway for lipoprotein metabolism, stability of cellular membranes, silico analysis revealed multiple well-conserved putative TTP-binding sites and de novo choline production in the liver. We identified pemt as one of the in the 3’UTR of PPARα and PDK4, consistent with the possibility of direct highly up-regulated genes in obese mice by DNA chip. To investigate the regulation of mRNA stability by TTP. We show that TTP is downregulated in role of pemt in metabolic syndrome, we generated pemt knockout mice and the of diabetic mice, and that TTP KO in primary hepatocytes increases subjected to high-fat high-sucrose (HF) diet. Although pemt-/- mice showed the levels of key metabolic enzymes, PDK4 and PPARα, both of which are obesity resistant phenotype and normal insulin sensitivity under HF diet, implicated in diabetes. prominent steatohepatitis with multiple tumors was observed. In the liver Supported By: National Institutes of Health (F30DK102341 to K.T.S.) of pemt-/- mice under HF, TUNEL-positive apoptosis cells were increased. Histologically, accumulation of F4/80-positive macrophages and enhanced 256‑LB fibrosis were also observed in pemt-/- mice under HF compared with Hepatokine IGFBP-2 Is Increased by PPARα during Fasting pemt+/+. Next, we found the novel localization of pemt in the nuclei besides SEUNG-SOON IM, JAE-HOON BAE, DAE-KYU SONG, BYUNG-CHUL OH, JI-YOUNG the known cellular distribution in endoplasmic reticulum. By using nuclear CHA, Daegu, Republic of Korea, Incheon, Republic of Korea extracts of the liver, clathrin heavy chain (CHC) was identified as an interac- Insulin-like growth factor (IGF)-binding protein-2 (IGFBP-2), one of the tive molecule with pemt by immunoprecipitation and subsequent LC-MS/ most abundant circulating IGFBPs, is known to attenuate the biological ac- MS analysis. We also found that pemt forms a complex with p53 and CHC tion of IGF-1. Although the effect of IGFBP-2 in preventing metabolic disorder by immunoprecipitation and western blot analysis. Overexpression of pemt

is well known, its regulatory mechanism remains unclear. Herein, we dem- suppressed p53 mediated transcriptional activity by luciferase reporter as- onstrated the transcriptional regulation of the IGFBP-2 gene by peroxisome say. In turn, the expressions of p53-target genes; cleaved caspase 3, Bax, proliferator-activated receptor (PPAR) α in the liver. During fasting, both and p21 were increased in the liver of pemt-/- mice under HF. Our investi- Igfbp-2 and PPARα expressions increased. Wy14,643, a selective PPARα gation revealed the deficiency of pemt resulted in increased expression of I ntegrated POSTERS agonist, significantly induced IGFBP-2 gene expression in primary cultured CHC, which has been reported to promote tumor growth and angiogenesis. hepatocytes. However, IGFBP-2 gene expression in Pparα null mice was In conclusion, pemt deficiency and subsequent facilitation of CHC-p53 tran- Physiology/Obesity not affected by either fasting or Wy14,643. In addition, through transient scriptional pathways continuously promote hepatocyte apoptosis, tissue transfection and chromatin immunoprecipitation assay in fasted livers, we inflammation, and fibrosis, which ultimately lead to steatohepatitis. determined that PPARα bound to the putative PPAR-response element be- tween -511 bp and -499 bp on the IGFBP-2 gene promoter, indicating that the 259‑LB IGFBP-2 gene transcription is directly activated by Pparα. To explore the role NF-kB Inhibits Hepatic Insulin Sensitivity by Upregulation of cAMP of Pparα in IGF-1 signaling, we treated primary cultured hepatocytes with JIANPING YE, BILUN KE, ZHIYUN ZHAO, VINCENT MANGANIELLO MANGANI­ Wy14,643 and observed a decrease in the number of IGF-1 receptors and ELLO, BIN WU, Baton Rouge, LA, Bethesda, MD, Guangzhou, China in Akt phosphorylation. No inhibition was observed in the hepatocytes iso- Inflammation regulates glucose and fatty acid metabolism in liver. How- lated from Pparα null mice. These results suggest that PPARα controls IGF-1 ever, the signaling pathway remains to be characterized. To this point, we signaling through the upregulation of hepatic IGFBP-2 transcription during tested the role of transcription factor NF-kB in liver by inactivating the sub- fasting and Wy14,643 treatment. unit p65 (RelA) gene. Liver p65 knockout mice (L-p65-KO) were generated in Supported By: Korea Healthcare Technology R&D Project (A120864)

ADA-Funded Research For author disclosure information, see page LB98.

LB64 Integrated Physiology—Liver

C57BL/6 gene background by crossing floxed p65 and Alb-cre mice. The NF- were significantly increased in the LIRKO model, both mRNA and protein kB inactivation did not alter growth, reproduction and body weight in mice levels returned to low levels in mice lacking both liver insulin receptor and on the regular chow or a high fat diet (HFD). In KO mice, systemic insulin sen- Fox01 (LIRFKO): a) mRNA: (LIRKO 70.5±14.3 vs. LIRFKO 1.0±0.2, p=0.004, sitivity was improved on HFD as indicated by insulin and glucose tolerance. n=6); b) protein: (LIRKO 125.5±20.6 vs. LIRFKO 5.9±0.8, p=0.0006 n=6). In Hepatic insulin sensitivity was enhanced as indicated by increased pyruvate agreement with a role for serpinB1 in β-cell growth, LIRFKO mice exhibit re- tolerance, Akt phosphorylation and decreased expression of gluconeogenic duced β-cell area (control 0.5±0.04 vs. LIRKO 1.75±0.35, p=0.01; control vs. genes in hepatocytes. In liver of KO mice, a decrease in intracellular cAMP LIRFKO 0.6±0.08%, p=0.4, n=5-6) due to attenuation of β-cell proliferation was observed with reduced CREB phosphorylation. An increase in cAMP as revealed by Ki67 staining (control 0.55±0.02 vs. LIRKO 2.0±0.43, p=0.03; clearance was observed with increased activity of cyclic nucleotide phos- control vs. LIRFKO 0.38±0.08% Ki67+ β-cells, p=0.1, n=5-6). Together, these phodiesterase 3B (PDE3B), whose expression was enhanced in mRNA and data implicate Fox01 as a regulator of serpinB1 in mediating β-cell compen- protein. p65 was found to mediate TNF-α activity to inhibit expression of satory response to insulin resistance. PDE3B gene at three NF-kB binding sites in the PDE3B gene promoter. Body composition, food intake, energy expenditure, systemic and hepatic inflam- 262‑LB mation were not significantly altered in KO mice on HFD. These data suggest Perilipin 5 Phosphorylation in Lipolysis of Nonadipocytes that in inflammatory responses, NF-kB may inhibit hepatic insulin sensitiv- MICHELLE B. TREVINO, TIMOTHY KING, SO HYUN PARK, YUI MACHIDA, SUCHA- ity by up-regulation of cAMP pathway through suppressing transcription of RITA DUTTA, YUMI IMAI, Norfolk, VA PDE3B gene. Adipocytes increase lipolysis through (PKA) mediated Supported By: DK068036 phosphorylation of perilipin (PLIN) 1 that increases access and activity of li- pases at lipid droplets (LD). In non-adipocytes such as hepatocytes and beta 260‑LB cells, lipolysis and resultant metabolites are critical for provision of energy Leucine Synergizes with Phosphodiesterase 5 (PDE5) Inhibitors and and for cellular signaling including PPARa activation and augmentation of Metformin to Reverse Hepatic Lipid Accumulation and Inflammation insulin secretion. However, the regulation of lipolysis in these cells without and Treat Nonalcoholic Fatty Liver Disease (NAFLD) PLIN1 is poorly understood. PLIN5 is a LD protein increased in beta cells and LIZHI FU, FENFEN LI, QIANG CAO, XIN CUI, BINGZHONG XUE, HANG , ANTJE hepatocytes in fasted mice when lipolysis is important (Trevino MB, Diabetes BRUCKBAUER, MICHAEL B. ZEMEL, Atlanta, GA, Knoxville, TN in press). Here, we report that serine155 (S155) of mouse PLIN5 is phospho- Sirt1 and AMPK regulate hepatic lipid and energy metabolism and are rylated (P-PLIN5) in vivo in response to nutritional cues, and PKA resistant therapeutic targets for NAFLD. We previously demonstrated that L-leucine S155 mutant (S155A) blunts lipolysis and expression of genes regulated by (leu) has a unique role as an allosteric activator of Sirt1, enabling synergy PPARa. When P-PLIN5 was assessed in the liver from fed and 24h fasted with metformin (met) to increase insulin sensitivity and reverse NAFLD in C57BL6 male mice by LC/ESI-MS/MS (Q-Exactive, Thermo Fisher), S155 mice. PDE5 inhibitors converge on the Sirt1/AMPK pathway via eNOS/NO phosphorylation (P-S155) was increased to 2.5 fold (p<0.005) in fasted liver signaling, and leu also synergizes with sildenafil (sild) to inhibit both steato- in which cAMP level is elevated from glucagon. PKA dependence of P-S155 sis and inflammation. Here we demonstrate the potential for multi-compo- was confirmed in primary hepatocytes expressing PLIN5; PKA inhibitor H89 nent activation of this pathway with leu (0.5 mM), met (10 M) and sild (1 nM) reduced the rise of P-S155 by cAMP analog (1mM 8-Br-cAMP, p<0.005). In to yield greater therapeutic efficacy in NAFLD. Leu-met-sild activated Sirt1 beta cells, cAMP increases postprandially in response to glucose and GLP- to a greater degree than leu-met or leu-sild, resulting in markedly greater 1. Expectantly, S155/P-S155 ratio was 5.3 fold (p<0.05) in islets from mice stimulation of hepatocyte fat oxidation (~60%, p<0.01) and inhibition of refed 1h after fasting compared with fasted mice. S155A PLIN5 expressed in palmitate-induced triglyceride accumulation (~70%, p<0.001). To evaluate AML12 cells blunted an increase in lipolysis upon 1mM 8-Br-cAMP treatment this synergy in vivo, non-alcoholic steatohepatitis (NASH) was induced in (p<0.05) in agreement with recent data in COS7 cells (JBC 2015:290:1295). mice via high fat diet supplemented with cholesterol and cholate (HF/ATH Finally, 1mM 8-Br-cAMP increased the expression of PPARa and its target diet); mice were then treated with combinations of leu (24 g/kg diet), met genes in AML12 cells expressing WT PLIN5, while the response was blunted (0.25 g/kg diet; <20% of therapeutic dose) and sild (25 mg/kg diet; <10% in S155A AML12 cells. The above data along with our recent data (Trevino therapeutic dose). The HF/ATH diet caused a ~6-fold increase in alanine ami- MB, Diabetes in press) support a model that P-PLIN5 regulates lipolysis in notransferase (p<0.0001) which was modestly reduced by leu-met and leu- non-adipocytes aiding a switch in lipid metabolism during fasting in the liver sild (30-40%, p<0.01) and further reduced by leu-met-sild (60%, p<0.0001). and postprandial insulin secretion in beta cells. The HF/ATH diet also caused increases in liver mass and a marked increase Supported By: National Institutes of Health (R01DK090490, R01DK090490- in liver fat content (~7-fold, p<0.0001). Leu-met and leu-sild elicited modest 02W1) reductions in both, while the leu-met-sild combination reduced liver mass (p<0.003) and liver fat to a significantly greater degree (38%, p=0.02). These 263‑LB data demonstrate preclinical therapeutic potential for leucine combined ApoA1 Knockout Mice Manifest Decreased Energy Expenditure and with sub-therapeutic levels of metformin and sildenafil in the treatment of Are Prone to High-fat Diet-induced Whole-Body Insulin Resistance NAFLD and NASH. JOAO-PAULO G. CAMPOREZ, VARMAN T. SAMUEL, KITT F. PETERSEN, MICHAEL J. JURCZAK, GERALD I. SHULMAN, New Haven, CT 261‑LB Alterations in the expression of Apolipoprotein C3 (ApoC3) and A5 (ApoA5) Fox01 Regulates Hepatic SerpinB1 Gene Expression and Partici‑ have both been shown to have effects on ectopic lipid deposition as well as pates in Compensatory β-Cell Growth Response to Insulin Resis‑ insulin action in mice and humans. However, whether alterations in Apolipo- tance protein A1 (ApoA1) expression can also alter ectopic lipid deposition and in-

ABDELFATTAH EL OUAAMARI, INSUG O-SULLIVAN, WENWEI ZHANG, SHAN- sulin action is unknown. In order to address this question we studied ApoA1 SHAN XU, CHONG WEE LIEW, TERRY G. UNTERMAN, ROHIT N. KULKARNI, Bos- knockout (KO) mice or wild type (WT) mice fed a high-fat diet. ApoA1 KO mice ton, MA, Chicago, IL displayed an ~80% increase in body fat compared with WT mice (P<0.001). We previously reported that adaptive β-cell growth in response to insulin Associated with the increased body fat, KO mice displayed a ~15% reduction resistance is mediated by hepatic factors in the liver-specific insulin recep- in energy expenditure (P<0.01). ApoA1 KO mice displayed a ~40% decrease I ntegrated tor knockout (LIRKO) mouse. Using differential proteomics, we identified in plasma triglycerides (TAG) (P<0.001) and a ~80% decrease in plasma cho- POSTERS the factor as serpinB1. Here we report that the lesterol (P<0.001), associated with a ~25% decrease in liver VLDL export (Fox01) is a transcriptional regulator of serpinB1. Liver-specific expression (P<0.001). In addition, KO mice displayed increased TAG and diacylglycerol Physiology/Obesity of constitutively active Fox01 in transgenic mice (Tg) induced a dramatic (DAG) content in both liver (~140% and ~45%, P<0.01) and skeletal muscle increase in hepatic serpinB1 mRNA (Tg 25.4±2.8 vs. control 1.5±0.2, p=0.01, (~115% and ~70%, P<0.01). Consistent with increased DAG content, PKCε n=3-4) and protein (Tg 5.7±0.5 vs. control 0.9±0.1, p=0.008, n=3-4) levels. activation in liver and PKCθ activation in muscle were increased by ~60% Consistent with a role for Fox01 in fasting/feeding states, 18h-starved (P<0.01) and ~35% (P<0.01), respectively, in KO mice. To assess whole-body mice show enhanced hepatic serpinB1 gene expression when compared to insulin sensitivity, euglycemic-hyperinsulinemic clamps were performed. mice re-fed for 6h after fasting (fasted 8.3±1.0 vs. refed 1.5±0.3, p=0.005, The glucose infusion rate (GIR) was ~45% less in KO mice compared with n=3-4). The stimulatory action of fasting on serpinB1 mRNA levels was control mice (P<0.01), demonstrating impaired whole body insulin sensitiv- blunted in mice lacking FOXO proteins in the liver (WT-fasted 8.3±1.0 vs. ity in KO mice. This reduction in GIR was accounted by both reductions in KO-fasted 1.9±0.7, p=0.004, n=3-4). Furthermore, while hepatic expression whole-body glucose uptake (~15%, P<0.05) and suppression of endogenous of serpinB1 mRNA (control 1.6±0.3 vs. LIRKO 70.5±14.3, p=0.005, n=5-6) glucose production (~65%, P<0.001) compared with WT mice. In conclusion, and protein (control 10.3±5.6 vs. LIRKO 125.5±20.6, p=0.0004, n=5-6) levels these data demonstrate that absence of ApoA1 in mice promotes reductions

ADA-Funded Research For author disclosure information, see page LB98.

LB65 Integrated Physiology—Macronutrient Metabolism and Food Intake

in both plasma TAG and cholesterol concentrations but exacerbates high-fat Integrated Physiology—Macronutrient feeding-induced liver and muscle insulin resistance by decreasing energy Metabolism and Food Intake expenditure and increasing ectopic lipid content (TAG/DAG) in both liver and muscle, leading to increased PKCε and PKCθ activation in these organs. 266‑LB Loss of Insulin Receptors in Vascular Endothelial Cells Reduces In‑ 264‑LB sulin Signaling in Brain and Peripheral Tissues Maternal Malnutrition Induces Defective Autophagy Leading to MASAHIRO KONISHI, MASAJI SAKAGUCHI, WEIKANG CAI, CHRISTIAN RASK- Glycogen Accumulation in the Liver of Newborn Wistar Rats MADSEN, C. RONALD KAHN, Boston, MA JUAN DE TORO-MARTÍN, ELISA FERNÁNDEZ-MILLÁN, ESTHER LIZÁRRAGA- Insulin resistance is central to the pathophysiology of obesity, type 2 dia- MOLLINEDO, FERNANDO ESCRIVÁ-PONS, CARMEN ÁLVAREZ-ESCOLÁ, Madrid, betes and metabolic syndrome. Recent data indicate that insulin resistance Spain is also present in neurodegenerative diseases like Alzheimer’s disease. Dys- Among the mechanisms by which an adverse intrauterine environment function of insulin signaling in vascular endothelial cells may be a component could increase the susceptibility to develop type 2 diabetes in the adulthood, of insulin resistance. However, the effects of vascular insulin resistance on defective hepatic autophagy has emerged as a potential contributor to this insulin action in brain and other tissues are not fully understood. In this pathology. We then focused this work on glycogen autophagy during the study, we investigated effects of insulin receptor (IR) knockout specifically perinatal period. We developed a model of global food-restriction achieved in vascular endothelial cells (EndoIR-KO mice) by breeding mice with a cre by restricting maternal nutrition from the last third of gestation onwards transgene driven by the VE-Cadherin promoter and IRlox/lox mice. Following to 35% of ad libitum intake. A caesarean was practised just before birth intravenous insulin injection (5U), phosphorylation of IR and Akt in interscap- and changes in liver glycogen and in autophagic markers were measured ular BAT and soleus muscle was decreased in EndoIR-KO by 66% and 58%, during the first 3 and 6h of life. No caloric intake was permitted, and the respectively, while signaling in liver was not altered. In control mice, insulin newborns were maintained at 37º C. At birth, offspring from undernourished also induced phosphorylation of IR in the prefrontal cortex, hippocampus and dams (U) exhibited increased liver glycogen (2.5-fold) content than controls hypothalamus, and these were attenuated in EndoIR-KO mice by 46%, 90% (C). The amount of liver glycogen precipitously diminished at 3 and 6h in C and 82% with no change in IR protein levels. In EndoIR-KO mice, food intake rats whereas it remained significantly elevated in U neonates, which also was greater than control by 18% under random fed. In addition, the glucose- showed a lower phosphorylation of AMPKα at both 3 and 6h. Consequently, lowering response to intraperitoneal insulin injection (0.75 U/kg) was sig- mTOR activation was enhanced in U livers. Atg7 was significantly decreased nificantly delayed (latency of half-maximal reduction: 10.1±1.2 vs. 23.4±5.0 at both times in U livers. Importantly, C livers showed a marked induction of min in control and EndoIR-KO), while maximal glucose reduction levels were LC3BII conversion between 3 and 6h while in U animals LC3 lipidation was similar. Thus, loss of IR specifically in vascular endothelial cells negatively markedly reduced. Impairment of the autophagic flux was confirmed by the affects insulin signaling and functions in brain, skeletal muscle and fat, but accumulation of p62 in the liver of U rats. In agreement with the increased not liver. These results suggest that transendothelial transit of circulating autophagic activity in C neonates, quantitative electron microscopy showed insulin via insulin receptors in vascular endothelial cells is a rate-limiting abundant autophagic vesicles containing glycogen and almost no cytoplas- factor for onset of insulin action, especially in brain, skeletal muscle and fat mic glycogen in C livers. In contrast, the number of autophagic vesicles was which are separated from the circulation by vascular endothelial cells with clearly reduced in U newborns after 6h of fasting and vast areas of cytoplas- tight junctions preventing rapid access of insulin to the target cells. mic glycogen were observed. These results highlight that maternal undernu- Supported By: National Institutes of Health (R01DK031036) trition lead to defective hepatic autophagy in the offspring and consequently could compromise hepatic metabolic function, favouring insulin resistance development in the adulthood. 267‑LB Supported By: MINECO (BFU2011/25420); CIBERDEM (ISCIII); CAM (S2010/ CD47 Regulates Adipose Tissue Lipolysis by Suppressing cGMP/ BMD-2423) PKG Signaling HEATHER L. NORMAN-BURGDOLF, SHUXIA WANG, Lexington, KY CD47 is a ubiquitously expressed transmembrane cell receptor involved 265‑LB in immune cell regulation, self-recognition, and cell signaling. Specifically, Targeted Induction of Ceramide Degradation Reveals Roles for Ce‑ CD47 regulates the cyclic GMP (cGMP)/protein kinase G (PKG) pathway by ramides in Nonalcoholic Fatty Liver Disease and Glucose Metabo‑ suppressing soluble guanylyl cyclase (sGC)-dependent activation of cGMP lism and downstream PKG activity. Recently, this specific pathway has been JONATHAN XIA, WILLIAM HOLLAND, PHILIPP SCHERER, Dallas, TX identified as a key regulatory mechanism for the browning phenomenon as- Sphingolipids have garnered attention for their role in insulin resistance sociated with healthy adipocyte function including lipolysis, mitochondrial and lipotoxic cell death. Aberrant accumulation of ceramides correlates with biogenesis, and UCP1 activation. Although CD47 has been well character- hepatic insulin resistance and steatosis. We recently demonstrated that the ized in cancer and ischemia models, adipose tissue expression has never insulin sensitizing and cytoprotective actions of adiponectin are linked to the been explored. In the current study we determined the effect of CD47 on deacylation of ceramides, mediated by adiponectin receptors. To further in- adipocyte lipolysis. First, male 8-week old CD47 deficient and wildtype (WT) vestigate the tissue-specific effects of local changes in ceramidase activity, littermate controls were exposed to a cold tolerance test (CTT, 4° C) for 6 we have developed transgenic mice inducibly expressing acid ceramidase, hours and plasma free glycerol levels were measured. Ex vivo lipolysis of to trigger the deacylation of ceramides. This represents the first inducible both perigonadal and subcutaneous depots from either CD47 deficient or genetic model that acutely manipulates ceramides in adult mouse tissues, WT mice in basal or 10uM isoproterenol-treated conditions were assayed. allowing us to directly assess the impact of ceramide lowering on insulin In addition, in vitro studies with fully differentiated 3T3-L1 cells treated with

sensitivity. Hepatic overexpression of acid ceramidase prevents hepatic a combination of cGMP agonist and/or CD47 functional blocking antibody steatosis and prompts improvements in insulin action in liver and adipose were completed. We found that CD47 deficient mice had a significant in- tissue. Conversely, overexpression of acid ceramidase within adipose tissue crease in plasma free glycerol after 6-hour CTT (p<.05). Similarly, CD47 de- prevents hepatic steatosis and insulin resistance. Induction of ceramidase ficient perigonadal (p=.0514) and subcutaneous (p<.01) tissue explants had activity in either tissue promotes a lowering of hepatic ceramide and re- elevated free glycerol release with both vehicle and 10uM isoproterenol I ntegrated POSTERS duced activation of the ceramide-activated atypical protein kinase C isoform treatments compared with WT tissue explants. In vitro data showed dif- PKC-zeta. Ceramides induce hepatic lipid uptake via PKC-zeta induced acti- Physiology/Obesity ferentiated 3T3-L1 cells treated with either 8-cCPT-cGMP and/or anti-CD47 vation of CD36, thereby promoting hepatic steatosis. These observations blocking antibody exhibited increased lipolysis compared to controls (p<.05). suggest the existence of a rapidly acting “cross-talk” between liver and These studies suggest CD47 plays a novel role in regulating adipocyte lipoly- adipose tissue sphingolipids, critically regulating glucose metabolism and sis specifically by suppressing cGMP/PKG signaling. hepatic lipid uptake. Supported By: T32DK007778-14 Supported By: R01DK55758, 1P01DK088761, F30DK100095091

ADA-Funded Research For author disclosure information, see page LB98.

LB66 Integrated Physiology—Muscle

268‑LB 270‑LB T Lymphocytes Are Critically Involved in Diet-induced Lipid Me‑ Pyruvate Dehydrogenase Kinase 4 Mediates Free Fatty Acid-in‑ tabolism in the Liver duced Mitochondrial Dysfunction and Insulin Resistance in Skel‑ MARIA MOISIDOU, SEVASTI KARALIOTA, KOSTANTIA KODELLA, ELISAVET etal Muscle: Identification of aN ovel Regulator of Insulin Signaling KODELLA, STAMATIS THEOHARIS, DIMITRIS SKOKOS, MARK SLEEMAN, KATIA by Quantitative Proteomics KARALIS, Athens, Greece, Tarrytown, NY, Melbourne, Australia KENTARO MURAKAMI, MASAKI YAMABI, MASAYUKI OHTA, MALLARY HOIDAL, Hepatic deposition of lipids, or liver steatosis, is a cardinal sign of starva- MARY C. WHELAN, IWAO YAMADA, PIERO RICCHIUTO, MASANORI AIKAWA, tion as well as hypercaloric diets, such as high-fat diet, and obesity. Emerg- SASHA SINGH, KEN MIZUNO, Boston, MA ing evidence demonstrates the critical role of immune cells in metabolic Increased levels of free fatty acids (FFA) in plasma are associated with processes, and the impact of immunometabolism in the pathogenesis of a insulin resistance-related disorders and diseases such as obesity and type 2 variety of diseases. The aim of this study was to elucidate the role of lym- diabetes mellitus (T2DM). These high levels of plasma FFA play an important phocytes in diet-induced non-alcoholic fatty liver disease, NAFLD. Histology role in the development of insulin resistance. Although the evidence sug- of the livers of Rag1-/- mice, either following starvation for 24hrs or high-fat gests that mitochondrial dysfunction by FFA in skeletal muscle cells play diet for ten weeks, had normal morphology. In contrast, profound steato- an important role in insulin signaling impairment, the mechanisms involved sis was detected in the livers from wild-type mice following either dietary in insulin resistance induced by FFA remain incompletely understood. To intervention. Gene expression analysis of liver tissues identified activation determine how FFA induces mitochondrial dysfunction and impairs insulin of genes involved in lipid oxidation pathway in the Rag1-/- and significant signaling in skeletal muscle, we isolated mitochondrial proteins from C2C12 decrease of genes involved in the glyconeogenesis pathway, compared to myotubes treated with palmitate, oleate, or bovine serum albumin (control) the wild type mice. In support of the above, indirect calorimetry analysis for 24 hours before insulin stimulation, and performed quantitative pro- under normal feeding states showed significant decrease in the respiratory teomic analysis using the isobaric tandem mass tagging system (TMTTM). exchange ratio of the Rag1-/- mice, reflecting more efficient lipid versus Palmitate significantly increased or decreased 226 mitochondrial proteins carbohydrate utilization. Adoptive transfer of CD8+, but not CD4+, T cells in C2C12 myotubes. Specifically, palmitate stimulation markedly induced rescued the phenotype of the Rag1-/- liver indicating the critical role of these pyruvate dehydrogenase kinase 4 (PDK4) (1.6-fold vs. control). Moreover, en- cells in lipid metabolism in the liver. The mechanism(s) driving this effect are forced expression of PDK4 decreased phopsphorylation of AKT (pAKT/AKT, still unclear, with preliminary evidence indicating altered autophagy as a pu- -19% vs. control) and citrate synthase activity (-12% vs. control) under insu- tative critical node in this process. In summary, our results provide evidence lin stimulation conditions in C2C12 myotubes. In addition, PDK4 expression for the critical role of lymphocytes in diet-induced hepatic lipid metabolism decreased mtDNA levels (-25% vs. control P=0.035). These results indicate and raise the possibility of immunotherapy against liver steatosis, a common that, in skeletal muscles, FFA may modulate insulin sensitivity and mitochon- side effect of various therapeutic interventions or pathological processes. drial function via PDK4, leading to insulin resistance. In conclusion, PDK4 Supported By: Synergasia; HRAKLEITOS may be a novel therapeutic target for obesity or T2DM. Supported By: Kowa Company, Ltd.

Integrated Physiology—Muscle 271‑LB Mechanism by which Caloric Restriction Improves Insulin Sensitiv‑ 269‑LB ity in Sedentary Obese Adults Effects of Type 2 Diabetes and Obesity on the Expression of Mito‑ MATTHEW L. JOHNSON, KLAUS DISTELMAIER, IAN LANZA, BRIAN IRVING, chondrial Proteins in Skeletal Muscle MATTHEW M. ROBINSON, ADAM R. KONOPKA, GERALD I. SHULMAN, K. SREE- LAURA FORMENTINI, ALEXANDER J. RYAN, LESLIE CARTER, JOSE M. CUEZVA, KUMARAN NAIR, Rochester, MN, New Haven, CT THEODORE P. CIARALDI, ROBERT R. HENRY, Madrid, Spain, La Jolla, CA, San Di- Caloric restriction (CR) improves insulin sensitivity and reduces the inci- ego, CA dence of diabetes in obese individuals. The underlying mechanisms whereby Mitochondria (Mito) play key roles in cellular metabolism and bioener- CR improves insulin sensitivity are not clear. We evaluated the effect of getics, the execution of cell-death and intracellular signaling. Due to the 16-weeks of CR on whole-body insulin sensitivity by pancreatic clamp be- multiplicity of Mito functions it has been documented that Mito dysfunc- fore and after CR in 11 obese participants (BMI=35 kg/m2) in comparison tion is implicated in the genesis and development of many different human with a matched control period (CON, N=9, BMI=34 kg/m2). Participants in pathologies, including type 2 diabetes (T2D). A key transducer in energy the CR group lost on average 10.1 ± 1.2% of total bodyweight, while no conservation and reactive oxygen species signaling is the mitochondrial H+- change was found in the CON group (+0.8 ± 0.6%). Compared to CON, CR ATP synthase. Its physiological inhibitor, the Mito ATPase Inhibitory Factor 1 increased the glucose infusion rate required to maintain euglycemia dur- (IF1) acts as a master regulator of energy metabolism, playing a crucial role ing hyperinsulinemia that fully suppressed endogenous glucose production in metabolic adaptation to enhanced aerobic glycolysis. In cancer, IF1 over- (p < 0.0001). This improvement in peripheral insulin sensitivity was not ac- expression triggers Mito hyperpolarization and the subsequent production companied by changes in skeletal muscle mitochondrial oxidative capacity of superoxide radicals, resulting in a cellular adaptive response that includes or oxidant emissions, nor was there changes in skeletal muscle ceramide, resistance to cell death. Despite the emerging role of Mito bioenergetics diacylglycerol, or amino acid metabolite levels. However, the CR induced in controlling skeletal muscle (SkM) metabolism during T2D, the basic cell improvement in insulin sensitivity occurred in concert with increased post biology of IF1 and its’ involvement in this pathology remain basically un- absorptive whole body lipid oxidation and reduced levels of skeletal muscle known. We compared the expression of IF1 and other proteins regulating the thioredoxin-interacting protein (TXNIP) expression following hyperinsuline- structure/activity of Mito in SkM biopsies from obese (BMI>30) type 2 dia- mia. Furthermore, the changes in TXNIP expression correlated with changes in whole body insulin sensitivity for all participants over the 16-week period.

betic (O-T2D), lean (BMI <27) diabetic (nO-T2D), obese non diabetic (O-nT2D) and lean non diabetic (nO-nT2D) subjects, correlating the protein expression Together these results support a likely role of TXNIP in CR induced improve- with BMI, FI, FG and HOMA-IR parameters. We found a significant increase ment in insulin sensitivity. (180%) in the expression of IF1 in obese subjects, regardless of the presence Supported By: R01DK41973 (to K.S.N.); U24DK100469; DK50456; T32DK007198 of T2D. However, a reduction (80% of nT2D) in β-F1 ATPase, the catalytic (to M.L.J.); KL2TR000136-07 (to M.L.J.); KL2RR024151 (to B.I.); T32DK007352 (to I ntegrated subunit of the H+-ATP synthase, was present in O-T2D compared to healthy M.M.R., A.R.K.); UL1TR000135; Mayo Foundation; Murdock-Dole Professorship (to POSTERS subjects. T2D subjects presented higher levels of the mitochondrial redox K.S.N.) sensor SOD2 and a tendency for a negative regulation of the Mito fusion Physiology/Obesity controller OPA1. In conclusion, our data support the hypothesis that obesity and T2D can contribute in different ways to perturbations in the SkM Mito network, thus facilitating muscle dysfunction. Supported By: U.S. Department of Veterans Affairs; National Institutes of Health

ADA-Funded Research For author disclosure information, see page LB98.

LB67 Integrated Physiology—Other Hormones

Integrated Physiology—Other Hormones proteolytically derived peptides could modulate insulin release. After estab- lishing the presence of VGF in β-cell lines, we screened the effect of several 272‑LB C-terminal VGF-derived peptides, including TLQP-21 and TLQP-62, on glucose stimulated insulin secretion (GSIS) in beta-cell lines and on glucose toler- Understanding the Mechanism of Cholesterol Lowering Effect of ance in vivo. TLQP-62 increased insulin secretion in several insulinoma cell GLP1-R/GCGR Co-agonists lines in both low and high glucose conditions. Conversely, TLQP-21 only had LI-PING SUN, HONG-PING GUAN, XIAODONG YANG, MICHELE PACHANSKI, weak effect at the low glucose concentration while mildly, but significantly, SHENG-PING WANG, CARLOS G. RODRÍGUEZ, ANDREA NAWROCKI, STEVE PRE- potentiated GSIS in vitro. We also found that the mechanism of action of VIS, LIANGSU WANG, PAUL CARRINGTON, Kenilworth, NJ TLQP-62-stimulated insulin secretion is via increased intracellular calcium The glucose-lowering and anti-obesity effects of GLP-1R/GCGR co-agonist mobilization and fast expression of the insulin 1 gene. Furthermore, we com- have been demonstrated in preclinical rodent and NHP models and are now pared the efficacy of the two peptides in improving glucose homeostasis in being tested in the clinic. The lipid-lowering efficacy, especially the decrease vivo in mice. TLQP-62, but not TLQP-21, dose-dependently improved glucose in LDL cholesterol, has been demonstrated with dosing of GLP-1R/GCGR co- tolerance in the glucose tolerance test. Together, our findings suggest that agonist. Here, using a pair feeding scheme in the Oxymax metabolic system, TLQP-62 is the most potent VGF peptide on insulin secretion and glucose we showed that GLP-1R/GCGR co-agonist lowered plasma cholesterol levels homeostasis. Further studies are required to understand its mechanism of independent of body weight loss in mice. Specifically, glucagon signaling action. Our study suggests that TLQP-62 can be considered a novel strong was responsible for the plasma cholesterol lowering. In contrast to wild- insulinotropic peptide that can be targeted for innovative anti-diabetic drug type mice, GLP-1R/GCGR co-agonist did not change plasma cholesterol lev- discovery programs. els in LDLR knockout mice. Western blot analysis showed that LDLR protein Supported By: Minnesota Partnership for Biotechnology and Medical Genomics level in liver was increased. We further demonstrated that GLP-1R/GCGR co- (to A.B.); National Institutes of Health-National Institute of Diabetes and Digestive agonist promoted uptake of fluorescently labeled DIL-LDL in primary human and Kidney Diseases (DK102496 to A.B.); Ministry of Education, University and hepatocytes in a dose-dependent manner, while liraglutide did not. Using a Research (to R.P.) D2O tracer study, we have shown that GLP-1/GCGR co-agonist decreased levels of newly synthesized cholesterol in liver and secretion of newly made cholesterol in plasma in wild-type mice. The D2O tracer study was repeated 275‑LB in LDLR knockout mice and the GLP-1/GCGR co-agonist also inhibited newly Preserved Enteroendocrine Secretion after Meal Challenge across synthesized cholesterol in liver of this model. Using dual 13C-cholesterol and Glucose Tolerance (GT): Lack of Correlation with Beta Cell Function (BCF) D6-cholesterol tracers dosed i.v. and p.o., respectively, we have shown that GLP-1/GCGR co-agonist did not affect intestinal cholesterol absorption. In HARTMUT RUETTEN, MATHIAS GEBAUER, RALPH H. RAYMOND, R. PAUL ROB- conclusion, GLP-1/GCGR co-agonist lowers plasma cholesterol level by de- ERTSON, PETER SAVAGE, SUDHA S. SHANKAR, DARKO STEFANOVSKI, MARIA creasing hepatic cholesterol synthesis and increasing LDLR-mediated lipo- T. VASSILEVA, ADRIAN VELLA, KATHRYN F. WRIGHT, DAVID A. FRYBURG, FOR FOUNDATION FOR NIH BETA CELL PROJECT TEAM, Frankfurt, Germany, Skillman, protein uptake primarily through the glucagon signaling. NJ, Seattle, WA, Bethesda, MD, Indianapolis, IN, Philadelphia, PA, Rochester, MN, 273‑LB East Lyme, CT Although it is known that meal ingestion stimulates gut enteroendocrine Investigating Translation of as a Target Engagement Bio‑ secretion (ES) and BCF, the relationship between ES and BCF is not known marker for Glucagon and GLP1/GCGR Receptor Co-agonists across GT populations. In studies examining BCF in subjects with normal FRANKLIN LIU, JULIE LAO, HAIHONG ZHOU, CARLOS G. RODRIGUEZ, LEI CHEN, glucose tolerance (NGT), prediabetes (PDM), and type 2 DM (T2DM), total ERIC MUISE, MICHAEL E. LASSMAN, ANDREA NAWROCKI, STEPHEN PREVIS, and active GLP-1, GIP, PYY, and glucagon (glgn) were measured before and DAVID E. KELLEY, SANDRA C. SOUZA, Kenilworth, NJ, Rahway, NJ after a mixed meal (MTT). We hypothesized that these responses were as- Glucagon-like peptide 1 and glucagon receptor (GLP1R/GCGR) co-agonism sociated with BCF. ES was assessed in overnight fasted subjects before and has been investigated for the treatment of T2D. While there are methods for 30, 60 and 120 min after 470 kCal MTT. Table summarizes responses pre- assessing GLP1 activation, less is known about surrogate markers for GCGR and 30-min post MTT. Parameters of insulin secretion ( tot) and sensitivity activation. It has been recently reported that glucagon stimulates produc- Φ (SI) and disposition index (DItot) were estimated using minimal model. BCF: tion of Kisspeptin (Kiss) (Cell Metab 2014, 19:667) and Kiss was shown to be ES association was conducted using Spearman’s Rank correlations. Before elevated in serum of humans with T2D and serum and livers in mouse mod- the MTT, ES was generally higher for T2DM versus NGT and PDM. MTT in- els of metabolic dysfunction. These observations suggest Kiss is a potential creased total and active GLP-1, GIP and PYY at 30 min. Changes were gener- biomarker for GCGR activation, and our laboratory investigated the use of ally comparable across GT populations except glgn which showed increases Kiss to monitor GCGR target engagement. In agreement with reported in across the GT Populations NGT

but not to the level previously reported. Unexpectedly, human hepatocytes treated with GLP1R/GCGR co-agonists failed to increase Kiss mRNA expres- sion, raising questions on the utility of circulating Kiss as a biomarker for GCGR agonism in clinical studies. Evaluation of Kiss in humans treated with glucagon or GCGR agonists may determine the utility of Kiss as a biomarker I ntegrated POSTERS for GCGR activation and increase understanding the metabolic role of Kiss

Physiology/Obesity in mice vs. humans.

274‑LB Role of C-terminal VGF-derived Peptides on Insulin Secretion and Glucose Homeostasis CHERYL CERO, PAMELA PETROCCHI-PASSERI, ALESSANDRO CUTARELLI, CLAU- DIO FRANK, CINZIA SEVERINI, ROBERTA POSSENTI, ALESSANDRO BARTOLO- Supported By: Foundation for the National Institutes of Health Biomarkers Con- MUCCI, Minneapolis, MN, Rome, Italy sortium One of the most common features of early type 2 diabetes mellitus (T2DM) is low insulin secretion for the degree of insulin sensitivity which is commonly reduced in this disease. The abundant presence of the granin protein VGF (nonacronymic) in pancreatic islets suggests that some of its

ADA-Funded Research For author disclosure information, see page LB98.

LB68 Integrated Physiology—Other Hormones

276‑LB GLP-1R with GLP-1, Exendin-4 (Ex4) or Liraglutide (Lira) for 0, 5, 10, 15, 30, or Insulin-like Peptide 5 (INSL5) in Patients with Type 2 Diabetes 60 minutes (all 100nM). No differences in ACC or ERK1/2 phosphorylation JENNY E. BLAU, MARY F. WALTER, VIVIANA BAUMAN, KRISTINA I. ROTHER, were observed between these GLP-1R agonists. Ongoing experiments are Bethesda, MD testing effects of these GLP-1R agonists on Akt, AMPK, and CREB phos- Insulin-like peptide 5 (INSL5), a member of the insulin/ superfam- phorylation. We then tested the hypothesis that GLP-1R agonists may dif- ily, is a product of enteroendocrine L cells, known to secrete glucagon-like ferentially target specific hypothalamic nuclei. Food intake was measured in peptide 1 (GLP-1). INSL5 and its receptor have recently been proposed as response to targeted injections of GLP-1 vs. Ex4 into the ARC, paraventricu- targets for diabetes drug development due to the glucose dependent, direct lar nucleus (PVN) or ventromedial hypothalamus (VMH) in C57Bl/6 mice. Our insulinotrophic effect on beta cells (shown in vitro studies in rodent islets) results demonstrate that Ex4 suppressed food intake when targeted to the and due to INSL5’s potential auto/paracrine effect on promoting GLP-1 se- ARC, PVN, and VMH in a dose-dependent manner while GLP-1 only reduced cretion. Little is known about INSL5’s function and regulation in humans. We food intake when targeted to the PVN, but with a magnitude lower than Ex4. tested 13 healthy, normal weight and obese individuals with and without In sum, our preliminary data indicate that different GLP-1R agonists do not type 2 diabetes mellitus (T2DM). INSL5 was measured with an RIA (Phoenix engage distinct signaling pathways in POMC neurons of the ARC. Instead, Pharmaceuticals, range 20-2560 pg/ml) after an overnight fast (>8 hours), the anorectic potential of GLP-1R agonists may be determined by the brain and in 2 subjects after 16 and 60 hours of continued fasting. Eight partici- region engaged by these peptides. Further studies will investigate other pants underwent an oral glucose tolerance test (OGTT). In non-diabetic lean signaling cascades as well as other brain regions to further elucidate the and obese individuals (n=8), concentrations were at or below the lower limit mechanisms underlying Glp-1r agonist differences in anorectic potency. of detection and remained undetectable after a prolonged fast. In contrast, Supported By: American Diabetes Association (1-14-CD-01 to J.E.A.) in patients with T2DM, INSL5 was detectable (n=5) and increased with glu- cose administration. The highest value (163 pg/mL) was found in an obese 279‑LB patient with poorly controlled T2DM (BMI 36 kg/m2, HbA1c 10.6%). Based GIP (3-30) Is a Potent Glucose-dependent Insulinotropic Polypep‑ on these preliminary results, we hypothesize that INSL5 may play a com- tide (GIP) Receptor Antagonist In Vitro and In Vivo pensatory role in individuals with T2DM to counterbalance the prevailing LÆRKE S. HANSEN, ALEXANDER H. SPARRE-ULRICH, BERIT SVENDSEN, MIKKEL relative insulin deficiency. CHRISTENSEN, BOLETTE HARTMANN, FILIP K. KNOP, JENS JUUL HOLST, METTE M. ROSENKILDE, Copenhagen, Denmark, Hellerup, Denmark 277‑LB The intestinal hormone glucose-dependent insulinotropic polypeptide Sleeve Gastrectomy Improves the Glycemic State in a Glucose In‑ (GIP) functions within lipid, bone, and glucose homeostasis. The human GIP tolerant Lipocalin Prostaglandin D2 Synthase (L-PGDS) Knockout receptor (hGIP R) is GαS-coupled and 7TM family B. High affinity ligands will Mouse Model be important tools to explore the role of GIP in adiposity, osteogenesis, and SUNIL KUMAR, RAYMOND G. LAU, THOMAS PALAIA, CHRISTOPHER E. HALL, glucose homeostasis. hGIP (1-30) is suggested to be a naturally occurring KENETH HALL, COLLIN BRATHWAITE, LOUIS RAGOLIA, Mineola, NY GIP variant in humans. We here show that hGIP (3-30) - a presumed DPP-IV- Sleeve gastrectomy (SG), ameliorates metabolic complications in obese degradation product of hGIP (1-30), is a potent antagonist in vitro and in vivo and diabetic subjects. Recently, L-PGDS has been considered an emerging with high affinity to the human GIP R. All in vitro assays were performed on target for diabetes and metabolic disorders; however, the mechanism in- transiently transfected COS-7 cells expressing hGIP R. Radiolabeled 125I- volved in the regulation of glucose metabolism is not fully understood yet. As hGIP (1-42) was used for competition binding, and cAMP-accumulation was per our previous studies, L-PGDS knockout mice showed accelerated glucose measured using an enzyme fragment assay. In situ pancreas perfusions in intolerance and insulin resistance. Therefore, in this study, we examined the rats were performed with a single-pass system (10 mM glucose) through role of L-PGDS in diabetes and metabolic syndrome using L-PGDS knockout arteries and collected effluent from the portal vein. hGIP (3-30) displaced (KO) mice which underwent sleeve gastrectomy (SG). The aim of the study 125I-hGIP (1-42) with high affinity (IC50 of 2.6nM [logIC50 -8.6±0.04, n=12), was to determine the effect of sleeve gastrectomy on the glucose intoler- thus with an affinity close to hGIP (1-30) and hGIP (1-42) (IC50 of 0.89nM ated L-PGDS knockout mice model. L-PGDS knockout mice were divided into and 0.67nM). In the cAMP assay, hGIP (3-30) did not stimulate hGIP R but two groups, sham surgery (n=4) and sleeve gastrectomy (n=4). Mice were showed potent antagonistic properties with a dose-dependent right-shift kept on diabetogenic diet and all the fasting parameters were measured 12 of the hGIP (1-42) dose-response curve on 4-fold for 100nM hGIP (3-30). weeks post surgery. Data were analyzed by unpaired t-test with the signifi- Schild plot analysis revealed competitive antagonistic properties of hGIP (3- cance (p<0.05). Results of our oral glucose tolerance test with the challenge 30) with a Ki of 15nM (Hill-slope 0.93±0.02). The antagonistic property was of 2gm/kg glucose dose showed significant glycemic improvement in the SG confirmed in pancreas perfusion studies, where 100nM hGIP (3-30) reduced group compared to the sham group and clearly depicted the beneficial effect glucagon and significantly somatostatin secretion induced by 1nM GIP (1-42), of sleeve gastrectomy. Surprisingly, there was no difference in fasting insu- whereas it stimulated de novo and potentiated hGIP (1-42)-induced insulin lin level in both the groups. and peptide YY levels in the SG group secretion. GIP (3-30) is a highly potent competitive antagonist of the hGIP were significantly increased by 2.7 fold and 3.7 fold respectively, compared receptor. Given its presumed presence in the , it could serve as to sham group. We measured the pre and post surgery weight in both the tool compound for further elucidation of the GIP physiology and thereby in groups and found that the SG group gained 16.5% less weight compared to turn for future pharmacological intervention of this system. the sham group. Leptin levels were also increased by 8.4% in the SG group compared to the sham group. Collectively, based on the present results, it can 280‑LB be concluded that SG ameliorated metabolic disorder in glucose intolerated Long-Term Treatment of DA-1241, a Novel GPR119 Agonist, Improved L-PGDS knockout mice model and proved the strong correlation between L- Glucose Control via Preserved Beta Cell Mass in a Progressive Dia‑ PGDS and sleeve gastrectomy. Further studies need to be performed to find

betic Mice Model the actual mechanism of action of L-PGDS in sleeve gastrectomy. MI-KYUNG KIM, TAE HYOUNG KIM, YE-HWANG CHEONG, YU NA CHAE, IL- HOON JUNG, KWAN-HOO LEE, SEUL MIN CHOI, JAE SUNG YANG, MOON-HO 278‑LB SON, KYUNG KOO KANG, Yongin, Republic of Korea Probing Mechanisms for the Differential Anorectic Effects of Glu‑ Activation of GPR119 highly expressed in pancreas and intestine is known I ntegrated cagon-like Peptide-1 (GLP-1) Receptor (GLP1R) Agonists to be involved in glucose and lipid metabolism. There are few reports on POSTERS chronic efficacy in disease animal model and some GPR119 agonists sug-

JACOB D. BROWN, MELISSA A. BURMEISTER, JENNIFER E. AYALA, JULIO E. Physiology/Obesity AYALA, Orlando, FL gested an issue on loss of effect after repeated administration. To demon- GLP-1 is a gut hormone known for its insulinotropic and satiety-promoting strate the long-term efficacy of our novel GPR119 agonist therefore, DA-1241 effects. Type 2 diabetes therapies that elevate GLP-1 levels (DPP-4 inhibi- was administered for 10 weeks in a progressive diabetic mice model induced tors) are weight neutral while GLP-1 mimetics (e.g. Exenatide, Liraglutide) by streptozotocin (STZ) injection with a high-fat diet (HF) feeding to causes cause weight loss via reduced food intake. Using cell-based and in vivo dysregulation of glucose and lipid metabolism. HF/STZ control mice showed methods, we aimed to elucidate the mechanism underlying this divergence overt hyperglycemia, while DA-1241 treatment significantly suppressed in anorectic effects between GLP-1R agonists. We hypothesized that GLP-1 blood glucose rise from two weeks after administration and its efficacy per- and GLP-1 mimetics induce divergent intracellular signaling cascades in sati- sisted during the rest of the treatment period. Hypertriglycemia and fatty ety-promoting (POMC) neurons of the arcuate nucleus liver were attenuated by DA-1241 treatment as well, indicating simultaneous (ARC). We tested this by measuring phosphorylation of acetyl CoA carboxy- glucose and lipid control at the same dose. Preserved islet structure and lase (ACC) and ERK1/2 after treating POMC-derived cells overexpressing the higher beta cell mass in DA-1241-treated group support its glucose-lowering effect. However, GSK263A, an another GPR119 agonist, showed no signifi-

ADA-Funded Research For author disclosure information, see page LB98.

LB69 Obesity—Animal

cant effects on glucose control and pancreatic beta cell mass, with only a impaired. It is possible that hepatic FGF21 inhibits lipolysis while promotes trend of a decrease in hepatic triglycerides. Then we investigated underlying lipid uptake in adipocytes. These data collectively suggest that circulating mechanisms of the effect on beta cells. DA-1241 protected beta cells from FGF21 is mainly derived from the liver. Hepatic FGF21 regulates lipid me- death caused by endoplasmic reticulum stress through reducing the expres- tabolism in adipocytes, and therefore protects mice against diet-induced sion of stress molecules and stimulated beta cell replication, which may par- hyperglycemia and insulin resistance possibly via reducing ectopic lipid ac- tially account for the higher beta cell mass in DA-1241-treated HF/STZ mice. cumulation in non-adipose tissues such as the liver and skeletal muscles. Taken together, this study suggested that i) DA-1241 has a chronic glucose- Supported By: Collaborative Research Fund Group Research Projects of Hong lowering effect without tachyphylaxis issue, ii) the metabolic improvement Kong on glucose and lipid by DA-1241 treatment can be observed at a same dose level, and iii) DA-1241 has a direct beneficial effect on pancreatic beta cells, 283‑LB which may partially contribute to its anti-diabetic effect. Liraglutide Reduces Lipogenetic Signals in Visceral Adipose of Db/ db Mice with AMPK Activation and A Akt Suppression YIMIN SHAO, GEHENG YUAN, JUNQING ZHANG, XIAOHUI GUO, San Diego, CA, Obesity—Animal Beijing, China Liraglutide, a glucagon-like peptide-1 (GLP-1) analogue, has been proved to 281‑LB reduce body weight and visceral adipose tissue (VAT) in human studies. In this study, we aimed at examining lipogenetic signals changes in VAT after Withdrawn weight-loss with liraglutide in db/db mice. The mice were divided into 2 groups: liraglutide-treated group (n=14, 8-week old, fasting glucose>10mmol/l, lira- glutide 300μg/kg twice a day for 4 weeks) and control group (n=14, saline). We found body weight gain, food intake were reduced after liraglutide treat- ment (p<0.05). Compared to the control group, the VAT weights were signifi- cantly lower in the treated group (2.32±0.37g vs. 3.20±0.30g, p<0.01) than that in control group. In VAT, compared with control group, the lipogenetic transcription factors peroxisome proliferator-activated receptor-γ (PPARγ) and CCAAT/enhancer-binding protein-α (C/EBPα) expressions were both re- duced with phospho- 5’-monophosphate-activated protein kinase (pAMPK) and phospho-acetyl-CoA carboxylase (pACC) increased 3.5-fold and 2.31-fold respectively, while the phospho-serine/threonine kinase Akt (pAkt) and phospho-p38 mitogen-activated protein kinase (pP38MAPK) were reduced 0.38-fold and 0.62-fold respectively (p<0.01). In conclusion, VAT was reduced after weight loss with AMPK activation and Akt suppression with liraglutide treatment, which was associated with reduction of lipogenetic process in VAT.

284‑LB Lipoprotein Lipase Represses SND1, a Novel SREBP-regulated Gene, to Improve the Adipose Tissue Phenotype of Mice BEIBEI ZHU, PHILIP A. KERN, BRIAN S. FINLIN, Lexington, KY Lipoprotein lipase (LpL) hydrolyzes the triglyceride core of lipoproteins and also acts as a bridge to allow for the uptake of the hydrolyzed cholesterol- rich remnant particle. Transgenic mice that express LpL in adipose tissue under the control of the adiponectin promoter (AdipoQ-LpL) have improved glucose metabolism when challenged with a high fat diet. This is mediated by an improved adipose phenotype, including increased expression of the anti-inflammatory adipokine adiponectin. To identify the mechanism for reduced inflammation, we performed a microarray on adipose tissue from mice challenged with a high fat diet for 10-days. Pathway analysis of the microarray revealed that genes regulated by sterol regulated element- 282‑LB binding protein (SREBP) transcription factors were repressed; this could Hepatic FGF21 Protects Mice against Diet-Induced Lipid Dys­ be caused by increased remnant uptake by the transgene. One of the most regulation and Insulin Resistance significantly repressed genes was SND1 (P<0.001). Since SND1 is implicated ZHE HUANG, TSZ-HANG LEE, CHI-MING WONG, KAREN SIU-LING LAM, AIMIN in cholesterol metabolism in the liver, we determined whether it is also an XU, Hong Kong, China SREBP-regulated gene in adipocytes by treating differentiated 3T3L1 adi- Fibroblast growth factor 21 (FGF21) is a potent metabolic hormone pro- pocytes with SREBP2 siRNA. This treatment significantly repressed SND1 duced by a number of organs. It has been shown to confer multiple meta- mRNA 2.2 fold (P=0.015). Since SND1 is pro-inflammatory in the liver, we

bolic benefits on obesity. Therapeutic administration of FGF21 or its analog next determined whether reducing SND1 would dampen adipocyte inflam- protects against diet-induced obesity and hyperglycemia in both rodents and matory responses. We treated differentiated 3T3L1 adipocytes with con- humans. However, the physiological roles of FGF21 remain ambiguous. Since trol or SND1 siRNA and then treated the cells with 100 ng/mL recombinant the liver is the major source of circulating FGF21, we propose that the endo- tumor necrosis factor (TNF) alpha. The SND1 siRNA treated cells had 1.9 crine actions of FGF21 derived from the liver may account for its metabolic fold lower MCP1 expression in response to TNF alpha than control siRNA I ntegrated POSTERS effects on lipid metabolism. We therefore generated the liver-specific FGF21 treated adipocytes (P<0.05). Consistent with this, IL-1 beta, IL-6, and TNF al- KO (LiverKO) mice by utilizing the Cre-loxP recombination system. LiverKO pha were also lower in SND1 siRNA treated adipocytes (P<0.05). These data Physiology/Obesity mice and their age-matched wild-type (WT) littermates were fed a high fat suggest that SND1 is an important link between SREBP2 and inflammation diet (HFD) for 20 weeks and assessed for the metabolic phenotypes. Circu- in adipocytes. Reducing SND1 by inhibiting the SREBP2 pathway in adipose lating FGF21 was significantly elevated in WT mice during fasting or HFD tissue may be part of the mechanism of improved adipose tissue function in feeding. However, this elevation of circulating FGF21 was completely abol- AdipoQ-LpL mice. ished in LiverKO mice, suggesting the liver is the major source of circulating Supported By: P20GM103527-06; DK039176; UL1TR000117; DK071349 FGF21. LiverKO mice treated with HFD showed a significant reduction in body fat mass when compared to WT mice, as revealed by NMR body composi- tion analyzer suggesting resistance to obesity was mainly attributed to the loss of hepatic FGF21. Interestingly, although LiverKO mice were leaner, they developed more severe glucose intolerance and insulin resistance after HFD feeding as shown by GTT and ITT. In addition, LiverKO mice had higher serum triglyceride and free fatty acid levels suggesting that lipid homeostasis is ADA-Funded Research For author disclosure information, see page LB98.

LB70 Obesity—Animal

285‑LB anti-obesity and anti-diabetic properties. SR4 increased mitochondrial respi- The Anti-obesity Action of ACAM by Modulating the Dynamics of ration, dissipated mitochondrial membrane potential, induced mitochondrial Cell Adhesion and Actin Polymerization in Adipocytes swelling, and depleted ATP in cells and liver mitochondria. Oral feeding of SR4 KAZUTOSHI MURAKAMI, JUN EGUCHI, ATSUKO NAKATSUKA, TOMOKAZU significantly reduced body weight gain, prevented hyperlipidemia and insulin NUNOUE, JUN WADA, Okayama, Japan resistance, and improved glycemic control in both high fat-diet induced obese We identified adipocyte adhesion molecule (ACAM) which belongs to CTX and diabetic db/db mice. SR4 treatment also decreased liver triglycerides and gene family. ACAM is predominantly expressed in white adipose tissues and prevented hepatic steatosis in both animal models. Mitochondrial uncoupling up-regulated in obese subjects. Two immunoglobulin-like domains exist in extra- by SR4 results to activation of AMPK, leading to the phosphorylation and in- cellular segment and they are involved in the adhesion process and homophilic hibition of acetyl-CoA carboxylase, an inhibitor of mitochondrial β-oxidation. aggregation of the cells. To explore the functional role of ACAM in obesity, we Gene analyses by real time PCR showed SR4 significantly suppressed the generated ACAM transgenic (Tg) mice driven by aP2 promoter. Under high fat mRNA expression of several lipogenic genes as well as gluconeogenic genes high sucrose (HFHS) diet, the increase in body weight was significantly reduced in the liver of obese mice. RNA sequencing results showed that 689 genes in Tg mice compared with wild type (WT) mice and the fat pad weight and adi- were differentially expressed in liver of db/db mice after SR4 treatment (122 pocyte size in Tg mice were reduced. In glucose tolerance and insulin sensitivity upregulated, 567 downregulated). analysis by DAVID indicated tests, plasma glucose levels were significantly lower in Tg mice. To further give up-regulated amino acid metabolism and down-regulated cell division and cell insights into the mechanism for the reduction of lipid accumulation in adipose cycle processes. These data demonstrates that SR4 may be a promising com- tissues, we investigated the role of ACAM by using 3T3-L1 cells and Tg mice. As pound for treatment of T2DM and obesity. a result, we identifiedγ -actin as interacting proteins forming protein complexes Supported By: Isaac and Jacquelin Moradi; City of Hope National Medical with ACAM. Next, we investigated the expression of ACAM and polymerized Center; Beckman Research Institute form of actin (F-actin) by Phalloidin staining. In WT mice under HFHS diet, both F-actin and ACAM were faintly stained surrounding the adipocytes in epididymal 288‑LB adipose tissues, while they colocalized and accentuated in a patchy fashion. By Blood Glucose Control by AgRP Neurons and Glutamate transmission electron microscopy, in WT mice under HFHS diet the distance of AYKUT G. ÜNER, GABRIEL H.M. GONÇALVES, WENJING LI, MATHEUS PORCE­ plasma membranes between adjacent adipocytes was ~100-200 nm. In contrast, BAN, ONUR KEÇIK, NICOLE CARON, MILENA SCHÖNKE, ERIC DELPIRE, KENJI we confirmed the zone with an intercellular space of ~10-20 nm, the structure SAKIMURA, YOUNG-BUM KIM, CHRISTIAN BJØRBÆK, Boston, MA, Nashville, of zonula adherens, in Tg mice fed HFHS diet. By immunoelectron microscopy, TN, Niigata, Japan the zonula adherens was associated with immunogold particles when the sec- This study investigates the role of N-methyl-d-aspartate receptors (NM- tions were stained with γ-actin or ACAM-specific antibodies. In conclusion, the DARs) in agouti-related peptide (AgRP) and pro-opiomelanocortin (POMC) ACAM-mediated homophilic adhesion of adipocytes and formation of zonula ad- neurons on glucose homeostasis. Hypothalamic AgRP and POMC neurons play herens promoted the actin polymerization inhibited the adipocyte hypertrophy, critical roles in control of energy balance. These neurons can also orchestrate which resulted in the improvement of obesity. beneficial blood glucose control, but the underlying processes are not under- Supported By: Japan Ministry of Education, Culture, Sports, Science and Tech- stood. NMDARs typically consist of the obligatory GluN1 subunit and different nology (26461362) GluN2 subunits, the latter exerting differential effects on channel activity and neuronal functions. Glutamatergic input via NMDARs is pivotal for regulation 286‑LB of neuronal activity and plasticity. Currently, the role of NMDARs and specific Female Mice Fed a Western Diet Demonstrate Mineralocorticoid GluN2 subunits in AgRP and POMC neurons on glucose homeostasis regula- Receptor-mediated Ultrastructural Remodeling of Perivascular tion is unknown. To investigate this, we used cre-lox technology to delete Adipose Tissue and Aortic Stiffness GluN2A or GluN2B from AgRP or POMC neurons in mice. We show that loss of MELVIN HAYDEN, VINCENT DEMARCO, JAMES R. SOWERS, Columbia, MO GluN2B from AgRP neurons reduces body weight, fat mass, and food intake, Perivascular adipose tissue (PVAT) is considered to be more than a mechani- whereas GluN2B in POMC neurons and GluN2A in AgRP or POMC neurons are cal structural support of the aorta vasculature and is capable of producing not required for normal energy balance. Deletion of GluN2B in AgRP neurons . To explore diet-related changes in PVAT female mice were fed a reduces the number of AgRP neurons and dendritic length. Remarkably, loss high fat/high fructose (western) diet (WD) for 16 weeks. Descending thoracic of GluN2B in AgRP neurons of the obese and severely diabetic Lepob/ob mice aortas with intact PVAT were examined by transmission electron microscopic fully corrects hyperglycemia, without influencing body weight and food intake. (TEM). WD fed mice developed in vivo aortic stiffness, as demonstrated by an These mice are also more sensitive to leptin’s anti-obesity actions. Finally, to increase in pulse wave velocity, and endothelial and vascular smooth muscle selectively assess the ability of neuronal activity to control blood glucose bal- stiffness, assessed ex vivo by atomic force microscopy. PVAT tissue was ance, we activated AgRP neurons by DREADD (designer receptors exclusively comprised of white-like (WAT) and brown-like adipose tissue (BAT) with BAT activated by designer drug) technology and observed an increase in fasted adipocytes predominating. In the WD mice, PVAT remodeling consisted of at- glucose levels in lean mice. The results show that GluN2B-NMDARs in AgRP tenuation of the innermost region of WAT adipocytes, increases in mast cells, neurons can regulate body weight and blood glucose levels, and suggests that lymphocytes and macrophages and collagen deposition, all of which were these effects involve altered AgRP neuronal activity/structure and modulation prevented with low-dose (LSp). In concert with these TEM of central leptin action. Inhibition of GluN2B-NMDARs in AgRP neurons may be changes, LSp attenuated the WD-induced increase in aortic stiffness. Be- considered an avenue for development of novel anti-diabetes and anti-obesity cause aortic stiffening may be the nexus between cardiovascular, kidney and therapies. cerebral vascular disease, especially in obese, insulin resistant and diabetic Supported By: National Institutes of Health (R01DK94040 to C.B.) women, these TEM and functional findings may have translational importance to the current obesity epidemic which is driven by consumption of a WD. 289‑LB Supported By: National Institutes of Health (R01HL073101, R01HL107910); U.S. Clc-5 Deficient Mice, a Novel Murine Model for Investigating the Department of Veterans Affairs (to J.R.S.) Role of Gut Microbiota in Obesity and Metabolic Syndrome YING DONG, SHI JIN, XUHANG LI, Baltimore, MD 287‑LB We have identified Clc-5 knockout (Clc-5KO) mice as a completely novel animal SR4, a Novel Mitochondrial Uncoupler, Improves Metabolic Altera‑ model of obesity and metabolic syndromes. Clc-5 (chloride channel 5) functions I ntegrated tions in Obese and Diabetic Mice primarily as an electrogenic 2Cl-/1H+exchanger. A phenotype of Clc-5 deficient POSTERS JAMES L. FIGAROLA, JYOTSANA SINGHAL, GEORGE W. ROGER, CHARLES WAR- mice is strikingly similar to human Dent’s disease. Recently, we have identified DEN, LU YANG, XIWEI WU, TIMOTHY SYNOLD, SHARAD S. SINGHAL, DAVID a unique and previously unrecognized phenotype of Clc-5KO mice: they are all Physiology/Obesity HORNE, SAMUEL RAHBAR, ARTHUR RIGGS, Duarte, CA, Billerica, MA (100%) markedly obese on regular diet, with a body weight 25-35% higher than The number of people suffering from type 2 diabetes mellitus (T2DM) is age-matched WT mice. QNMR showed that Clc-5KO mice were constituted of skyrocketing worldwide and has been closely linked to the soaring obesity 21% of total body fat (only 7% in WT). MRI analysis indicated a dramatic in- epidemic. T2DM if left untreated, can cause severe and sometimes fatal com- crease in both subcutaneous and visceral (abdominal) fats. All Clc-5KO exhibited plications. Most current treatments ameliorate the hyperglycemic symptom glucose intolerance and >3-fold elevated levels of systemic proinflammatory IL-6 of the disease but are not effective in correcting its underlying cause. De- and MCP-1 (than WT), remarkably similar to those in human obesity. They also velopment of new drugs with new mechanisms of action, in particular those exhibit a 3-10-fold increase in the expression of a panel of diabetes/obesity- targeting the cause of insulin resistance, is important to improve diabetes related genes in the liver, including PPARγ, LXRα, RXRα, CD36, SRA (class A therapy. Recent studies have shown that targeting mitochondrial respiration, scavenger receptor), leptin-R, SREBP2, AMPKβ, and GHRP-R, all of which are the specifically by mild uncoupling agents, is very promising in treating T2DM hallmarks of metabolic syndromes. More surprisingly, Clc-5KO mice had similar symptoms. Here, we show that SR4 is a novel mitochondrial uncoupler with food assumption as the age-matched WT, suggesting that they acquire a more

ADA-Funded Research For author disclosure information, see page LB98.

LB71 Obesity—Animal

efficient dietary energy harvesting mechanism. We found a weakened bacterial creased immune cell infiltration in fat depots preserves metabolic health in killing capacity of the macrophages in Clc-5KO compared to those in WT. Co- obesity remains though unclear. Accordingly, we studied the role of endothe- caging littermate WT with Clc-5KO mice led to a marked improvement of glucose lial expressed P-selectin in insulin sensitivity in mice with DIO. Wild-type intolerance and decreased body fats in Clc-5KO mice while an impaired glucose (WT) and P-selectin deficient (Psel-/-) C57BL/6 mice were given ad libitum intolerance in WT. These data clearly indicate that it is the altered intestinal flora access to either a low fat (10% fat) or a high fat (60% fat) chow for 16 weeks. that enable the Clc-5KO mice a higher energy-harvesting efficiency from dietary No differences in total body weight gain, adiposity, or fasting plasma glu- foods, while the WT microbiota can diminish this efficiency. We conclude that cose were recorded between the WT and Psel-/- (p<0.01 vs. low fat WT). Clc-5 plays a critical and previously unrecognized role in lipid/glucose metabo- Mice were then studied by intravital microscopy (IVM) to measure kinetics lism via modulating gut flora, and Clc-5KO mice can be used as a novel model of of leukocyte rolling (LR) and leukocyte adhesion (LA) in the microcirculation obesity, diabetes or metabolic syndromes. of the mesenteric fat pads. In WT mice, administration of high fat food in- Supported By: National Institutes of Health-National Institute of Diabetes and creased LR and LA in the visceral fat microcirculation (p<0.001 vs. low fat Digestive and Kidney Diseases WT). In contrast, high fat feeding failed to increase LR and LA in P-sel-/- mice (NS vs. low fat WT). High fat fed WT and Psel-/- mice showed no differ- 290‑LB ences in glucose tolerance tests and insulin sensitivity tests (p<0.01 vs. low fat WT). Fasting insulin levels were elevated in both WT and Psel-/- DIO Withdrawn mice (p<0.05 vs. low fat WT). Serum TNFa concentrations were significantly elevated in WT high fat fed mice as compared to both WT low fat fed and Psel-/- high fat fed mice (p<0.05). Taken together, these data indicate that P- selectin deletion protects against local and systemic inflammation following high fat feeding but has no effect on insulin sensitivity. These data suggest that blockade of immune cell accumulation in visceral adipose depots alone may not reduce insulin resistance associated with obesity. Supported By: R01DK096521 (to R.S)

293‑LB Myeloperoxidase Downregulates Signaling in Endothelial Cells via Activation of Calpain ZIENAB A. ETWEBI, ROSARIO SCALIA, Philadelphia, PA Obesity and type 2 diabetes mellitus have been associated with insulin resistance, and chronic low-grade inflammation. Myeloperoxidase (MPO) is a peroxidase enzyme secreted by activated neutrophils, which is associ- ated with endothelial dysfunction and, more recently, insulin resistance. The calcium dependent protease calpain has also been associated with insulin resistance and type 2 diabetes. Accordingly, we tested the hypothesis that MPO downregulates adiponectin receptor function in endothelial cells via activation of calpain. Mouse lung microvascular endothelial cells (MMVEC) were stimulated with 10 nM MPO for 30, 60, 120, 180, 240 minutes. Levels of (AdipoR2) and calpain, along with the downstream target of adiponectin signaling 5’ AMP activated protein kinase (AMPK), were measured by immunoblot analyses. MPO time dependently decreased AdipoR2 abundance (P<0.0001) while significantly increased µ-calpain activ- ity (p<0.0001). Pretreatment of MMVECs with the selective calpain inhibitor ZLLAl (100 µM) prevent MPO-induced calpain activation (P<0.0001 vs. MPO 291‑LB alone), and preserved AdipoR2 abundance (P<0.01 vs. MPO alone). Inhibition Actin Filament-associated Protein 1 Is a Novel Regulator of Glucose of calpain activity also increased AMPK phosphorylation levels in the face and Lipid Metabolism of MPO (p<0.001 versus MPO alone). At the transcriptional level, we found JAYDE T. HOOVEN, JOSEPH MAUCERI, STEPHEN J. COLLINS, HOLLY CORKILL, evidence of increased AdipoR2 mRNA levels in MMVEC exposed to MPO. JESS M. CUNNICK, YOUNGJIN CHO, Scranton, PA Taken together, our data first demonstrate a role for calpain in the down- With the current epidemic of obesity leading to an increase in the preva- regulation of adiponectin receptor signaling in states of leukocyte-mediated lence of type 2 diabetes, the discovery of the new molecular mechanisms endothelial inflammation. that regulate lipid and glucose metabolism is vital to the development of Supported By: R01DK096521 (to R.S.) therapeutic interventions. Recent studies have shown that members of the Src family of kinases contribute to numerous physiological functions includ- 294‑LB ing the regulation of glucose homeostasis and lipid metabolism. Actin Fila- The Role of the Duffy Antigen Receptor for Chemokines in Meta‑ ment Associated Protein 1 (AFAP1) is an adaptor protein of Src family kinases, bolic Disease including Src and Fyn. We have shown that AFAP1 physiologically regulates TYLER W. BENSON, TAPAN K. CHATTERJEE, DANIEL S. WEINTRAUB, ORISHE­ the activity of Src. We now show, that in mice that no longer express AFAP1,

BAWO B. POPOOLA, BRAIN , KAN HUI YIEW, MATTHEW J. CROWE, glucose tolerance and insulin sensitivity are enhanced compared to wild JAMES MINTZ, JULIA BRITTAIN, DAVID W. STEPP, VLADIMIR BOGDONOV, NEAL type controls. Furthermore, the average weight and visceral adiposity of the L. WEINTRAUB, Augusta, GA, Cincinnati, OH AFAP1 knockout mouse is reduced. Interestingly, mice no longer express- Inflammation in adipose tissues contributes to obesity-related insulin resis- ing AFAP1L2, an isoform of AFAP1, also show improved glucose tolerance tance and metabolic disease, a growing worldwide problem. The Duffy Antigen I ntegrated POSTERS and reduced total body fat compared to wild type mice (International Mouse Receptor for Chemokines (DARC) is expressed on erythrocytes and regulates Phenotyping Consortium). These findings suggest that AFAP1 regulates glu- inflammation by binding chemokines such as MCP-1 to buffer inflammatory Physiology/Obesity cose utilization and lipid storage in response to insulin and that AFAP1 may responses. DARC allele variants protect against malaria and are prevalent in provide a therapeutic target for the treatment of diabetes. certain African and Asian populations. We hypothesized that genetic deletion of DARC would augment adipose tissue inflammation and glucose intolerance 292‑LB in the setting of diet-induced obesity. Eight week-old male Wild Type (WT) P-Selectin Deficiency Does Not Attenuate Insulin Resistance in and DARC-/- mice (C57BL/6 background) were maintained either on chow diet Obesity or switched to high fat diet (HFD, 60% calories from fat) for up to 24 weeks. KYLE PRESTON, ROSARIO SCALIA, Philadelphia, PA Thereafter, metabolic phenotyping was performed, mice were subsequently The relationship between inflammation and the metabolic complications euthanized, and tissues and blood were collected for analysis. Food intake, associated with diet induced obesity (DIO) remains poorly understood. Re- energy expenditure and locomotion during HFD were similar between WT cent studies show that deletion of the high-affinity counter-receptor for and DARC-/- mice, leading to equivalent body-weight gain and adipose tissue P-selectin, P-selectin glycoprotein ligand-1 (PSGL-1), attenuates immune mass. Compared to WT mice, HFD-fed DARC-/- mice exhibited lower plasma cell infiltration into fat depots of chronically high fat fed mice. Whether de- levels of the DARC-bound cytokines MCP-1, CCL11 and CXCL5, but higher adi- ADA-Funded Research For author disclosure information, see page LB98.

LB72 Obesity—Human pose tissue MCP-1 mRNA expression, greater numbers of adipose tissue mac- and could be a strategy for promoting insulin sensitivity and preventing rophages, and significantly larger adipocytes in the visceral adipose depots, the pathogenesis of type 2 diabetes. implying enhanced adipose tissue inflammation. In addition, glucose tolerance Supported By: American Diabetes Association (11-BS-84 to D.L.); and insulin sensitivity were significantly more impaired in DARC-/- mice com- 1R01AT00707701 pared to WT mice on HFD. We conclude that loss of DARC predisposes to HFD-induced adipose tissue inflammation and metabolic disease. These novel 297‑LB findings may be pertinent to the pathogenesis of obesity-related metabolic Pellino3 Deficiency Improves Diet-induced Hepatic Steatosis and disease in populations that commonly express DARC allele variants. Inflammation JUNG-HUN LEE, JIN-SIK BAE, YUN-SEUNG JUNG, SUNTAEK HONG, JI-YOUNG 295‑LB CHA, Incheon, Republic of Korea PARP14 Plays a Key Role in Adipocyte Differentiation: A Potential Obesity-related inflammation has been implicated in the pathogenesis of Novel Target for Obesity insulin resistance, which is a hallmark of type 2 diabetes. In this study, we NORIYUKI INOUE, HIROSHI IWATA, TAKUYA HARA, ANDREW MLYNARCHIK, investigated the potential role of E3 ubiquitin ligase Pellino 3 on obesity, in- MALLARY HOIDAL, MARY WHELAN, KEN MIZUNO, MASANORI AIKAWA, Bos- flammation, and insulin resistance. Pellino3 deficient and wild-type mice were ton, MA fed high fat diet to study the impact of Pellino3 deficiency on the development We recently reported that poly ADP polymerase 14 (PARP14), a mono- of obesity and insulin resistance. We determined various metabolic profiles, ribosylation enzyme, induces pro-inflammatory activation of macrophages glucose clearance and insulin sensitivity. We also determined the mechanism and promotes the progression of arterial disease in mice. We found that not by which Pellino3 deficiency affects the expression of genes involved in en- only hematopoietic cells but also adipocytes express PARP14. Adipose tissue ergy metabolism, insulin signaling, and inflammation. After feeding a high-fat of obese mice expressed higher levels of PARP14 mRNA than did lean mice diet (HFD) for 10-17 weeks, Pellino3 deficient mice showed less weight gain (3.6-folds, p<0.001, n=6-8/group). We thus hypothesized that PARP14 associ- and adiposity than wild-type controls. Pellino3 deficiency improved hepatic steatosis, glucose tolerance and insulin sensitivity. The decreased hepatic ates with molecular mechanisms for obesity. PARP14 protein levels increased TG content in HFD-fed Pellino3 deficient mice was associated with altered during the differentiation of 3T3-L1 cells into adipocytes. Enforced expression expression of genes involved in fatty acid synthesis and fatty acid uptake, of PARP14 enhanced PPAR transcriptional activity in the luciferase system γ cholesterol efflux, and fatty acid -oxidation, indicative of altered liver physi- for the PPARs response element PPRE (3.0-folds, p<0.05). Ribosylation assays β ology. In addition, Pellino3 deficient mice displayed a marked suppression of demonstrated that PARP14 directly ribosylates PPARγ. These results indicate the c-Jun NH2-terminal kinase (JNK) activation by high fat diet, accompanied that PARP14 and PPARγ interact with each other. PARP14 silencing suppressed by decreased expression of inflammatory cytokines. These data suggest that adipocyte differentiation in 3T3-L1. Moreover, mouse embryonic fibroblasts in a HFD context, Pellino3 deficiency protects against diet induced obesity and (MEFs) extracted from PARP14-deficient mice did not induce adipocyte differ- its associated metabolic dysregulation, in part through a decrease in hepatic entiation unlike control MEFs (p<0.001, Fig. A and B). These findings suggest lipid accumulation and a decrease in systemic inflammation. that ADP-ribosylation of PPARγ by PARP14 regulates adipocyte differentiation, Supported By: Ministry of Food and Drug Safety (14182MFDS978) indicating that PARP14 may be a novel therapeutic target for obesity.

Obesity—Human

298‑LB Human Beige Adipocytes Generated from Capillary Networks Di‑ rectly Improve Systemic Metabolic Homeostasis SO YUN MIN, RAZIEL ROJAS-RODRIGUEZ, JAMIE KADY, MINWOO NAM, MAR- CUS COOPER, TIMOTHY FITZGIBBONS, MICHAEL A. BREHM, SILVIA COR­VERA, Worcester, MA Adipose tissue is composed of white adipocytes, which are specialized for energy storage, and brown adipocytes, which are specialized for thermogenesis. Recent studies have revealed a new class of thermogenic adipocytes arising within white adipose tissue in response to adrenergic stimulation or cold ex- posure, a phenomenon known as browning. These beige adipocytes are pres- ent in human adults and their abundance correlates with a lean phenotype and reduced risk of metabolic diseases. To understand the mechanisms underlying browning and metabolic benefit, it is necessary to identity the progenitors of Supported By: Kowa Company, Ltd. beige cells, the mechanisms that control their proliferation and differentiation, and the features underling their association with improved metabolism. Numer- 296‑LB ous studies in mouse have shown that adipocyte progenitors reside within the Long-Term Effects of Genisteinn, Sulforaphane, capillaries of adipose tissue depots. To determine whether adipocyte progeni- and Kaempferol on Insulin Resistance in Diet-induced Obese Mice tors also reside within human adipose tissue capillaries we have used an in vitro HANA ALKHALIDY, JING LUO, AIHUA WANG, KYUNG-SHIN SUH, WEI ZHEN, system in which hydrogels and pro-angiogenic conditions are used to expand DONGMIN LIU, Blacksburg, VA human subcutaneous adipose tissue capillary networks. We find that the growth of adipose tissue capillaries is accompanied by proliferation of adipocyte pro-

Insulin resistance and a progressive decline in functional β-cell mass are hall- marks of developing type 2 diabetes (T2D). Thus, searching for natural, low-cost genitors, identified by single cell cloning. Unexpectedly, these progenitors give compounds to simultaneously target these two defects could be a promising rise to beige adipocytes with expression of UCP1, as well as of other brown strategy to prevent the pathogenesis of T2D. Here, we found that natural com- adipose tissue-specific genes, resulting in a thermogenic phenotype character- pounds sulforaphane and kaempferol improve insulin sensitivity by increasing ized by augmented uncoupled oxygen consumption. When implanted into mice, I ntegrated energy metabolism and glucose uptake in skeletal muscle cells in vitro, while iso- adipocytes derived from human progenitors integrate into the circulatory sys- POSTERS flavone genistein promotes pancreatic beta-cell function and glucose tolerance tem, as assessed by the presence of human adiponectin in the mouse circulation, in mice. We further show that oral administration of genistein (G), sulforaphane and the mice implanted with human beige adipocytes display improved glucose Physiology/Obesity (S), G in combination with Kaempferol (K) (G+K), or G+S significantly improved tolerance. In summary, our results have identified functional human beige adipo- glucose and insulin sensitivity in high-fat diet (HFD)-fed obese mice. Notably, cyte progenitors residing within capillary networks, enabling their biochemical G+S is more potent than any other treatments in controlling blood glucose, while and functional characterization. treatment with either G+K or G+S completely restored insulin sensitivity to the Supported By: National Institutes of Health (R01DK089101, R24OD018259, levels comparable to those of lean mice. These desirable metabolic effects R01DK089185); American Heart Association (12FTF11260010) produced by these treatments were not due to changes in body weight or fat deposit in obese mice. However, we observed that obese mice also treated with compounds ultimately developed the similar magnitude of hyperglycemia and insulin resistance as the control obese mice after mice were fed the HFD for over 16 weeks. These results suggest that a combination therapy with sulforaphane

ADA-Funded Research For author disclosure information, see page LB98.

LB73 Obesity—Human

299‑LB the Band and LCD group. Fasting glucose levels decreased dramatically after Impact of Sulfonylurea (SFU) Use on Weight Loss (WL) Achieved surgery (RYGB=112±8 to 94±5mg/dL, SG=110±5 to 88±3mg/dL; Band=103±4 with Lorcaserin (LOR) to 97±3mg/dL) but had returned to baseline levels in the LCD group (116±12 CAROLINE M. APOVIAN, RANDI FAIN, ALAN GLICKLICH, TONY MA, WILLIAM to 113±14mg/dL) by 1 year. At 2 months, metabolic adaptation was observed SHANAHAN, Boston, MA, Woodcliff Lake, NJ, San Diego, CA in all surgery groups (SG=-164±62kcal; RYGB=-216±48kcal; Band=-186±66kcal; all P<0.05), a reduction which persisted only in the RYGB group (-183±35kcal) at LOR is a 5-HT2C receptor agonist indicated for chronic weight management in obese patients (pts)/overweight pts w/ ≥1 comorbidity. In Phase 3 trials, WL 1 year. No metabolic adaptation was observed in the LCD group at 2 months or w/LOR was lower in pts w/type 2 diabetes (T2DM) than in those w/o T2DM, 1 year. There were no associations between the degree of metabolic adapta- which may be due to the weight-gaining effect of SFUs. This post-hoc analysis tion and % weight loss or changes in circulating leptin, T3 and T4 in any of the focuses on the effect of LOR on WL and glycemic parameters (GPs) stratified groups studied. In conclusion, despite a large metabolic adaptation occurring 2 by SFU use in the BLOOM-DM trial, where T2DM pts were treated w/LOR 10 months after SG, Band and RYGB, only RYGB had persistent metabolic adapta- mg BID or placebo (PBO) for 52 wks. Pts were taking SFU alone (+SFU/-MET tion after one year. Our results suggest that there are unique mechanisms of [metformin]), MET alone (-SFU/+MET), or both (+SFU/+MET). In the unstratified RYGB in decreasing energy expenditure which require further investigation. population, LOR showed significant improvements vs. PBO for all WL and GPs Supported By: Ethicon Endo-Surgery, Inc. evaluated, and for the majority of these in the stratified populations (Table 1). However, categorical and absolute WL was less in pts taking LOR+SFU w/or 301‑LB w/o MET vs. pts taking LOR+MET alone. In contrast, pts taking LOR+SFU w/ Established BMI-associated Genetic Variants and Their Longitudi‑ or w/o MET achieved greater improvements in HbA1c and FPG vs. pts taking nal Associations with Cardiometabolic Traits: The GLACIER Study MET alone. This analysis suggests that reduced efficacy of LOR on WL in pts SHAFQAT AHMAD, ALAITZ POVEDA, DMITRY SHUNGIN, INÊS BARROSO, GÖRAN w/T2DM may be due, in part, to SFU use. Pts on MET but not taking SFUs had HALLMANS, FRIDA RENSTRÖM, PAUL W. FRANKS, Malmö, Sweden, Umeå, Swe- WL comparable to previously published data in pts w/o T2DM. den, Cambridge, United Kingdom Table. Mean Changes in WL and GPs in All Pts and Pts Stratified by SFU and Recent genome-wide meta-analyses have reported associations of 97 in- MET Use Following 52 Wks of LOR Treatment (MITT/LOCF). dependent loci with body mass index (BMI). We tested whether these loci are LOR PBO also associated with 10-year changes in BMI and other cardiometabolic traits in the GLACIER Study, a population-based prospective cohort study from northern a b a b All +SFU -SFU +SFU All +SFU -SFU +SFU Sweden. For the current follow-up analyses, complete data on 3,541 GLACIER -MET +MET +MET -MET +MET +MET Study participants was available. The GRS was calculated by summing the BMI- Weight loss (%) associated alleles at each genetic variant. The degree to which genetic predispo- sition to obesity, conveyed by these variants, impacts other cardiometabolic risk n 251 19 125 107 248 22 123 103 markers was determined by testing genetic associations with 10-year changes ≥5% 37.5 26.3 43.2* 32.7† 16.1 9.1 16.3 17.5 in a variety of clinical markers (blood concentrations of fasting and 2-h , ≥10% 16.3 15.8 20.8* 11.2† 4.4 0 3.3 6.8 triglycerides, total cholesterol, and systolic and diastolic blood pressures) were Weight (kg) tested separately and combined using principal components analysis. Cross-trait associations (suggestive of pleiotropy and mediation) of 97 BMI-associated ge- n 251 19 125 107 248 22 123 103 netic variants/or a GRS comprised of these variants with cardiometabolic traits Baseline mean 103.5 103.2 104.9 102.0 102.3 98.9 101.7 103.6 were tested by comparing genetic associations with a given trait with/without Change from -4.9 -4.7 -5.7* -4.1† -1.9 -0.7 -1.7 -2.3 adjustment for BMI. Regression models were adjusted for baseline age, age2, baseline fasting time (where relevant), sex, follow-up time, and population substructure. -39 HbA1c (%) The GRS was significantly associated with higher BMI P( =1.2 x 10 ), triglyc- erides (P=0.002), SBP (P=0.037) and DBP (P=0.008) at baseline without BMI n 238 16 122 100 232 21 115 96 adjustment. At 10 years follow-up, the GRS was significantly associated with in- Baseline mean 8.1 8.1 7.8 8.3 8.0 8.2 8.0 8.1 creased BMI (P=0.018) and decreased total cholesterol concentration (P=0.039), Change from -0.9 -1.0 -0.9* -1.0† -0.4 -0.4 -0.5 -0.4 the latter of which was without BMI adjustment. Collectively, established BMI- baseline associated variants convey modest time-dependent associations with long-term FPG (mg/dL) changes in BMI and serum total cholesterol. These findings suggest a role for effect-modification by factors that change with time. n 242 19 117 106 244 22 122 100 Supported By: Novo Nordisk (to P.W.F.); Swedish Research Council (to P.W.F.); Baseline mean 163.3 169.1 154.3 172.8 160.0 162.7 161.4 157.6 Swedish Heart Lung Foundation (to P.W.F.); Skåne Health Authority (to P.W.F.); Change from -29.2 -36.4 -23.8* -33.8‡ -11.3 -7.6 -13.0 -10.1 Basque Government (to A.P.) baseline ap<0.0001 vs. PBO for all comparisons (previously reported data of mean/ 302‑LB mean change from baseline are presented for each parameter); bp-values not In Vivo Assessment of Adipocyte Cellular Kinetics in Abdominal provided for +SFU/-MET group due to small sample size. *p≤0.001 vs. PBO and Femoral Subcutaneous Adipose Tissue in Women -SFU/+MET; †p<0.001 vs. PBO +SFU/+MET; ‡p=0.002 vs. PBO +SFU/+MET. URSULA WHITE, MARK FITCH, MARC HELLERSTEIN, ERIC RAVUSSIN, Baton FPG=fasting plasma glucose; HbA1c=glycated hemoglobin; LOR=lorcaserin; Rouge, LA, Berkeley, CA MET=metformin; MITT/LOCF=modified intent-to-treat/last-observation-carried- Adipose tissue (AT) distribution, rather than overall excess adiposity, may forward; PBO=placebo; SFU=sulfonylurea. Supported By: Eisai Inc. be a better determinant of metabolic health. Upper body fat is classically associated with the complications of obesity, while lower body fat may be somewhat protective. Studies suggest that fat expansion involves depot spe- 300‑LB cific cellular mechanisms. We assessed in vivo adipogenesis in subcutaneous Metabolic Adaptation Persists 1 Year after Gastric Bypass, but Not AT from the abdominal (scABD) and femoral (scFEM) depots using the 8 week Sleeve or Band Bariatric Surgery incorporation of deuterium (2H) into the DNA of adipocytes and preadipocytes

I ntegrated CHARMAINE TAM, LEANNE M. REDMAN, FRANK GREENWAY, ERIC RAVUSSIN, 2

POSTERS in 25 obese women (14 Black; 11 White; 31 ± 6 years; BMI 32.6 ± 2.7 kg/m ; Sydney, Australia, Baton Rouge, LA 44.3 ± 4.1% body fat). Measures of new DNA synthesis denote cell formation Physiology/Obesity Weight loss often results in metabolic adaptation, i.e. a decrease in en- or proliferation in the adipose depots. Cellular preadipocyte and adipocyte ergy expenditure larger than that expected on the basis of the loss in fat-free formation rates both correlated positively with overall % body fat (p < .05). mass and fat mass. Preclinical data suggests that metabolic adaptation may Notably, preadipocytes and adipocytes had higher proliferation rates in the be blunted in response to bariatric surgery, but it is not known whether this scFEM depot relative to the scABD (*p< .05; ***p< .001 in Figure). Also, the differs with the type of surgery. In this study, we assessed sedentary en- proliferation rate of adipocytes was positively correlated to that of preadipo- ergy expenditure (24hEE) in a metabolic chamber at baseline, 2 months and cytes in each depot. This in vivo method will prove useful to assess adipocyte 1 year after Roux-en-Y bypass (RYGB), sleeve gastrectomy (SG), gastric band kinetics in relation to body composition or in response to a variety of interven- (Band) or low-calorie diet (LCD) (n=32: 29F/3M; 4 with diabetes; age=45.8±12.1y; tions, such as diet, exercise or pharmacological treatment. BMI=48.1±9.0kg/m2). Metabolic adaptation at follow-up was calculated as the Supported By: National Institutes of Health-National Institute of Diabetes and difference between measured energy expenditures and energy expenditures Digestive and Kidney Diseases (R01DK090607-S) predicted from body composition, sex and age at baseline. Data are presented as mean±SEM. After 1 year, SG and RYGB groups had achieved similar weight loss (SG=-35.6±3.1%; RYGB=-36.0±3.1%), with -17.6±1.8% and -3.0±1.6% in ADA-Funded Research For author disclosure information, see page LB98.

LB74 Obesity—Human

304‑LB HNF4A Regulates Betatrophin during the Progression of Insulin Re‑ sistance CAROLINE BONNER, VALÉRY GMYR, VIOLETA RAVERDY, GURVAN QUENIAT, ERICKA MOERMAN, CÉDRIC BEAUCAMPS, NATHALIE DELALLEAU, JULIEN THEVENET, AMAR ABDERRAHMANI, ROBERT CAIAZZO, JULIE KERR-CONTE, FRANÇOIS PATTOU, Lille, France Insulin resistance (IR) is associated with beta cell expansion in adults, and a failure to do so in response to metabolic demand is a key feature of type 2 diabetes (T2D). Studies in mice suggest that circulating betatrophin (C19orf80 gene) link IR and beta cell functional mass, but the mechanisms involved are unclear. Since Hepatocyte-Nuclear-Factor-4-alpha (HNF4A) is a key regulator of important hepatic genes, we hypothesized whether HNF4A was required to regulate betatrophin during IR. In a cross sectionnal clinical study C19orf80 mRNA expression was induced in the liver by IR and cor- related with serum betatrophin concentrations, body mass index, and beta cell functional mass, as estimated by HOMA-B. In contrast, and despite IR, there was a significant decline in betatrophin in T2D subjects. Similar bipha- sic gene expression patterns were identified for HNF4A, and putative bind- ing sites for HNF4A were identified on the C19orf80 promoter. In patients with grade 3 obesity, surgical weight loss was associated with a simulta- neous decrease in betatrophin serum levels, IR and HOMA-B. Collectively, these findings suggest that hepatic HNF4A is a critical transcription factor required for betatrophin liver expression and secretion, in close relation with IR and beta cell mass function, which is lost during T2D. 303‑LB Significant Effects of HM11260C on Body Weight over 20 Weeks in Obese Subjects without Diabetes: A Randomized, Double-Blind, Placebo-Controlled Study RICHARD E. PRATLEY, JAHOON KANG, PANKYUNG KIM, EUNHWA KWAK, OAKPIL HAN, SIYOEN KIL, KYUHOON GEE, IN YOUNG CHOI, SE CHANG KWON, MICHAEL TRAUTMANN, MARCUS HOMPESCH, Orlando, FL, Seoul, Republic of Korea, Chula Vista, CA

HM11260C (HM) is a novel long acting GLP-1R agonist with a T1/2 of ~ 158 hrs resulting in a flat PK profile. This 20-week, randomized, double-blind, pla- cebo (PBO) controlled, parallel group study was designed to evaluate the efficacy, safety, and tolerability of once a week (QW) or every other week (Q2W) doses of HM in obese subjects without diabetes. 297 subjects (mean age 43.4 yrs and BMI 35.5 kg/m2) were randomized to one of four HM doses (4 mg QW, 6 mg QW, 6 mg Q2W, or 8 mg Q2W) or to PBO. HM was ad- ministered subcutaneously for 20 weeks. The diet and exercise regimens remained unchanged during the study. The body weight loss with HM 4mg QW, 6 mg QW, 6 mg Q2W and 8 mg Q2W was 6.2 kg, 7.8 kg, 7.0 kg and 7.1 kg (LS Mean, p<0.0001 all HM treatment groups), whereas the body weight gain was observed with PBO (0.8 kg). More subjects in the HM treatment groups achieved significant body weight loss ≥5% or ≥10%, and the mean reductions in waist circumference and BMI from baseline were greater, com- pared with PBO. The most frequent adverse events were gastrointestinal events which were observed relatively frequently and increased injection site reactions which were less common (Table 1). In conclusion, all doses of HM meaningfully reduced body weight and were well tolerated. These results warrant further studies to assess titration schemes as well as the long-term efficacy and safety of HM in obesity.

I ntegrated POSTERS Physiology/Obesity

305‑LB Spleen Attenuation Was Correlated with Intramuscular Adipose Tissue in Skeletal Muscle at Steady State and during Exercise KYUNG AH HAN, KYUNG WAN MIN, HONG KYU LEE, Seoul, Republic of Korea Spleen enlargement was commonly seen in patients with nonalcoholic fatty liver. Ectopic lipids can be depleted during exercise. We hypothesized that spleen as another site of ectopic fat deposition is related to the intra- muscular adipose tissue in skeletal muscle or hepatic steatosis and also with insulin sensitivity in type 2 diabetes. We assessed BMI, total abdominal

ADA-Funded Research For author disclosure information, see page LB98.

LB75 Obesity—Human

(TAF), subcutaneous fat (SAF) and visceral fat (VAF), liver and spleen attenu- subgroups had broadly comparable adverse events (AEs). In both liraglutide ation (HA and SA), intramuscular adipose tissue (IMAT), at midthigh level 3.0 mg subgroups (BMI< or ≥35) a greater proportion of subjects had nau- using computed tomography, and measured circulating retinol binding pro- sea (34 vs. 32%) and vomiting (11% vs. 20%) than placebo (nausea: 12 vs. tein 4 (RBP4), adiponectin/leptin ratio (ALR), free fatty acid (FFA), and insulin 15%; vomiting: 8% vs. 4%). Documented symptomatic hypoglycemia (FPG sensitivity by homeostatic model assessment insulin resistance (HOMA-IR) ≤70 mg/dL) rates were similar with liraglutide 3.0 mg in both BMI subgroups at baseline, and after 12 week exercise program. Total 56 women with type 2 (1.07 vs. 0.70 events/PYE), as was severe hypoglycemia, seen in 3 subjects diabetes (age 56±2 years; BMI 27.1±3.1 kg/m2) completed the lifestyle modi- with concomitant SU. In summary, effects of liraglutide 3.0 mg, as adjunct to fication program including exercise. BMI decreased to 26.3±3.2 kg/m2 after Dand E, on weight loss, associated metabolic effects and safety profile were intervention. SA was correlated with visceral fat (r=-.302, p=0.02), IMAT (r=- consistent across predefined baseline BMI subgroups. .314, p=0.016), adiponectin/leptin ratio (r=-.366, p=0.005), RBP-4 (r=-.262, Table. p=0.047), HOMA-IR (r=-.265, p=0.044), but not with TAF, SAF, LA or FFA. at baseline. SA was also correlated with visceral fat (r=-.302, p=0.02), IMAT (r=-.314, p=0.016), ALR (r=-.366, p=0.005), RBP-4 (r=-.262, p=0.047), HOMA- IR (r=-.265, p=0.044), but not with TAF, SAF, LA or FFA at 3 month. Change of SA from baseline was also correlated with change of IMAT (r=.231, p=0.045). In conclusion, spleen attenuation was connected with intramuscular adipose tissue and insulin resistance at steady-state, and during exercise. It sug- gested that spleen might be the another site of ectopic fat deposition in type 2 diabetes.

306‑LB Leptin Secretion Is Modified by C-Peptide in Human Visceral Adi‑ pose Tissue SARA GARCIA-SERRANO, CAROLINA GUTIERREZ-REPISO, FRANCISCA RO- DRIGUEZ-PACHECO, EVA GARCIA-ESCOBAR, JUAN GARCIA-ARNES, SERGIO VALDES, MONTSERRAT GONZALO, JUAN F. COBOS-BRAVO, FRANCISCO J. MORENO-RUIZ, ALBERTO RODRIGUEZ-CAÑETE, EDUARDO GARCIA FUENTES, Málaga, Spain C-peptide has been found to be a bioactive peptide, acting as a hormone Supported By: Novo Nordisk independent of insulin. C-peptide could be involved in the regulation of the synthesis of different adipocytokines in human adipose tissue. We aim to 308‑LB determine whether C-peptide levels could be associated with leptin levels. Contribution of Low-Frequency Variants to Variation in Body Mass First, we analyzed the association between serum C-peptide and leptin lev- Index (BMI) els with an intravenous glucose tolerance test (IVGTT). After, we performed RUTH J.F. LOOS, VALERIE TURCOT, YINGCHANG LU, HEATHER M. HIGHLAND, an in vitro study in human visceral adipose tissue (VAT) to analyze the ef- TODD L. EDWARDS, TONU ESKO, MARIELISA GRAFF, ANNE E. JUSTICE, M. fect of C-peptide on leptin secretion. C-peptide significantly correlated with CAROLINA MEDINA-GOMEZ, CLAUDIA SCHURMANN, ROBERT A. SCOTT, K. SIN different variables: glucose (r=0.342, p<0.0001), insulin (r=0.605, p<0.0001), LO, SUTESH S. SIVAPALARATNAM, LORRAINE SOUTHAM, KATHY STIRRUPS, insulin sensitivity (SI) (r=-0.500, p=0.0001), area under curve of insulin (AUCI) THOMAS W. WINKLER, HANIEH YAGHOOTKAR, KRISTIN L. YOUNG, L. ADRIENNE (r=0.448, p=0.003) and leptin (r=0.370, p<0.0001). C-peptide was associ- CUPPLES, TIMOTHY M. FRAYLING, JOEL N. HIRSCHHORN, GUILLAUME LETTRE, ated in a multiple regression analysis model with leptin (p=0.011, β=0.476) CECILIA M. LINDGREN, KARI E. NORTH, INGRID BORECKI, BBMRI, GOT2D, and insulin levels (p<0.001, β=0.556) (R2=0.640) after adjusting the model CHARGE, GIANT CONSORTIUM, New York, NY, Montreal, QC, Canada, Houston, TX, for age, gender, body mass index (BMI), glucose and SI. The AUCC-peptide Nashville, TN, Tartu, Estonia, Chapel Hill, NC, Rotterdam, Netherlands, Cambridge, correlated significantly with different variables: insulin (r=0.291, p=0.041), United Kingdom, Amsterdam, Netherlands, Hinxton, United Kingdom, Regensburg, AUCI (r=0.512, p<0.0001) and leptin (r=0.470, p=0.001). In a multiple linear re- Germany, Exeter, United Kingdom, Boston, MA, Cambridge, MA, St. Louis, MO gression model, the AUCC-peptide was associated with BMI (p=0.006; β=- Over 95 BMI-associated loci have been identified by genome-wide as- 0.514), leptin (p=0.003; β=0.572), SI (p=0.021; β=-0.441) and AUCI (p=0.019, sociation studies (GWAS), the vast majority of which are common and have β=-0.304) (R2=0.630) after adjusting the model for age, gender, glucose and small effects. While low-frequency exonic variants are known to cause insulin. We found a significant increase in leptin secretion into the medium extreme and early-onset obesity, little is known about their role in obe- after a 24 hours incubation with 10 nM C-peptide (p=0.043) in human VAT sity susceptibility in the general population. To estimate the contribution explants from non-obese subjects, with no significant effect with 1 nM C- of low-frequency (MAF < 5%) single nucleotide variants (SNV) to BMI, we peptide. In human VAT explants from morbidly obese subjects, 1 and 10 nM performed a meta-analysis of exome array data in up to 249,395 individuals C-peptide induced an increased in leptin secretion (p=0.037 and p=0.047, of predominantly European ancestry from 79 studies. In each study, associa- respectively). In conclusion, we found a relation between serum C peptide tion was tested between ~ 250,000 SNVs and inverse normally transformed and leptin. Also, we found that C-peptide has an effect on leptin secretion. residuals of BMI, adjusted for age and sex. Study-specific association re- Supported By: Consejería de Economia, Innovacion, Ciencia y Empresa de la sults were combined using inverse variance-weighted meta-analysis. As- Junta de Andalucía, Spain (CTS-8081) sociations for 3 low-frequency variants reached array-wide significance (P < 5x10-7). A rare nonsynonymous SNV (MAF = 0.04%, Val830Ile) in an un-

307‑LB known protein-coding gene (KIAA0754, P = 4.8x10-7) increases BMI by ~2.5 Liraglutide 3.0 mg Efficacy and Safety by Baseline BMI in the SCALE kg.m-2 (or ~7.2 kg for a 1.7m-tall person). A second SNV, in the first intron of Diabetes Trial: Post-hoc Analysis GPR61 (3.7%, P = 2.8x10-21, ~1.0 kg/allele), is flanked by a more common cod- VANITA R. ARODA, JULIO ROSENSTOCK, JOANNA UDDÉN HEMMINGSSON, ing SNV (6.6%, P = 1.3x10-10, ~500 g/allele) in SYPL2. While fine-mapping is I ntegrated POSTERS MELANIE DAVIES, TRINE V. SKJØTH, BIRGITTE CLAUDIUS, HAROLD BAYS, needed to determine the causal gene in this locus, GPR61 is a strong biologi- Hyattsville, MD, Dallas, TX, Stockholm, Sweden, Leicester, United Kingdom, Søborg, cal candidate as GRP61-deficient mice exhibit obesity and hyperphagia. The Physiology/Obesity Denmark, Louisville, KY third SNV is a missense variant (3.7%, Pro180Ser) in ZBTB7B (P = 3.8x10-8, SCALE Diabetes (NCT01272232) randomized 846 adults (age 54.9 y, M 650 g/allele), located at the downstream-end of a long-range association 50%, BMI 37 kg/m2, A1C 7.9%, T2D duration 7.3 y) 2:1:1 to liraglutide 3.0 mg, peak (1Mb) of common SNVs (MAF > 25%) that include coding variants in 1.8 mg, or placebo as adjunct to diet and exercise (D and E) for 56 wk. This EFNA1 and UBQLN4. Conditional analyses and functional follow-up to deter- analysis compared efficacy and safety results for individuals with baseline mine whether the low-frequency and common SNVs represent independent BMI < or ≥35 kg/m2 treated with liraglutide 3.0 mg for weight management signals are ongoing. We conclude that large-scale meta-analyses of exome or placebo. Data are LS means (efficacy) or observed means (LOCF). Overall array data will uncover low frequency SNVs with effects larger than the withdrawals rates were 23.4% for liraglutide 3.0 mg vs. 34.0% for placebo. common GWAS-identified loci. Ongoing analyses include an expansion of At 56 wk, greater mean and categorical weight loss, and greater improve- the sample (> 450,000), gene-based analyses and functional follow-up. ments in glycemic parameters, SBP, and IWQoL-Lite physical function score were seen with liraglutide 3.0 mg vs. placebo in both subgroups. Treatment effects were independent of baseline BMI subgroup (p>0.05) (Table). BMI

ADA-Funded Research For author disclosure information, see page LB98.

LB76 Obesity—Human

309‑LB 311‑LB Blood Lead Level Associates with Higher Body Mass Index and Weight Loss after Gastric Bypass Surgery in Human Obesity Re‑ Prevalence of Obesity in Chinese Women veals Novel Changes in Skeletal Muscle Proteome YINGLI LU, NINGJIAN WANG, CHI CHEN, XIAOMIN NIE, BING HAN, QIN LI, YI LATOYA E. CAMPBELL, PAUL R. LANGLAIS, SAMANTHA E. DAY, JOON YOUNG CHEN, CHUNFANG ZHU, YINGCHAO CHEN, FANGZHEN XIA, XIAOQI PU, ZHEN KIM, TONYA R. BENJAMIN, ELENA A. DE FILIPPIS, LAWRENCE J. MANDARINO, CANG, CHAOXIA ZHU, MENG LU, YING MENG, HUI GUO, DONGPING LIN, Shang- JAMES A. MADURA II, LORI R. ROUST, DAWN K. COLETTA, Tempe, AZ, Scotts- hai, China dale, AZ, Phoenix, AZ Objective: Lead may be an endocrine and metabolism disrupter. Limited Weight loss after roux-en-Y gastric bypass (RYGB) is associated with im- studies have explored the association between blood lead level (BLL) and provements in skeletal muscle insulin sensitivity. However, the molecular obesity and there is few Investigations of BLL in general adults in China. We mechanisms to explain this phenomenon are not entirely clear. Here, we in- aimed to investigate the relationship of BLL with body mass index (BMI) and vestigated the role of obesity and weight loss after RYGB on the human skel- obesity in Chinese adults. etal muscle proteome. Muscle biopsies were obtained basally from seven Methods: Our data were population based and from 16 sites in East China. insulin-resistant morbidly obese (BMI >40 kg/m2) female subjects (45.1±3.6 5558 adults were enrolled with a mean±SD age of 53±13 years. BLL was years) pre and 3 months post-RYGB with euglycemic hyperinsulinemic measured by atomic absorption spectrometry. Obesity was defined as BMI clamps to assess insulin sensitivity. Four age-matched (48.5±4.7 years) lean ≥30kg/m2 and overweight as 25≤BMI<30kg/m2. The associations of BLL (BMI <25 kg/m2) insulin sensitive (M value: 7.8±0.5 mg/kg.min) females were with BMI were analyzed by linear regression and association of BLL with studied for comparative purposes. Significant improvements in fasting plas- obesity and overweight by multinomial logistic regression analyses. ma glucose: 104.2±7.8 vs. 86.7±3.1 mg/dl, BMI: 42.1±2.2 vs. 35.3±1.8 kg/m2 Results: Medians (interquartile range) of BLL were 44.0μg/L (29.0-62.2) and M value: 2.6±0.4 vs. 3.6 ±0.4 mg/kg·min were demonstrated in the pre for men and 37.8μg/L (25.1-54.4) for women. In women BLL was significantly vs. post-RYGB, all P<0.05. Quantitative mass spectroscopy analysis of the correlated with BMI but in men this correlation was not observed. In linear skeletal muscle identified 2,877 quantifiable proteins. Firstly, we identified regression, after full adjustment for age, residence area, economic status, that 395 proteins exhibited significantly altered expression levels between smoking, diabetes, dyslipidemia and hypertension, BMI was still associated the lean vs. obese pre-RYGB analysis, and KEGG pathway analysis revealed with BLL (β=0.006, P<0.01) in women. In fully adjusted model by logistic patterns of decreased abundance in ribosomal and oxidative phosphoryla- regression analyses, BLL significantly associated with obesity, not over- tion proteins in obesity. Secondly, we demonstrated that the expression of weight in women. Odds ratio (95% confidence interval) of obesity for each 280 proteins differed significantly in the pre versus post-RYGB analysis, and 1-standard deviation increment of log-transformed BLL was 1.28 (1.07-1.53) 49 proteins were normalized to levels observed in the lean healthy females in women and 0.94 (0.77-1.16) in men. following weight loss after RYGB. The weight loss after RYGB revealed an Conclusions: BLLs in Chinese adults were much higher than those in devel- increased abundance and normalization of ribosomal, MAP kinase and colla- oped countries. BLL associated with higher BMI and prevalence of obesity gen proteins. Our results provide evidence that obesity and weight loss after in Chinese women. Concerted efforts are warranted to reduce adult lead RYGB have a dynamic effect on the skeletal muscle proteome. exposure in China. Supported By: Mayo Clinic-Arizona State University Supported By: National Natural Science Foundation of China (81270885, 81070677); Clinical Potential Subject Construction of Shanghai Jiaotong Uni- 312‑LB versity School of Medicine (2014); Ministry of Science and Technology in China (2012CB524906); Science and Technology Commission of Shanghai Municipality Withdrawn (14495810700); Fund for Outstanding Academic Leaders in Shanghai (12XD1403100)

310‑LB Jejunal De Novo Lipogenesis and Lipoproteins Synthesis Is Altered in Morbidly Obese Subjects with High Insulin Resistance CAROLINA GUTIERREZ-REPISO, FRANCISCA RODRIGUEZ-PACHECO, JUAN GAR- CIA-ARNES, SERGIO VALDES, MONTSERRAT GONZALO, FRANCISCO J. MORE- NO-RUIZ, ALBERTO RODRIGUEZ-CAÑETE, MIGUEL A. ALAMINOS, GUILLERMO ALCAIN-MARTINEZ, LUIS VAZQUEZ-PEDREÑO, SARA GARCIA-SERRANO, EDU- ARDO GARCIA FUENTES, Málaga, Spain The dyslipidemia associated with type 2 diabetes mellitus (T2DM) is an important risk factor for atherosclerotic cardiovascular disease. However, until now little attention has been paid to the role that the intestine might play in these metabolic diseases. The aim of this research was to determine the relation between insulin resistance and intestinal de novo lipogenesis/ lipoprotein synthesis in morbidly obese subjects. Jejunal mRNA expression of different genes involved in the intestinal de novo lipogenesis/lipoprotein synthesis was analyzed in three groups of morbidly obese subjects: with low insulin resistance (MO-low-IR), with high insulin resistance (MO-high- IR) (both groups without treatment for T2DM), and with T2DM and treat- ment with metformin (MO-metf-T2DM). In the MO-high-IR group, apo A-IV

(p=0.016), ACLY (p=0.045), PDHB (p=0.043) and SREBP-1c (p=0.019) mRNA expression levels were significantly higher and ACC1 (p=0.011) and FAS (p=0.042) significantly lower than in the MO-low-IR group. When the MO- low-IR and MO-metf-T2DM groups were compared, these significant dif- I ntegrated ferences were maintained in ACLY (p=0.043) and PDHB (p=0.042) mRNA POSTERS expression levels. Between the MO-high-IR and MO-metf-T2DM groups, there are only significant differences in FAS mRNA expression (p=0.049). Physiology/Obesity HOMA-IR correlated with apo A-IV (r=0.530; p=0.004), DGAT2 (r=0.411, p=0.033), PDHB (r=0.495, p=0.019), SREBP-1c (r=0.540; p=0.002), ACLY mR- NA expression (r=0.605; p=0.006). In conclusion, the jejunum of MO-high-IR has a decreased mRNA expression of genes involved in de novo fatty acid synthesis and an increase of genes involved in acetyl-CoA and lipoprotein synthesis. This effect is attenuated by metformin. Supported By: Instituto de Salud Carlos III (PI12/00338)

ADA-Funded Research For author disclosure information, see page LB98.

LB77 Obesity—Human

313‑LB 315‑LB The Different Contributions of β-Cell Dysfunction and Insulin Resis‑ Preoperative Prediction of Type 2 Diabetes Mellitus Remission af‑ tance to the Progression of Type 2 Diabetes in Obese and Non­obese ter Bariatric Surgery: Retrospective Validation of Diabetes Remis‑ Chinese People sion Scoring Tool (DiaRem) JIA LIU, YING WANG, YANJIN HU, YUAN XU, SONG LENG, GUANG WANG, Beijing, DANIEL J. LIN, ROHAN LAKHANI, RANGANATHA RAO, JENNY ABRAHAM, China NEHA SHAH, LOUISE HALDER, HARPAL S. RANDEVA, THOMAS M. BARBER, β-cell dysfunction plays a prominent role in type 2 diabetes (T2D) etiol- NARASIMHA MURTHY, VINOD MENON, SUDHESH KUMAR, NARENDRA L. ogy, and obesity is a major cause of insulin resistance and T2D. This study REDDY, Coventry, United Kingdom aimed to assess the different roles of β-cell dysfunction and insulin resis- DiaRem score is a preoperative prediction tool of type 2 diabetes (T2D) tance in the progression from normal glucose tolerance to T2D in obese and remission after Roux-en-Y gastric bypass (RYGB). This study aimed to extend non-obese Chinese people. A total of 3254 participants aged ≥ 25 years, the validation of DiaRem score to sleeve gastrectomy (SG) and laparoscopic including 1,843 healthy controls and 1,411 newly diagnosed T2D patients adjustable gastric band (LAGB) surgeries. A retrospective study of bariatric were recruited. All participants were categorized into the non-obese con- patients at a University hospital involving consecutive patients undergoing trol, obese control, non-obese T2D and obese T2D groups. The obese sub- RYGB, SG, and LAGB, between February 2009 and July 2014 was undertaken jects had higher homeostasis model assessment of insulin resistance and utilizing UK National Bariatric Surgery Registry. Preoperative predictors and β-cell function (HOMA-IR and HOMA-β) than the non-obese ones, whether post-operative T2D status at 12 months were obtained from electronic and in the control group or the T2D group (all P<0.01). Higher HOMA-IR and lower case note records. DiaRem (weighted factors: age, HbA1c, T2D drugs, insulin HOMA-β were observed in non-obese T2D patients when compared with use) was applied and stratified into 5 categories (0-2, 3-7, 8-12, 13-17, 18-22). non-obese controls (all P<0.01). The obese T2D group had lower HOMA-β T2D remission was defined using ADA’s 2009 criteria (HbA1c {%}: Complete than the obese control group (P<0.01). There was no significant difference <6.0; Partial 6.0-6.5; no remission >6.5). Out of 248 patients, 81 T2D patients in HOMA-IR between the obese T2D and obese control groups. The decline (♂:22, ♀:59 female; Mean age 49 years {range 29-71}, Mean BMI 49.1 kg/ of β-cell function, together with persistent insulin resistance, accounts for m2 {37.4-64}) underwent 42 SG, 24 LAGB, and 15 RYGB. At 12 months, 54% the progression from normal glucose tolerance to T2D in obese people, while (44/81) were in T2D remission; 12% (10/81) in partial remission, 34% (27/81) the decline in β-cell function mainly contributes to the progression in non- in non-remission. On DiaRem stratification, T2D remission for SG: 0-2 (80%, obese people. n=15), 3-7 (92%, n=13), 8-12 (20%, n=5), 13-17 (0%, n=8), and 18-22 (0%, n=1); for LAGB: 0-2 (50%, n=6), 3-7 (31%, n=13), 8-12 (0%, n=2), 13-17 (0%, n=2), and 18-22 (0%, n=1); for RYGB: 0-2 (100%, n=4), 3-7 (83%, n=6), 8-12 (100%, n=1), 13-17 (100% n=2), 18-22 (0%, n=2). DiaRem score cut off ≤7 showed remission in SG 86%, LAGB 37%, and RYGB 90%. Pearson correlation for DiaRem scores with SG (r= -0.91); LAGB (r= -0.67), and RYGB (r= -0.63). Dia- Rem score reliably predicted T2D remission rates in SG and RYGB, and was unreliable in LAGB. Proposed score ≤7 predicted high remission probability in SG and RYGB. Strong negative correlation in SG indicated that DiaRem score can be successfully applied in SG group of patients.

316‑LB Aberrant Expression of IR-B, the Metabolic Isoform of Insulin Re‑ Supported By: Major National Basic Research Program of P.R. China ceptor, in Endometrial Cancer and Hyperplasia (2011CB503904); National Natural Science Foundation of China (81270369, FARRAH SALEH, CLARE A. FLANNERY, GINA CHOE, KATHERINE ARAQUE, TE- 81070244, 30770873); Beijing Natural Science Foundation (7142060) RESA WOOD, HUGH S. TAYLOR, New Haven, CT, Newark, NJ Obesity is a risk factor for endometrial hyperplasia and cancer, suggesting 314‑LB that hyperinsulinemia may contribute to pathogenesis. The insulin receptor Metabolic Syndrome: Is Waist Circumference the Correct “Entrance splice variant IR-B is known for metabolic activity versus IR-A which is known Criteria?” for mitogenic activity. We previously found IR-B is 2-fold higher in secretory KATRINE DRAGSBÆK, JESPER S. NEERGAARD, MORTEN KARSDAL, CLAUS than proliferative endometrium, and insulin regulates glycogen synthesis in CHRISTIANSEN, Herlev, Denmark endometrial glands, which secrete glycogen in preparation for implantation. Large waist circumference (WC) has become the “entrance criteria” for Thus, we hypothesized that IR-B expression is regulated by progesterone, defining metabolic syndrome (MS) used to identify patients at greater risk and may be reduced by hyperinsulinema. Given obesity-driven risk, we also of developing cardiovascular diseases (CVD) and type 2 diabetes (T2DM). investigated IR-B in hyperplasia and adenocarcinoma. IR-B mRNA was quan- This study aimed to investigate the risk of developing CVD and T2DM based tified in normal proliferative (n=25) and secretory (n=18) endometrium from on number of metabolic risk factors rather than WC in subjects stratified on women of mean BMI 29 kg/m2, endometrial hyperplasia (n=5, BMI 34), and BMI and body composition. Demographics, DEXA scans and serum samples adenocarcinoma (n=11, BMI 37) by qRT-PCR. IR-B was also quantified in pri- were collected from 1999-2001 on 5855 women aged 73.1±6.3. CVD and mary endometrial epithelial and stromal cells (n=4) treated with estradiol T2DM diagnoses were collected from Danish National Disease Registries 10nM, progesterone 1µM, E+P, or insulin 1 or 100nM. IR-B was not altered by primo 2015. Stratification was made on body composition (central/periph- either estradiol or progesterone in vitro (p=NS). IR-B expression and BMI did eral (C/P) fat mass ratio stratified into quartiles, Q1-Q4) and BMI (<18.5, not correlate in either cycle phase, and IR-B was not significantly changed by 18.5-24.9, 25.0-29.9, ≥30). Metabolic health was assessed by triglycerides, insulin in primary cells at either concentration (p=NS). In hyperplasia, mean

HDL-cholesterol, blood pressure, and fasting glucose. The presence of MS IR-B was 5.5-fold higher than normal proliferative (p<0.001) and 2.8-fold and number of abnormalities were assessed by International Diabetes higher than secretory endometrium (p=0.007). In adenocarcinoma, IR-B was Federation criteria. Subjects diagnosed prior to enrollment were excluded 3-fold higher than the proliferative tissue (p<0.01) but similar to the secre- from analysis. Incidence and relative risks (RR) for development of CVD and tory phase (p=NS). We show that IR-B likely has a physiological role in the I ntegrated POSTERS T2DM in subjects with ≥2 MS risk factors were calculated for all BMI and endometrium during the secretory phase, but surprisingly was not regulated body composition groups. The RR for developing CVD and T2DM were in- directly by sex . IR-B was not altered by insulin in vitro, nor correlat- Physiology/Obesity creased within all groups regardless of BMI or body composition for subjects ed to BMI, a clinical indicator of hyperinsulinemia. Higher IR-B expression in having ≥2 MS risk factors. RR for CVD stratified on body composition: Q1: endometrial hyperplasia and cancer is consistent with increased metabolic RR=1.22 (95% CI: 1.05-3.53), Q2: RR=1.18 (1.06-1.31), Q3: RR=1.25 (1.14-1.36), activity, and may reflect a contribution of IR-B in abnormal proliferation. Q4: RR=1.12 (0.95-1.26). RR for T2DM stratified on body composition: Q1: Supported By: National Institutes of Health-Eunice Kennedy Shriver National RR=1.44 (0.79-2.64), Q2: RR=4.26 (3.82-4.76), Q3: RR=2.64 (2.41-2.89), Q4: Institute of Child Health and Human Development RR=2.74 (2.37-3.16). The incidence of T2DM increased significantly with both increasing C/P ratio and BMI. However, CVD incidence did not increase sig- nificantly between weight groups emphasizing that number of risk factors, rather than BMI or body composition, are the denominator for CVD outcome. Number of risk factors rather than WC should be used for optimal identifica- tion of patients at increased risk of CVD due to MS. Supported By: Danish National Research Foundation

ADA-Funded Research For author disclosure information, see page LB98.

LB78 Islet Biology—Apoptosis

317‑LB 319‑LB Exenatide Blunts the Thermic Effect of Food in Nondiabetic Women Development of a Novel Broad Range, Highly Specific and Highly NATASHA KASID, SOPHIE COMTE-PERRET, ELENA TOSCHI, JULIET R. TRIPALDI, Sensitive Chemiluminescent ELISA Assay for Measuring Glucagon TAHEREH GHORBANI, ELEFTHERIA MARATOS FLIER, JODY DUSHAY, Boston, MA in Blood-derived Samples Exenatide, a glucagon-like peptide 1 receptor agonist, causes increased NIRAJA PATEL, SEAMUS WEBB, JAMES LULO, JULIE DONALDSON, COLLIN satiety and weight loss through peripheral and central mechanisms not SHAW, CHRIS WISHERD, STACY DION, MARTIN BLANKFARD, Salem, NH fully understood. We are conducting a randomized, single-blind, placebo- Glucagon is a well-known and important which has been controlled study investigating weight change with BID exenatide versus demonstrated to play a vital role in many biological functions, particularly hypocaloric diet in non-diabetic women with BMI 28-48kg/m2. Subjects gluconeogenesis and . The glucagon peptide is conserved receiving exenatide follow an ad lib diet while those in the diet arm follow in all mammals. Glucagon is secreted from α-cells in the pancreas in re- a hypocaloric diet and administer BID injections of placebo. Subjects who sponse to low circulating glucose levels. Glucagon levels in normal patients lose ≥ 5% body weight at 3 months continue treatment for 1 year. To date, can range from 50-250pg/mL (14-72 pM) depending upon food intake. The 35% of subjects randomized to exenatide (E) lost 5.5% (range 5.2-9.8) body main function of glucagon is to act as a counter-regulatory hormone to insu- weight at 3 months and 7.1% (4.6-10.3) at 6 months. In the diet (D) group, lin. Because of this, glucagon is an attractive and popular biological target 34% of subjects lost 6.4% (5.4-9.6) body weight at 3 months and 9.7% with regard to glucose homeostasis. Glucagon is part of a larger proglu- (5.2-12.9) at 6 months. Nausea assessed by visual analog scale was simi- cagon protein which is enzymatically cleaved to form smaller, related pep- lar in both groups. Resting metabolic rate (RMR) measured by indirect tides with various biological functions. The ability to accurately quantitate calorimetry decreased by a similar degree in both groups at 3 months glucagon levels across a large dynamic range, using a reasonable sample (E-8.6% [(0.0-18.3%]), D-6.5% ([0.5-17.0%]) p = 0.93) and at 6 months (E-5.0% size is highly desirable to any researcher. The Glucagon Chemiluminescence ([0.2-14.4]), D-2.4% ([-5.5-5.4]), p = 0.17). The thermic effect of food (TEF) fol- ELISA, developed by ALPCO, offers researchers a robust and highly specific lowing ingestion of 240ml Boost® was measured by indirect calorimetry. assay for measuring glucagon in serum, EDTA-treated plasma, and heparin- At baseline, E and D subjects had a similar postprandial increase in RMR treated plasma. Using a sample size of 50µL or less, the assay demonstrates (E 13.1%, D 13.7%, p=0.87). At 3 months, D subjects maintained the increase a high degree of sensitivity (approximately 20pg/mL (5.7pM)) without any in RMR while E subjects demonstrated significant blunting (P 11.1%, E 3.3%, substantial cross-reactivity to other associated proteins/peptides, particu- p = 0.004). The postprandial increase in RMR was maintained at 6 months larly oxyntomodulin (no cross-reactivity up to 100ng/mL (22nM)). No matrix in D but not E subjects (P 11.3%, E 2.8%, p = 0.077). Blunting of TEF in E interferences were observed, as determined by spike and recovery as well subjects and preservation of TEF in D subjects were independent of weight as dilutional linearity tests in the noted matrices, giving the end user confi- loss. We find that a similar proportion of subjects randomized to E versus D dence in the accuracy and consistency of the results in each experiment. The are early responders and weight loss is independent of nausea. Exenatide assay was designed with the end user in mind and allows for a simple, quick, is associated with blunting of TEF compared to hypocaloric diet. This effect and reliable method for accurate quantitation of glucagon in test samples. is maintained at 6 months and is independent of weight loss. The effect of exenatide on TEF may be related to delayed gastric emptying or mechanisms not fully understood. Islet Biology—Apoptosis Supported By: AstraZeneca 320‑LB 318‑LB Assessing a Potential Protective Action of Glibenclamide against Histone Mark Modifications of Depot-specificG enes in Human Adi‑ Streptozotocin-induced Beta Cell Damage In Vivo pose Tissue YUMIKO NAKAMURA, JOSEPH BRYAN, Seattle, WA ADELINE DIVOUX, TIMOTHY OSBORNE, STEVEN R. SMITH, Orlando, FL, Winter Sulfonylureas, through their inhibitory action on SUR1/ABCC8, the regu- Park, FL latory subunit of SUR1/Kir6.2-type KATP channels in pancreatic beta cells, Increased lower body fat is associated with reduced cardiometabolic risk. stimulate insulin secretion and have been a therapy for type 2 diabetes for The molecular basis for depot differences in gluteal (G-Fat) compared with >50 years. Recent work shows SUR1 also partners with TRPM4/TRPM4, abdominal (A-Fat) subcutaneous adipocyte function is poorly understood. a Ca2+-activated, non-selective cation channel inhibited by ATP which is Our recent studies profiling gene expression in these two depots identified widely expressed including in beta cells. Inhibition of SUR1/TRPM4 chan- major differences in the expression of HOX genes. These differences are nels by glibenclamide (GBC) or knockout of SUR1 has beneficial effects in maintained in vitro during preadipocyte differentiation, suggesting that epi- multiple models of CNS trauma, thus we asked if GBC might protect beta genetic differences are likely to play a major role in phenotypic differences cells from acute damage due to streptozotocin (STZ). Continuous twice daily between A-Fat and G-Fat. We prepared chromatin from cultured preadi- administration of GBC to C57/Bl6 mice reduced blood sugar transiently, but pocytes that were isolated from A-Fat and G-Fat of 5 obese women and animals became insensitive to GBC and were euglycemic within two days. evaluated by ChIP-qPCR histone H3K4 and H3K27 trimethylation (activation Administration of high (200 mg/Kg x 1) or low (50 mg/Kg x 5) dose STZ pro- and repression marks, respectively) patterns within the 5’ flanking region duced hyperglycemia (>400 mg/dl) in controls while GBC-treated animals of the HOXA3, HOXA5, HOXB8, HOXC13 and HOTAIR genes. mRNA expres- remained euglycemic and minimal changes in islet morphology. Insulin val- sion was evaluated by RT-qPCR. We first confirmed that HOXA3, HOXA5 and ues were dramatically reduced with STZ alone, but showed no significant HOXB8 genes were up-regulated in abdominal preadipocytes, HOXC13 and changes in GBC/STZ treated animals implying elevated insulin is not a major HOTAIR up-regulated in gluteal cells. H3K4me3 was significantly enriched factor in maintaining euglycemia. SUR1-/- mice were partially protected at the HOXA3, HOXA5 and HOXB8 promoter regions in abdominal preadipo- from STZ; added GBC had no effect, i.e., GBC protected wildtype beta cells cytes compared to gluteal preadipocytes. H3K27me3 was decreased at the more effectively than total deletion of SUR1. We attempted to implicate same promoter regions. Conversely, analysis of the promoter region of the TRPM4 by administering flufenamic acid (FA), a semi-selective antagonist of HOTAIR gene revealed an enrichment of H3K4me3 level and a decrease of TRPM4 channels. FA, given 12 hours after STZ, partially protected as judged the H3K27me3 level in the gluteal cells compared to the abdominal counter- by reduced hyperglycemia. The results are consistent with the idea that GBC parts. In summary, H3K4me3 and H3K27me3 marks matched the observed inhibition of the stimulatory actions of SUR1 on Kir6.2/KCNJ11 and TRPM4 differential HOX gene expression between A-Fat and G-Fat. These gene- channels by GBC reduces STZ-induced changes in cation flux that contribute specific chromatin data provide new evidence that specific epigenetic his- to beta cell death. tone modifications play an important role in gene expression differences in A-Fat vs. G-Fat. Because HOTAIR associates with the PRC2 repression com- 321‑LB plex that adds the H3K27me3 mark to chromatin, these findings also support DJ-1 Protects Pancreatic Beta Cells from Cytokine and Strepto­ and extend our earlier work implicating HOTAIR, as a potential upstream zotocin-mediated Diabetes regulator of several other downstream epigenetic events in adipose tissue. DEEPAK JAIN, DANIEL EBERHARD, JAN EGLINGER, ECKHARD LAMMERT, Lund, Sweden, Düsseldorf, Germany DJ-1 is an anti-oxidant protein, highly expressed in pancreatic islet and POSTERS

known to play an important role in maintenance of glucose tolerance in I slet Biology/ mice. Pancreatic islets are highly prone to oxidative stress owing to low I nsulin Secretion expression of anti-oxidant enzymes. The purpose of the present study was to evaluate the role of DJ-1 under challenging oxidative stress environment

ADA-Funded Research For author disclosure information, see page LB98.

LB79 Islet Biology—Beta Cell—Development and Postnatal Growth

by treating DJ-1 K.O. mice with multiple low-doses of streptozotocin (MLDS) As nutrient-sensing GPCRs are well described to contribute to aspects of treatment. Streptozotocin (STZ) is a beta cell toxin, which kills beta cells by β cell function, we examined the role of FFAR2 in regulating an important both necrosis and apoptosis and also generates oxidative stress. Compared aspect of β cell function, β cell mass. We conducted morphometric analysis to controls, DJ-1 K.O. mice were severely glucose intolerant following the of β cell mass in neonatal (1 day, P1), adolescent (21 days, P21) and adult MLDS treatment. Insulin levels were significantly reduced, and fasting and (26 weeks) wild type (WT) and Ffar2-/- mice. These data revealed dimin- random blood glucose concentrations were significantly higher in DJ-1 K.O. ished β cell mass in Ffar2-/- mice at all time points, suggesting a role for mice compared to controls. Beta cell death and apoptosis were significantly FFAR2 in the regulation of β cell mass and development. We next examined increased in DJ-1 K.O. mice, and DJ-1 K.O. islets were more susceptible for β cell proliferation by immunohistochemistry and probed for β cell death cytokine-induced apoptosis. There was a drastic reduction in number of in- using serum unmethylated preproinsulin DNA as a biomarker of β cell death. sulin secretory granules as well as in the number of mitochondria in DJ-1 We observed increased β cell proliferation, accompanied by a simultaneous K.O. animals compared to controls. We also observed increase in beta cell increase in β cell death in Ffar2-/- mice at P21, but not P1 or 26 weeks. To death and apoptotic cells as measured by calcein-ethidium bromide and determine whether Ffar2 deletion imparts an intrinsic impairment in β cell TUNEL staining after STZ treatment in the absence of DJ-1 protein. Accord- proliferation, we analyzed ex vivo β cell proliferation in WT and Ffar2-/- is- ingly treatment of isolated islets with streptozotocin from wild type mice led lets, and observed no differences in proliferation at basal conditions or in to increase in DJ-1 protein expression, indicating its protective role against response to (PRL) or Exendin-4, two potent stimulators of β cell the toxin. Taken together our results revealed that DJ-1 could alleviate the proliferation. Taken together, these data suggest that genetic deletion of toxic effect of STZ treatment leading to balanced beta cell death, however Ffar2 leads to impaired β cell mass during prenatal development, as well under oxidative stress conditions in the absence of DJ-1 protein, a combined as an imbalance of β cell death and renewal during adolescence, resulting effect of increased ROS production, insulin degranulation, and disturbance in impaired β cell mass into adulthood. However, genetic deletion of Ffar2 of mitochondrial number and morphology culminates in unbalanced increase does not appear to affect the overall proliferative capacity of the β cell in in cell death and therefore a suboptimal release of insulin upon glucose response to well-known mediators of β cell proliferation. Future studies are stimulation. needed to directly examine the role and mechanism by which FFAR2 medi- ates the development, survival, and maintenance of β cell mass.

Islet Biology—Beta Cell—Development and 324‑LB Postnatal Growth Activation of GLP-1 and Signaling in Glp-1r-Overexpress‑ ing Mice Induces β-Cell Neogenesis and Maturation 322‑LB SHUGO SASAKI, TAKESHI MIYATSUKA, MITSUYOSHI TAKAHARA, FUMIYO KU- Beta Cell Targeted Gene Delivery for Enhanced Beta Cell Prolifera­ BO, KAZUYUKI MIYASHITA, YUICHI YAMAMOTO, TETSUYUKI YASUDA, YOSHIYA tion KAWAGUCHI, HARUHIKO AKIYAMA, HIDEAKI KANETO, TAKA-AKI MATSUOKA, BRIAN LU, STACEY LEBER, KIRAN KURMI, JASON M. TONNE, TOSHIE SAKUMA, HIROTAKA WATADA, IICHIRO SHIMOMURA, Osaka, Japan, Tokyo, Japan, Kyoto, MIGUEL MUNOZ-GOMEZ, MOUSTAFA EL KHATIB, EGON J. JACOBUS AMBU- Japan, Gifu, Japan LUDI, YOGISH C. KUDVA, YASUHIRO IKEDA, Rochester, MN Lineage conversion of non-β-cells into insulin-producing cells has been Type 2 diabetes mellitus (T2DM) is characterized by a combination of rela- proposed as a therapy for the cure of diabetes. Whereas GLP-1 and its de- tive insulin deficiency, beta-cell dysfunction, and beta-cell death. T2DM has rivatives have been shown to induce β-cell neogenesis in vitro and β-cell become a major health issue worldwide. Current treatments for T2DM can- mass expansion in vivo, there has been no direct evidence that the acti- not offer the same level of glycemic control as healthy, insulin-producing vation of GLP-1 signaling actually regulates cell fate decisions in vivo. We beta-cells. Increasing the number of beta-cells should increase total insulin therefore aimed to clarify the role of the GLP-1 receptor (GLP-1R) in β-cell production and lower blood glucose. As beta-cells mostly regenerate by differentiation. In the 2014 annual meeting, we reported the development replication from existing beta-cells, increasing beta-cell proliferation should of new mouse model in which GLP-1 receptor (GLP-1R) can be induced in a increase beta-cell mass. Based on the success of glucokinase activators in time- and tissue-specific manner (CAG-CAT-GLP-1R) and analyzed exocrine- increasing beta-cell proliferation, we sought to induce beta-cell proliferation to-β reprogramming using Sox9-CreER; CAG-CAT-GLP-1R (SC; GLP-1R) and by AAV-mediated beta-cell targeted glucokinase gene delivery. Young and Sox9-CreER; ROSA26-lacZ (SC;lacZ) mice. Here, we further investigated aged C57BL/6J mice maintained on normal diet or high fat diet (HFD) were the extent to which the newly-generated β cells have been reprogrammed given an intraperitoneal injection of promoter-restricted AAV8 expressing and how GLP-1 and gastrin induces the exocrine-to-β reprogramming. The liver glucokinase (GCK) under the mouse insulin 2 promoter. Following in- overexpression of GLP-1R, together with gastrin and exendin-4 promoted jection, we saw markedly increased liver GCK expression in the pancreas. formation of islet-like clusters, whereas exendin-4 alone or gastrin alone Beta-cell proliferation was increased in all treated groups compared to con- failed to induce the cluster formation. Over 80% of newly-generated insulin- trol (young mice, 2-fold; aged mice, 6-fold; aged HFD mice, 3-fold), and mice producing cells in SC; GLP-1R mice were positive for Pdx1, Nkx6.1 and Mafa, maintained on HFD showed improvements in glucose tolerance tests (p<0.02 but negative for amylase and other endocrine hormones. In addition, they by 60 minutes). These data support the use of glucokinase gene delivery for were positive for urocortin3. These results suggest that newly-generated enhanced beta-cell proliferation. Prompted by the reports of betatrophin, insulin-producing cells partially acquired characteristics of mature β cells. we also sought to induce beta-cell proliferation by AAV-mediated delivery On the other hand, the treatment with exndin-9-39 (GLP-1R antagonist) dete- of betatrophin. Young and aged C57BL/6J mice maintained on normal diet riorated the efficiency of β-cell neogenesis in SC; GLP-1R mice treated with or HFD were given an intraperitoneal injection of promoter-restricted AAV8 gastrin alone, suggesting that the β-cell neogenesis by gastrin is partially expressing betatrophin under the cytomegalovirus (CMV) promoter or the mediated through GLP-1 signaling pathway. Thus, activation of GLP-1 and elastase (ELS) promoter. We saw largely negative results with betatrophin gastrin signaling induces β-cell neogenesis and maturation in the exocrine gene delivery (no significant beta-cell proliferation with CMV promoter; lineage, which may hence lead to a potential therapy to cure diabetes by 2-fold beta-cell proliferation in aged HFD mice with ELS promoter). Our data generating surrogate β cells. do not support the use of betatrophin for enhancing beta-cell proliferation. Supported By: Mayo Foundation; Eisenberg Stem Cell Trust; Mayo Center for 325‑LB Regenerative Medicine Multiple MicroRNAs Coordinately Regulate Beta Cell Proliferation through Targeting MeCP2 323‑LB SUDHIR GOPAL TATTIKOTA, FERDINAND VON MEYENN, THOMAS RATHJEN, Genetic Deletion of FFAR2 Results in Impaired β-Cell Mass ADITYA KHEDKAR, JEAN HAUSSER, NORBERT EICHNER, VARUN K. PANDEY, STEPHANIE R. VILLA, MEDHA PRIYADARSHINI, MICHAEL R. BRODSKY, AN- UMA D. KABRA, BÉATRICE CHANE-WOON-MING, MATTHIAS SURY, MATTHIAS THONY R. ANGUEIRA, ROCKANN MOSSER, SARAH TERSEY, RAGHAVENDRA G. SELBACH, ROBERT P. ZINZEN, MIHAELA ZAVOLAN, LENA ELIASSON, MATTHIAS MIRMIRA, MAUREEN A. GANNON, BRIAN T. LAYDEN, Chicago, IL, Nashville, TN, TSCHÖP, MARTIN JASTROCH, SÉBASTIEN PFEFFER, GUNTER MEISTER, WOLF Indianapolis, IN REIK, SEBASTIAN KADENER, ADRIAN BIRD, MARC FRIEDLÄNDER, MATTHEW N. Free Fatty Acid Receptor 2 (FFAR2) is a G protein-coupled receptor (GPCR) POY, Berlin, Germany, Babraham, United Kingdom, Basel, Switzerland, Regensburg,

POSTERS Germany, Jerusalem, Israel, Munich, Germany, Strasbourg, France, Malmö, Sweden, I slet Biology/ activated by short chain fatty acids, in particular . This receptor is

I nsulin Secretion expressed in many metabolically relevant tissues such as adipose, gut, and Cambridge, United Kingdom, Edinburgh, United Kingdom, Stockholm, Sweden pancreatic islets. Reports of increased expression in pancreatic islets dur- Numerous pathways including the microRNA (miRNA) pathway within the ing insulin resistance suggest FFAR2 involvement in β cell compensation. pancreatic beta cell have been implicated in regulating its function during states of insulin resistance and type 2 diabetes (T2D). Here in this study, we

ADA-Funded Research For author disclosure information, see page LB98.

LB80 Islet Biology—Beta Cell—Stimulus-Secretion Coupling and Metabolism show that global alterations in miRNA expression in the islets of hypergly- negative cells are dedifferentiated hormone-producing cells, possibly rep- cemic and insulin resistant ob/ob mice are reversed after restoration of insu- resenting a sub-population of beta cells, some of which transdifferentiated lin sensitivity indicating miRNAs respond to changes in metabolic demand. to somatostatin- or glucagon-immunoreactive cells. The data are consistent We found that the expression levels of miR-184, a known regulator of beta with a model in which pancreatic endocrine cells lose their terminally dif- cell growth and function, were increased upon fasting while on the other ferentiated features in T1D, possibly implicating a process of beta cell dedif- hand, high extracellular glucose concentrations suppressed its expression ferentiation in the pathogenesis of the disease. in mouse pancreatic islets. Furthermore, we also uncovered an additional Supported By: German Center for Diabetes Research cluster of miRNAs that includes miR-152 to be regulated in the islets accord- ing to insulin sensitivity. Computational analyses predicted that this cluster potentially targets several important genes including Pten and Methyl CpG Islet Biology—Beta Cell— binding protein 2 (MeCP2), a gene previously implicated in Rett’s syndrome. Stimulus-Secretion Coupling and In the pancreatic islets of doxycycline induced transgenic mice overexpress- Metabolism ing miR-152 (dox-152) specifically in the beta cells, we in deed observed re- duced MeCP2 protein expression indicating it is a direct target of miR-152. In addition, analyses of the derived from either dox-152 transgenic 328‑LB or MeCP2 knockout (MeCP2KO) mice revealed a significant increase in the Roles of the Circadian Clock in Alpha- and Beta-Cell Transcriptome pancreatic beta cell mass. Together, these results highlight the adaptive role and Hormone Secretion in Mouse and Human Pancreatic Islet of the miRNA pathway and demonstrate the presence of multiple miRNAs CHARNA DIBNER, Geneva, Switzerland coordinately promoting beta cell function in response to hyperglycemia and Circadian oscillation of biological processes has been described in organ- insulin resistance. isms ranging from photosynthetic bacteria to vertebrate. There is growing evidence for a connection between metabolic syndromes, including diabe- tes, and the circadian clockwork. We have established triple reporter mouse 326‑LB allowing isolating pure alpha- and beta-cells (proGlucagon-Venus and Insu- Changes in Beta Cell Differentiation in Response to Glucolipotoxic lin-Cherry reporters), and characterize circadian rhythm in thus isolated cells Stress (Per2::luciferase reporter). Employing this model, we identified subsets of CHRISTINA REERS, GERALDINE PARENTY, KAIHUI HU HE, MARTIN SCHNEIDER, islet genes expressed in a circadian manner in both alpha- and beta-cells, STEFANIE SCHREIBER, THERESA KLISCH, ANNA GUHL, MATTHIAS AUSTEN, and those oscillating in alpha- or beta-cells only. This data shed a new light Göttingen, Germany on the alpha- and beta-cell differential circadian transcriptome. Importantly, Recent findings suppose that beta-cell dedifferentiation significantly con- we show that circadian is indispensable for proper insulin secretion by tributes to the apparent loss of beta-cell mass in T2D and possibly also T1D. analyzing blood insulin content in clock proficient and deficient mice. More- Agents preserving or restoring the mature beta-cell phenotype have the over, siClock mediated clock disruption in human islet resulted in decreased potential to be complementary to existing therapeutic options and to delay secretion levels of both insulin and glucagon, highlighting importance of or stop disease progression. Our goal was to establish the response of rat functional clock for the proper function of human islet. Disruption of the tem- islet beta-cell differentiation marker expression to glucolipotoxic stress. We poral programming of physiology, as occurs during shift work, jet lag, and have emphasized quantification of molecular differentiation markers with ageing, has detrimental effects on human health. It is thus of major impor- relevance in human T2D and diabetic animal models. As MafA is a sensitive tance identifying the physiological basis of circadian rhythmicity. Our study marker of beta-cell maturity, we have quantified changes in nuclear MafA highlights the importance of alpha- and beta-cell circadian oscillator, their expression in insulin-positive beta-cells after 48h of glucolipotoxic chal- impact on islet transcriptome and function, and sheds light on the cross-talk lenge (25 mM glucose + 250 µM palmitate) by fluorescent imaging. Image between alpha- and beta-cell clocks in mouse and human model systems. analysis was conducted with Image J based scripts. Reduction of nuclear By dissecting the rodent and human pancreas oscillator function we hope to MafA expression upon stress stimulus in primary rat cells was 0.35 ± 0.5% advance the understanding of clockwork connection to T2D. MafA+/Ins+ cells vs. 70 ± 5% MafA+/Ins+ cells in controls (p <0.001; n=15 Supported By: SNRF; European Foundation for the Study of Diabetes experiments). A similar setup was established as secondary assay with hu- man primary beta-cells (34 ± 6% MafA+/Ins+ cells upon stress stimulus vs. 57 ± 15% MafA+/Ins+ cells in controls, p <0.05; n= 5 experiments). Loss of 329‑LB MafA expression in stressed rat beta-cells was completely reversible after A Novel GLP-1 Receptor Interacting Protein ATP6ap2 Regulates In‑ 72h of recovery in normal culture medium. We have identified compounds sulin Secretion in Pancreatic Beta Cells which were able to prevent loss of glucolipotoxicity induced loss of MafA FEIHAN F. DAI, ALPANA BHATTACHARJEE, YING LIU, MING ZHANG, XINYE WANG, expression. A subset of these compounds also prevented dedifferentiation MICHAEL B. WHEELER, Toronto, ON, Canada in human islet beta-cells. In conclusion, preservation of beta-cell dedifferen- GLP1 activates its receptor, GLP1R, to enhance insulin secretion. The acti- tiation may translate into improved beta-cell function. Our findings confirm vation and transduction of GLP1R requires complex interactions with a host that agents which prevent loss of beta cell dedifferentiation marker expres- of accessory proteins, most of which remain largely unknown. In this study, sion could be promising candidate beta-cell protective agents active both in we used a membrane-based split ubiquitin yeast two-hybrid (MYTH) assay rodents and in humans. to identify novel GLP1R interactors in both mouse and a human islets. Among these, the V-type ATPase associated protein 6 (ATP6ap2), was identified in both mouse and human islet screens. ATP6ap2 was shown to be abundant 327‑LB in in islets where it was primarily localized to beta cells. When GLP1R and Pancreatic Endocrine Cell Dedifferentiation in Type 1 Diabetes ATP6ap2 were co-expressed in beta cells, GLP1R was shown to directly in- ANNA-MARIA ORDELHEIDE, HANS-ULRICH HÄRING, DOMENICO ACCILI, Tübin- teract with ATP6ap2, as assessed by co-immunoprecipitation. In INS-1 cells, gen, Germany, New York, NY overexpression of ATP6ap2 did not affect insulin secretion, however, siRNA In type 2 diabetes (T2D), pancreatic beta cell failure is associated with knockdown decreased both glucose stimulated- and GLP1-induced insulin beta cell dedifferentiation. It’s not known whether dedifferentiation also secretion (GIIS). Decreases in GIIS were accompanied by attenuated GLP1 occurs in type 1 diabetes (T1D). To answer this question, we analyzed pan- stimulated cAMP accumulation. Since ATP6ap2 is a subunit required for V- creatic tissue sections from 11 controls and 16 T1D donors from the nPOD da- ATPase assembly of insulin granules, it has been reported to be involved in tabase. To assess dedifferentiation, we performed immunohistochemistry granule acidification. In accordance with this, we observed impaired insulin with insulin, glucagon, somatostatin, and a newly identified marker of beta granule acidification upon ATP6ap2 knock-down but paradoxically increased cell dedifferentiation, aldehyde dehydrogenase isoform 1A3 (ALDH1A3). In proinsulin secretion. Importantly ATP6ap2 is also known as the renin recep- control islets, we detected insulin-, glucagon, and somatostatin-producing tor, and we further show that it mediates renin’s insulinotropic properties in cells. We identified two sub-populations of ALDH1A3-immunoreactive cells, beta cells. Taken together our findings identify a group of proteins that in- one that was hormone-positive and one that was hormone-negative. In T1D teract with the GLP1R. We further show that one interactor, ATP6ap2, plays subjects, insulin-immunoreactive cells were rare. In contrast, the number of a novel dual role in beta cells, modulating both GLP1R signalling and insulin glucagon-positive cells rose threefold, as did the number of somatostatin- processing to affect insulin secretion. POSTERS positive cells. The number of ALDH1A3-immunoreactive/hormone-positive Supported By: Novo Nordisk; Canadian Institutes of Health Research I slet Biology/ cells increased in T1D in a manner commensurate with the overall increase. I nsulin Secretion The number of ALDH1A3-immunoreactive/hormone-negative cells also in- creased. Interestingly, we also saw rare residual beta cells with ALDH1A3 immunoreactivity in T1D. We suggest that ALDH1A3-positive/hormone-

ADA-Funded Research For author disclosure information, see page LB98.

LB81 Islet Biology—Beta Cell—Stimulus-Secretion Coupling and Metabolism

330‑LB (GSIS) from pancreatic beta cells. However, a debate has existed since the Utility of Mip-CreERT Mice with Artifactual Expression of Human 1970’s concerning whether or not beta-cell cAMP signaling is essential for in Pancreatic Beta Cell Research glucose alone to stimulate insulin secretion. Here we report that GSIS from DANIEL OROPEZA, NATHALIE JOUVET, LIONEL BUDRY, KHALIL BOUYAKDAN, isolated human and rat islets is cAMP-dependent, as revealed through the SARAH SCZELECKI, GABRIELLE PERRON, VALERIE BERGERON, JOSHUA C. use of a highly membrane permeable para-acetoxybenzyl (pAB) ester prod- NEUMAN, HARPREET BRAR, RACHEL FENSKE, CLEMENCE MEUNIER, JULIE LA- rug that is a derivative of the cAMP antagonist Rp-cAMPS. Kinetic assays of COMBE, JONATHAN E. CAMPBELL, MICHELLE E. KIMPLE, DANIEL J. DRUCKER, perifused islets demonstrate that pretreatment of human or rat islets with ROBERT A. SCREATON, VINCENT POITOUT, MATHIEU FERRON, THIERRY ALQUIER, 10 micromolar Rp-8-Br-cAMPS-pAB leads to a marked inhibition (up to 80%) JENNIFER L. ESTALL, Montreal, QC, Canada, Madison, WI, Toronto, ON, Canada, Ot- of first-phase GSIS, as measured in response to a step-wise increase of glu- tawa, ON, Canada cose concentration. In contrast, second-phase GSIS is inhibited to a smaller There is growing concern over confounding artifacts associated with be- extent, and neither phase of GSIS is affected by a negative control pAB ta-cell-specific Cre-recombinase transgenic models, raising questions about compound. Using an assay for cAMP-regulated gene expression, or an assay their general usefulness in research. The inducible beta-cell-specific trans- for A-kinase activity reporter activation, we validate that in living cells, low genic (MIP-CreERT1Lphi) mouse was designed to circumvent many of these is- micromolar concentrations of Rp-8-Br-cAMPS-pAB inhibit cAMP-dependent sues and we investigated whether this tool effectively addressed concerns protein kinase (PKA) activation. BRET analysis also validates that Rp-8-Br- of ectopic expression and disruption of glucose metabolism. Recombinase cAMPS-pAB inhibits PKA dissociation and therefore activation under condi- activity was absent from the CNS using a reporter line and high-resolution tions in which the holoenzyme’s C-alpha catalytic subunit is reconstituted microscopy. Despite increased pancreatic insulin content, MIP-CreERT mice with the type 1 or type 2 regulatory subunit isoforms. Novel actions of Rp- on chow diet had normal blood glucose levels, glucose tolerance and insulin cAMPS-based analogs to antagonize cAMP sensor Epac1 and Epac2 activa- sensitivity, and equivalent insulin secretion in response to glucose in vivo and tion are also validated in an in vitro Rap1 activation assay, or in a FRET assay in vitro. Unexpectedly, MIP-CreERT mice were protected from high-fat/STZ- using genetically-encoded biosensors. Thus, in addition to revealing the induced hyperglycemia and this was not due to inhibition of STZ-mediated cAMP-dependence of first-phase GSIS, these findings establish a pAB-based beta-cell death. Ectopic human growth hormone (hGH) was highly expressed chemistry for the synthesis of highly membrane permeable prodrug deriva- in MIP-CreERT islets, potentially explaining increased insulin content, islet tives of Rp-cAMPS that act with micromolar or even nanomolar potency to number and mass following high-fat/STZ. However, circulating insulin levels inhibit cAMP signaling in living cells. remained similar to controls, while STZ-associated increases in alpha-cell Supported By: American Diabetes Association (7-12-BS-077 to G.G.H.); National number and serum glucagon were significantly blunted by presence of the Institutes of Health-National Institute of Diabetes and Digestive and Kidney Dis- transgene. These studies reveal important new insight into the strengths eases (R01DK069575) and limitations of using the MIP-CreERT mouse line for beta-cell research. Supported By: Canadian Diabetes Association (OG3123843JE) 333‑LB Serotonin Is a Paracrine Signal that Stimulates Insulin Secretion in 331‑LB Human Pancreatic Islets β-catenin Is Required for Incretin Potentiated Insulin Secretion JOANA ALMACA, JUDITH T. MOLINA, DANUSA MENEGAZ, ALEJANDRO CAICE- from Pancreatic β-Cells and Regulates Insulin Vesicle Localization DO, Miami, FL BRIE SORRENSON, EMMANUELLE COGNARD, WILLIAM E. HUGHES, YANYUN Endocrine cells and neurons share many features despite their different FU, WEIPING HAN, PETER SHEPHERD, Auckland, New Zealand, Sydney, Australia, embryonic origins. In particular, islet beta cells share with serotonergic Singapore, Singapore neurons a common ability to synthesize, store and release serotonin (5-HT; We recently provided evidence that modulating the Wnt signaling factor Ohta Y et al (2011) Diabetes). 5-HT has been shown to play an important role -catenin in the INS-1E -cell model affects glucose-stimulated insulin secre- in mouse islet plasticity. For instance, under conditions of higher metabolic tion and found that the levels of -catenin can be dynamically regulated in demand such as pregnancy, 5-HT stimulates beta cell proliferation (Kim et these cells by changes in glucose levels. Here we have extended our prelimi- al (2010) Nat Med) and glucose-stimulated insulin secretion (Ohara-Imaizumi nary findings to investigate whether -catenin is also required for the effect M (2013) PNAS) in pregnant mice. The role of 5-HT as a local paracrine signal of incretin hormones and whether it has a role in the acute events regulating in human islets is not known. We found that a subset of beta cells contained insulin secretory vesicle trafficking. We found that reducing -catenin lev- high levels of 5-HT in islets of non-pregnant human donors, which contrasts els using siRNA knockdown attenuates GSIS in a range of -cell models and with low levels of 5-HT found in isles of non-pregnant mice. Human beta blocks the ability of GLP-1 to potentiate this. This could be mimicked in both cells also expressed tryptophan hydroxylase isoform 1 (Tph1), the rate-limit- -cell models and isolated islets by short-term exposure to the -catenin inhibi- ing enzyme for 5-HT biosynthesis in nonneuronal tissues, and produced 5-HT tory drug pyrvinium, suggesting that -catenin is required for the processes in vitro, as suggested by a significant decrease in the number of 5-HT posi- regulating trafficking and/or release of pre-existing insulin granules rather tive cells after islet incubation with the Tph inhibitor p-chlorophenylalanine. than for those regulated by gene expression. This was further supported by Using 5-HT biosensors, we observed that, besides synthesizing and storing the finding that short-term treatment with a GSK3 inhibitor, which is known 5-HT, human islets were also able to release 5-HT in a glucose-dependent to increase -catenin levels, results in an increase in insulin secretion. Us- and pulsatile manner that resembles insulin secretion. To determine if 5-HT ing total internal reflectance fluorescence (TIRF) microscopy, we found that has any autocrine/paracrine effect, we examined in perifusion studies how -catenin is required for the glucose- and incretin- induced depletion of insulin exogenous 5-HT affects glucose-stimulated insulin secretion from human vesicles from near the plasma membrane and that lack of -catenin perturbs islets. 5-HT (0.1, 1 μM) amplified glucose-induced insulin secretion. This ef- insulin vesicle release from the cell periphery. We found that overexpression fect was not mediated by the 5-HT receptors 5-HT2 or 5-HT3 as cytoplasmic of the transcriptional co-activator of β-catenin, TCF7L2, attenuated insulin calcium levels in intact human islets or in dispersed human beta cells did not secretion, which implies the importance of β-catenin in insulin secretion is change upon 5-HT application. 5-HT can bind as well to other G-protein cou- not solely due to transcriptional effects. Overall we present a requirement pled receptors (5-HT1, 5-HT4-7) that use cAMP as intracellular messenger. for -catenin in the mechanisms that are involved in modulating insulin secre- We are currently identifying which 5-HT receptors are expressed in human tory vesicle localization and/or fusion. islet cells and mediate the stimulatory effect on insulin secretion. Supported By: Health Research Council of New Zealand; National Heart Foun- dation of New Zealand 334‑LB Preserving Pdx1 Expression in Diabetic β-Cells Improves Glycemic 332‑LB Control In Vivo Rp-cAMPS-pAB Prodrugs Reveal the cAMP Dependence of Human YUICHI YAMAMOTO, TAKESHI MIYATSUKA, KAZUYUKI MIYASHITA, SHUGO and Rat Islet First-Phase Glucose-stimulated Insulin Secretion SASAKI, FUMIYO KUBO, NAOKI SHIMO, TETSUYUKI YASUDA, TAKAAKI MATSU­ COLIN A. LEECH, FRANK SCHWEDE, OLEG G. CHEPURNY, MELANIE KAUFHOLZ, OKA, HIDEAKI KANETO, IICHIRO SHIMOMURA, Suita, Japan, Tokyo, Japan, Osaka, DANIELA BERTINETTI, YINGMIN ZHU, FANG MEI, XIAODONG CHENG, JOCELYN Japan E. MANNING FOX, PATRICK E. MACDONALD, HANS-G GENIESER, FRIEDRICH W. Pdx1 has been shown to play a crucial role in maintaining mature β-cell

POSTERS function, regulating several -cell-related genes, such as insulin and Slc2a2 I slet Biology/ HERBERG, GEORGE G. HOLZ, Syracuse, NY, Bremen, Germany, Kassel, Germany, β

I nsulin Secretion Houston, TX, Edmonton, AB, Canada (Glut2). In addition, Pdx1 expression levels are compromised in the islets of Adenosine-3’,5’-cyclic monophosphate (cAMP) elevating agents such as human diabetic patients and rodent models. When we quantified the ex- the incretin hormone GLP-1 potentiate glucose-stimulated insulin secretion pression levels of Pdx1 in islets of Ins2Akita (Ins2Wt/C96Y) mice, in which a dominant mutation in the Ins2 gene causes β-cell failure, Pdx1 was sig-

ADA-Funded Research For author disclosure information, see page LB98.

LB82 Islet Biology—Beta Cell—Stimulus-Secretion Coupling and Metabolism nificantly decreased compared with control Ins2Wt/Wt littermates (p=0.03). ATP usage. During acute regulation of insulin secretion by cytochrome c and To test whether preserving expression of Pdx1 affects the phenotypes of L-type calcium channels, flux of electrons from cytochrome c to H2O2 ensure Ins2Akita mice, we generated a transgenic mouse “Pdx1-CreER; CAG-CAT- that secretion is only sensitive to changes in extracellular glucose and not Pdx1 (βPdx1)” that conditionally and specifically expressed Pdx1 in β cells, energy needs of the cell. and crossed βPdx1 mice with Ins2Akita mice. In the islets of βPdx1; Ins2Aki- Supported By: American Diabetes Association (1-13-IN-53, 1-15-IN-65 to I.S.) ta mice, over 80% of β cells expressed transgenic Pdx1, which was detected by immunohistochemistry for FLAG-tag epitope (Miyatsuka et al. Genes Dev 337‑LB 20, 1435-1440, 2006). The βPdx1; Ins2Akita mice at 8 weeks of age exhib- Changes in Glucose-stimulated Insulin Secretion and TORC1 Sig‑ ited significantly lower HbA1c (5.1 ± 0.3 vs. 7.1 ± 1.1, p=0.01) and fasting naling in Response to Glucolipotoxicity plasma glucose levels (258.0 ± 23.6 vs. 333.4 ± 58.2, p=0.04), compared with KAREL A. ERION, BARBARA E. CORKEY, JUDE T. DEENEY, LUCIA E. RAMEH, Bos- the control Ins2Akita littermates. Furthermore, real-time PCR revealed that ton, MA glucokinase (Gck) was upregulated in βPdx1; Ins2Akita mice compared with The metabolic stress caused by diet-induced obesity is accompanied by Ins2Akita littermates. Thus, sustained expression of Pdx1 improved glucose insulin hypersecretion. In cultured cells, exposure to high levels of glucose profile of diabetic Ins2Akita mice, suggesting the critical role of Pdx1 in regu- and/or fatty acids can result in metabolic stress or glucolipotoxicity (GLT). lating β-cell function under diabetic conditions. GLT increase basal insulin secretion through ROS, although the molecular mechanisms involved are not clear. Target of Rapamycin Complex 1 (TORC1) 335‑LB is a kinase complex involved in the regulation of anabolic processes that Investigating the Role of the Zinc Transporting Protein ZnT8 in the control cell mass in response to nutrients and growth factors. A high fat Pathogenesis of Type 2 Diabetes diet results in elevated TORC1 activity in peripheral tissues as well as in KRISTINA NORDÉN, DEEPAK JAIN, JULIA BROSNAN, ANN-MARIE LA RONDE- b-cells. Hyperactivation of TORC1 in b-cells by knockout of the TORC1 in- RICHARD, JENS LAGERSTEDT, Lund, Sweden, Boston, MA hibitor Tsc2 results in hyperinsulinemia. Conversely, TORC1 inhibition by ra- The zinc transporting protein ZnT8, encoded by the SLC30A8 gene, is pamycin treatment of isolated islets inhibits insulin secretion and prevents located in the membranes of the insulin secretory granules (ISG). A single adaptation to hyperglycemia in obese mice. In order to better understand the nucleotide polymorphism (SNP), introducing a switch from a tryptophan (W) molecular mechanisms that contribute to GLT-induced insulin hypersecre- to an arginine (R) at amino acid position 325 in this protein, has by genome tion, we examined the effects of chronic exposure to high glucose on TORC1 wide association studies been linked to an increased risk of developing type signaling in b-cells. INS-1 cells were cultured in low (4 mM) or high (11 mM) 2 diabetes (T2D). The amino acid switch is believed to confer an altered zinc glucose to mimic the normoglycemic or hyperglycemic state, respectively. transporting capacity of the ZnT8 protein. This would induce a local effect Cells cultured in high glucose had increased basal insulin secretion and a on the zinc dependent packing, and storage of the insulin hexamers in the left shift in the glucose concentration dependency for insulin secretion, as ISGs and potentially also affect peripheral tissues due to an increased he- compared to cells in low glucose. Phosphorylation of the TORC1 substrate patic clearance of the secreted insulin. Additionally, and surprisingly, loss- p70S6K and S6 was significantly lower in cells cultured under low glucose, of-function mutations in the SLC30A8 gene have recently been shown to but the fold response to growth factor and amino acid stimulation was in- confer protection against T2D in human subjects. In order to investigate the creased, as compared to cells in high glucose. In addition, cells cultured in effect of the SNP on ZnT8 structure and function we have set up produc- high glucose had increased phosphorylation of PIP4k, a novel substrate for tion of this protein in insect cells utilizing the Baculovirus Expression Vector TORC1. PIP4k localized to Golgi in INS-1 cells cultured in 4 mM glucose, but System (BEVS). Protein carrying either a W or an R at position 325 has been in 11 mM glucose, PIP4k localized to cytoplasmic vesicles. Together, these successfully expressed and membranes from the ZnT8 producing cells have results indicate that TORC1 signaling is affected by GLT and may contribute been isolated. To be able to evaluate the zinc transporting capacity of the to hyperinsulinemia in obese patients. ZnT8 variants, these membranes have been incorporated into giant unilamel- Supported By: National Institutes of Health (DK63219, DK035914) lar vesicles (GUVs). By employing fluorescently labeled antibodies we can show that the recombinantly expressed ZnT8 protein is properly inserted 338‑LB into the lipid bilayer of the GUVs and that it is evenly distributed over the The GEFs Kalirin/Trio Contribute to Beta-granule Remodeling and surface of the vesicles. A major advantage with the GUV-approach is that a Exocytosis defined chemical composition of the lumenal and exterior environment with REGINA KULIAWAT, Bronx, NY regard to, e.g., pH, ions, and fluorescent zinc probes, can be established that Insulin secretion from pancreatic β cells is a finely tuned integration of allow for detailed kinetic analyses of ZnT8 variant-specific zinc fluxes. metabolic events and signaling pathways that regulate the fusion compe- tence of granules. Newly synthesized, immature granules (ISGs) undergo 336‑LB maturation that includes content removal and association with the F-actin Interaction of L-type Calcium Channels with Cytochrome c and H2O2 rich cortex. Together these events contribute to granule competence for exo- in the Regulation of Insulin Secretion by Pancreatic Beta Cells cytosis. Because the Rho GDP/GTP exchange factors (GEFs) Kalirin and Trio ADAM S. NEAL, HUILIANG ZHANG, AUSTIN ROUNTREE, KELLY KERNAN, WIL- regulate vesicular budding from ISGs in non β cells, we targeted the GEFs by LIAM OSBORNE, WANG WANG, IAN SWEET, Seattle, WA small molecule inhibitors or genetic ablation and characterized proinsulin/ The redox state of cytochrome c plays a signaling role in the regulation of insulin release by direct exocytosis or vesicular budding. Inhibition of activ- insulin secretion over and above its role in transferring electrons in the elec- ity (Kalirin/Trio) or Kalirin depletion stabilized phalloidin stained F-actin to tron transport chain. The redox state of the protein is exquisitely sensitive the actin depolymerizing toxin cytochalasin D and simultaneously impaired to glucose, while being unaffected by energy usage and changes in cytosolic glucose stimulated hormone output. Delivery of viral protein VSVG to the calcium. These intrinsic mechanisms are unique to the beta cell and their plasma membrane (constitutive secretion) was intact; release of newly syn- impairment has been shown to lead to impaired glucose-stimulated insulin thesized proinsulin/insulin through constitutive-like vesicular budding, was secretion. We tested the hypothesis that the critical stability of cytochrome attenuated. Membrane depolarization or stimulation with high glucose plus c occurs through buffering of electron flow to H2O2. Real time experiments the incretin GLP-1 bypassed Kalirin/Trio requirement. Islet exposure to these were carried out using a perifusion system loaded with islets or INS-1 cells. secretagogues under basal conditions, including pharmacological manipu- Genetically-encoded sensors (HyPer), in the presence and absence of cata- lations of the submembrane actin barrier did not restore constitutive-like lase, were used to measure H2O2. Buffering of reduced cytochrome c by secretions. We conclude that exocytosis of granules already at the plasma production of H2O2 was tested by measuring cytochrome c, H2O2 and oxy- membrane (first-phase) and the second sustained phase that depends on gen consumption in response to agents affecting cytosolic calcium via either newly recruited “Restless Newcomers” can bypass Kalirin/Trio function.

L-type calcium channels or calcium release from the endoplasmic reticulum. The relatively stronger reliance on GEF activity for newly made granules and During exposure of cells to agents that altered calcium influx through L-type ISG derived vesicles suggests that organelle localized, Kalirin/Trio targets calcium channels (including diazoxide, nimodipine, BayK 8644 and potassi- are molecular mediators of exocytosis. um) H2O2 generation was inversely proportional to changes in calcium influx and proportional to the flow of electrons from cytochrome c away from res- POSTERS

piration. Consistent with studies where calcium from L-type calcium chan- I slet Biology/ nels had preferential access to machinery regulating exocytosis, increased I nsulin Secretion cytosolic calcium induced by a blocker of SERCA (thapsigargin) had little affect on H2O2. Calcium-mediated flow of electrons from cytochrome c to H2O2 accounts for the stability of reduced cytochrome c during changes in

ADA-Funded Research For author disclosure information, see page LB98.

LB83 Islet Biology—Signal Transduction

Islet Biology—Signal Transduction diet (HFD) for 14 weeks. We observed no difference in starved or glucose-in- duced insulin levels between CD-fed control and Dox-treated mice. 14 weeks 339‑LB of HFD feeding resulted in elevated starved insulin levels in control mice but not in NOX5-expressing mice. Glucose injection increased insulin levels by Regulation of Polypyrimidine-Tract Binding Protein Expression by 50% in control HFD-fed mice but failed to induce insulin secretion in NOX5 Insulin Signaling Pathway in Pancreatic -Cell β transgenic mice. In vitro, islets isolated from control HFD-fed mice showed JEONG JAE SHIN, JIHYE KIM, JUNG SEOK KIM, JUN GI RHO, WOOK KIM, Suwon, a 1.5 fold increase in insulin secretion upon glucose exposure. By contrast, Republic of Korea islets derived from Dox-treated HFD-fed mice lacked glucose-induced insu- Polypyrimidine tract-binding protein 1 (PTBP1), also named hnRNP I, sta- lin response. Taken together, our data demonstrate that elevated levels of bilizes preproinsulin mRNA by binding to the 3’-UTR in pancreatic cells. β NOX5-derived ROS might contribute to deteriorated -cell function and de- However, the underlying mechanism that regulates PTBP1 expression in β sign NOX5 as a potential therapeutic target to maintain insulin secretion in pancreatic -cells is not clear. We now report that PTBP1 is present in both β obese and diabetic patients. mouse and human pancreatic β cells, where its levels are regulated by the Supported By: Ernst and Lucie Schmidheiny Foundation; Société Francophone insulin receptor (IR) signaling pathway. PTBP1 abundance in immortalized β de Diabète cells isolated from the pancreas of wild-type (βIRWT) mice was significantly higher and more glucose-inducible than that in β cells isolated from an in- sulin receptor (IR)-null (βIRKO) mouse. Consistently, treatment with insulin 342‑LB elevated PTBP1 levels in βIRWT cells, but not in βIRKO. These findings were Mitochondrial GTP Contributes to ChREBP Activity and Susceptibil‑ also true in other β-cell lines (MIN6 and βTC6). In sum, our results identify ity to Cell Death in INS-1-derived Cell Lines insulin as a pivotal regulator of PTBP1 expression in pancreatic β cells. LEE B. HONIG, BENNETT J. DAVENPORT, NAGESHA G. KONDEGOWDA, ANILA K. MADIRAJU, REBECCA L. PONGRATZ, RUPANGI C. VASAVADA, DIRK HOMANN, 340‑LB RICHARD G. KIBBEY, DONALD SCOTT, New York, NY, New Haven, CT Carbohydrate Response Element Binding Protein (ChREBP) is a glucose- EphA4-mediated Juxtacrine Signaling Regulates Glucagon Secre‑ sensing transcription factor necessary for a glucose-stimulated proliferation tion through Changes in F-Actin Density in pancreatic beta cells, a process that drives adaptive beta cell mass expan- TROY HUTCHENS, DAVID W. PISTON, Nashville, TN, St. Louis, MO sion. ChREBP also drives Txnip expression, leading to apoptosis in response The therapeutic success of insulin in the clinical management of diabetes to glucolipotoxicity. The mechanisms of activation or inhibition of ChREBP has led to a robust understanding of the molecular mechanisms underlying activity are poorly understood, but important for beta cell function. We -cell function and insulin secretion. However, the cellular and molecular β aimed to determine if mitochondrial GTP (mtGTP) influences ChREBP activity mechanisms underlying -cell function and glucagon secretion remain poor- α via generation of cytoplasmic phosphoenolpyruvate (PEP). By RT-PCR and ly understood despite the critical role that dysfunctional glucagon secretion BrdU staining, respectively, we found that INS-1-derived 832/13 cells over- and hyperglucagonemia play in the pathophysiology of diabetes. Glucagon expressing the ATP isoform of Succinyl CoA Synthetase (SCS-ATP, reduced secretion from flow-sorted -cells is increased over that from islets, and α relative mtGTP) exhibit attenuated glucose-stimulated gene expression and it is not inhibited by glucose elevation, similar to what is seen in diabetes. proliferation compared to controls (both by ~25%, p <0.05, n=3). ChREBP These data suggest that intra-islet signaling, through either paracrine or jux- Beta promoter activity was significantly decreased in response to glucose in tacrine pathways, plays an important role in the tonic inhibition of glucagon SCS-ATP cells compared to 832/13 cells (~45%, p<0.01, n=3). Interestingly, secretion. Here, we present new data in support of novel juxtacrine-medi- SCS-ATP cells had significantly lower relative Txnip mRNA expression (54%, ated regulation of glucagon secretion where contact-dependent signaling p<0.01, n=5). Upon exposure to 20 mM glucose and 0.5 mM palmitate, SCS- through the EphA4 receptor is responsible for tonic inhibition of glucagon ATP overexpression conferred resistance to glucolipotoxicity as per FACS secretion by maintaining a dense F-actin network. In isolated islets, stimula- Annexin V staining (50%, p<0.05, n=4) and cleaved caspase 3 immunostain- tion of EphA signaling results in a 41±8% decrease in glucagon secretion and ing (42%, p<0.05, n=3). Exposure of SCS-ATP cells to cytokines resulted in a 11±3% increase in -cell F-actin density. Conversely, inhibition of EphA α significant protection from cell death (66%, p=0.0001, n=4). Conversely, signaling and EphA4-specific signaling results in a 212±63% and 99±38% in- overexpression of the GTP-binding isoform (SCS-GTP, increased mtGTP) re- crease in glucagon secretion respectively, with a 44±2% decrease in -cell α sulted in an upward trend of glucose-stimulated gene expression, ChREBP F-actin density associated with inhibited EphA signaling. -cell-specific α Beta and LPK promoter activity. The rates of both glucose-stimulated prolif- knockout of EphA4 results in a 53±6% increase in glucagon secretion from eration and response to cell death were found to be comparable to controls. isolated islets and a 32±5% decrease in -cell F-actin density. Restoring α In conclusion, mtGTP was identified as a potential novel regulator of ChREBP EphA signaling in sorted -cells corrects glucagon hypersecretion and α activity in INS-1 832/13 cells, possibly through the generation of PEP and the restores normal glucose-inhibition of glucagon secretion, reducing gluca- formation of an ATP-regenerating system. gon secretion by 81±2% at high glucose. This juxtacrine-mediated model of glucagon secretion opens a new pathway for therapeutically targeting glucagon secretion, an important step in addressing the multiple hormone dysfunctions of diabetes. Supported By: F30DK098838; T32GM07347; R01DK098659

341‑LB Beta Cell–specific Overexpression of the NADPH Oxidase 5 (NOX5) Deteriorates Islet Function in High-Fat Diet-exposed Mice CHRISTELLE VEYRAT-DUREBEX, DOMENICO BOSCO, KARIM BOUZAKRI, CARO- LINE AROUS, GERHARD CHRISTOFORI, CHRISTOPHER KENNEDY, ILDIKO SZAN- TO, Geneva, Switzerland, Basel, Switzerland, Ottawa, ON, Canada RReactive oxygen species (ROS) play important roles in islet insulin se- cretion and β-cell survival. NADPH oxidases (NOX-es) are ROS-producing enzymes that are present in islets. NOX5 is a particular isoform expressed in human but not in rodents, and its activity is induced by Ca2+, a major regula- tor of insulin secretion. We applied RT-PCR in isolated human islets and vali- dated expression of NOX2, NOX4 and NOX5 mRNAs. In situ hybridization on pancreatic sections confirmed the presence of NOX5 mRNA in the majority of islet cells. Real-time PCR demonstrated an upregulation of NOX5 in islets upon hyperglycemic (16.7mM) incubation. In line with these results, immu- nofluorescence detected NOX5 labeling in insulin-positive cells in dispersed human islets in the presence of 16.7mM glucose, though not in direct colo- POSTERS I slet Biology/ calization with insulin-containing vesicles. To investigate the role of NOX5 in I nsulin Secretion insulin secretion, we created mice with doxycycline-inducible, β-cell specific expression of NOX5. Mice were provided or not with doxycycline (Dox) and then were administered either a control chow (CD) or a high-fat containing

ADA-Funded Research For author disclosure information, see page LB98.

LB84 SUBJECT Index

Abdominal adiposity 183‑LB Cardiometabolic traits 301‑LB DJ-1 321‑LB Aboriginal Australians 162‑LB Cardiovascular complications 6‑LB DPP-4 inhibitor 95‑LB, 127‑LB, 133‑LB, 216‑LB Acarbose 117‑LB Cardiovascular diseases 314‑LB Drug transport 128‑LB Actin polymerization 285‑LB Cardiovascular magnetic resonance 163‑LB Dumping syndrome 4‑LB Acute myocardial infarction 13‑LB Cardiovascular outcomes 111‑LB Dyslipidemia 41‑LB, 42‑LB SUBJECT IN DE X Add-on therapy 115‑LB Carrageenan 38‑LB Early pregnancy 152‑LB Adeno-associated virus 223‑LB Cell adhesion 285‑LB, 292‑LB Ectopic fat 305‑LB Adherence 49‑LB, 135‑LB Cell cycle 151‑LB Education 47‑LB Adipocyte 226‑LB, 234‑LB, 267‑LB Ceramides 265‑LB Effects of metformin and lifestyle interventions Adipocyte hypertrophy 228‑LB Cerebral blood flow 249‑LB 17‑LB Adipocyte progenitors 298‑LB Chikungunya 184‑LB Emollient 44‑LB Adipocyte protein 2 108‑LB Childhood obesity 144‑LB Empagliflozin 118‑LB, 119‑LB Adiponectin 22‑LB, 55‑LB, 224‑LB, 227‑LB ChREBP 342‑LB Employee wellness 140‑LB Adiponectin signaling 293‑LB Chronic hyperglycemia 31‑LB, 163‑LB EndoC 208‑LB Adipose 222‑LB Chronic kidney disease 25‑LB Endometrial cancer 316‑LB Adipose inflammation 294‑LB Circadian clock 328‑LB Endoplasmic-reticulum-associated protein Adipose tissue 233‑LB, 240‑LB, 302‑LB Circulating microvesicles 16‑LB degradation 234‑LB Adipose tissue distribution 318‑LB Clc-5 289‑LB Endothelial progenitor cells 16‑LB Adipose triglyceride lipase 231‑LB Clinical studies 100‑LB Enteroendocrine 275‑LB Adolescent 146‑LB Closed-loop 99‑LB Epidemiology 178‑LB, 179‑LB AFAP1 291‑LB Closed-loop control 101‑LB Epigenetics 151‑LB Affordable Care Act 136‑LB Closed-loop technology 66‑LB eQTL mapping 202‑LB Aging 252‑LB CLOUD 70‑LB Exenatide 134‑LB, 317‑LB AGP standardized glucose reporting 79‑LB CNX-013-B2 120‑LB Exercise 53‑LB, 54‑LB, 56‑LB, 98‑LB AgRP neurons 288‑LB Collaborative goal setting 64‑LB Exocytosis 332‑LB Air pollution 179‑LB Colorectal cancer 186‑LB Exome chip 204‑LB Akita mouse 334‑LB Colorectal cancer survivor 54‑LB Exome variation 308‑LB ALDH1A3 327‑LB Comparative effectiveness 115‑LB Exonic rare variant 200‑LB All-cause mortality 7‑LB Complement 216‑LB Famine exposure 61‑LB Alpha-cell glucagon secretion 340‑LB Continuous glucose monitoring 74‑LB, 75‑LB, Fasting 47‑LB Antibiotic 149‑LB 80‑LB, 81‑LB, 116‑LB, 143‑LB Fasting blood glucose 82‑LB Aortic stiffness 286‑LB Continuous subcutaneous insulin infusion 81‑LB Fasting hyperglycemia 38‑LB ApoA1 263‑LB Controlled-release mitochondrial protonophore Fatty acids 177‑LB, 250‑LB Apoptosis 258‑LB, 321‑LB 113‑LB Fibroblast growth factor 21 282‑LB Arginine 253‑LB Coronary artery calcium 17‑LB Fibroblast growth factor 23 22‑LB Artificial pancreas 97‑LB, 98‑LB, 100‑LB, 101‑LB Coronary artery disease 10‑LB Fitness 55‑LB AS160 247‑LB Corticosteroids 93‑LB Follicle-stimulating hormone 161‑LB Association mapping 201‑LB Cost savings 79‑LB Food craving 173‑LB Atherosclerosis 1‑LB C-peptide 147‑LB, 237‑LB, 306‑LB Free fatty acid 270‑LB Autoantibodies 29‑LB Cutaneous nevi 167‑LB Free fatty acid receptor 2 323‑LB Autoantigen 213‑LB Cyclic 332‑LB Functional foods 172‑LB Autoimmune diabetes 102‑LB Cyclin-dependent kinase inhibitor 2A 10‑LB Functional MRI 249‑LB Autoimmunity 218‑LB Cytochrome c 336‑LB Gastric inhibitory polypeptide 279‑LB Autonomic neuropathy 29‑LB, 30‑LB, 146‑LB Depression 170‑LB Gastroparesis 90‑LB Autophagy 244‑LB, 264‑LB Dextromethorphan 121‑LB GCGR 272‑LB Bariatric surgery 300‑LB, 311‑LB, 315‑LB Diabetes 28‑LB, 61‑LB, 121‑LB, 161‑LB, 165‑LB, GCKR 191‑LB Basal insulin 87‑LB 167‑LB, 170‑LB, 211‑LB, 214‑LB, 255‑LB, Gemigliptin 127‑LB Basal insulin peglispro 88‑LB, 89‑LB 257‑LB Gender differences 188‑LB Berberine 238‑LB Diabetes distress 67‑LB Gene delivery 322‑LB Beta catenin 331‑LB Diabetes duration 237‑LB Gene expression 199‑LB Beta cell 280‑LB, 323‑LB, 342‑LB Diabetes knowledge 52‑LB Gene expression omnibus 229‑LB Beta cell dedifferentiation 327‑LB Diabetes management software 70‑LB Gene-diet intervention 198‑LB Beta cell differentiation 326‑LB Diabetes remission 315‑LB Gene-environment interactions 174‑LB Beta cell dysfunction 313‑LB Diabetes risk factors 175‑LB Genetic risk score 198‑LB, 301‑LB Beta cell function 145‑LB Diabetes screening in Asian Americans 166‑LB Genome-wide association study 193‑LB, 207‑LB Beta cell neogenesis 324‑LB Diabetes-associated autoantibodies 147‑LB Genomics 199‑LB Beta cell proliferation 322‑LB, 325‑LB Diabetic dyslipidemia 126‑LB Gestational diabetes 155‑LB, 156‑LB, 157‑LB, Betatrophin 304‑LB Diabetic foot ulcers 45‑LB 159‑LB, 160‑LB Blood glucose monitoring 77‑LB, 78‑LB Diabetic ketoacidosis 241‑LB Glargine analog 84‑LB Body weight 317‑LB Diabetic kidney disease 114‑LB Glibenclamide 320‑LB Brown adipose tissue 232‑LB Diabetic nephropathy 19‑LB, 23‑LB GLP-1 18‑LB, 105‑LB, 154‑LB, 272‑LB, 276‑LB, Brown rice 175‑LB Diabetic neuropathy 30‑LB 303‑LB, 307‑LB Caloric restriction 245‑LB, 252‑LB, 271‑LB Diabetic retinopathy 33‑LB, 34‑LB, 37‑LB GLP-1 agents 130‑LB cAMP-PKA 129‑LB Diagnostic marker 213‑LB GLP-1 receptor 324‑LB, 329‑LB Canagliflozin 131‑LB Digital tracking device 49‑LB, 137‑LB GLP-1 receptor agonists 107‑LB Carbohydrate counting 148‑LB Dipeptidyl peptidase 4 132‑LB, 164‑LB GLP-1 secretagogues 112‑LB Cardiac safety 246‑LB Disease management 140‑LB Glucagon 2‑LB, 122‑LB, 196‑LB, 273‑LB, 319‑LB

LB85 Glucagon like peptide-1 132‑LB Insulin receptor knockout 266‑LB Mitochondria 269‑LB, 270‑LB Glucagon receptor antibody 106‑LB Insulin resistance 20‑LB, 227‑LB, 229‑LB, 235‑LB, Mitochondrial dysfunction 287‑LB Glucagon-like peptide-1 analogues 104‑LB 236‑LB, 238‑LB, 239‑LB, 250‑LB, 259‑LB, Monoclonal antibody 108‑LB Glucolipotoxicity 337‑LB 261‑LB, 263‑LB, 296‑LB, 310‑LB, 313‑LB Monogenic diabetes 191‑LB, 192‑LB Glucose intolerance 248‑LB Insulin secretion 331‑LB, 336‑LB MR spectroscopy 31‑LB Glucose monitoring 73‑LB Insulin sensitivity 60‑LB, 271‑LB mTOR complex 2 236‑LB Glucose oxidation 6‑LB Insulin therapy 51‑LB Multi-ethnic cohort study 193‑LB Glucose sensor 76‑LB Insulin-degrading enzyme 218‑LB Multivitamin 176‑LB Glucose transport 245‑LB Insulin-dependent diabetes mellitus 96‑LB Muscle 206‑LB SUBJECT IN DE X Glucose variation 65‑LB Insulinization 11‑LB Muscle perfusion 56‑LB GluN2B 288‑LB Insulin-like peptide 5 (INSL5) 276‑LB Myeloperoxidase 293‑LB Glycan engineering 210‑LB Insulin-producing cells 220‑LB Myopia 203‑LB Glycated albumin 211‑LB Integrated omics 208‑LB Myths 51‑LB Glycated CD59 160‑LB Interacting proteins 329‑LB NADPH oxidase 5 341‑LB Glycemia 62‑LB Interferon regulatory factor 6 242‑LB NASH 258‑LB Glycemic control 53‑LB, 91‑LB, 110‑LB, 184‑LB Interleukin-1 receptor-associated kinase 235‑LB Niacin 224‑LB Glycogen 264‑LB Intestine 310‑LB Nitrotyrosine 32‑LB Glycogen Supercompensation 59‑LB Intracellular calcium 274‑LB Non-alcoholic fatty liver disease 134‑LB, 260‑LB GPR119 122‑LB, 280‑LB Islet 251‑LB Non-alcoholic steatohepatitis 113‑LB, 260‑LB GPR40 251‑LB Islet transplantation 221‑LB Novel basal insulin 82‑LB Granule maturation 338‑LB Kidney function 24‑LB Obesity 152‑LB, 195‑LB, 222‑LB, 278‑LB, 289‑LB, Group prenatal care 156‑LB Kisspeptin 273‑LB 303‑LB, 308‑LB, 309‑LB Guidelines 41‑LB, 42‑LB LANCL2 69‑LB Obesity in pregnancy 153‑LB HbA1c 168‑LB Latent autoimmune diabetes in adults 212‑LB Obesity-related kidney disease 18‑LB Health insurance 136‑LB Lead exposure 309‑LB Observational multinational study 169‑LB Health services utilization and expense 26‑LB Leakage 36‑LB Overexpression 194‑LB Healthcare costs 142‑LB Leptin 40‑LB, 306‑LB Oxidative stress 172‑LB Heart failure 164‑LB Life course 182‑LB, 183‑LB Paralemmin 212‑LB Hepatic steatosis 297‑LB Lifestyle trials 180‑LB PARP14 295‑LB Hepatitis C 185‑LB Linkage disequilibrium genetic maps 201‑LB, PCSK2 196‑LB Hepatocyte nuclear factor-4-alpha 304‑LB 202‑LB PCSK9 40‑LB Hepato-preferential insulin action 89‑LB Lipid dysregulation 282‑LB Pdx1 334‑LB High dose insulin 83‑LB Lipidomics 239‑LB Pediatrics 143‑LB High risk adolescents and young adults 50‑LB Lipids 243‑LB Pellino 297‑LB Hippo 34‑LB Lipocalin 223‑LB Perfluorocarobons 24‑LB Histone modifications 318‑LB Lipogenesis 283‑LB Perilipin 5 262‑LB Histopathology 192‑LB Lipolysis 262‑LB Pharmacogenetics 197‑LB Homocysteine 257‑LB Lipoprotein 284‑LB Pharmacokinetics 106‑LB Hospital diabetes management 3‑LB Lipotoxicity 39‑LB Phosphatases 247‑LB Human beige adipocytes 298‑LB Liraglutide 4‑LB, 83‑LB Phosphodiesterase type 5 inhibitor 7‑LB, 9‑LB Human islet 333‑LB Liver 261‑LB Physician communication 63‑LB Human leukocyte antigen 217‑LB Liver enzyme 200‑LB Pioglitazone 169‑LB Human regular U-500 insulin 197‑LB Long-acting insulin 84‑LB, 86‑LB Pirfenidone 45‑LB Hyperkalemia 125‑LB Long-term 221‑LB PKPD model 86‑LB Hypoglycemia 1‑LB, 3‑LB, 78‑LB, 116‑LB Long-term type 1 diabetes 57‑LB Plasminogen activator inhibitor-1 12‑LB Hypoglycemia overtreatment 5‑LB Lorcaserin 299‑LB Pleiotropy 203‑LB Hypothalamic neurogenesis 205‑LB Low-dose Pioglitazone 110‑LB Point-of-care testing 168‑LB IGFBP-2 256‑LB L-PGDS 277‑LB Polarization 242‑LB IL6 polymorphism 178‑LB MafA 326‑LB Polyethylene glycol 88‑LB Immune cell 292‑LB Maternal nutritional intake 158‑LB Polypyrimidine tract-binding protein 339‑LB Immunosuppression 219‑LB Meal tolerance test 253‑LB Postprandial 62‑LB Immunotherapy 217‑LB Measurement imprecision 71‑LB Prandial insulin 92‑LB Implantable sensor 73‑LB Measuring glucagon 319‑LB Prediabetes 14‑LB, 182‑LB In vivo adipogenesis 302‑LB Medicare 139‑LB Prevalence 165‑LB Incarceration 52‑LB Medication adherence 142‑LB Progesterone 19‑LB Incretin 275‑LB, 278‑LB Medication safety renal tubular harm 26‑LB Proinsulin secretion 338‑LB Incretin based therapies 124‑LB Mediterranean diet 48‑LB Race 15‑LB Infant body composition 158‑LB Membrane fluidity and inflammation 177‑LB Racial disparities 141‑LB Inflammation 28‑LB, 123‑LB, 228‑LB, 233‑LB, Mesenchymal precursor cell 23‑LB RAGE gene 190‑LB 240‑LB, 259‑LB, 284‑LB Mesenchymal stem cells 219‑LB, 220‑LB Randomized Clinical Trial 111‑LB, 153‑LB Inhaled insulin 96‑LB Metaanalysis 124‑LB Ranibizumab 37‑LB Injuries 171‑LB Metabolic adaptation 300‑LB Rapid-acting insulins 107‑LB Inpatient diabetes 93‑LB Metabolic disorder 294‑LB Rasch analysis 67‑LB Insulin 85‑LB, 231‑LB Metabolic memory 8‑LB Reactive oxygen species 341‑LB Insulin action 254‑LB Metabolic syndrome 314‑LB Real-world use 87‑LB Insulin analogs 246‑LB Metabolism 268‑LB Recurrent cardiovascular events 162‑LB Insulin clearance 254‑LB Metabolomics 241‑LB Red wine polyphenols 60‑LB Insulin delivery 76‑LB Metformin 117‑LB, 128‑LB, 129‑LB, 131‑LB Renin-angiotensin-aldosterone system 125‑LB Insulin glargine 91‑LB, 95‑LB Methylglyoxal 35‑LB Resilience 150‑LB Insulin pump 148‑LB Microarray 33‑LB Retinal screening 141‑LB Insulin receptor 316‑LB MicroRNA 8‑LB, 55‑LB, 325‑LB agonist 120‑LB

LB86 Ribosylation 295‑LB Src kinases 291‑LB TRPA1 agonists 112‑LB RNA-binding proteins 255‑LB Starvation 268‑LB Type 1 diabetes 48‑LB, 50‑LB, 171‑LB, 188‑LB, RPE barrier 36‑LB Streptozotocin 320‑LB 190‑LB Saroglitazar 126‑LB Stress 150‑LB Type 2 diabetes 119‑LB, 176‑LB, 186‑LB, 195‑LB, Saxagliptin 133‑LB Structural equation model 64‑LB 207‑LB Self-monitoring of blood glucose 71‑LB, 139‑LB Sulfonylurea 299‑LB UCP1 232‑LB Self-reported outcomes 63‑LB Sulforaphane 296‑LB Ultra-rapid insulin 92‑LB Sensor augmented pump therapy 80‑LB suPAR 25‑LB Uncontrolled diabetes 135‑LB Serotonin 333‑LB Synip 20‑LB Uncoupling 287‑LB Severe hypoglycemia 2‑LB Systemic review 137‑LB Upper respiratory tract infections 94‑LB SUBJECT IN DE X Sex hormone-binding globulin 159‑LB Technology-smart phone app 68‑LB Urinary C-peptide 189‑LB Sexual dysfunction 57‑LB Technosphere insulin inhalation powder 94‑LB User’s perspectives 66‑LB SGLT-2 Inhibitor 39‑LB, 118‑LB, 130‑LB TEDDY 149‑LB Vascular endothelial cells 266‑LB SGLT-3 21‑LB Testosterone 9‑LB Vascular smooth muscle cells 12‑LB SHARE 5‑LB Therapeutic 69‑LB Vascular tone 21‑LB Sitagliptin 13‑LB Toll-like receptors 214‑LB Vildagliptin 123‑LB Skeletal muscle 269‑LB TORC1 337‑LB Visceral adipose tissue 283‑LB Skeletal muscle proteome 311‑LB Torin1 244‑LB Visceral fat 104‑LB Skin xerosis 44‑LB Transcription 206‑LB Waist to hip ratio 204‑LB Sleep 65‑LB Transcription factor 7–like 2 194‑LB, 205‑LB Weight loss 173‑LB Sleeve gastrectomy 277‑LB Transcriptional regulation for adipogenesis 230‑LB Within-visit blood pressure variability 14‑LB Small fiber neuropathy 32‑LB Translational research 180‑LB Zinc transport in beta cells 335-LB Sorcs 248‑LB Transplant 185‑LB Spleen attenuation 305‑LB Trial net 187‑LB

LB87 ABSTRACT Author Index

The number following the refers to the abstract number, not the page number. A number in bold beside an author’s name indicates the presenting author.

Abderrahmani, Amar 304‑LB Arndt, Kelly 192‑LB Below, Jennifer E. 199‑LB Abdi, Reza 210‑LB, 219‑LB Aroda, Vanita R. 17‑LB, 307‑LB Belton, Anne 63‑LB Abdul-Ghani, Muhammad 195‑LB Aronson, Ronnie 107‑LB Beltran, Yobana 51‑LB Abel, E. Dale 244‑LB Arous, Caroline 341‑LB Benjamin, Tonya R. 311‑LB Abraham, Jenny 315‑LB Arslan, Banu 154‑LB Benson, Tyler W. 294‑LB Abulizi, Abudukadier 113‑LB Arthur, John 24‑LB Benware, Sheila 76‑LB Abumrad, Nada 250‑LB Arumugam, Kokila 175‑LB Bergenstal, Richard M. 79‑LB Accili, Domenico 327‑LB Arya, Rector 195‑LB Berger, Zack 115‑LB Adachi, Yusuke 151‑LB Aryal, Pratik 243‑LB Bergeron, Valerie 330‑LB Adams Huet, Beverley 83‑LB Ashankyty, Ibraheem 19‑LB Bergman, Richard N. 254‑LB Adler, Sharon G. 114‑LB Asimakopoulou, Andriana 147‑LB Bertinetti, Daniela 332‑LB Adrion, Christine 13‑LB Assaad-Khalil, Samir H. 47‑LB Betteridge, John 111‑LB Agarwal, Ayush K. 90‑LB Atalay, Nesil 154‑LB Beula, Sara 41‑LB, 42‑LB ABSTRACT AUTHOR IN DE X Agrawal, Prabhat K. 90‑LB Atkins, Ashley 50‑LB Bhad, Prafulla 122‑LB Ahmad, Shafqat 301‑LB Atkinson, Mark A. 149‑LB, 192‑LB Bhakoo, Kishore Kumar 31‑LB, 163‑LB Ahn, Ki-Yong 54‑LB, 55‑LB Austen, Matthias 326‑LB Bhansali, Anil 110‑LB Aikawa, Masanori 270‑LB, 295‑LB Ayala, Iriscilla 205‑LB Bhat, Dattatreya 182‑LB Ajena, Aboajela 16‑LB Ayala, Jennifer E. 278‑LB Bhatt, Deepak L. 15‑LB Akinbosoye, Osayi 49‑LB Ayala, Julio E. 278‑LB Bhattacharjee, Alpana 329‑LB Akiyama, Haruhiko 324‑LB Azzi, Jamil 219‑LB Bhattacharyya, Sumit 38‑LB Akkari, P. Anthony 197‑LB Bach, Leon A. 66‑LB Bianco, Suzy 104‑LB Akolkar, Beena 149‑LB Bae, Jae-Hoon 256‑LB Biddinger, Sudha B. 40‑LB Al Dhuhouri, Jamila S. 41‑LB, 42‑LB Bae, Jin-Sik 297‑LB Bihl, Ji C. 16‑LB Al Hammadi, Fatema H. 41‑LB, 42‑LB Bae, Kwi-Hyun 257‑LB Bird, Adrian 325‑LB Al Nuaimi, Asma A. 41‑LB, 42‑LB Bae, Su Ah 3‑LB Birk, Jesper 59‑LB Al Shaikh, Sarah 41‑LB, 42‑LB Ba-Essa, Ebtesam M. 47‑LB Bjørbæk, Christian 288‑LB Alaminos, Miguel A. 310‑LB Bagger, Jonatan I. 132‑LB Blangero, John 195‑LB Albu, Jeanine 138‑LB Bahceci, Mitat 154‑LB Blankenship, Jennifer M. 53‑LB Alcain-Martinez, Guillermo 310‑LB Bahijri, Suhad M. 47‑LB Blankfard, Martin 319‑LB Ali, Mohammed K. 180‑LB Bahmanyar, Shahram 169‑LB Blaser, Martin J. 149‑LB Ali, Nahed 47‑LB Bahn, Gideon 1‑LB Blau, Jenny E. 276‑LB Ali, Nasiri 113‑LB Bai, Ramya 175‑LB Boehnke, Michael 206‑LB Alkanani, Aimon 217‑LB Baidal, David A. 189‑LB Bogdonov, Vladimir 294‑LB Alkarni, Meyad A. 211‑LB Baik, Sei Hyun 170‑LB Bohnett, Lucas 5‑LB Alkhaddo, Jamil B. 93‑LB Bailey, Kathleen A. 194‑LB Bolen, Shari 115‑LB Alkhalidy, Hana 296‑LB Bajaj, Mandeep 227‑LB Bonner, Caroline 304‑LB Alkorta-Aranburu, Gorka 192‑LB Balk, Ethan M. 96‑LB Borecki, Ingrid 204‑LB, 308‑LB Almaca, Joana 333‑LB Balliro, Courtney 72‑LB Borowiec, Maciej 191‑LB Almeda-Valdes, Paloma 45‑LB Balo, Andrew 5‑LB Bosco, Domenico 341‑LB Alquier, Thierry 330‑LB Baltaro, Richard J. 78‑LB Bose, Namrata 89‑LB Al-Trad, Bahaa 19‑LB Banks, Michaela 144‑LB Boss, Anders 94‑LB Álvarez-Escolá, Carmen 264‑LB Bañuls, Celia 172‑LB Bouchaert, Emanuel 10‑LB Alzaid, Aus 63‑LB Barber, Thomas M. 315‑LB Boulware, David 187‑LB Amblee, Ambika 116‑LB Baron, Michelle A. 135‑LB Bouyakdan, Khalil 330‑LB Amer, Ahmed 122‑LB Barquiel, Beatriz 188‑LB Bouzakri, Karim 341‑LB Ammar, Hala 16‑LB Barrett-Connor, Elizabeth L. 17‑LB Brady, Matthew J. 194‑LB Andersen, Emilie S. 132‑LB Barroso, Inês 301‑LB Branigan, Deborah 98‑LB Anderson, Rozalyn M. 252‑LB Barta, William 52‑LB Brar, Harpreet 330‑LB Andreasen, Camilla 132‑LB Bartolomucci, Alessandro 274‑LB Brathwaite, Collin 277‑LB Andrew, Toby 201‑LB, 202‑LB, 203‑LB Bassaganya-Riera, Josep 69‑LB Braun, Barry 53‑LB Angueira, Anthony R. 323‑LB Batra, Manav 130‑LB Bray, George 173‑LB, 174‑LB, 198‑LB Anil, Tharappel M. 120‑LB Bauman, Viviana 276‑LB Brazg, Ronald 100‑LB Anjana, Ranjit M. 175‑LB, 180‑LB Bayeva, Marina 255‑LB Breen, Matthew 76‑LB Annabi, Firas A. 47‑LB Bays, Harold 307‑LB Brehm, Michael A. 298‑LB Anton, Stephen D. 173‑LB Beaucamps, Cédric 304‑LB Brehm, Tyler J. 242‑LB Antosik, Karolina 191‑LB Beauregard, Natalie 150‑LB Brenner, Christoph 13‑LB Anup, Mammen O. 120‑LB Beck, Andrew 206‑LB Breton, Marc D. 99‑LB Apovian, Caroline M. 299‑LB Becker, Alexander 13‑LB Briddell, Robert 219‑LB Araque, Katherine 316‑LB Beckman, Kenneth 207‑LB Briley, Annette L. 153‑LB Araujo, Renata 62‑LB Bee, Yong Mong 220‑LB Brismar, Kerstin 216‑LB Ardehali, Hossein 255‑LB Beeravolu, Swathi 3‑LB Brito-Sanfiel, Miguel 95‑LB Ardissone, Alexandria N. 149‑LB Belfort De Aguiar, Renata 249‑LB Brittain, Julia 294‑LB Arias, Edward B. 245‑LB Bell, Graeme I. 194‑LB Brodsky, Michael R. 323‑LB Armstrong, Debra A. 89‑LB Bell, Ruth 153‑LB Broedl, Uli 118‑LB,

LB88 Brosen, Kim 128‑LB Charles, Rene 184‑LB Corkill, Holly 291‑LB Brosius III, Frank C. 114‑LB Chatterjee, Tapan K. 294‑LB Corvera, Silvia 298‑LB Brosnan, Julia 335‑LB Chattopadhyay, Munmun 28‑LB Costacou, Tina 24‑LB Brown, Jacob D. 278‑LB Chaudhuri, Ajay 130‑LB Coster, Adelle C. 239‑LB Brown, Rebecca J. 40‑LB Chaudhuri, Rima 239‑LB Covington-Kolb, Sarah 156‑LB Browne, Jessica L. 67‑LB Chen, Chi 61‑LB, 161‑LB, 309‑LB Cox, Nancy J. 199‑LB Bruckbauer, Antje 260‑LB Chen, Hong-Chi 12‑LB Craig, Jagriti 131‑LB Brüning, Jens C. 233‑LB Chen, Huntga 133‑LB Craig, Maria 237‑LB Bryan, Joseph 320‑LB Chen, Lei 273‑LB Crandall, Jill 17‑LB Buckingham, Bruce A. 99‑LB Chen, Liwei 156‑LB Croker, Helen 153‑LB Budoff, Matthew 17‑LB Chen, Lulu 8‑LB Cromack, Douglas T. 195‑LB Budry, Lionel 330‑LB Chen, Yanfang 16‑LB Crowe, Matthew J. 294‑LB Burak, Mehmet Furkan 108‑LB Chen, Yi 61‑LB, 161‑LB, 309‑LB Cudejko, Céline 10‑LB Buring, Julie E. 176‑LB, 177‑LB Chen, Yidong 205‑LB Cuezva, Jose M. 269‑LB Burke, Paivi M. 89‑LB Chen, Yimei 159‑LB Cui, Xin 260‑LB Burmeister, Melissa A. 278‑LB Chen, Yingchao 61‑LB, 161‑LB, 309‑LB Cunnick, Jess M. 291‑LB Burns, Cheryl 3‑LB Cheng Lee Ping, Peter 31‑LB Cupples, L. Adrienne 204‑LB, 308‑LB Buzzetti, Raffaella 95‑LB Cheng, Xiaodong 332‑LB Curie, Justin 171‑LB Cai, Weikang 266‑LB Cheong, Ye-Hwang 280‑LB Curran, Joanne E. 195‑LB Caiazzo, Robert 304‑LB Chepurny, Oleg G. 112‑LB, 332‑LB Cutarelli, Alessandro 274‑LB ABSTRACT AUTHOR IN DE X Caicedo, Alejandro 333‑LB Chernausek, Steven 155-LB,157‑LB Dabelea, Dana 17‑LB, 171‑LB Callan, Judith A. 68‑LB Cherñavvsky, Daniel 99‑LB Dabra, Shakun 134‑LB Calle, Roberto A. 253‑LB Chevalier, Soazig 95‑LB Dagogo-Jack, Samuel 15‑LB Caloyeras, John 140‑LB Chhabra, Mohinish 134‑LB Dai, Feihan F. 329‑LB Campa, David 141‑LB Chin, Alex J. 133‑LB Dai, Hongji 167‑LB Campbell, Jonathan E. 330‑LB Chinchwadkar, Manoj 183‑LB Dandona, Paresh 130‑LB Campbell, Latoya E. 311‑LB Chines, Peter 206‑LB Dangott, Bryan J. 78‑LB Camporez, Joao-Paulo G. 263‑LB Chisholm, Don J. 239‑LB Dasari, Paul S. 143‑LB Campos, Hannia 177‑LB Cho, Yoon Hi 237‑LB Davenport, Bennett J. 342‑LB Campos, Maribel 14‑LB Cho, Youngjin 291‑LB Davidson, Jaime A. 139‑LB Canepa, Ronald J. 149‑LB Chodavarapu, Praneeta 158‑LB Davies, Melanie 307‑LB Cang, Zhen 61‑LB, 161‑LB, 309‑LB Choe, Gina 316‑LB Davis, Lori 122‑LB Canney, Lori 2‑LB, 92‑LB Choi, Dong Seop 85-LB,170‑LB Davis, Timothy M. 162‑LB Cao, Qiang 260‑LB Choi, In Young 105‑LB, 303‑LB Davis, Wendy A. 162‑LB Capehorn, Matthew 63‑LB Choi, Kyung Mook 170‑LB Davis-Ajami, Mary L. 26‑LB Cappell, Katherine 164‑LB Choi, Seul Min 280‑LB Davis-Richardson, Austin G. 149‑LB Capuano, George 131‑LB Choi, Siak Leng 88‑LB, 89‑LB Day, Samantha E. 311‑LB Carbo, Adria 69‑LB Choi, Soomin 105‑LB De Filippis, Elena A. 311‑LB Cardamone, Maria D. 240‑LB Chorev, Michael 160‑LB De Souza, Errol 2‑LB, 92‑LB Cárdenas, Jose L. 30‑LB Christensen, Mette M. 128‑LB de Toro-Martín, Juan 264‑LB Cardillo, Tracy E. 114‑LB Christensen, Mikkel 279‑LB De Vito, Katerina M. 177‑LB Cargill, Robert S. 76‑LB Christiansen, Claus 314‑LB Deacon, Carolyn 132‑LB Carless, Melanie 195‑LB Christie, Michael R. 213‑LB Deeg, Mark A. 197‑LB Carley, David W. 65‑LB Christofori, Gerhard 341‑LB Deeney, Jude T. 337‑LB Carls, Ginger S. 135‑LB, 142‑LB Christopher, Michael J. 239‑LB DeFronzo, Ralph A. 195‑LB Carmody, David 192‑LB Christopher, Solomon 169‑LB Dehennis, Andrew D. 73‑LB Caron, Nicole 288‑LB Chuck, Leonard 131‑LB DeJesus, Adam 255‑LB Carrington, Paul 272‑LB Ciaraldi, Theodore P. 89‑LB, 269‑LB Del Gaudio, Daniela 192‑LB Cartee, Greg 245‑LB, 247‑LB Clargo, Alison 108‑LB Del Prato, Stefano 105‑LB Carter, Leslie 269‑LB Claudius, Birgitte 307‑LB Delalleau, Nathalie 304‑LB Casellini, Carolina M. 32‑LB Cobos-Bravo, Juan F. 306‑LB Della Bartola, Luca 168‑LB Castle, Jessica R. 98‑LB Cochrane, Katie 150‑LB Delpire, Eric 288‑LB Catalano, Patrick M. 152‑LB, 158‑LB Cognard, Emmanuelle 331‑LB DeMarco, Vincent 286‑LB Cavalcante, Lilian L. 123‑LB Cohen, Neale 53‑LB Demirpence, Mustafa 154‑LB Cederquist, Carly T. 240‑LB Cohen, Ronald 194‑LB Demirpence, Nur 154‑LB Cefalu, William T. 166‑LB Coletta, Dawn K. 311‑LB Dempsey, Paddy C. 53‑LB Cero, Cheryl 274‑LB Colin, Laurence 122‑LB D’Eon, Stephanie 57‑LB Cha, Dae Ryong 127‑LB Collins, Francis S. 206‑LB, 208‑LB DeSalvo, Daniel J. 99‑LB Cha, Ji-Young 256‑LB, 297‑LB Collins, Stephen J. 291‑LB Dibner, Charna 328‑LB Chabtini, Lola 219‑LB Colman, Peter 66‑LB DiMeglio, Linda A. 145‑LB, 187‑LB Chacra, Antonio 111‑LB Colman, Ricki J. 252‑LB Ding, Eric L. 177‑LB Chae, Yu Na 280‑LB Comstock, Dawn 171‑LB Dion, Stacy 319‑LB Chakrabarti, Amitava 110‑LB Comte-Perret, Sophie 317‑LB Distelmaier, Klaus 271‑LB Chamberlain, James J. 74‑LB, 75‑LB Condon, John 98‑LB Divoux, Adeline 318‑LB Champagne, Catherine M. 173‑LB Conley, John 76‑LB do Bem, Daniela A. 11‑LB Chan, Lawrence C. 227‑LB Consani, Cristina 168‑LB Dobkin, Julie 157‑LB Chan, You-Ping 84‑LB Constable, R.T. 249‑LB Dolin, Paul 169‑LB Chane-Woon-Ming, Béatrice 325‑LB Conway, Baqiyyah 24‑LB Donaghue, Kim C. 237‑LB Chang, Evan 129‑LB Cooper, Julian 69‑LB Donaldson, Julie 319‑LB Chang, Hsiang-Chun 255‑LB Cooper, Marcus 298‑LB Dong, Ying 289‑LB Chapel, Sunny 86‑LB Corkey, Barbara E. 337‑LB Donnelly, Conor Brian 210‑LB

LB89 Dopita, Dana 74‑LB, 75‑LB Flannery, Clare A. 316‑LB Gonçalves, Nadmy A. 11‑LB Dorchy, Harry R. 147‑LB Flynn, Angela C. 153‑LB Gonçalves, Rita de Cássia R. 11‑LB Down, Susan 63‑LB Fodor, William 219‑LB Gonzalez, Noemi 188‑LB Doyle, Carl 108‑LB Fogelfeld, Leon 116‑LB González-Ortiz, Manuel 131‑LB Dragsbæk, Katrine 314‑LB Forisch, Michael 137‑LB Gonzalo, Montserrat 306‑LB, 310‑LB Drucker, Daniel J. 330‑LB Formentini, Laura 269‑LB Gopala, Aralakuppe S. 120‑LB Duffin, Kevin L. 114‑LB Fourcaudot, Marcel 195‑LB Gordon, Tom 29‑LB Duggirala, Ravindranath 195‑LB Fowler, Robert 164‑LB Gorgel, Ahmet 154‑LB Dumenci, Levent 64‑LB Fox, Caroline S. 204‑LB Göring, Harald H. 195‑LB Dunstan, David 53‑LB Frank, Claudio 274‑LB Gormsen, Lars C. 128‑LB Duris, Christine 21‑LB Franks, Paul W. 301‑LB Gottlieb, Peter A. 217‑LB Dushay, Jody 317‑LB Franz, Wolfgang-Michael 13‑LB Gottlieb, Rebecca 100‑LB Dutta, Pinaki 110‑LB Fraser, Ian 23‑LB Gowtham, Raj 120‑LB Dutta, Sucharita 262‑LB Frayling, Timothy M. 308‑LB Grabmaier, Ulrich 13‑LB Duvvuru, Suman 197‑LB Frenkel, Dan 218‑LB Grady, Mike 70‑LB Dyer, Thomas D. 195‑LB Friedländer, Marc 325‑LB Graff, Emily C. 224‑LB Dziadowicz, Helena M. 252‑LB Frois, Christian 135‑LB, 142‑LB Graff, Marielisa 308‑LB Eberhard, Daniel 321‑LB Frokiaer, Jørgen 128‑LB Graff, Misa 204‑LB Eckel, Juergen 246‑LB Fryburg, David A. 253‑LB, 275‑LB Grarup, Niels 204‑LB Edelman, Steven 63‑LB Fu, Alex Z. 164‑LB Greeley, Siri Atma W. 192‑LB ABSTRACT AUTHOR IN DE X Edwards, Josh 32‑LB Fu, Lizhi 260‑LB Greenbaum, Carla J. 187‑LB Edwards, Todd L. 308‑LB Fu, Yanyun 331‑LB Greenfield, Jerry R. 239‑LB Efstratiou, Efthimia 48‑LB Fuentes, Blanca 51‑LB Greenway, Frank 300‑LB Eglinger, Jan 321‑LB Fukuda, Takuya 212‑LB Greulich, Sabrina 246‑LB Eguchi, Jun 258‑LB, 285‑LB Fukui, Michiaki 212‑LB Griffith, Julie 50‑LB Ehrich, Marion 69‑LB Fung, Anne 37‑LB Grohmann-Izay, Barbara J. 137‑LB Eichner, Norbert 325‑LB Fusong, Jiang 165‑LB Groh-Wargo, Sharon 158‑LB Ekhlaspour, Laya 72‑LB Gaglia, Jason L. 189‑LB Grosman, Benyamin 66‑LB, 100‑LB El Khatib, Moustafa 322‑LB Galli-Tsinopoulou, Assimina 48‑LB Gross, Myron 207‑LB El Ouaamari, Abdelfattah 261‑LB Gamerman, Victoria 63‑LB Guan, Hong-Ping 272‑LB El Youssef, Joseph 98‑LB Gandomani, Ben S. 143‑LB Guan, Meiping 18‑LB Eliasson, Lena 325‑LB Gandour, Richard 69‑LB Gudiksen, Anders 59‑LB Elks, Carrie M. 226‑LB Gang, Xiaokun 229‑LB Guerci, Bruno 107‑LB Elsasser, Ulrich 118‑LB Gannon, Maureen A. 323‑LB Guertin, David A. 236‑LB El-Shahawy, Mohamed 125‑LB Garcia Fuentes, Eduardo 306‑LB, 310‑LB Guhl, Anna 326‑LB Elston Lafata, Jennifer 64‑LB Garcia, Arturo 71‑LB Guimaraes, Sergio B. 123‑LB Erdos, Michael 206‑LB, 208‑LB Garcia-Arnes, Juan 306‑LB, 310‑LB Gune, Shamika 37‑LB Eringa, Etto C. 56‑LB, 60‑LB Garcia-Escobar, Eva 306‑LB Guo, Hui 61‑LB, 161‑LB, 309‑LB Erion, Karel A. 337‑LB Garcia-Sanchez, Ricardo 133‑LB Guo, Xiaohui 283‑LB Escrivá-Pons, Fernando 264‑LB Garcia-Serrano, Sara 306‑LB, 310‑LB Gutierrez, Absalon 227‑LB Esko, Tonu 308‑LB Garg, Satish K. 87‑LB, 217‑LB Gutierrez-Repiso, Carolina 306‑LB, 310‑LB Estall, Jennifer L. 330‑LB Garhyan, Parag 88‑LB, 89‑LB, 106‑LB Ha, Kyoung Soo 85‑LB Etwebi, Zienab A. 293‑LB Garlish, Rachel 108‑LB Haas, Joseph V. 114‑LB Evans-Molina, Carmella 145‑LB, 187‑LB Gaziano, J.M. 176‑LB Haas, Mary 40‑LB Eze, Ikenna C. 178‑LB, 179‑LB Gebauer, Mathias 275‑LB Hackett, Geoffrey I. 7‑LB, 9‑LB Fain, Randi 299‑LB Gee, Kyuhoon 105‑LB, 303‑LB Hadjadj, Samy 119‑LB Fall, Caroline 182‑LB, 183‑LB Genieser, Hans-G 332‑LB Hage, Camilla 216‑LB Fang, Han 224‑LB Genovese, Maria I. 62‑LB Haghiac, Maricela 152‑LB Farabi, Sarah S. 65‑LB Genter, Pauline 141‑LB Hagopian, William A. 149‑LB Farook, Vidya S. 195‑LB Gentile, Sandro 107‑LB Hailu, Hanna 108‑LB Federici, Adalberto 44‑LB Gerbase, Margaret 178‑LB, 179‑LB Halder, Louise 315‑LB Federici, Giovanni 44‑LB Geyer, Susan 145‑LB Hall, Christopher E. 277‑LB Feferman, Leo 38‑LB Ghanian, Sheila 252‑LB Hall, Keneth 277‑LB Feltbower, Richard 213‑LB Ghanim, Husam 130‑LB Hallmans, Göran 301‑LB Feng, Bin 222‑LB Ghannam, Ameen 164‑LB Halperin, Jose 160‑LB Feng, Yue 251‑LB Ghorbani, Tahereh 317‑LB Han, Bing 61‑LB, 161‑LB, 309‑LB Fenske, Rachel 330‑LB Ghosh, Pamela 160‑LB Han, Byoung Geun 127‑LB Fenwick, Eva K. 67‑LB Ghosh, Sujoy 126‑LB Han, Jing 33‑LB, 34‑LB Ferguson-Smith, Anne 151‑LB Giacaglia, Luciano 62‑LB Han, Kyung Ah 305‑LB Fernández-Millán, Elisa 264‑LB Giampietro, Ottavio 168‑LB Han, Oak Pil 105‑LB, 303‑LB Ferron, Mathieu 330‑LB Gilgen, Emily 74‑LB, 75‑LB Han, Sang Youb 127‑LB Fiad, Tarek M. 41‑LB, 42‑LB Giovenale, Sharon 124‑LB Han, Weiping 331‑LB Figarola, James L. 287‑LB Glicklich, Alan 299‑LB Han, Xinping 112‑LB Fink, Jeffrey C. 26‑LB Glynn, Robert J. 176‑LB Hanas, Ragnar 148‑LB Finlin, Brian S. 284‑LB Gmyr, Valéry 304‑LB Hanefeld, Markolf 107‑LB Fiorina, Paolo 219‑LB Gnys, Piotr 191‑LB Hanis, Craig L. 199‑LB Fischer, Annelie 121‑LB Godfrey, Keith M. 153‑LB Hanna, Paul 21‑LB Fish, Lisa 93‑LB Goldberg, Ronald 17‑LB Hannpu, Sarah 10‑LB Fishbane, Steven N. 125‑LB Gomez, Ana Maria 80‑LB Hanseman, Dennis 173‑LB Fitch, Mark 302‑LB Gomez-Perez, Francisco J. 45‑LB Hansen, Lærke S. 279‑LB Fitzgibbons, Timothy 298‑LB Gonçalves, Gabriel H. 288‑LB Hansen, Lars 133‑LB

LB90 Hansen, Mads Bau 59‑LB Hooven, Jayde T. 291‑LB Jenkins, Alicia 6‑LB, 237‑LB Hansen, Troels K. 216‑LB Horne, David 287‑LB Jenkinson, Christopher P. 195‑LB Hansraj, Patil A. 120‑LB Horsburgh, Jodie C. 66‑LB Jensen, Jonas B. 128‑LB Hantel, Stefan 118‑LB Horton, Edward S. 17‑LB Jensen, Michael D. 61‑LB Hao, Gaimei 33‑LB, 34‑LB Hoshina, Sari 190‑LB Jeon, Jae-Han 257‑LB Hao, Pindan 138‑LB Hota, Debasish 110‑LB Jeon, Justin Y. 54‑LB, 55‑LB Hara, Takuya 295‑LB Hotamisligil, Gökhan S. 108‑LB Jeong, Kyung Hwan 127‑LB Hardy, Thomas A. 106‑LB Hoti, Fabian 169‑LB Jessen, Niels 128‑LB Häring, Hans-Ulrich 327‑LB Hou, Liqiong 238‑LB Ji, Linong 87‑LB Harris, Stuart 122‑LB Houweling, Leanne 169‑LB Jia, Weiping 165‑LB Harrison, Lindsay 83‑LB Howard, Andrew 251‑LB Jiang, Hui 206‑LB Harsha, Krishna Reddy 120‑LB Howells, Louise 108‑LB Jiang, Jenny 49‑LB Hartig, Sean M. 227‑LB Hsia, Daniel S. 166‑LB Jianjun, Liu 207‑LB Hartmann, Bolette 132‑LB, 279‑LB Hsiao, Jong-Kai 12‑LB Jiao, Ping 222‑LB Hartmann, Thorsten 246‑LB Hsu, Chi-Yuan 207‑LB Jin, Shi 289‑LB Hastings, Stephanie M. 57‑LB Hu He, Kaihui 326‑LB Jo, Young-II 127‑LB Hauguel-de Mouzon, Sylvie 152‑LB Hu, Frank B. 167‑LB, 175‑LB Joglekar, Charudatta 182‑LB, 183‑LB Hausser, Jean 325‑LB Hu, Ling 61‑LB Johnson, Jennal L. 197‑LB Haw, J.S. 241‑LB Hu, Shirley L. 195‑LB Johnson, Matthew L. 271‑LB Hayden, Melvin 286‑LB Hu, Yanjin 313‑LB Johnson, William D. 166‑LB ABSTRACT AUTHOR IN DE X Hayek, Salim S. 25‑LB Hu, Ying Ying 192‑LB Johnston, Stephen 164‑LB Hayes, Louise 153‑LB Huang, Tao 174‑LB, 198‑LB Jones, Dean P. 241‑LB Hazra, Daya K. 90‑LB Huang, Tian Lian 232‑LB Jose, Aimee 81‑LB He, Jie 33‑LB, 34‑LB Huang, Zhe 223‑LB, 282‑LB Joshi, Shashank R. 126‑LB He, Ling 129‑LB Hughes, Kristen 100‑LB Joshi, Suyog 183‑LB He, Qin 222‑LB Hughes, William E. 331‑LB Joshipura, Kaumudi J. 14‑LB He, Yan Ling 122‑LB Huh, Yeamin 86‑LB Jouvet, Nathalie 330‑LB Heard-Costa, Nancy L. 204‑LB Hutchens, Troy 340‑LB Juarez-Comboni, Sonia C. 45‑LB Heberlein, Emily 156‑LB Hutfless, Susan 115‑LB Judd, Robert L. 224‑LB Heier, Jeffrey S. 37‑LB Huyghe, Jeroen 206‑LB Jung, II-Hoon 280‑LB Heinemann, Lutz 94‑LB Hwang, Janice J. 249‑LB Jung, Yun-Seung 297‑LB Heintjes, Edith M. 169‑LB Iacobellis, Gianluca 104‑LB Jurczak, Michael J. 113‑LB, 263‑LB Heise, Tim 121‑LB Ibrahim, Mahmoud 47‑LB Justice, Anne E. 204‑LB, 308‑LB Heizer, Patrick 69‑LB Ikeda, Yasuhiro 322‑LB Kabadi, Udaya M. 91‑LB Hejna, Jeanne 130‑LB Im, Hae Kyung 199‑LB Kabra, Uma D. 325‑LB Heller, Simon 107‑LB Im, Kyung Ah 15‑LB Kadener, Sebastian 325‑LB Hellerstein, Marc 302‑LB Im, Seung-Soon 256‑LB Kady, Jamie 298‑LB Henao, Diana 80‑LB Imai, Yumi 262‑LB Kahn, Barbara B. 243‑LB Hendrieckx, Christel 66‑LB Imboden, Medea 178‑LB, 179‑LB Kahn, C. Ronald 232‑LB, 266‑LB Henry, Robert R. 89‑LB, 269‑LB Imig, John D. 21‑LB Kahn, Jonathan 194‑LB Herberg, Friedrich W. 332‑LB Innes, Karen 24‑LB Kalsekar, Iftekhar 164‑LB Herman, William H. 47‑LB Inoue, Noriyuki 295‑LB Kamenov, Zdravko 214‑LB Hernández, Antonio 172‑LB Inouye, Karen 108‑LB Kandror, Konstantin V. 231‑LB Herranz, Lucrecia 188‑LB Ioacara, Sorin 73‑LB Kane, Penelope 146‑LB Herrlich, Andreas 219‑LB Ipp, Eli 141‑LB Kaneko, Shizuka 82‑LB Highland, Heather M. 204‑LB, 308‑LB Iqbal, Nayyar 133‑LB Kaneto, Hideaki 324‑LB, 334‑LB Hillard, Mallory 72‑LB Irving, Brian 271‑LB Kang, Dong-Woo 54‑LB Hillman, Natalia 188‑LB Itescu, Silviu 23‑LB Kang, Jahoon 86‑LB, 105‑LB, 303‑LB Hingst, Janne R. 59‑LB Iwasaki, Yorihiro 82‑LB Kang, Kyung Koo 280‑LB HIrate, Mitsuru 39‑LB Iwata, Hiroshi 295‑LB Kang, Shin-Wook 127‑LB Hirschhorn, Joel N. 308‑LB Iyoha, Emannuel 115‑LB Karaderi, Tugce 204‑LB Hirshberg, Boaz 15‑LB Jackson, Anne 206‑LB Karaliota, Sevasti 268‑LB Hissa, Marcelo R. 123‑LB Jackson, Jeffrey A. 197‑LB Karalis, Katia 268‑LB Hissa, Miguel N. 123‑LB Jackson, Michael 29‑LB Karsdal, Morten 314‑LB Hmaguchi, Masahide 212‑LB Jacober, Scott J. 89‑LB Kasid, Natasha 317‑LB Hoch, Emily 140‑LB Jacobs, Peter G. 98‑LB Kattah, William 30‑LB Hoevenaars, Femke M. 56‑LB Jacobus Ambuludi, Egon J. 322‑LB Katz, Laurence B. 70‑LB Hoffmann, Ellen 13‑LB Jaffar, Amina 3‑LB Kaufholz, Melanie 332‑LB Hoffmann-Petersen, Ingeborg T. 216‑LB Jagannath, Madanahalli R. 120‑LB Kaufman, Francine 100‑LB Hoidal, Mallary 270‑LB, 295‑LB Jain, Deepak 321‑LB, 335‑LB Kawaguchi, Yasushi 190‑LB Holland, William 265‑LB Jaiswal, Ashok D. 126‑LB Kawaguchi, Yoshiya 324‑LB Holmes-Truscott, Elizabeth 67‑LB Jakobsen, Steen 128‑LB Kawamoto, Manabu 190‑LB Holst, Jens Juul 132‑LB, 279‑LB Jakoby, Michael G. 3‑LB Kazakos, Kyriakos 48‑LB Holt, Charlotte B. 216‑LB James, David E. 239‑LB Ke, Bilun 259‑LB Holz, George G. 112‑LB, 332‑LB Janes, Jonathan M. 114‑LB Keady, Joyce 50‑LB Homann, Dirk 342‑LB Janka-Zires, Marcela 45‑LB Keçik, Onur 288‑LB Hompesch, Marcus 2‑LB, 92‑LB, 105‑LB, 303‑LB Januszewski, Andrzej S. 237‑LB Keenan, Hillary A. 57‑LB Hong, Biling 175‑LB Jasper, Susan 111‑LB Kefaloyianni, Eirini 219‑LB Hong, Suntaek 297‑LB Jastroch, Martin 325‑LB Keith-Hynes, Patrick 99‑LB Honig, Lee B. 342‑LB Jean-Baptiste, Eddy 184‑LB Kelkar, Rohini 183‑LB Hontecillas, Raquel 69‑LB Jelaska, Ante 119‑LB Kelley, David E. 273‑LB

LB91 Kelly, Ronan P. 106‑LB Krishnaswamy, Kamala 175‑LB Leiter, Lawrence A. 15‑LB Kemnitz, Joseph W. 252‑LB Kronenberg, Florian 178‑LB, 179‑LB Leng, Jiyan 6‑LB Kemppainen, Kaisa M. 149‑LB Ku, Bon Jeong 85‑LB Leng, Song 313‑LB Kennedy, Christopher 341‑LB Kuang, Lin 161‑LB Lentucci, Claudia 240‑LB Kern, Philip A. 284‑LB Kubo, Fumiyo 324‑LB, 334‑LB Leonardi, Anthony 255‑LB Kernan, Kelly 336‑LB Kudva, Yogish C. 322‑LB Lerakis, Stamatios 25‑LB Kerr, Peter G. 23‑LB Kuhadiya, Nitesh D. 130‑LB Lernmark, Åke 149‑LB Kerr-Conte, Julie 221‑LB, 304‑LB Kuliawat, Regina 338‑LB Lettre, Guillaume 308‑LB Kesireddy, Veena 3‑LB Kulkarni, Rohit N. 261‑LB Levenson, Amy E. 40‑LB Khai Koon, Heng 207‑LB Kumar, Ashish 178‑LB, 179‑LB Levin, Philip A. 94‑LB Khazaezadeh, Nina 153‑LB Kumar, Satish 195‑LB Levy, Brian L. 70‑LB Khedkar, Aditya 325‑LB Kumar, Sudhesh 315‑LB Li, Bin 61‑LB Khowaja, Ameer 93‑LB Kumar, Sunil 277‑LB Li, Fenfen 260‑LB Kibbey, Richard G. 342‑LB Kumareswaran, Kavita 66‑LB Li, Guo Dong 220‑LB Kiens, Bente 59‑LB Künzli, Nino 178‑LB, 179‑LB Li, Hui 112‑LB Kil, Siyoen 86‑LB, 105‑LB, 303‑LB Kurmi, Kiran 322‑LB Li, Ji 6‑LB Kim, Bong-Jo 200‑LB Kurtz, Natalie 66‑LB, 100‑LB Li, Liwu 235‑LB Kim, Dong-II 54‑LB, 55‑LB Kusmartseva, Irina 192‑LB Li, Nina 251‑LB Kim, Dong-Wook 257‑LB Kutoh, Eiji 39‑LB Li, Qin 61‑LB, 161‑LB, 309‑LB Kim, Doo Man 85‑LB Kwak, Eunhwa 303‑LB Li, Ruifeng 175‑LB ABSTRACT AUTHOR IN DE X Kim, In Joo 85‑LB Kwon, Se Chang 105‑LB, 303‑LB Li, Wangen 159‑LB Kim, Jae Bum 228‑LB Kyoong, Andrew 66‑LB Li, Wenjing 288‑LB Kim, Jihye 339‑LB Kyrgios, Ioannis 48‑LB Li, Xingwang 208‑LB Kim, Ji-Young 54‑LB La Ronde-Richard, Ann-Marie 335‑LB Li, Xuhang 289‑LB Kim, Jongoh 227‑LB LaBell, Elizabeth S. 88‑LB Li, Zihao 159‑LB Kim, Joon Young 311‑LB Laca, Jose 51‑LB Liang, Weiqiang 159‑LB Kim, Jung Seok 339‑LB Lacadie, Cheryl 249‑LB Liao, Yi-Chun 12‑LB Kim, Mi-Kyung 280‑LB Lacombe, Julie 330‑LB Liao, Yunfei 8‑LB Kim, Nam-Ho 127‑LB Laffel, Lori M. 50‑LB Lichliter, Jason 23‑LB Kim, Nam-Kyu 54‑LB, 55‑LB Lage, Adrianne 144‑LB Liew, Chong Wee 261‑LB Kim, Nan Hee 170‑LB Lagerstedt, Jens 335‑LB Lightwood, Dan 108‑LB Kim, Pankyung 303‑LB Lakhani, Rohan 315‑LB Lim, Sai Kiang 220‑LB Kim, Sin Gon 85‑LB, 170‑LB Lakka, Timo 206‑LB Lin, Daniel J. 315‑LB Kim, Soohyun Park 235‑LB Lakshmi, Mudigere N. 120‑LB Lin, Dongping 61‑LB, 161‑LB, 309‑LB Kim, Sung Gyun 127‑LB Lam, Eric Chen Quin 89‑LB Lin, Su F. 78‑LB Kim, Sung-Woo 257‑LB Lam, Karen Siu-Ling 223‑LB, 282‑LB Lin, Yung-Chieh 12‑LB Kim, Tae Hyoung 280‑LB Lam, Meghan 250‑LB Lincoff, A.M. 111‑LB Kim, Tae Joon 170‑LB Lammert, Eckhard 121‑LB, 321‑LB Lindberg, Iris 196‑LB Kim, Wook 339‑LB Langlais, Paul R. 311‑LB Linder, Marie 169‑LB Kim, Yong-Seong 85‑LB Lanza, Ian 271‑LB Lindgren, Cecilia M. 204‑LB, 308‑LB Kim, Young Jin 200‑LB Lao, Julie 251‑LB, 273‑LB Lingvay, Ildiko 83‑LB Kim, Young-Bum 288‑LB Larco, Nancy C. 184‑LB Linnebjerg, Helle 89‑LB Kim, Yun Kyoung 200‑LB Larco, Philippe 184‑LB Lious, Daniel 116‑LB Kimple, Michelle E. 330‑LB Larrivee, Sandra 166‑LB Liu, Ching-Ti 204‑LB King, George L. 57‑LB Larsen, Peter 146‑LB Liu, Dongmin 296‑LB King, Timothy 262‑LB Lassance Gomes, Luciana 152‑LB Liu, Franklin 273‑LB Kingwell, Bronwyn A. 53‑LB Lassman, Michael E. 273‑LB Liu, Hangsheng 140‑LB Kircher, Robert 101‑LB Lau, Raymond G. 277‑LB Liu, Jia 313‑LB Klisch, Theresa 326‑LB Lau, Winston 201‑LB, 202‑LB, 203‑LB Liu, Jiajun 114‑LB Knadler, Mary P. 88‑LB, 89‑LB Lautsch, Norman 72‑LB Liu, Quan 6‑LB Knoblauch, Nicholas W. 199‑LB Lavalle-González, Fernando J. 95‑LB Liu, Ying 159‑LB, 329‑LB Knop, Filip K. 132‑LB, 279‑LB Lavin, Philip T. 125‑LB Liu, Yuanhang 205‑LB Knutsen, Chad 76‑LB Layden, Brian T. 323‑LB Liu, Yujia 229‑LB Ko, Yi-An 25‑LB Le, Yun-Zheng 36‑LB Lizárraga-Mollinedo, Esther 264‑LB Kobiernicki, Frances 192‑LB Leach, Jake 5‑LB Lizarzaburu, Juan C. 51‑LB Kodella, Elisavet 268‑LB Leber, Alexander 13‑LB Lo, K. Sin 308‑LB Kodella, Kostantia 268‑LB Leber, Stacey 322‑LB Loh, Margaret 66‑LB Koistenen, Heikki 206‑LB Lee, Douglas S. 253‑LB Loh, Yik Wen 237‑LB Kokovay, Erzsebet 205‑LB Lee, Hong Kyu 305‑LB Lombard, Julian H. 21‑LB Kolar, Matthew J. 243‑LB Lee, In-Kyu 257‑LB Loos, Ruth J. 204‑LB, 308‑LB Kondegowda, Nagesha G. 342‑LB Lee, Jennifer 243‑LB Lopez, Claudia 111‑LB Konishi, Masahiro 266‑LB Lee, Jimmy Tsz-Hang 223‑LB Lopez-Gutierrez, Joel 45‑LB Konopka, Adam R. 271‑LB Lee, Jisoo 63‑LB Lu, Brian 322‑LB Koratkar, Revati 207‑LB Lee, Junga 55‑LB Lu, Christine 136‑LB Korhonen, Pasi 169‑LB Lee, Jung-Hun 297‑LB Lu, Meng 61‑LB, 161‑LB, 309‑LB Kornfeind, Ellyn 32‑LB Lee, Kwan-Hoo 280‑LB Lu, Qi 174‑LB Koroscil, Thomas M. 16‑LB Lee, Mi Kyung 54‑LB, 55‑LB Lu, Yang 141‑LB Krasner, Alan 2‑LB, 92‑LB Lee, Tsz-Hang 282‑LB Lu, Yingchang 308‑LB Kraus, Morey 219‑LB Lee, Woohyung 105‑LB Lu, Yingli 61‑LB, 161‑LB, 309‑LB Kretzler, Matthias 114‑LB Leech, Colin 112‑LB, 332‑LB Lu, Yongke 204‑LB Krischer, Jeffrey P. 149‑LB, 187‑LB Lehman, Donna M. 195‑LB, 205‑LB Lubree, Himangi 182‑LB

LB92 Lucas, Anthony 10‑LB Meissner, Thomas 121‑LB Na, Ki-Ryang 127‑LB Lulo, James 319‑LB Meister, Gunter 325‑LB Nagarajan, Lakshmipriya 175‑LB Lund, Asger 132‑LB Melissinos, Michail 48‑LB Nagel, Friederike 63‑LB Lundqvist, Kristin 148‑LB Mellbin, Linda G. 216‑LB Naik, Sarita 249‑LB Luo, Jing 296‑LB Mendivil, Carlos O. 30‑LB Nair, K. Sreekumaran 271‑LB Luo, Oscar 208‑LB Menegaz, Danusa 333‑LB Nakamura, Katherine 5‑LB Luque-Fernandez, Miguel A. 160‑LB Meng, Shu 220‑LB Nakamura, Naoto 212‑LB Lv, Tiantian 33‑LB, 34‑LB Meng, Ying 61‑LB, 161‑LB, 309‑LB Nakamura, Yumiko 320‑LB Ly, Trang T. 99‑LB Menon, Venu 111‑LB Nakatsuka, Atsuko 258‑LB, 285‑LB Lynes, Mattew D. 232‑LB Menon, Vinod 315‑LB Nam, Minwoo 298‑LB Lyv, Fuping 18‑LB Merino-Trigo, Ana 95‑LB Narayan, K.M. Venkat 180‑LB Ma, Jian-Xing 155‑LB Merton, Kate 131‑LB Narisu, Narisu 206‑LB Ma, Tony 299‑LB Meunier, Clemence 330‑LB Nasr, Gamela 47‑LB Ma, Xiaotang 16‑LB Miao, Ji 40‑LB Nassar, Wael F. 102‑LB Maarouf, Omar H. 219‑LB Michels, Aaron W. 217‑LB Nawrocki, Andrea 272‑LB, 273‑LB MacDonald, Patrick E. 332‑LB Milani, Massimo 44‑LB Neal, Adam S. 336‑LB Machida, Yui 262‑LB Milaszewski, Kerry 50‑LB Neale, Helen 108‑LB Macias, William L. 114‑LB Milhem, Tyler 76‑LB Neergaard, Jesper S. 314‑LB MacIsaac, Richard J. 66‑LB Min, Ae-Kyung 257‑LB Nelson, Scott M. 153‑LB Madiraju, Anila K. 342‑LB Min, Jihee 55‑LB Neuman, Joshua C. 330‑LB ABSTRACT AUTHOR IN DE X Madura II, James A. 311‑LB Min, Kyung Wan 305‑LB Nhan, Trinh 124‑LB Magyar, Kendra 72‑LB Min, So Yun 298‑LB Nicholls, Stephen 111‑LB Maheshwari, Pradeep K. 90‑LB Minium, Judi 152‑LB Nie, Xiaomin 309‑LB Mahesula, Swetha 205‑LB Mintz, James 294‑LB Nie, Yaohui 222‑LB Majak, Maila 169‑LB Mirmira, Raghavendra G. 323‑LB Nissen, Steven E. 111‑LB Makdissi, Antoine 130‑LB Misha’l, Aly A. 47‑LB Niu, Jianmin 159‑LB Malik, Vasanti S. 175‑LB, 177‑LB Mitrovich, Connor 150‑LB Nobrega, Marcelo A. 194‑LB Mallikarjuna, Shwetha 3‑LB Miura, Junnosuke 190‑LB Noel, Guillaume 84‑LB Manan, Jyotika 134‑LB Miyashita, Kazuyuki 324‑LB, 334‑LB Nordén, Kristina 335‑LB Mandarino, Lawrence J. 311‑LB Miyatsuka, Takeshi 324‑LB, 334‑LB Norman-Burgdolf, Heather L. 267‑LB Manganiello, Vincent Manganiello 259‑LB Mizuno, Ken 270‑LB, 295‑LB North, Kari E. 204‑LB, 308‑LB Maniatis, Nikolas 201‑LB, 202‑LB, 203‑LB Mlynarchik, Andrew 295‑LB North, Paula E. 21‑LB Manning Fox, Jocelyn E. 332‑LB Mlynarski, Wojciech 191‑LB Norton, Luke 195‑LB Mansmann, Ulrich 13‑LB Modi, Devangi 29‑LB Nowlan, Molly 171‑LB Manson, JoAnn E. 167‑LB, 176‑LB, 177‑LB Moerman, Ericka 304‑LB Nunlee-Bland, Gail 139‑LB Maratos Flier, Eleftheria 317‑LB Mohammad Moradi, Shayan 47‑LB Nunoue, Tomokazu 285‑LB Marcinak, John 111‑LB Mohan, Viswanathan 175‑LB, 180‑LB Obrosova, Irina G. 32‑LB Marquard, Jan 121‑LB Mohanasundaram, Daisy 29‑LB Odede, Geofrey 108‑LB Marquez, Eladio 208‑LB Mohlke, Karen L. 204‑LB, 206‑LB Ogawa, Daisuke 258‑LB Martin, Brittany 50‑LB Mohseni, Mahshid 104‑LB Oh, Byung-Chul 256‑LB Martin, Holly R. 197‑LB Moisidou, Maria 268‑LB Oh, Kook-Hwan 127‑LB Martin, Jennifer A. 106‑LB Molina, Judith T. 333‑LB Oh, Kyoung-Jin 230‑LB Maruthur, Nisa M. 115‑LB Mondesir, Debbie 72‑LB Oh, Minsuk 55‑LB Mather, Kieren J. 17‑LB Moon, Sanghoon 200‑LB Ohta, Masayuki 270‑LB Matheson, Don 101‑LB Moore, Adrian 108‑LB Okada, Junichi 20‑LB Mathieu, Chantal 133‑LB Moore, Robert 210‑LB Okada, Shuichi 20‑LB Matsuoka, Taka-Aki 324‑LB, Mora, Edwin 80‑LB O’Neal, David 237‑LB, 66‑LB Matsushita, Kanae 212‑LB Moreno-Ruiz, Francisco J. 306‑LB, 310‑LB O’Rahilly, Stephen 197‑LB Matteucci, Elena 168‑LB Morgan, Diana 213‑LB Orchard, Trevor J. 17‑LB Mauceri, Joseph 291‑LB Morley, Thomas S. 233‑LB Ordelheide, Anna-Maria 327‑LB Mauseth, Richard 101‑LB Morris, Andrew P. 193‑LB Orduz, Arturo 30‑LB Mazzone, Theodore 111‑LB Morris, Heather L. 64‑LB O’Reilly, Eilis J. 177‑LB McCarthy, Mark I. 204‑LB Morris, Kristin 76‑LB Oropeza, Daniel 330‑LB McDaniel, Kristen 217‑LB Morrow, Linda 2‑LB, 92‑LB Orr, Gregory 49‑LB Mcdonald, Molly 144‑LB Morton-Eggleston, Emma B. 136‑LB Oruk, Guzide Gonca 154‑LB McElrtah, Thomas F. 160‑LB Mosser, Rockann 323‑LB Osakai, Aya 20‑LB McEwen, Laura N. 47‑LB Mounayar, Marwan 210‑LB, 219‑LB Osawa, Mari 190‑LB McGuire, Darren K. 111‑LB Mudaliar, Sunder 89‑LB Osborne, Timothy 318‑LB McKenney, Sarah 100‑LB Mudgett, John 251‑LB Osborne, William 336‑LB McLaughlin, Kerry A. 213‑LB Muise, Eric 273‑LB Osei, Kwame 15‑LB McTigue, Kathleen M. 68‑LB Mullapudi, Kamesh 76‑LB Osganian, Stavroula 144‑LB Meah, Farah 145‑LB Mullen, Deborah M. 79‑LB Østergaard, Jakob A. 216‑LB Medina-Gomez, M.C. 308‑LB Muniyappa, Ranganath 40‑LB O-Sullivan, In Sug 261‑LB Mehta, Aditya 130‑LB Munk, Ole L. 128‑LB Oteng-Ntim, Eugene 153‑LB Mehta, Cyrus 111‑LB Muñoz, Oscar 80‑LB Otter, Silke 121‑LB Mehta, Ravindra L. 114‑LB Munoz-Gomez, Miguel 322‑LB Otto, Michael 143‑LB Mei, Fang 332‑LB Munoz-Torres, Francisco 14‑LB Ouwens, Margriet 246‑LB Mei, Yong 97‑LB Murakami, Kazutoshi 258‑LB, 285‑LB Owen, Neville 53‑LB Meijer, Rick I. 60‑LB Murakami, Kentaro 270‑LB Pachanski, Michele 272‑LB Meikle, Peter J. 239‑LB Murthy, Narasimha 315‑LB Packham, David K. 23‑LB Meinicke, Thomas 119‑LB Mynatt, Randall L. 226‑LB Palaia, Thomas 277‑LB

LB93 Pallardo, Felipe 188‑LB Possenti, Roberta 274‑LB Riggs, Arthur 287‑LB Pallavi, Puttrevana M. 120‑LB Poston, Lucilla 153‑LB Rivera, Alba D. 14‑LB Pan, Kewu 223‑LB Pouwer, Frans 67‑LB Robertson, R. Paul 253‑LB, 275‑LB Pandey, Varun K 325‑LB Poveda, Alaitz 301‑LB Robinson, Matthew M. 271‑LB Pankratz, Nathan 207‑LB Poy, Matthew N. 325‑LB Robson, Stephen C. 153‑LB Panlasigui, Neil 150‑LB Prakash, Prashant K. 90‑LB Rocha, Hermano A. 123‑LB Parenty, Geraldine 326‑LB Pratley, Richard E. 303‑LB Rocha, Milagros 172‑LB Pargal, Summi 3‑LB Predmore, Zachary 140‑LB Rochat, Thierry 178‑LB, 179‑LB Parikh, Lisa 249‑LB Preiser, Nicholas 98‑LB Rodríguez, Carlos G. 272‑LB, 273‑LB Parikh, Neha 100‑LB Preston, Kyle 292‑LB Rodriguez, Henry 187‑LB Park, Anna 230‑LB Previs, Stephen 273‑LB Rodriguez-Cañete, Alberto 306‑LB, 310‑LB Park, Hyoungchun 127‑LB Previs, Steve 272‑LB Rodriguez-Pacheco, Francisca 306‑LB, 310‑LB Park, Ji-Hye 54‑LB, 55‑LB Price, David A. 71‑LB Roger, George W. 287‑LB Park, Keun-Gyu 257‑LB Prince, Melvin J. 88‑LB, 89‑LB Rojas-Rodriguez, Raziel 298‑LB Park, So Hyun 262‑LB Priyadarshini, Medha 323‑LB Rollins, Derrick K. 97‑LB Park, Sun-Hee 127‑LB Probst-Hensch, Nicole 178‑LB, 179‑LB Rondon, Martin 80‑LB Park, Tae-Joon 200-LB Pu, Xiaoqi 61‑LB, 309‑LB Rosenblit, Paul D. 94‑LB Park, Tae Sun 85‑LB Puckrein, Gary A. 139‑LB Rosenkilde, Mette M. 279‑LB Park, Yousung 170‑LB Puppala, Sobha 195‑LB Rosenstock, Julio 107‑LB, 111‑LB, 131‑LB, Parker, Stephen 206‑LB, 208‑LB Puri, Vishwajeet 231‑LB 307‑LB ABSTRACT AUTHOR IN DE X Parkin, Christopher G. 81‑LB, 139‑LB Pyun, Bo-Jeong 35‑LB Rosman, Paul M. 77‑LB Parson, Henri 32‑LB Qi, Ling 234‑LB Ross-Degnan, Dennis 136‑LB Parthasarathy, Vijayalaksmi 175‑LB Qi, Lu 173‑LB, 198‑LB Rossi, Luca 168‑LB Pascual, Michael 150‑LB Qiu, Rong 131‑LB Rother, Kristina I. 276‑LB Pasko, Dorota 204‑LB Quek, Jonathan Caleb 220‑LB Rountree, Austin 336‑LB Pasquarello, Cindy 50‑LB Queniat, Gurvan 304‑LB Roust, Lori R. 311‑LB Pasquel, Francisco J. 241‑LB Quinn, Lauretta T. 65‑LB Rovira-Llopis, Susana 172‑LB Patel, Nashita 153‑LB Qunibi, Wajeh 125‑LB Roy, Anirban 100‑LB, 66‑LB Patel, Niraja 319‑LB Quon, Michael J. 235‑LB Roy-Duval, Christine 107‑LB Patel, Pankaj 126‑LB Quyyumi, Arshed A. 25‑LB Ruan, Yijun 208‑LB Patiño, Jorge E. 30‑LB Radford, Elizabeth J. 151‑LB Rubio-Puchol, Olalla 172‑LB Patti, Mary-Elizabeth 151‑LB Radovick, Sally 129‑LB Ruetten, Hartmut 275‑LB Pattou, François 221‑LB, 304‑LB Ragolia, Louis 277‑LB Ruiz, Tiffany 157‑LB Paumelle, Réjane 10‑LB Rahbar, Samuel 287‑LB Russell, Steven J. 72‑LB Pears, Skye 29‑LB Rajagopalan, Sujit 110‑LB Rutkowski, Joseph M. 22‑LB Peng, Jinghua 129‑LB Ramasamy, Boominathan 31‑LB Ryan, Alexander J. 269‑LB Pereira, Mark A. 207‑LB Rameh, Lucia E. 337‑LB Rydén, Lars 216‑LB Perissi, Valentina 240‑LB Randeva, Harpal S. 315‑LB Sacks, Frank M. 173‑LB, 174‑LB, 198‑LB Peroni, Odile D. 243‑LB Ranetti, Aurelian Emil 133‑LB Sackstein, Robert 210‑LB Perron, Gabrielle 330‑LB Ranjani, Harish 180‑LB Saghatelian, Alan 243‑LB Perry, Rachel J. 113‑LB Rao, Ranganatha 315‑LB Saito, Tsugumichi 20‑LB Pery, Billy 77‑LB Raphael, Frederica 184‑LB Sakaguchi, Masaji 266‑LB Pessin, Jeffrey E. 20‑LB Rask-Madsen, Christian 266‑LB Sakai, Shinobu 210‑LB Petersen, Kitt F. 263‑LB Rasmussen, Henrik S. 125‑LB Sakimura, Kenji 288‑LB Petri, Renata T. 11‑LB Rathjen, Thomas 325‑LB Sakuma, Toshie 322‑LB Petrocchi-Passeri, Pamela 274‑LB Raverdy, Violeta 304‑LB Saleh, Farrah 316‑LB Pettus, Jeremy H. 89‑LB, 95‑LB Ravishankar, Aarthi 213‑LB Sales, Vicencia M. 151‑LB Pfeffer, Sébastien 325‑LB Ravussin, Eric 300‑LB, 302‑LB Salomon, Arthur 222‑LB Pichotta, Philip 2‑LB, 92‑LB Raymond, Ralph 253‑LB, 275‑LB Salsali, Afshin 118‑LB Picklesimer, Amy 156‑LB Raz, Itamar 15‑LB Samocha-Bonet, Dorit 239‑LB Piecuch, Emaly 208‑LB Read, Linda 3‑LB Samovski, Dmitri 250‑LB Pihoker, Cate 150‑LB Reagan, Louise A. 52‑LB Samuel, Varman T. 263‑LB Pilegaard, Henriette 59‑LB Reaven, Peter D. 1‑LB Sanchez, Rosalia 188‑LB Pillai, Sreekumar G. 197‑LB Reddy, Narendra L. 315‑LB Sandall, Jane 153‑LB Pinney, Sara E. 157‑LB Reddy, Ravi 98‑LB Sanders, Thomas A. 153‑LB Piron, Matthew 194‑LB Redman, Leanne M. 300‑LB Santos, Rosa F. 62‑LB Piston, David W. 340‑LB Reers, Christina 326‑LB Saremi, Aramesh 1‑LB Pitale, Ameya 143‑LB Rees, Gwyn 67‑LB Sasaki, Shugo 324‑LB, 334‑LB Pittas, Anastassios G. 96‑LB Regner, Kevin R. 21‑LB Sathyanarayana, Padma 227‑LB Pober, David 57‑LB Reik, Wolf 325‑LB Satin-Smith, Marta 99‑LB Poitout, Vincent 330‑LB Reiser, Jochen 25‑LB Sattar, Naveed 153‑LB Polidori, David 254‑LB Renström, Frida 301‑LB Savage, Peter 275‑LB Pollin, Toni I. 196‑LB Resalat, Navid 98‑LB Sawicki, Konrad T. 255‑LB Polonsky, William H. 63‑LB Rewers, Arleta 171‑LB Scalia, Rosario 292‑LB, 293‑LB Polsky, Sarit 217‑LB Rewers, Marian 149‑LB Schade, David S. 17‑LB Pongratz, Rebecca L. 342‑LB Reynolds, Vincent L. 106‑LB Schalkwijk, Casper G 10‑LB Poole, Lucinda A. 66‑LB Rho, Jun Gi 339‑LB Schatz, Desmond 149‑LB Popoola, Orishebawo B. 294‑LB Ricchiuto, Piero 270‑LB Scherer, Philipp E. 22‑LB, 233‑LB, 265‑LB Popova, Dora 214‑LB Richardson, Carolyn C. 213‑LB Schindler, Christian 178‑LB, 179‑LB Porceban, Matheus 288‑LB Richter, Erik A. 59‑LB Schliess, Freimut 121‑LB Porksen, Niels 89‑LB Ridderstrale, Martin 118‑LB Schneider, Martin 326‑LB

LB94 Schönke, Milena 288‑LB Simmons, Rebecca A. 157‑LB Sundaresan, Sinju 250‑LB Schreiber, Stefanie 326‑LB Sims, Emily K. 187‑LB Sundelin, Elias 128‑LB Schulz, Christina-Alexandra 174‑LB Singh, Avinainder 134‑LB Super, Dennis 158‑LB Schurmann, Claudia 308‑LB Singh, Bhupinder 125‑LB Sury, Matthias 325‑LB Schwede, Frank 332‑LB Singh, Kiran P. 134‑LB Svendsen, Berit 279‑LB Scirica, Benjamin M. 15‑LB Singh, Maneet 231‑LB Sweet, Ian 336‑LB Scott, Donald 342‑LB Singh, Sasha 270‑LB Syed, Ismail 243‑LB Scott, Laura 206‑LB Singhal, Jyotsana 287‑LB Synold, Timothy 287‑LB Scott, Robert A. 204‑LB, 308‑LB Singhal, Sharad S. 287‑LB Szanto, Ildiko 341‑LB Screaton, Robert A. 330‑LB Sinha, Manasi 72‑LB Tabatabai, Niloofar M. 21‑LB Sczelecki, Sarah 330‑LB Sinha, Rajita 249‑LB Tahara, Yumiko 82‑LB Seed, Paul T. 153‑LB Sinha, Vikram P. 89‑LB Tailleux, Anne 10‑LB Seely, Ellen W. 160‑LB Sivapalaratnam, Sutesh S. 308‑LB Taitel, Michael 49‑LB Segal, Jodi 115‑LB Sjöstrand, Annika 148‑LB Takahara, Mitsuyoshi 324‑LB Segal, Karen R. 23‑LB Skerrett, Donna 23‑LB Takahashi, Yusuke 155‑LB Seielstad, Mark 207‑LB Skjøth, Trine V. 307‑LB Takaike, Hiroko 190‑LB Sekar, Sakthivel 63‑LB, 131‑LB Skokos, Dimitris 268‑LB Tam, Charmaine 300‑LB Selbach, Matthias 325‑LB Sleeman, Mark 268‑LB Tamanini, Filippo 201‑LB, 202‑LB Seo, Dongju 249‑LB Smith, Brian 219‑LB Tan, Ruo-Ding 142‑LB Seo, Ji A. 170‑LB Smith, Steven R. 318‑LB Tanenberg, Robert J. 78‑LB ABSTRACT AUTHOR IN DE X Seo, Ji Hye 170‑LB Smulders, Yvo M. 56‑LB, 60‑LB Tang, Cheng Cai 106‑LB Seramani, Sankar 31‑LB, 163‑LB Sohler, Nancy 138‑LB Tang, Huilin 124‑LB Sereika, Susan M. 68‑LB Sohn, Hae-Young 13‑LB Tang, Yuefeng 236‑LB Serné, Erik H. 56‑LB, 60‑LB Solhjou, Zhabiz 219‑LB Tantawi, Hyam R. 47‑LB Serpas, Lilian 141‑LB Somesh, Baggavalli P. 120‑LB Tattikota, Sudhir Gopal 325‑LB Sesso, Howard D. 176‑LB Son, Jee Woong 86‑LB Taylor, Ann 122‑LB Sever, Sanja 25‑LB Son, Moon-Ho 280‑LB Taylor, D.L. 206‑LB Severini, Cinzia 274‑LB Song, Dae-Kyu 256‑LB Taylor, Hugh S. 316‑LB Sha, Haibo 234‑LB Song, Yiqing 167‑LB, 176‑LB Teague, April M. 143‑LB, 155‑LB, 157‑LB Shah, Chirag P. 37‑LB Sontheimer, Alexandra 243‑LB Temprosa, Marinella 17‑LB Shah, Kaanan 199‑LB Sorrenson, Brie 331‑LB Tennagels, Norbert 246‑LB Shah, Neha 315‑LB Sosenko, Jay M. 145‑LB Tersey, Sarah 323‑LB Shah, Parag 126‑LB Souhami, Elisabeth 107‑LB Thaker, Vidhu 144‑LB Shah, Viral 217‑LB Soumerai, Stephen 136‑LB Theisen, Daniel 13‑LB Shamsi, Farnaz 232‑LB Southam, Lorraine 204‑LB, 308‑LB Theiss, Hans D. 13‑LB Shanahan, William 299‑LB Souza, Sandra C. 273‑LB Theoharis, Stamatis 268‑LB Shang, Jin 251‑LB Sowers, James R. 286‑LB Thevenet, Julien 304‑LB Shankar, Sudha S. 197‑LB, 253‑LB, 275‑LB Sparre-Ulrich, Alexander H. 279‑LB Thibodeau, Asa 208‑LB Shanmugham, Satya 99‑LB Speight, Jane 66‑LB, 67‑LB Thiel, Steffen 216‑LB Shao, Yimin 283‑LB Sperling, Laurence S. 25‑LB Thombare, Aparna 78‑LB Sharifi, Amin 66‑LB Spiegelman, Donna 175‑LB Thompson, David M. 155‑LB Sharma, Naveen 245‑LB Spirakis, Ruth 81‑LB Thompson, Michael 185‑LB Sharma, Pragya 247‑LB Staels, Bart 10‑LB Tian, Suyan 229‑LB Shaw, Collin 319‑LB Staimez, Lisa R. 180‑LB Tinahones, Francisco J. 107‑LB She, Jin-Xiong 149‑LB Stansfield, Brain 294‑LB Tinsley, Liane 57‑LB Shebani, Zachariah 116‑LB Staten, Myrlene 253‑LB Tique, Claudia R. 30‑LB Sheehan, John 164‑LB Stefanovski, Darko 275‑LB Tobacman, Joanne K. 38‑LB Shehata, Kristal 203‑LB Steinbeck, Gerhard 13‑LB Tomokazu, Nunoue 258‑LB Shepherd, Peter 331‑LB Stella, Peter 95‑LB Tong, Jenny 173‑LB Sherwin, Robert S. 249‑LB Stephens, Ella 50‑LB Tonks, Katherine 239‑LB Shi, Hang 260‑LB Stephens, Jacqueline M. 226‑LB Tonne, Jason M. 322‑LB Shibusawa, Ryo 20‑LB Stepp, David W. 294‑LB Toppari, Jorma 149‑LB Shimo, Naoki 334‑LB Stier, Christine K. 4‑LB Torres, Jason M. 199‑LB Shimoda, Yoko 20‑LB Stirban, Alin 121‑LB Torres, Lizardo 51‑LB Shimomura, Iichiro 324‑LB, 334‑LB Stirrups, Kathy 308‑LB Toschi, Elena 317‑LB Shin, Jeong Jae 339‑LB Stitzel, Michael L. 208‑LB Toumilehto, Jaakko 206‑LB Shin, Myung 251‑LB Stolz, Daiana 178‑LB, 179‑LB Trautmann, Michael 105‑LB, 303‑LB Shon, Ho Sang 85‑LB Stram, Daniel O. 207‑LB Trawley, Steve 66‑LB Short, Kevin R. 143‑LB Straznicky, Nora 53‑LB Trevino, Michelle B. 262‑LB Shulman, Gerald I. 113‑LB, 263‑LB, 271‑LB Stringham, Heather 206‑LB Tripaldi, Juliet R. 317‑LB Shungin, Dmitry 301‑LB Strongman, Helen 169‑LB Tripathy, Devjit T. 195‑LB Shyong, Tai E. 207‑LB Su, Xiong 250‑LB Triplett, Eric W. 149‑LB Siddiqui, Uzma Mohammad 185‑LB Suarez-Cuervo, Catalina 115‑LB Tryggestad, Jeanie B. 155‑LB Siegle, Greg J. 68‑LB Subkhangulova, Aygul 248‑LB Tsachalina, Theofaneia 48‑LB Sievers, Felix 121‑LB Suh, Kyung-Shin 296‑LB Tsai, Katherine 164‑LB Sigrist, Kirsten 222‑LB Sumner, Anne 254‑LB Tschöp, Matthias 325‑LB Silk, Maria E. 114‑LB Sun, Chenglin 229‑LB Tseng, Eva 115‑LB Silvia, Maria Elizabeth R. 62‑LB Sun, Li-Ping 272‑LB Tseng, Yu-Hua 232‑LB Sim, Thuan Kai Jelvin 220‑LB Sun, Qi 167‑LB, 177‑LB Tu, Weiping 61‑LB Simell, Olli G. 149‑LB Sun, Wanqing 6‑LB Tumlin, James A. 114‑LB Siminerio, Linda 68‑LB Sun, Xiao Jian 235‑LB Tung, Gregory 171‑LB

LB95 Tuomilehto, Jaakko 47‑LB Wang, Tiange 174‑LB, 198‑LB Xia, Jonathan 265‑LB Turcot, Valerie 204‑LB, 308‑LB Wang, Tiansheng 124‑LB Xiao, Xianchao 229‑LB Tuttle, Edward 135‑LB, 142‑LB Wang, Wang 336‑LB Xu, Aimin 223‑LB, 239‑LB, 282‑LB Tuttle, Katherine 114‑LB Wang, Wei 33‑LB, 34‑LB Xu, Haiyan 222‑LB Tütüncüoglu, Aliye P. 154‑LB Wang, Xiaojin 61‑LB Xu, Jing 242‑LB Ucar, Duygu 208‑LB Wang, Xiaolin 73‑LB Xu, Liou 139‑LB Uchigata, Yasuko 190‑LB Wang, Xinye 329‑LB Xu, Ping 145‑LB Uddén Hemmingsson, Joanna 307‑LB Wang, Ying 313‑LB Xu, Shanshan 261‑LB Umpierrez, Guillermo E. 241‑LB Ward, Glenn M. 66‑LB Xu, Yuan 313‑LB Üner, Aykut G. 288‑LB Ward, W. Kenneth 76‑LB Xue, Bingzhong 260‑LB Unterman, Terry G. 38‑LB, 261‑LB Wardecki, Marek 107‑LB Xue, Ruidan 232‑LB Uppal, Karan 241‑LB Warden, Charles 287‑LB Xue, Yaoming 18‑LB Uribe-Bruce, Liliana 2‑LB Wardle, Jane 153‑LB Xuhong, Hou 165‑LB Uribe-Wiechers, Ana C. 45‑LB Warren, Graham 70‑LB Yaghootkar, Hanieh 308‑LB Vaidya, Anand 160‑LB Watada, Hirotaka 324‑LB Yajnik, Chittaranjan 182‑LB, 183‑LB Valdes, Jorge 5‑LB Watanabe, Eiko 51‑LB Yajnik, Pallavi 182‑LB Valdes, Sergio 306‑LB, 310‑LB Watanabe, Richard M. 206‑LB Yale, Jean-François 95‑LB Valera, Jose 51‑LB Watson, Karol E. 17‑LB Yamabi, Masaki 270‑LB van Hinsbergh, Victor W. 56‑LB Webb, Seamus 319‑LB Yamada, Eijiro 20‑LB van Poelgeest, Erik M. 56‑LB Weber, Mary Beth 180‑LB Yamada, Iwao 270‑LB ABSTRACT AUTHOR IN DE X van Polanen, Nynke 22‑LB Wedick, Nicole M. 175‑LB Yamada, Masanobu 20‑LB Vander Heiden, Anna 83‑LB Weindruch, Richard 252‑LB Yamaguchi, Satoshi 258‑LB Vanhoutte, Jonathan 10‑LB Weintraub, Daniel S. 294‑LB Yamamoto, Yuichi 324‑LB, 334‑LB Vantyghem, Marie Christine 221‑LB Weintraub, Neal L. 294‑LB Yamanaka, Hisashi 190‑LB Vargas, Gabriela 51‑LB Welch, Ryan 206‑LB Yamazaki, Masahiro 212‑LB Vasavada, Rupangi C. 342‑LB Welters, Alena 121‑LB Yan, Jing-He 122‑LB Vassileva, Maria T. 253‑LB, 275‑LB Wen, Xiaoquan 206‑LB Yang, Alex 125‑LB Vasudevan, Sudha 175‑LB Weng, Jianping 87‑LB Yang, Hyuk In 55‑LB Vazquez-Pedreño, Luis 310‑LB Wentzell, Katherine 50‑LB Yang, Jae Sung 280‑LB Vehik, Kendra 149‑LB West, Shauna 108‑LB Yang, Juhong 186‑LB Vella, Adrian 275‑LB Westcott, Gregory P. 96‑LB Yang, Lu 287‑LB Vellanki, Priyathama 241‑LB Wharam, James F. 136‑LB Yang, Shaojuan 159‑LB Vendelbo, Mikkel H. 128‑LB Wheeler, Heather E. 199‑LB Yang, Wenying 117‑LB Venkataranganna, Marikunte V. 120‑LB Wheeler, Michael B. 329‑LB Yang, Xiaodong 251‑LB, 272‑LB Vento, Flor 51‑LB Whelan, Mary 270‑LB, 295‑LB Yao, Li 205‑LB Verma, Mahesh K. 120‑LB White, Ariel 108‑LB Yap, Chui Sun 220‑LB Veyrat-Durebex, Christelle 341‑LB White, Ursula 302‑LB Yasuda, Tetsuyuki 324‑LB, 334‑LB Victor, Victor M. 172‑LB Whitlock, Kathryn B. 150‑LB Ye, Jenny 107‑LB Vikentieva, Elena 214‑LB Whitworth, Melissa K. 153‑LB Ye, Jianping 259‑LB Villa, Stephanie R. 323‑LB Willett, Walter C. 175‑LB Yeo, Kwee Poo 106‑LB Villanes, Sofia 51‑LB Williams, Michelle 160‑LB Yepes, Carlos A. 80‑LB VIllena, Lorena 51‑LB Williams, Rachael 169‑LB Yerges-Armstrong, Laura 196‑LB Vilsbøll, Tina 132‑LB Williamson, Donald A. 173‑LB Yiew, Kan Hui 294‑LB Vinik, Aaron I. 32‑LB Willnow, Thomas 248‑LB Yi-Frazier, Joyce P. 150‑LB Vishwanath, Anu 155‑LB Wilson, Lisa 115‑LB Yik Ying, Teo 207‑LB Viswanathan, Prabhakar 111‑LB Wiltshire, Esko 146‑LB Yilmaz, Hamiyet 154‑LB von Eckardstein, Arnold 178‑LB, 179‑LB Winkler, Thomas W. 204‑LB, 308‑LB Ying, Wei 242‑LB von Meyenn, Ferdinand 325‑LB Winters, Alexandra H. 196‑LB Yogeshwari, Sivakumaran 120‑LB von Oettingen, Julia 184‑LB Wisherd, Chris 319‑LB Yoo, Hye Jin 170‑LB von Ziegler, Franz 13‑LB Wnendt, Stephan 121‑LB Yoon, Sun Ae 127‑LB Voskanyan, Gayane 100‑LB Woerdeman, Jorn 60‑LB Yore, Mark M. 243‑LB Wada, Asuka 39‑LB Woerle, Hans J. 119‑LB Yorek, Mark A. 32‑LB Wada, Jun 258‑LB, 285‑LB Wohlfart, Paulus 246‑LB Young, Edwin 138‑LB Walker, Tomas 5‑LB, 71‑LB Wojtaszewski, Jørgen F.P. 59‑LB Young, Kristin L. 204‑LB, 308‑LB Walter, Mary F. 276‑LB Wolford, Brooke 206‑LB, 208‑LB Yu, Ji Hee 170‑LB Wanders, Desiree 224‑LB Wondisford, Fredric E. 129‑LB Yuan, Geheng 283‑LB Wang, Aihua 296‑LB Wong, Chi-Ming 223‑LB, 282‑LB Yuan, Jian-Min 207‑LB Wang, Bingshun 61‑LB Wood, Teresa 316‑LB Yun, Nari 86‑LB Wang, Fang 159‑LB Woon Puay, Koh 207‑LB Zaharieva, Emanuela 214‑LB Wang, Fei 124‑LB Wouters, Kristiaan 10‑LB Zangeneh, Farhad 139‑LB Wang, Guang 313‑LB Wright, Kathryn F. 275‑LB Zavolan, Mihaela 325‑LB Wang, Guixia 229‑LB Wronkowitz, Nina 246‑LB Zeller, Cordula 118‑LB Wang, Haiyan 245‑LB Wu, Bin 259‑LB Zemel, Michael B. 260‑LB Wang, Hong-Liang 33‑LB, 34‑LB Wu, Di 100‑LB Zeng, Yanmei 18‑LB Wang, Liangsu 251‑LB, 272‑LB Wu, Hongyu 177‑LB Zera, Chloe 160‑LB Wang, Lu 176‑LB Wu, Jimmy 112‑LB Zevallos, Juan C. 14‑LB Wang, Ningjian 61‑LB, 161‑LB, 309‑LB Wu, Jun 26‑LB Zhang, Dongming 235‑LB Wang, Pin-Wen 37‑LB Wu, Xiwei 287‑LB Zhang, Fang 136‑LB Wang, Renwei 207‑LB Wu, Yan 33‑LB, 34‑LB Zhang, Huiliang 336‑LB Wang, Sheng-Ping 251‑LB, 272‑LB Wunderlich, F.T. 233‑LB Zhang, Jinping 117‑LB Wang, Shuxia 267‑LB Xia, Fangzhen 61‑LB, 161‑LB, 309‑LB Zhang, Junqing 283‑LB

LB96 Zhang, Ming 329‑LB Zhao, Zhiyun 259‑LB Zhu, Chaoxia 61‑LB, 161‑LB, 309‑LB Zhang, Puhong 87‑LB Zhen, Wei 296‑LB Zhu, Chunfang 61‑LB, 161‑LB, 309‑LB Zhang, Quanjiang 244‑LB Zheng, Yan 174‑LB, 198‑LB Zhu, Meili 36‑LB Zhang, Shu 119‑LB Zheng, Yang 6‑LB Zhu, Yingmin 332‑LB Zhang, Tong 159‑LB Zhong, Xueyu 8‑LB Ziegler, Anette-Gabriele 149‑LB Zhang, Wenwei 261‑LB Zhou, Beiyan 242‑LB Ziegler, Thomas R. 241‑LB Zhang, Xi 167‑LB Zhou, Haihong 273‑LB Zinman, Bernard 111‑LB Zhang, Yiyi 238‑LB Zhou, Joanna 152‑LB Zinzen, Robert P. 325‑LB Zhao, Peng 226‑LB Zhou, Junwen 124‑LB Zubatov, Yelena 138‑LB Zhao, Tieyun 238‑LB Zhu, Beibei 284‑LB ABSTRACT AUTHOR IN DE X

LB97 ABSTRACT Author DISCLOSURE INFORMATION

AUTHOR RELATIONSHIP/COMPANY AUTHOR RELATIONSHIP/COMPANY Abderrahmani, Amar ���������������������������� Disclosed no conflict of interest. Aroda, Vanita R. ����������������������������������� Consultant: Novo Nordisk Inc., Sanofi U.S., VeraLight, Inc.; Abdi, Reza �������������������������������������������� Disclosed no conflict of interest. Research Support: Aegerion Pharmaceuticals, Inc., Abdul-Ghani, Muhammad �������������������� Disclosed no conflict of interest. Pharmaceuticals, LLC., Bayhill Therapeutics, Abel, E. Dale ���������������������������������������� Disclosed no conflict of interest. Concert Pharmaceuticals, GlaxoSmithKline, Interkrin Abraham, Jenny ����������������������������������� Disclosed no conflict of interest. Therapeutics, Merck & Co., Inc., Novo Nordisk Abulizi, Abudukadier ���������������������������� Disclosed no conflict of interest. Inc., Roche USA, Sanofi U.S., Shionogi Inc., Takeda Abumrad, Nada ������������������������������������ Disclosed no conflict of interest. Pharmaceuticals U.S.A., Inc., VeraLight, Inc. Accili, Domenico ���������������������������������� Disclosed no conflict of interest. Aronson, Ronnie ����������������������������������� Advisory Panel: Janssen Pharmaceuticals, Novo Adachi, Yusuke ������������������������������������� Employee: Ajinomoto Group. Nordisk, Inc., Sanofi;Consultant: AstraZeneca Adams Huet, Beverley ������������������������� Disclosed no conflict of interest. Pharmaceuticals LP, Bristol-Myers Squibb Company, Adler, Sharon G. ����������������������������������� Advisory Panel: Baxter, Eli Lilly and Company; Consultant: Medtronic, Sanofi, Takeda Pharmaceutical Baxter, Eli Lilly and Company, Retrophin; Research Company Ltd; Other Relationship: AstraZeneca Support: Baxter, Eli Lilly and Company, Retrophin. Pharmaceuticals LP, BD Medical Diabetes Care, Adrion, Christine ���������������������������������� Disclosed no conflict of interest. Boehringer Ingelheim Pharmaceuticals, Inc., Bristol- Agarwal, Ayush K. �������������������������������� Disclosed no conflict of interest. Myers Squibb Company, Novo Nordisk, Inc., Sanofi, Agrawal, Prabhat K. ����������������������������� Disclosed no conflict of interest. Takeda Pharmaceutical Company Ltd.; Research Ahmad, Shafqat ����������������������������������� Disclosed no conflict of interest. Support: Abbott Laboratories, Inc., Andromeda Ahn, Ki-Yong ���������������������������������������� Disclosed no conflict of interest. Biotech Ltd, AstraZeneca Pharmaceuticals LP, BD Aikawa, Masanori �������������������������������� Research Support: Kowa Pharmaceuticals. Medical Diabetes Care, Boehringer Ingelheim Ajena, Aboajela ����������������������������������� Disclosed no conflict of interest. Pharmaceuticals, Inc., Bristol-Myers Squibb Company, Akinbosoye, Osayi �������������������������������� Disclosed no conflict of interest. ConjuChem, Diartis Pharmaceuticals, Eli Lilly and Akiyama, Haruhiko ������������������������������� Disclosed no conflict of interest. Company, Essem Research, GlaxoSmithKline, ICON, Akkari, P. Anthony �������������������������������� Consultant: Eli Lilly and Company; Employee: Cabernet Janssen Pharmaceuticals, Medpace, Medtronic, Pharmaceuticals. Merck, Novartis Pharmaceuticals Corporation, Novo Akolkar, Beena ������������������������������������� Disclosed no conflict of interest. Nordisk, Inc., Piramal BD, Quintiles, Regeneron Al Dhuhouri, Jamila S. ������������������������� Disclosed no conflict of interest. Pharmaceuticals, Roche Pharmaceuticals, Sanofi, Al Hammadi, Fatema H. ����������������������� Disclosed no conflict of interest. Takeda Pharmaceutical Company Ltd, Tolerx. Al Nuaimi, Asma A. ����������������������������� Disclosed no conflict of interest. Arous, Caroline ������������������������������������ Disclosed no conflict of interest. Al Shaikh, Sarah ���������������������������������� Disclosed no conflict of interest. Arslan, Banu ����������������������������������������� Disclosed no conflict of interest.

AUTHOR D I SCLOSURE Alaminos, Miguel A. ���������������������������� Disclosed no conflict of interest. Arthur, John ������������������������������������������ Disclosed no conflict of interest. Albu, Jeanine ��������������������������������������� Research Support: Merck & Co., Inc., Novo Nordisk Inc., Arumugam, Kokila �������������������������������� Disclosed no conflict of interest. Weight Watchers International, Inc. Arya, Rector ����������������������������������������� Disclosed no conflict of interest. Alcain-Martinez, Guillermo ������������������ Disclosed no conflict of interest. Aryal, Pratik ������������������������������������������ Disclosed no conflict of interest. Ali, Mohammed K. ������������������������������� Disclosed no conflict of interest. Ashankyty, Ibraheem ���������������������������� Disclosed no conflict of interest. Ali, Nahed �������������������������������������������� Disclosed no conflict of interest. Asimakopoulou, Andriana �������������������� Disclosed no conflict of interest. Ali, Nasiri ��������������������������������������������� Disclosed no conflict of interest. Assaad-Khalil, Samir H. ����������������������� Disclosed no conflict of interest. Alkanani, Aimon ����������������������������������� Disclosed no conflict of interest. Atalay, Nesil ����������������������������������������� Disclosed no conflict of interest. Alkarni, Meyad A. �������������������������������� Disclosed no conflict of interest. Atkins, Ashley �������������������������������������� Disclosed no conflict of interest. Alkhaddo, Jamil B. ������������������������������� Research Support: Eli Lilly and Company. Atkinson, Mark A. �������������������������������� Disclosed no conflict of interest. Alkhalidy, Hana ������������������������������������ Disclosed no conflict of interest. Austen, Matthias ��������������������������������� Disclosed no conflict of interest. Alkorta-Aranburu, Gorka ���������������������� Disclosed no conflict of interest. Ayala, Iriscilla ��������������������������������������� Disclosed no conflict of interest. Almaca, Joana ������������������������������������� Disclosed no conflict of interest. Ayala, Jennifer E. ��������������������������������� Disclosed no conflict of interest. Almeda-Valdes, Paloma ����������������������� Disclosed no conflict of interest. Ayala, Julio E. �������������������������������������� Disclosed no conflict of interest. Alquier, Thierry ������������������������������������� Disclosed no conflict of interest. Azzi, Jamil �������������������������������������������� Disclosed no conflict of interest. Al-Trad, Bahaa �������������������������������������� Disclosed no conflict of interest. Bach, Leon A. ��������������������������������������� Speaker’s Bureau: Sanofi. Álvarez-Escolá, Carmen ����������������������� Disclosed no conflict of interest. Bae, Jae-Hoon ������������������������������������� Disclosed no conflict of interest. Alzaid, Aus ������������������������������������������� Advisory Panel: AstraZeneca, Boehringer Ingelheim, Bae, Jin-Sik ������������������������������������������ Disclosed no conflict of interest. Hikma, Janssen, Merck Serono, Takeda; Speaker’s Bae, Kwi-Hyun ������������������������������������� Disclosed no conflict of interest. Bureau: AstraZeneca, Boehringer Ingelheim, Hikma, Bae, Su Ah ������������������������������������������� Disclosed no conflict of interest. Janssen, Merck Serono, Novo Nordisk. Ba-Essa, Ebtesam M. ��������������������������� Disclosed no conflict of interest. Amblee, Ambika ����������������������������������� Research Support: AstraZeneca Pharmaceuticals LP. Bagger, Jonatan I. �������������������������������� Disclosed no conflict of interest. Amer, Ahmed ���������������������������������������� Employee: Novartis Pharmaceuticals Corporation. Bahceci, Mitat �������������������������������������� Disclosed no conflict of interest. Ammar, Hala ����������������������������������������� Disclosed no conflict of interest. Bahijri, Suhad M. ��������������������������������� Disclosed no conflict of interest. Andersen, Emilie S. ������������������������������ Disclosed no conflict of interest. Bahmanyar, Shahram ��������������������������� Research Support: Centre for Pharmacoepidemiology (CPE) Anderson, Rozalyn M. �������������������������� Disclosed no conflict of interest. at Karolinska Institute has contracts with several Andreasen, Camilla ������������������������������ Disclosed no conflict of interest. pharmaceutical companies and performs research for Andrew, Toby ���������������������������������������� Disclosed no conflict of interest. them through research grants. Angueira, Anthony R. ��������������������������� Disclosed no conflict of interest. Bahn, Gideon ���������������������������������������� Disclosed no conflict of interest. Anil, Tharappel M. ������������������������������� Disclosed no conflict of interest. Bai, Ramya ������������������������������������������� Disclosed no conflict of interest. Anjana, Ranjit M. ��������������������������������� Disclosed no conflict of interest. Baidal, David A. ����������������������������������� Disclosed no conflict of interest. Annabi, Firas A. ������������������������������������ Disclosed no conflict of interest. Baik, Sei Hyun �������������������������������������� Disclosed no conflict of interest. Anton, Stephen D. �������������������������������� Disclosed no conflict of interest. Bailey, Kathleen A. ������������������������������� Disclosed no conflict of interest. Antosik, Karolina ���������������������������������� Disclosed no conflict of interest. Bajaj, Mandeep ������������������������������������ Advisory Panel: Genentech, Inc.; Research Support: Anup, Mammen O. ������������������������������� Disclosed no conflict of interest. American Diabetes Association, AstraZeneca, Apovian, Caroline M. ��������������������������� Consultant: Amylin, Arena, EnteroMedics, Johnson Boehringer Ingelheim Pharmaceuticals, Inc., and Johnson, Merck, Novo Nordisk, Nutrisystem, Bristol-Myers Squibb, Eli Lilly and Company, Novo Orexigen, Sanofi-Aventis, Zafgen;Research Nordisk Inc.; Speaker’s Bureau: Sanofi U.S., Takeda Support: Amylin, Aspire Bariatrics, Dr. Robert C. and Pharmaceuticals U.S.A., Inc. Veronica Atkins Foundation, Eli Lilly, GI Dynamics, Balk, Ethan M. �������������������������������������� Disclosed no conflict of interest. MetaProteomics, MYOS Corporation, Orexigen, Pfizer, Balliro, Courtney ���������������������������������� Disclosed no conflict of interest. Sanofi-Aventis; Speaker’s Bureau: Takeda. Balo, Andrew ��������������������������������������� Employee: Dexcom, Inc. Araque, Katherine �������������������������������� Disclosed no conflict of interest. Baltaro, Richard J. ������������������������������� Disclosed no conflict of interest. Araujo, Renata ������������������������������������� Disclosed no conflict of interest. Banks, Michaela ���������������������������������� Disclosed no conflict of interest. Ardehali, Hossein ��������������������������������� Disclosed no conflict of interest. Bañuls, Celia ���������������������������������������� Disclosed no conflict of interest. Ardissone, Alexandria N. ��������������������� Disclosed no conflict of interest. Barber, Thomas M. ������������������������������� Disclosed no conflict of interest. Arias, Edward B. ���������������������������������� Disclosed no conflict of interest. Baron, Michelle A. ������������������������������� Employee: Intarcia Therapeutics, Inc. Armstrong, Debra A. ���������������������������� Disclosed no conflict of interest. Barquiel, Beatriz ����������������������������������� Disclosed no conflict of interest. Arndt, Kelly ������������������������������������������ Disclosed no conflict of interest. Barrett-Connor, Elizabeth L. ����������������� Disclosed no conflict of interest.

LB98 AUTHOR RELATIONSHIP/COMPANY AUTHOR RELATIONSHIP/COMPANY Barroso, Inês ���������������������������������������� Disclosed no conflict of interest. Bouchaert, Emanuel ����������������������������� Disclosed no conflict of interest. Barta, William �������������������������������������� Disclosed no conflict of interest. Boulware, David ����������������������������������� Disclosed no conflict of interest. Bartolomucci, Alessandro �������������������� Disclosed no conflict of interest. Bouyakdan, Khalil �������������������������������� Disclosed no conflict of interest. Bassaganya-Riera, Josep �������������������� Disclosed no conflict of interest. Bouzakri, Karim ������������������������������������ Disclosed no conflict of interest. Batra, Manav ��������������������������������������� Disclosed no conflict of interest. Brady, Matthew J. ������������������������������� Disclosed no conflict of interest. Bauman, Viviana ���������������������������������� Disclosed no conflict of interest. Branigan, Deborah ������������������������������� Disclosed no conflict of interest. Bayeva, Marina ������������������������������������ Disclosed no conflict of interest. Brar, Harpreet ��������������������������������������� Disclosed no conflict of interest. Bays, Harold ����������������������������������������� Consultant: Amgen Inc., AstraZeneca Pharmaceuticals Brathwaite, Collin �������������������������������� Disclosed no conflict of interest. LP, Bristol-Myers Squibb Company, Catabasis Braun, Barry ����������������������������������������� Disclosed no conflict of interest. Pharmaceuticals, Inc., Daiichi-Sankyo Co., Ltd., Bray, George ����������������������������������������� Disclosed no conflict of interest. Eisai Co., Ltd., Isis Pharmaceuticals, Inc., Merck Brazg, Ronald ��������������������������������������� Research Support: Medtronic MiniMed, Inc. & Co., Inc., Novartis Corporation, Omthera, Vivus Breen, Matthew ����������������������������������� Employee: Pacific Diabetes Technologies, Inc.;Stock/ Inc., WPU Therapeutics; Research Support: Alere, Shareholder: Pacific Diabetes Technologies, Inc. Amarin Pharma, Inc., Amgen Inc., Ardea, Arisaph, Brehm, Michael A. ������������������������������� Disclosed no conflict of interest. AstraZeneca Pharmaceuticals LP, Boehringer Brehm, Tyler J. ������������������������������������� Disclosed no conflict of interest. Ingelheim Pharmaceuticals, Inc., Bristol-Myers Brenner, Christoph �������������������������������� Disclosed no conflict of interest. Squibb Company, Californian Raisin Board, Catabasis Breton, Marc D. ������������������������������������ Research Support: Animas Corporation, BD Medical- Pharmaceuticals, Inc., Cymabay, Eisai Co., Ltd., Diabetes Care, Dexcom, Inc., Insulet Corporation, Elcelyx Therapeutics, Inc., Eli Lilly and Company, LifeScan, Inc., Sanofi U.S., Tandem Diabetes Care, Esperion Therapeutics, Inc., Forest Pharmaceuticals, Inc. Inc., Gilead, Given, GlaxoSmithKline, Hanmi, High Briddell, Robert ������������������������������������ Disclosed no conflict of interest. Point Pharmaceuticals LLC, Hisun, Hoffman-La Briley, Annette L. ���������������������������������� Disclosed no conflict of interest. Roche Limited, Home Access, Janssen Research & Brismar, Kerstin ������������������������������������ Disclosed no conflict of interest. Development LLC, Merck & Co., Inc., Metabolex, Brito-Sanfiel, Miguel ���������������������������� Advisory Panel: Janssen, MSD; Speaker’s Bureau: Abbott, Nektar, Novartis Pharmaceuticals Corporation, Novo AstraZeneca, Eli Lilly, MSD, Novo Nordisk. Nordisk Inc., Omthera, Orexigen Therapeutics, Inc., Brittain, Julia ��������������������������������������� Disclosed no conflict of interest. Pfizer Inc., Pronova, Regeneron Pharmaceuticals, Inc., Brodsky, Michael R. ����������������������������� Disclosed no conflict of interest. Sanofi U.S., Takeda Pharmaceuticals U.S.A., Inc., Broedl, Uli �������������������������������������������� Employee: Boehringer Ingelheim GmbH. TIMI, TransTech Pharma, LLC., Trygg, Vivus Inc.,WPU Brosen, Kim ������������������������������������������ Disclosed no conflict of interest. Pharmaceuticals. Brosius III, Frank C. ������������������������������ Consultant: Eli Lilly and Company, Merck & Co., Inc.; Beaucamps, Cédric ������������������������������ Disclosed no conflict of interest. Research Support: Takeda Pharmaceuticals U.S.A., Beauregard, Natalie ����������������������������� Disclosed no conflict of interest. Inc. Beck, Andrew ��������������������������������������� Disclosed no conflict of interest. Brosnan, Julia �������������������������������������� Disclosed no conflict of interest. Becker, Alexander �������������������������������� Disclosed no conflict of interest. Brown, Jacob D. ����������������������������������� Disclosed no conflict of interest.

Beckman, Kenneth ������������������������������� Disclosed no conflict of interest. Brown, Rebecca J. ������������������������������� Disclosed no conflict of interest. AUTHOR D I SCLOSURE Bee, Yong Mong ����������������������������������� Disclosed no conflict of interest. Browne, Jessica L. ������������������������������� Disclosed no conflict of interest. Beeravolu, Swathi �������������������������������� Disclosed no conflict of interest. Bruckbauer, Antje ��������������������������������� Employee: NuSirt Biopharma; Stock/Shareholder: NuSirt Belfort De Aguiar, Renata �������������������� Disclosed no conflict of interest. Bopharma. Bell, Graeme I. ������������������������������������� Disclosed no conflict of interest. Brüning, Jens C. ����������������������������������� Disclosed no conflict of interest. Bell, Ruth ���������������������������������������������� Disclosed no conflict of interest. Bryan, Joseph �������������������������������������� Disclosed no conflict of interest. Below, Jennifer E. �������������������������������� Disclosed no conflict of interest. Buckingham, Bruce A. �������������������������� Advisory Panel: BD Medical-Diabetes Care, Medtronic Belton, Anne ���������������������������������������� Advisory Panel: Boehringer Ingelheim, Sanofi;Consultant: MiniMed, Inc., Novo Nordisk Inc., Sanofi U.S., Abbott, Lifescan Canada. Tandem Diabetes Care, Inc., Unomedical; Research Beltran, Yobana ������������������������������������ Disclosed no conflict of interest. Support: Bayer HealthCare, Dexcom, Inc., Insulet Benjamin, Tonya R. ������������������������������� Disclosed no conflict of interest. Corporation, LifeScan, Inc., Medtronic MiniMed, Inc., Benson, Tyler W. ���������������������������������� Disclosed no conflict of interest. Tandem Diabetes Care, Inc., The Leona M. and Harry Benware, Sheila ����������������������������������� Employee: Pacific Diabetes Technologies, Inc.;Stock/ B. Helmsley Charitable Trust, Unomedical. Shareholder: Pacific Diabetes Technologies, Inc. Budoff, Matthew ���������������������������������� Disclosed no conflict of interest. Bergenstal, Richard M. ������������������������ Employee: Abbott Diabetes Care, Bayer, DexCom, Johnson Budry, Lionel ����������������������������������������� Employee: Novartis AG. & Johnson, Medtronic and Roche. Burak, Mehmet Furkan ������������������������� Disclosed no conflict of interest. Berger, Zack ������������������������������������������ Disclosed no conflict of interest. Buring, Julie E. ������������������������������������� Disclosed no conflict of interest. Bergeron, Valerie ��������������������������������� Disclosed no conflict of interest. Burke, Paivi M. ������������������������������������� Disclosed no conflict of interest. Bergman, Richard N. ���������������������������� Disclosed no conflict of interest. Burmeister, Melissa A. ������������������������� Disclosed no conflict of interest. Bertinetti, Daniela �������������������������������� Disclosed no conflict of interest. Burns, Cheryl ���������������������������������������� Disclosed no conflict of interest. Betteridge, John ���������������������������������� Disclosed no conflict of interest. Buzzetti, Raffaella �������������������������������� Advisory Panel: Eli Lilly, Sanofi;Board Member: Abbott, Beula, Sara ������������������������������������������� Disclosed no conflict of interest. Takeda; Speaker’s Bureau: AstraZeneca, Eli Lilly, Bhad, Prafulla ��������������������������������������� Employee: Novartis Pharmaceuticals Corporation. Medtronic, Novartis, Novo Nordisk, Sanofi, Takeda. Bhakoo, Kishore Kumar ������������������������ Disclosed no conflict of interest. Cai, Weikang ���������������������������������������� Disclosed no conflict of interest. Bhansali, Anil ��������������������������������������� Disclosed no conflict of interest. Caiazzo, Robert ������������������������������������ Disclosed no conflict of interest. Bhat, Dattatreya ����������������������������������� Disclosed no conflict of interest. Caicedo, Alejandro ������������������������������� Disclosed no conflict of interest. Bhatt, Deepak L. ����������������������������������� Research Support: AstraZeneca Pharmaceuticals LP. Callan, Judith A. ���������������������������������� Disclosed no conflict of interest. Bhattacharjee, Alpana ������������������������� Disclosed no conflict of interest. Calle, Roberto A. ���������������������������������� Employee: Pfizer Inc.;Stock/Shareholder: Pfizer Inc. Bhattacharyya, Sumit ��������������������������� Disclosed no conflict of interest. Caloyeras, John ����������������������������������� Employee: Amgen Inc.; Stock/Shareholder: Amgen Inc. Bianco, Suzy ����������������������������������������� Disclosed no conflict of interest. Campa, David ��������������������������������������� Disclosed no conflict of interest. Biddinger, Sudha B. ������������������������������ Disclosed no conflict of interest. Campbell, Jonathan E. ������������������������� Disclosed no conflict of interest. Bihl, Ji C. ���������������������������������������������� Disclosed no conflict of interest. Campbell, Latoya E. ����������������������������� Disclosed no conflict of interest. Bird, Adrian ������������������������������������������ Disclosed no conflict of interest. Camporez, Joao-Paulo G. ��������������������� Disclosed no conflict of interest. Birk, Jesper ������������������������������������������ Disclosed no conflict of interest. Campos, Hannia ����������������������������������� Disclosed no conflict of interest. Bjørbæk, Christian ������������������������������� Disclosed no conflict of interest. Campos, Maribel ���������������������������������� Disclosed no conflict of interest. Blangero, John ������������������������������������� Disclosed no conflict of interest. Canepa, Ronald J. �������������������������������� Disclosed no conflict of interest. Blankenship, Jennifer M. ��������������������� Disclosed no conflict of interest. Cang, Zhen ������������������������������������������� Disclosed no conflict of interest. Blankfard, Martin ��������������������������������� Disclosed no conflict of interest. Canney, Lori ������������������������������������������ Employee: Biodel Inc.; Stock/Shareholder: Biodel Inc. Blaser, Martin J. ����������������������������������� Disclosed no conflict of interest. Cao, Qiang �������������������������������������������� Disclosed no conflict of interest. Blau, Jenny E. �������������������������������������� Disclosed no conflict of interest. Capehorn, Matthew ����������������������������� Advisory Panel: Boehringer Ingelheim, Eli Lilly, Merck Boehnke, Michael �������������������������������� Disclosed no conflict of interest. Sharp & Dohme, Novo Nordisk; Research Support: Bogdonov, Vladimir ������������������������������ Disclosed no conflict of interest. Cambridge Weight Plan, Lighter Life, Novo Nordisk; Bohnett, Lucas ������������������������������������� Employee: Dexcom, Inc. Speaker’s Bureau: Boehringer Ingelheim, Eli Lilly, Bolen, Shari ������������������������������������������ Disclosed no conflict of interest. Merck Sharp & Dohme; Stock/Shareholder: RIO Bonner, Caroline ����������������������������������� Disclosed no conflict of interest. Weight Management Ltd. Borecki, Ingrid �������������������������������������� Disclosed no conflict of interest. Cappell, Katherine ������������������������������� Employee: Truven Health Analytics. Borowiec, Maciej ��������������������������������� Disclosed no conflict of interest. Capuano, George ��������������������������������� Employee: Janssen Research & Development, LLC. Bosco, Domenico ��������������������������������� Disclosed no conflict of interest. Carbo, Adria ����������������������������������������� Disclosed no conflict of interest. Bose, Namrata ������������������������������������� Disclosed no conflict of interest. Cardamone, Maria D. ��������������������������� Disclosed no conflict of interest.

LB99 AUTHOR RELATIONSHIP/COMPANY AUTHOR RELATIONSHIP/COMPANY Cárdenas, Jose L. ��������������������������������� Disclosed no conflict of interest. Christopher, Solomon ��������������������������� Employee: EPID Research performs financially supported Cardillo, Tracy E. ����������������������������������� Employee: Eli Lilly and Company; Stock/Shareholder: Eli studies for several pharmaceutical companies Lilly and Company. including Takeda Development Centre Europe. Cargill, Robert S. ���������������������������������� Employee: Pacific Diabetes Technologies, Inc.;Stock/ Chuck, Leonard ������������������������������������� Disclosed no conflict of interest. Shareholder: Pacific Diabetes Technologies, Inc. Ciaraldi, Theodore P. ���������������������������� Consultant: Shionogi Inc. Carless, Melanie ���������������������������������� Disclosed no conflict of interest. Clargo, Alison ��������������������������������������� Employee: UCB Pharma. Carley, David W. ����������������������������������� Disclosed no conflict of interest. Claudius, Birgitte ��������������������������������� Employee: Novo Nordisk A/S; Stock/Shareholder: Novo Carls, Ginger S. ������������������������������������ Consultant: Intarcia Therapeutics, Inc. Nordisk A/S. Carmody, David ������������������������������������ Disclosed no conflict of interest. Cobos-Bravo, Juan F. ���������������������������� Disclosed no conflict of interest. Caron, Nicole ��������������������������������������� Disclosed no conflict of interest. Cochrane, Katie ������������������������������������ Disclosed no conflict of interest. Carrington, Paul ����������������������������������� Disclosed no conflict of interest. Cognard, Emmanuelle �������������������������� Disclosed no conflict of interest. Cartee, Greg ����������������������������������������� Disclosed no conflict of interest. Cohen, Neale ��������������������������������������� Disclosed no conflict of interest. Carter, Leslie ���������������������������������������� Disclosed no conflict of interest. Cohen, Ronald �������������������������������������� Disclosed no conflict of interest. Casellini, Carolina M. �������������������������� Disclosed no conflict of interest. Coletta, Dawn K. ���������������������������������� Disclosed no conflict of interest. Castle, Jessica R. ��������������������������������� Advisory Panel: Biodel Inc., Novo Nordisk Inc.; Speaker’s Colin, Laurence ������������������������������������ Employee: Novartis Pharmaceuticals Corporation. Bureau: Dexcom, Inc, Roche Diagnostics; Stock/ Collins, Francis S. ��������������������������������� Disclosed no conflict of interest. Shareholder: Pacific Diabetes Technologies. Collins, Stephen J. ������������������������������� Disclosed no conflict of interest. Catalano, Patrick M. ���������������������������� Disclosed no conflict of interest. Colman, Peter ��������������������������������������� Disclosed no conflict of interest. Cavalcante, Lilian L.A. ������������������������� Disclosed no conflict of interest. Colman, Ricki J. ����������������������������������� Disclosed no conflict of interest. Cederquist, Carly T. ������������������������������ Disclosed no conflict of interest. Comstock, Dawn ���������������������������������� Disclosed no conflict of interest. Cefalu, William T. ��������������������������������� Disclosed no conflict of interest. Comte-Perret, Sophie ��������������������������� Disclosed no conflict of interest. Cero, Cheryl ������������������������������������������ Disclosed no conflict of interest. Condon, John ��������������������������������������� Disclosed no conflict of interest. Cha, Dae Ryong ������������������������������������ Disclosed no conflict of interest. Conley, John ����������������������������������������� Stock/Shareholder: Pacific Diabetes Technologies, Inc. Cha, Ji-Young ��������������������������������������� Disclosed no conflict of interest. Consani, Cristina ���������������������������������� Disclosed no conflict of interest. Chabtini, Lola ��������������������������������������� Disclosed no conflict of interest. Constable, R. Todd ������������������������������� Disclosed no conflict of interest. Chacra, Antonio ����������������������������������� Disclosed no conflict of interest. Conway, Baqiyyah �������������������������������� Disclosed no conflict of interest. Chae, Yu Na ������������������������������������������ Disclosed no conflict of interest. Cooper, Julian �������������������������������������� Disclosed no conflict of interest. Chakrabarti, Amitava ��������������������������� Disclosed no conflict of interest. Cooper, Marcus ������������������������������������ Disclosed no conflict of interest. Chamberlain, James J. ������������������������ Speaker’s Bureau: AstraZeneca, Bristol-Myers Squibb, Corkey, Barbara E. �������������������������������� Disclosed no conflict of interest. Janssen Pharmaceutical Companies of Johnson & Corkill, Holly ����������������������������������������� Disclosed no conflict of interest. Johnson, Sanofi U.S. Corvera, Silvia �������������������������������������� Disclosed no conflict of interest. Champagne, Catherine M. ������������������� Disclosed no conflict of interest. Costacou, Tina �������������������������������������� Disclosed no conflict of interest. Chan, Lawrence C.B. ���������������������������� Disclosed no conflict of interest. Coster, Adelle C.F. �������������������������������� Disclosed no conflict of interest. Chan, You-Ping ������������������������������������� Disclosed no conflict of interest. Covington-Kolb, Sarah ������������������������� Disclosed no conflict of interest.

AUTHOR D I SCLOSURE Chane-Woon-Ming, Béatrice ��������������� Disclosed no conflict of interest. Cox, Nancy J. ��������������������������������������� Disclosed no conflict of interest. Chang, Evan ����������������������������������������� Disclosed no conflict of interest. Craig, Jagriti ���������������������������������������� Employee: Janssen Research & Development, LLC. Chang, Hsiang-Chun ���������������������������� Disclosed no conflict of interest. Craig, Maria ����������������������������������������� Disclosed no conflict of interest. Chapel, Sunny �������������������������������������� Disclosed no conflict of interest. Crandall, Jill ����������������������������������������� Disclosed no conflict of interest. Charles, Rene ��������������������������������������� Disclosed no conflict of interest. Croker, Helen ���������������������������������������� Disclosed no conflict of interest. Chatterjee, Tapan K. ����������������������������� Disclosed no conflict of interest. Cromack, Douglas T. ����������������������������� Disclosed no conflict of interest. Chattopadhyay, Munmun ��������������������� Disclosed no conflict of interest. Crowe, Matthew J. ������������������������������ Disclosed no conflict of interest. Chaudhuri, Ajay ������������������������������������ Disclosed no conflict of interest. Cudejko, Céline ������������������������������������ Disclosed no conflict of interest. Chaudhuri, Rima ����������������������������������� Disclosed no conflict of interest. Cuezva, Jose M. ����������������������������������� Disclosed no conflict of interest. Chen, Chi ���������������������������������������������� Disclosed no conflict of interest. Cui, Xin ������������������������������������������������� Disclosed no conflict of interest. Chen, Hong-Chi ������������������������������������ Disclosed no conflict of interest. Cunnick, Jess M. ���������������������������������� Disclosed no conflict of interest. Chen, Huntga ��������������������������������������� Employee: AstraZeneca Pharmaceuticals LP. Cupples, L. Adrienne ���������������������������� Disclosed no conflict of interest. Chen, Lei ���������������������������������������������� Employee: Merck & Co., Inc. Curie, Justin ����������������������������������������� Disclosed no conflict of interest. Chen, Liwei ������������������������������������������ Disclosed no conflict of interest. Curran, Joanne E. ��������������������������������� Disclosed no conflict of interest. Chen, Lulu �������������������������������������������� Disclosed no conflict of interest. Cutarelli, Alessandro ��������������������������� Disclosed no conflict of interest. Chen, Yanfang �������������������������������������� Disclosed no conflict of interest. Dabelea, Dana ������������������������������������� Disclosed no conflict of interest. Chen, Yi ������������������������������������������������ Disclosed no conflict of interest. Dabra, Shakun �������������������������������������� Disclosed no conflict of interest. Chen, Yidong ���������������������������������������� Disclosed no conflict of interest. Dagogo-Jack, Samuel �������������������������� Consultant: Boehringer Ingelheim Pharmaceuticals, Chen, Yimei ������������������������������������������ Disclosed no conflict of interest. Inc., Merck & Co.,Inc., Novo Nordisk Inc.; Research Chen, Yingchao ������������������������������������ Disclosed no conflict of interest. Support: AstraZeneca, Boehringer Ingelheim GmbH, Cheng Lee Ping, Peter �������������������������� Disclosed no conflict of interest. Bristol-Myers Squibb, Novo Nordisk Inc. Cheng, Xiaodong ���������������������������������� Disclosed no conflict of interest. Dai, Feihan F. ���������������������������������������� Disclosed no conflict of interest. Cheong, Ye-Hwang ������������������������������ Disclosed no conflict of interest. Dai, Hongji ������������������������������������������� Disclosed no conflict of interest. Chepurny, Oleg G. �������������������������������� Disclosed no conflict of interest. Dandona, Paresh ���������������������������������� Disclosed no conflict of interest. Chernausek, Steven ����������������������������� Disclosed no conflict of interest. Dangott, Bryan J. ��������������������������������� Disclosed no conflict of interest. Cherñavvsky, Daniel ����������������������������� Research Support: Dexcom, Inc. Dasari, Paul S. �������������������������������������� Disclosed no conflict of interest. Chevalier, Soazig ���������������������������������� Employee: Sanofi;Stock/Shareholder: Sanofi. Davenport, Bennett J. �������������������������� Disclosed no conflict of interest. Chhabra, Mohinish ������������������������������� Disclosed no conflict of interest. Davidson, Jaime A. ������������������������������ Disclosed no conflict of interest. Chin, Alex J. ����������������������������������������� Employee: AstraZeneca Pharmaceuticals LP, self. Davies, Melanie ����������������������������������� Advisory Panel: AstraZeneca Pharmaceuticals LP, Chinchwadkar, Manoj �������������������������� Disclosed no conflict of interest. Boehringer Ingelheim GmbH, Eli Lilly and Company, Chines, Peter ���������������������������������������� Disclosed no conflict of interest. Janssen Research & Development LLC, Merck Sharp Chisholm, Don J. ���������������������������������� Disclosed no conflict of interest. & Dohme, Novo Nordisk A/S, Sanofi U.S.;Consultant: Cho, Yoon Hi ����������������������������������������� Disclosed no conflict of interest. AstraZeneca Pharmaceuticals LP, Boehringer Cho, Youngjin ��������������������������������������� Disclosed no conflict of interest. Ingelheim GmbH, Eli Lilly and Company, Janssen Chodavarapu, Praneeta ������������������������ Disclosed no conflict of interest. Research & Development LLC, Merck Sharp & Dohme, Choe, Gina �������������������������������������������� Disclosed no conflict of interest. Novo Nordisk A/S, Sanofi U.S;Research Support: Eli Choi, Dong Seop ���������������������������������� Disclosed no conflict of interest. Lilly and Company, Novo Nordisk A/S, Sanofi U.S.; Choi, In Young �������������������������������������� Disclosed no conflict of interest. Speaker’s Bureau: AstraZeneca Pharmaceuticals LP, Choi, Kyung Mook �������������������������������� Disclosed no conflict of interest. Boehringer Ingelheim GmbH, Eli Lilly and Company, Choi, Seul Min ������������������������������������� Disclosed no conflict of interest. Janssen Research & Development LLC, Merck Sharp Choi, Siak Leng ������������������������������������ Employee: Eli Lilly and Company. & Dohme, Mitsubishi Tanabe Pharma Corporation., Choi, Soomin ���������������������������������������� Disclosed no conflict of interest. Novo Nordisk A/S, Sanofi U.S. Chorev, Michael ����������������������������������� Stock/Shareholder: Mellitus, LLC. Davis, Lori �������������������������������������������� Disclosed no conflict of interest. Christensen, Mette M.H. ��������������������� Disclosed no conflict of interest. Davis, Timothy M.E. ����������������������������� Advisory Panel: Merck Sharp & Dohme, Novo Nordisk Christensen, Mikkel ����������������������������� Disclosed no conflict of interest. A/S; Research Support: Merck Sharp & Dohme, Novo Christiansen, Claus ������������������������������ Stock/Shareholder: Nordic Bioscience. Nordisk A/S, Sanofi U.S., Takeda Pharmaceutical Christie, Michael R. ����������������������������� Disclosed no conflict of interest. Company Limited; Speaker’s Bureau: AstraZeneca, Christofori, Gerhard ����������������������������� Disclosed no conflict of interest. Boehringer Ingelheim GmbH, Bristol-Myers Squibb, Eli Christopher, Michael J. ������������������������ Disclosed no conflict of interest. Lilly and Company, Janssen Pharmaceutical Companies

LB100 AUTHOR RELATIONSHIP/COMPANY AUTHOR RELATIONSHIP/COMPANY of Johnson & Johnson, Merck Sharp & Dohme, Edwards, Josh �������������������������������������� Disclosed no conflict of interest. Novartis Pharmaceuticals Corporation, Novo Nordisk Edwards, Todd L. ���������������������������������� Disclosed no conflict of interest. A/S, Takeda Pharmaceutical Company Limited. Efstratiou, Efthimia ������������������������������ Disclosed no conflict of interest. Davis, Wendy A. ����������������������������������� Advisory Panel: Merck Sharp & Dohme, Novo Nordisk Eglinger, Jan ����������������������������������������� Disclosed no conflict of interest. A/S; Research Support: Merck Sharp & Dohme, Novo Eguchi, Jun ������������������������������������������� Disclosed no conflict of interest. Nordisk A/S, Sanofi U.S., Takeda Pharmaceutical Ehrich, Marion �������������������������������������� Disclosed no conflict of interest. Company Limited; Speaker’s Bureau: AstraZeneca, Eichner, Norbert ����������������������������������� Disclosed no conflict of interest. Boehringer Ingelheim GmbH, Bristol-Myers Squibb, Ekhlaspour, Laya ����������������������������������� Disclosed no conflict of interest. Eli Lilly and Company, Janssen Pharmaceutical El Khatib, Moustafa ����������������������������� Disclosed no conflict of interest. Companies of Johnson & Johnson, Merck Sharp El Ouaamari, Abdelfattah �������������������� Disclosed no conflict of interest. & Dohme, Novartis Pharmaceuticals Corporation, El Youssef, Joseph ������������������������������� Disclosed no conflict of interest. Novo Nordisk A/S, Takeda Pharmaceutical Company Eliasson, Lena �������������������������������������� Disclosed no conflict of interest. Limited. Elks, Carrie M. �������������������������������������� Disclosed no conflict of interest. Davis-Ajami, Mary L. ��������������������������� Disclosed no conflict of interest. Elsasser, Ulrich ������������������������������������� Employee: Boehringer Ingelheim GmbH. Davis-Richardson, Austin G. ���������������� Disclosed no conflict of interest. El-Shahawy, Mohamed ������������������������ Advisory Panel: ZS Pharma, Inc.; Research Support: Day, Samantha E. ��������������������������������� Disclosed no conflict of interest. Amgen Inc., Celgene Corporation, GlaxoSmithKline, De Filippis, Elena A. ����������������������������� Disclosed no conflict of interest. Sandoz, Inc., Takeda Pharmaceuticals U.S.A., Inc., ZS De Souza, Errol ������������������������������������� Board Member: Biodel Inc.; Employee: Biodel Inc.; Stock/ Pharma, Inc. Shareholder: Biodel Inc. Elston Lafata, Jennifer ������������������������� Disclosed no conflict of interest. de Toro-Martín, Juan ��������������������������� Disclosed no conflict of interest. Erdos, Michael ������������������������������������� Disclosed no conflict of interest. De Vito, Katerina M. ���������������������������� Disclosed no conflict of interest. Eringa, Etto C. �������������������������������������� Disclosed no conflict of interest. Deacon, Carolyn ����������������������������������� Advisory Panel: Bristol-Myers Squibb Company, Takeda Erion, Karel A. �������������������������������������� Disclosed no conflict of interest. Pharmaceutical Company Limited; Other Relationship: Escrivá-Pons, Fernando ������������������������ Disclosed no conflict of interest. Merck Sharp & Dohme, Prosidion. Esko, Tonu �������������������������������������������� Disclosed no conflict of interest. Deeg, Mark A. �������������������������������������� Employee: Eli Lilly and Company; Stock/Shareholder: Eli Estall, Jennifer L. ��������������������������������� Disclosed no conflict of interest. Lilly and Company. Etwebi, Zienab A. ��������������������������������� Disclosed no conflict of interest. Deeney, Jude T. ������������������������������������ Disclosed no conflict of interest. Evans-Molina, Carmella ����������������������� Disclosed no conflict of interest. DeFronzo, Ralph A. ������������������������������� Disclosed no conflict of interest. Eze, Ikenna C. ��������������������������������������� Disclosed no conflict of interest. Dehennis, Andrew D. ��������������������������� Disclosed no conflict of interest. Fain, Randi ������������������������������������������� Employee: Eisai Inc. DeJesus, Adam ������������������������������������ Disclosed no conflict of interest. Fall, Caroline ���������������������������������������� Disclosed no conflict of interest. Del Gaudio, Daniela ����������������������������� Disclosed no conflict of interest. Fang, Han ��������������������������������������������� Disclosed no conflict of interest. Del Prato, Stefano �������������������������������� Disclosed no conflict of interest. Farabi, Sarah S. ������������������������������������ Disclosed no conflict of interest. Delalleau, Nathalie ������������������������������ Disclosed no conflict of interest. Farook, Vidya S. ������������������������������������ Disclosed no conflict of interest. Della Bartola, Luca ������������������������������� Disclosed no conflict of interest. Federici, Adalberto ������������������������������� Disclosed no conflict of interest.

Delpire, Eric ������������������������������������������ Disclosed no conflict of interest. Federici, Giovanni �������������������������������� Disclosed no conflict of interest. AUTHOR D I SCLOSURE DeMarco, Vincent �������������������������������� Disclosed no conflict of interest. Feferman, Leo �������������������������������������� Disclosed no conflict of interest. Demirpence, Mustafa �������������������������� Disclosed no conflict of interest. Feltbower, Richard ������������������������������� Disclosed no conflict of interest. Demirpence, Nur ���������������������������������� Disclosed no conflict of interest. Feng, Bin ���������������������������������������������� Disclosed no conflict of interest. Dempsey, Paddy C. ������������������������������� Disclosed no conflict of interest. Feng, Yue ���������������������������������������������� Employee: Merck & Co., Inc. D’Eon, Stephanie ��������������������������������� Disclosed no conflict of interest. Fenske, Rachel ������������������������������������� Disclosed no conflict of interest. DeSalvo, Daniel J. ������������������������������� Disclosed no conflict of interest. Fenwick, Eva K. ������������������������������������ Disclosed no conflict of interest. Dibner, Charna �������������������������������������� Disclosed no conflict of interest. Ferguson-Smith, Anne ������������������������� Disclosed no conflict of interest. DiMeglio, Linda A. ������������������������������� Disclosed no conflict of interest. Fernández-Millán, Elisa ����������������������� Disclosed no conflict of interest. Ding, Eric L. ������������������������������������������ Disclosed no conflict of interest. Ferron, Mathieu ����������������������������������� Disclosed no conflict of interest. Dion, Stacy ������������������������������������������� Disclosed no conflict of interest. Fiad, Tarek M. ��������������������������������������� Disclosed no conflict of interest. Distelmaier, Klaus �������������������������������� Disclosed no conflict of interest. Figarola, James L. �������������������������������� Disclosed no conflict of interest. Divoux, Adeline ������������������������������������ Disclosed no conflict of interest. Fink, Jeffrey C. ������������������������������������� Disclosed no conflict of interest. Do Bem, Daniela Amg �������������������������� Disclosed no conflict of interest. Finlin, Brian S. �������������������������������������� Disclosed no conflict of interest. Dobkin, Julie ���������������������������������������� Disclosed no conflict of interest. Fiorina, Paolo ��������������������������������������� Disclosed no conflict of interest. Dolin, Paul �������������������������������������������� Employee: Takeda Development Centre Europe. Fischer, Annelie ������������������������������������ Disclosed no conflict of interest. Donaghue, Kim C. �������������������������������� Disclosed no conflict of interest. Fish, Lisa ���������������������������������������������� Research Support: Eli Lilly and Company. Donaldson, Julie ���������������������������������� Disclosed no conflict of interest. Fishbane, Steven N. ����������������������������� Advisory Panel: ZS Pharma, Inc.; Research Support: ZS Dong, Ying �������������������������������������������� Disclosed no conflict of interest. Pharma, Inc. Donnelly, Conor Brian �������������������������� Disclosed no conflict of interest. Fitch, Mark ������������������������������������������� Disclosed no conflict of interest. Dopita, Dana ���������������������������������������� Other Relationship: Animas Corporation, Insulet Fitzgibbons, Timothy ���������������������������� Disclosed no conflict of interest. Corporation, Medtronic MiniMed, Inc., Tandem Flannery, Clare A. ��������������������������������� Disclosed no conflict of interest. Diabetes Care, Inc. Flynn, Angela C. ����������������������������������� Disclosed no conflict of interest. Dorchy, Harry R. ����������������������������������� Disclosed no conflict of interest. Fodor, William �������������������������������������� Disclosed no conflict of interest. Down, Susan ���������������������������������������� Advisory Panel: Abbott, Astra Zeneca, Boehringer Fogelfeld, Leon ������������������������������������� Research Support: AstraZeneca Pharmaceuticals LP, Bayer Ingelheim, Bristol-Myers Squibb, Eli Lilly, Novo HealthCare, Boehringer Ingelheim Pharmaceuticals, Nordisk, Johnson and Johnson, Sanofi;Board Inc., Bristol-Myers Squibb Company, Calibra, Member: Forum for Injection Technique; Speaker’s Genkyotex, GlaxoSmithKline, Grifols USA, LLC, Merck Bureau: OmniaMed, SB Communications. & Co., Inc., Sanofi U.S. Doyle, Carl �������������������������������������������� Employee: UCB Pharma. Forisch, Michael ����������������������������������� Disclosed no conflict of interest. Dragsbæk, Katrine ������������������������������� Disclosed no conflict of interest. Formentini, Laura ��������������������������������� Disclosed no conflict of interest. Drucker, Daniel J. ��������������������������������� Disclosed no conflict of interest. Fourcaudot, Marcel ������������������������������ Disclosed no conflict of interest. Duffin, Kevin L. ������������������������������������� Employee: Eli Lilly and Company; Stock/Shareholder: Eli Fowler, Robert �������������������������������������� Employee: Truven Health Analytics. Lilly and Company. Fox, Caroline S. ������������������������������������ Disclosed no conflict of interest. Duggirala, Ravindranath ���������������������� Disclosed no conflict of interest. Frank, Claudio �������������������������������������� Disclosed no conflict of interest. Dumenci, Levent ���������������������������������� Disclosed no conflict of interest. Franks, Paul W. ������������������������������������ Disclosed no conflict of interest. Dunstan, David ������������������������������������� Disclosed no conflict of interest. Franz, Wolfgang-Michael ��������������������� Speaker’s Bureau: MSD. Duris, Christine ������������������������������������ Disclosed no conflict of interest. Fraser, Ian ��������������������������������������������� Disclosed no conflict of interest. Dushay, Jody ���������������������������������������� Advisory Panel: Janssen Pharmaceutical Companies of Frayling, Timothy M. ���������������������������� Disclosed no conflict of interest. Johnson & Johnson. Frenkel, Dan ����������������������������������������� Disclosed no conflict of interest. Dutta, Pinaki ����������������������������������������� Disclosed no conflict of interest. Friedländer, Marc ��������������������������������� Disclosed no conflict of interest. Dutta, Sucharita ����������������������������������� Disclosed no conflict of interest. Frois, Christian ������������������������������������� Consultant: Intarcia Therapeutics, Inc. Duvvuru, Suman ����������������������������������� Employee: Eli Lilly and Company. Frokiaer, Jørgen ������������������������������������ Disclosed no conflict of interest. Dyer, Thomas D. ����������������������������������� Disclosed no conflict of interest. Fryburg, David A. ���������������������������������� Stock/Shareholder: Pfizer Inc. Dziadowicz, Helena M. ������������������������ Disclosed no conflict of interest. Fu, Alex Z. �������������������������������������������� Consultant: Truven Health Analytics, AstraZeneca. Eberhard, Daniel ���������������������������������� Disclosed no conflict of interest. Fu, Lizhi ������������������������������������������������ Disclosed no conflict of interest. Eckel, Juergen �������������������������������������� Research Support: Sanofi-Aventis Deutschland GmbH. Fu, Yanyun �������������������������������������������� Disclosed no conflict of interest. Edelman, Steven ���������������������������������� Advisory Panel: Boehringer Ingelheim, Eli Lilly; Speaker’s Fuentes, Blanca ������������������������������������ Disclosed no conflict of interest. Bureau: Boehringer Ingelheim, EIi Lilly. Fukuda, Takuya ������������������������������������� Disclosed no conflict of interest.

LB101 AUTHOR RELATIONSHIP/COMPANY AUTHOR RELATIONSHIP/COMPANY Fukui, Michiaki ������������������������������������� Disclosed no conflict of interest. Greulich, Sabrina ��������������������������������� Disclosed no conflict of interest. Fung, Anne ������������������������������������������� Employee: Genentech, Inc. Griffith, Julie ���������������������������������������� Disclosed no conflict of interest. Fusong, Jiang ��������������������������������������� Disclosed no conflict of interest. Grohmann-Izay, Barbara J. ������������������� Disclosed no conflict of interest. Gaglia, Jason L. ����������������������������������� Disclosed no conflict of interest. Groh-Wargo, Sharon ���������������������������� Disclosed no conflict of interest. Galli-Tsinopoulou, Assimina ���������������� Disclosed no conflict of interest. Grosman, Benyamin ����������������������������� Employee: Medtronic MiniMed, Inc. Gamerman, Victoria ����������������������������� Employee: Boehringer Ingelheim Pharmaceuticals Inc. Gross, Myron ���������������������������������������� Disclosed no conflict of interest. Gandomani, Ben S. ������������������������������ Disclosed no conflict of interest. Guan, Hong-Ping ���������������������������������� Disclosed no conflict of interest. Gandour, Richard ���������������������������������� Disclosed no conflict of interest. Guan, Meiping ������������������������������������� Disclosed no conflict of interest. Gang, Xiaokun �������������������������������������� Disclosed no conflict of interest. Gudiksen, Anders ��������������������������������� Disclosed no conflict of interest. Gannon, Maureen A. ���������������������������� Disclosed no conflict of interest. Guerci, Bruno ��������������������������������������� Advisory Panel: Abbott, Boehringer Ingelheim, Eli Lilly, Garcia Fuentes, Eduardo ���������������������� Disclosed no conflict of interest. Novartis; Board Member: AstraZeneca, Bristol-Myers Garcia, Arturo ��������������������������������������� Employee: Dexcom, Inc. Squibb, GlaxoSmithKline, Novo Nordisk, Roche Garcia-Arnes, Juan ������������������������������ Disclosed no conflict of interest. Diagnostic, Sanofi;Research Support: Dinno Santé, Garcia-Escobar, Eva ������������������������������ Disclosed no conflict of interest. Eli Lilly, Medtronic, MSD, Novartis, Novo Nordisk, Garcia-Sanchez, Ricardo ���������������������� Employee: AstraZeneca Pharmaceuticals LP, self. Janssen, Johnson & Johnson, Sanofi, Vitalaire. Garcia-Serrano, Sara ��������������������������� Disclosed no conflict of interest. Guertin, David A. ���������������������������������� Disclosed no conflict of interest. Garg, Satish K. ������������������������������������� Consultant: Medtronic, Inc., Eli Lilly and Company, Guhl, Anna ������������������������������������������� Disclosed no conflict of interest. Roche USA, Sanofi U.S.;Research Support: Eli Lilly Guimaraes, Sergio B. ��������������������������� Disclosed no conflict of interest. and Company, Halozyme Therapeutics, Lexicon Gune, Shamika ������������������������������������� Employee: Genentech, Inc. Pharmaceuticals, Inc., MannKind Corporation, Merck Guo, Hui ����������������������������������������������� Disclosed no conflict of interest. & Co., Inc., Novo Nordisk Inc., Sanofi U.S. Guo, Xiaohui ����������������������������������������� Disclosed no conflict of interest. Garhyan, Parag ������������������������������������� Employee: Eli Lilly and Company; Stock/Shareholder: Eli Gutierrez, Absalon ������������������������������� Disclosed no conflict of interest. Lilly and Company, Eli Lilly and Company. Gutierrez-Repiso, Carolina ������������������� Disclosed no conflict of interest. Garlish, Rachel ������������������������������������� Employee: UCB Pharma. Ha, Kyoung Soo ������������������������������������ Disclosed no conflict of interest. Gaziano, J. Michael ����������������������������� Research Support: Pfizer Inc. Haas, Joseph V. ������������������������������������ Employee: Eli Lilly and Company; Stock/Shareholder: Eli Gebauer, Mathias ��������������������������������� Employee: Sanofi U.S.;Stock/Shareholder: Sanofi U.S. Lilly and Company. Gee, Kyuhoon ��������������������������������������� Disclosed no conflict of interest. Haas, Mary ������������������������������������������� Disclosed no conflict of interest. Genieser, Hans-G ��������������������������������� Disclosed no conflict of interest. Hackett, Geoffrey I. ������������������������������ Research Support: Bayer HealthCare, Bayer. Genovese, Maria Ines �������������������������� Disclosed no conflict of interest. Hadjadj, Samy �������������������������������������� Board Member: AstraZeneca, Bristol-Myers Squibb, Genter, Pauline ������������������������������������� Disclosed no conflict of interest. Sanofi U.S.;Consultant: AstraZeneca, Boehringer Gentile, Sandro ������������������������������������ Board Member: Sanofi;Consultant: Roche Diagnostics. Ingelheim GmbH, Bristol-Myers Squibb, Eli Lilly and Gerbase, Margaret ������������������������������� Disclosed no conflict of interest. Company, Novo Nordisk Inc., Sanofi U.S., Servier; Geyer, Susan ���������������������������������������� Disclosed no conflict of interest. Speaker’s Bureau: AstraZeneca, Boehringer Ingelheim Ghanian, Sheila ������������������������������������ Disclosed no conflict of interest. GmbH, Bristol-Myers Squibb, Eli Lilly and Company,

AUTHOR D I SCLOSURE Ghanim, Husam ������������������������������������ Disclosed no conflict of interest. Novo Nordisk Inc., Servier. Ghannam, Ameen �������������������������������� Employee: AstraZeneca Pharmaceuticals LP. Hage, Camilla ��������������������������������������� Disclosed no conflict of interest. Ghorbani, Tahereh �������������������������������� Disclosed no conflict of interest. Haghiac, Maricela �������������������������������� Disclosed no conflict of interest. Ghosh, Pamela ������������������������������������� Disclosed no conflict of interest. Hagopian, William A. ��������������������������� Disclosed no conflict of interest. Ghosh, Sujoy ���������������������������������������� Advisory Panel: Zydus Cadila. Hailu, Hanna ���������������������������������������� Employee: UCB Pharma. Giacaglia, Luciano �������������������������������� Disclosed no conflict of interest. Halder, Louise ��������������������������������������� Disclosed no conflict of interest. Giampietro, Ottavio ������������������������������ Disclosed no conflict of interest. Hall, Christopher E. ������������������������������ Disclosed no conflict of interest. Gilbert, Matthew ��������������������������������� Disclosed no conflict of interest. Hall, Keneth ����������������������������������������� Disclosed no conflict of interest. Gilgen, Emily ���������������������������������������� Other Relationship: Animas Corporation, Asante Hallmans, Göran ���������������������������������� Disclosed no conflict of interest. Solutions, Inc., Insulet Corporation, Medtronic Halperin, Jose �������������������������������������� Stock/Shareholder: Mellitus, LLC. MiniMed, Inc., Roche Diagnostics, Tandem Diabetes Han, Bing ���������������������������������������������� Disclosed no conflict of interest. Care, Inc. Han, Byoung Geun ������������������������������� Disclosed no conflict of interest. Giovenale, Sharon �������������������������������� Disclosed no conflict of interest. Han, Jing ���������������������������������������������� Disclosed no conflict of interest. Glicklich, Alan �������������������������������������� Employee: Arena. Han, Kyung Ah ������������������������������������� Disclosed no conflict of interest. Glynn, Robert J. ����������������������������������� Disclosed no conflict of interest. Han, OakPil ������������������������������������������� Disclosed no conflict of interest. Gmyr, Valéry ����������������������������������������� Disclosed no conflict of interest. Han, Sang Youb ������������������������������������ Disclosed no conflict of interest. Gnys, Piotr �������������������������������������������� Disclosed no conflict of interest. Han, Weiping ��������������������������������������� Disclosed no conflict of interest. Godfrey, Keith M. ��������������������������������� Research Support: Abbott Nutrition, Danone, Inc., Nestec. Han, Xinping ����������������������������������������� Disclosed no conflict of interest. Goldberg, Ronald ��������������������������������� Disclosed no conflict of interest. Hanas, Ragnar �������������������������������������� Advisory Panel: Abbott, Lillly; Consultant: BMC, Gomez, Ana Maria ������������������������������� Research Support: Novartis Pharmaceuticals Corporation; Medtronic, NovoNordisk; Speaker’s Bureau: Abbott, Speaker’s Bureau: AstraZeneca, Bristol-Myers Squibb, Menarini, Roche. Eli Lilly and Company, Medtronic MiniMed, Inc., Novo Hanefeld, Markolf �������������������������������� Advisory Panel: Bristol-Myers Squibb Company, Nordisk Inc. GlaxoSmithKline, Sanofi, Takeda Pharmaceuticals Gomez-Perez, Francisco J. ������������������� Disclosed no conflict of interest. USA, Inc.; Speaker’s Bureau: Bayer HealthCare Gonçalves, Gabriel H.M. ���������������������� Disclosed no conflict of interest. LLC, Eli Lilly and Company, GlaxoSmithKline, Roche Gonçalves, Nadmy A.Z. ������������������������ Disclosed no conflict of interest. Pharmaceuticals, Sanofi, Takeda Pharmaceuticals Gonçalves, Rita de Cássia R. ��������������� Disclosed no conflict of interest. USA, Inc. Gonzalez, Noemi ���������������������������������� Disclosed no conflict of interest. Hanis, Craig L. �������������������������������������� Disclosed no conflict of interest. González-Ortiz, Manuel ������������������������ Disclosed no conflict of interest. Hanna, Paul ������������������������������������������ Disclosed no conflict of interest. Gonzalo, Montserrat ���������������������������� Disclosed no conflict of interest. Hannpu, Sarah ������������������������������������� Disclosed no conflict of interest. Gopala, Aralakuppe S. ������������������������� Disclosed no conflict of interest. Hanseman, Dennis ������������������������������� Disclosed no conflict of interest. Gordon, Tom ����������������������������������������� Disclosed no conflict of interest. Hansen, Lærke S. ��������������������������������� Disclosed no conflict of interest. Gorgel, Ahmet �������������������������������������� Disclosed no conflict of interest. Hansen, Lars ���������������������������������������� Employee: Bristol-Myers Squibb Company, self. Göring, Harald H. ��������������������������������� Disclosed no conflict of interest. Hansen, Mads Bau ������������������������������� Disclosed no conflict of interest. Gormsen, Lars C. ���������������������������������� Disclosed no conflict of interest. Hansen, Troels K. ��������������������������������� Disclosed no conflict of interest. Gottlieb, Peter A. ��������������������������������� Disclosed no conflict of interest. Hansraj, Patil A. ����������������������������������� Disclosed no conflict of interest. Gottlieb, Rebecca ��������������������������������� Employee: Medtronic MiniMed, Inc.; Stock/Shareholder: Hantel, Stefan �������������������������������������� Employee: Boehringer Ingelheim GmbH. Medtronic, Inc. Hao, Gaimei ����������������������������������������� Disclosed no conflict of interest. Gowtham, Raj �������������������������������������� Disclosed no conflict of interest. Hao, Pindan ������������������������������������������ Disclosed no conflict of interest. Grabmaier, Ulrich ��������������������������������� Disclosed no conflict of interest. Hara, Takuya ����������������������������������������� Employee: Kowa Pharmaceuticals. Grady, Mike ������������������������������������������ Employee: LifeScan, Inc. Hardy, Thomas A. ��������������������������������� Employee: Eli Lilly and Company; Stock/Shareholder: Eli Graff, Emily C. �������������������������������������� Disclosed no conflict of interest. Lilly and Company. Graff, Marielisa ������������������������������������ Disclosed no conflict of interest. Häring, Hans-Ulrich ������������������������������ Disclosed no conflict of interest. Graff, Misa ������������������������������������������� Disclosed no conflict of interest. Harris, Stuart ���������������������������������������� Disclosed no conflict of interest. Grarup, Niels ���������������������������������������� Disclosed no conflict of interest. Harrison, Lindsay ��������������������������������� Disclosed no conflict of interest. Greeley, Siri Atma W. �������������������������� Disclosed no conflict of interest. Harsha, Krishna Reddy ������������������������� Disclosed no conflict of interest. Greenbaum, Carla J. ���������������������������� Disclosed no conflict of interest. Hartig, Sean M. ������������������������������������ Disclosed no conflict of interest. Greenfield, Jerry R. ������������������������������ Disclosed no conflict of interest. Hartmann, Bolette �������������������������������� Disclosed no conflict of interest. Greenway, Frank ���������������������������������� Disclosed no conflict of interest. Hartmann, Thorsten ����������������������������� Disclosed no conflict of interest.

LB102 AUTHOR RELATIONSHIP/COMPANY AUTHOR RELATIONSHIP/COMPANY Hastings, Stephanie M. ����������������������� Disclosed no conflict of interest. Horne, David ���������������������������������������� Disclosed no conflict of interest. Hauguel-de Mouzon, Sylvie ����������������� Disclosed no conflict of interest. Horsburgh, Jodie C. ����������������������������� Disclosed no conflict of interest. Hausser, Jean ��������������������������������������� Disclosed no conflict of interest. Horton, Edward S. �������������������������������� Disclosed no conflict of interest. Haw, J. Sonya �������������������������������������� Disclosed no conflict of interest. Hoshina, Sari ���������������������������������������� Disclosed no conflict of interest. Hayden, Melvin ������������������������������������ Disclosed no conflict of interest. Hota, Debasish ������������������������������������� Disclosed no conflict of interest. Hayek, Salim S. ������������������������������������ Disclosed no conflict of interest. Hotamisligil, Gökhan S. ����������������������� Research Support: UCB Pharma. Hayes, Louise ��������������������������������������� Disclosed no conflict of interest. Hoti, Fabian ������������������������������������������ Employee: EPID Research performs financially supported Hazra, Daya K. �������������������������������������� Advisory Panel: USV. studies for several pharmaceutical companies He, Jie �������������������������������������������������� Disclosed no conflict of interest. including Takeda Development Centre Europe. He, Ling ������������������������������������������������ Disclosed no conflict of interest. Hou, Liqiong ����������������������������������������� Disclosed no conflict of interest. He, Qin ������������������������������������������������� Disclosed no conflict of interest. Houweling, Leanne ������������������������������ Employee: Takeda Development Centre Europe. He, Yan Ling ����������������������������������������� Employee: Novartis Pharmaceuticals Corporation. Howard, Andrew ���������������������������������� Employee: Merck & Co., Inc. Heard-Costa, Nancy L. ������������������������� Disclosed no conflict of interest. Howells, Louise ������������������������������������ Employee: UCB Pharma. Heberlein, Emily ����������������������������������� Disclosed no conflict of interest. Hsia, Daniel S. ������������������������������������� Disclosed no conflict of interest. Heier, Jeffrey S. ����������������������������������� Consultant: Aerpio, Allergan, Inc., Genentech, Inc., Hsiao, Jong-Kai ������������������������������������ Disclosed no conflict of interest. Kala Pharmaceuticals, Regeneron Pharmaceuticals, Hsu, Chi-Yuan ��������������������������������������� Disclosed no conflict of interest. Inc.; Research Support: Genentech, Inc., Kala Hu He, Kaihui ��������������������������������������� Disclosed no conflict of interest. Pharmaceuticals, Ophthotech, Regeneron Hu, Frank B. ������������������������������������������ Disclosed no conflict of interest. Pharmaceuticals, Inc., Stealth Biotherapeutics. Hu, Ling ������������������������������������������������ Disclosed no conflict of interest. Heinemann, Lutz ���������������������������������� Advisory Panel: Biodel Inc., Eli Lilly and Company, Hu, Shirley L. ���������������������������������������� Disclosed no conflict of interest. Halozyme Therapeutics, Novo Nordisk, Sanofi; Hu, Yanjin ��������������������������������������������� Disclosed no conflict of interest. Employee: Science & Co.; Other Relationship: Profil Hu, Ying Ying ���������������������������������������� Disclosed no conflict of interest. Institut for Clinical Research, Profil Institut für Huang, Tao ������������������������������������������� Disclosed no conflict of interest. Stoffwechselforschung. Huang, Tian Lian ���������������������������������� Disclosed no conflict of interest. Heintjes, Edith M. �������������������������������� Other Relationship: Takeda Development Centre Europe. Huang, Zhe ������������������������������������������� Disclosed no conflict of interest. Heise, Tim �������������������������������������������� Disclosed no conflict of interest. Hughes, Kristen ������������������������������������ Research Support: Medtronic MiniMed, Inc. Heizer, Patrick ��������������������������������������� Disclosed no conflict of interest. Hughes, William E. ������������������������������ Disclosed no conflict of interest. Hejna, Jeanne �������������������������������������� Disclosed no conflict of interest. Huh, Yeamin ����������������������������������������� Disclosed no conflict of interest. Heller, Simon ���������������������������������������� Advisory Panel: AstraZeneca; Consultant: Eli Lilly, Novo Hutchens, Troy �������������������������������������� Disclosed no conflict of interest. Nordisk, Takeda; Speaker’s Bureau: Boeringher Hutfless, Susan ������������������������������������ Disclosed no conflict of interest. Ingelheim, Eli Lilly, Novo Nordisk, Takeda. Huyghe, Jeroen ������������������������������������ Disclosed no conflict of interest. Hellerstein, Marc ��������������������������������� Disclosed no conflict of interest. Hwang, Janice J. ��������������������������������� Disclosed no conflict of interest. Henao, Diana ��������������������������������������� Disclosed no conflict of interest. Iacobellis, Gianluca ������������������������������ Disclosed no conflict of interest. Hendrieckx, Christel ����������������������������� Disclosed no conflict of interest. Ibrahim, Mahmoud ������������������������������� Disclosed no conflict of interest.

Henry, Robert R. ����������������������������������� Advisory Panel: Amgen Inc., AstraZeneca Pharmaceuticals Ikeda, Yasuhiro ������������������������������������� Disclosed no conflict of interest. AUTHOR D I SCLOSURE LP, Boehringer Ingelheim GmbH, Bristol-Myers Im, Hae Kyung �������������������������������������� Disclosed no conflict of interest. Squibb Company, Elcelyx Therapeutics, Inc., Gilead, Im, Kyung Ah ���������������������������������������� Disclosed no conflict of interest. Intarcia Therapeutics, Inc., Janssen Pharmaceutical Im, Seung-Soon ������������������������������������ Disclosed no conflict of interest. Companies of Johnson & Johnson, Merck & Co., Inc., Imai, Yumi ��������������������������������������������� Disclosed no conflict of interest. Novo Nordisk Inc., Sanofi U.S., Vivus Inc.;Consultant: Imboden, Medea ���������������������������������� Disclosed no conflict of interest. Alere, Boehringer Ingelheim GmbH, Clin Met, Eisai Imig, John D. ���������������������������������������� Disclosed no conflict of interest. Co., Ltd., Gilead, Intarcia Therapeutics, Inc., Isis Innes, Karen ����������������������������������������� Disclosed no conflict of interest. Pharmaceuticals, Inc., Janssen Pharmaceutical Inoue, Noriyuki ������������������������������������� Employee: Kowa Pharmaceuticals. Companies of Johnson & Johnson, Sanofi U.S.; Inouye, Karen ��������������������������������������� Disclosed no conflict of interest. Research Support: Eli Lilly and Company, Hitachi, Ioacara, Sorin ��������������������������������������� Disclosed no conflict of interest. Sanofi U.S., Viacyte. Ipp, Eli �������������������������������������������������� Research Support: Bristol-Myers Squibb Company, Herberg, Friedrich W. ��������������������������� Disclosed no conflict of interest. California Community Foundation, Novo Nordisk Inc. Herman, William H. ����������������������������� Disclosed no conflict of interest. Iqbal, Nayyar ���������������������������������������� Employee: Bristol-Myers Squibb Company. Hernández, Antonio ����������������������������� Disclosed no conflict of interest. Irving, Brian ������������������������������������������ Disclosed no conflict of interest. Herranz, Lucrecia ��������������������������������� Disclosed no conflict of interest. Itescu, Silviu ����������������������������������������� Employee: Mesoblast Inc. Herrlich, Andreas ��������������������������������� Disclosed no conflict of interest. Iwasaki, Yorihiro ���������������������������������� Disclosed no conflict of interest. Highland, Heather M. �������������������������� Disclosed no conflict of interest. Iwata, Hiroshi ��������������������������������������� Disclosed no conflict of interest. Hillard, Mallory ������������������������������������ Disclosed no conflict of interest. Iyoha, Emannuel ����������������������������������� Disclosed no conflict of interest. Hillman, Natalia ����������������������������������� Disclosed no conflict of interest. Jackson, Anne �������������������������������������� Disclosed no conflict of interest. Hingst, Janne R. ����������������������������������� Disclosed no conflict of interest. Jackson, Jeffrey A. ������������������������������ Employee: Eli Lilly and Company; Stock/Shareholder: Eli HIrate, Mitsuru ������������������������������������� Disclosed no conflict of interest. Lilly and Company. Hirschhorn, Joel N. ������������������������������ Disclosed no conflict of interest. Jackson, Michael ��������������������������������� Disclosed no conflict of interest. Hirshberg, Boaz ������������������������������������ Employee: AstraZeneca Pharmaceuticals LP. Jacober, Scott J. ���������������������������������� Employee: Eli Lilly and Company; Stock/Shareholder: Eli Hissa, Marcelo R.N. ����������������������������� Disclosed no conflict of interest. Lilly and Company. Hissa, Miguel N. ���������������������������������� Disclosed no conflict of interest. Jacobs, Peter G. ����������������������������������� Board Member: Pacific Diabetes Technologies;Research Hmaguchi, Masahide ��������������������������� Disclosed no conflict of interest. Support: National Institute of Diabetes and Digestive Hoch, Emily ������������������������������������������ Disclosed no conflict of interest. and Kidney Diseases; Stock/Shareholder: Pacific Hoevenaars, Femke M.P. ���������������������� Disclosed no conflict of interest. Diabetes Technologies. Hoffmann, Ellen ����������������������������������� Disclosed no conflict of interest. Jacobus Ambuludi, Egon J. ����������������� Disclosed no conflict of interest. Hoffmann-Petersen, Ingeborg T. ���������� Disclosed no conflict of interest. Jaffar, Amina ���������������������������������������� Disclosed no conflict of interest. Hoidal, Mallary ������������������������������������ Disclosed no conflict of interest. Jagannath, Madanahalli R. ����������������� Disclosed no conflict of interest. Holland, William ���������������������������������� Disclosed no conflict of interest. Jain, Deepak ���������������������������������������� Disclosed no conflict of interest. Holmes-Truscott, Elizabeth ������������������ Disclosed no conflict of interest. Jaiswal, Ashok D. �������������������������������� Employee: Cadila Healthcare Ltd. Holst, Jens Juul ����������������������������������� Consultant: Merck Sharp & Dohme, Novartis Jakobsen, Steen ���������������������������������� Disclosed no conflict of interest. Pharmaceuticals Corporation, Novo Nordisk A/S, Jakoby, Michael G. ������������������������������ Speaker’s Bureau: Sanofi U.S. Roche USA; Other Relationship: GlaxoSmithKline, James, David E ������������������������������������ Disclosed no conflict of interest. Merck Sharp & Dohme, Novo Nordisk A/S. Janes, Jonathan M. ����������������������������� Employee: Eli Lilly and Company; Stock/Shareholder: Eli Holt, Charlotte B. ��������������������������������� Disclosed no conflict of interest. Lilly and Company. Holz, George G. ������������������������������������ Disclosed no conflict of interest. Janka-Zires, Marcela ��������������������������� Disclosed no conflict of interest. Homann, Dirk ��������������������������������������� Disclosed no conflict of interest. Januszewski, Andrzej S. ���������������������� Disclosed no conflict of interest. Hompesch, Marcus ������������������������������ Employee: Profil Institute for Clinical Research, Inc.; Jasper, Susan ��������������������������������������� Disclosed no conflict of interest. Stock/Shareholder: Profil Institute for Clinical Jastroch, Martin ���������������������������������� Disclosed no conflict of interest. Research, Inc. Jean-Baptiste, Eddy ����������������������������� Disclosed no conflict of interest. Hong, Biling ������������������������������������������ Disclosed no conflict of interest. Jelaska, Ante ��������������������������������������� Employee: Boehringer Ingelheim Pharmaceuticals, Inc. Hong, Suntaek �������������������������������������� Disclosed no conflict of interest. Jenkins, Alicia J. ���������������������������������� Research Support: Abbott, Medtronic, Inc., Sanofi Aventis. Honig, Lee B. ���������������������������������������� Disclosed no conflict of interest. Jenkinson, Christopher P. ��������������������� Disclosed no conflict of interest. Hontecillas, Raquel ������������������������������ Disclosed no conflict of interest. Jensen, Jonas B. ���������������������������������� Disclosed no conflict of interest. Hooven, Jayde T. ���������������������������������� Disclosed no conflict of interest. Jensen, Michael D. ������������������������������ Disclosed no conflict of interest.

LB103 AUTHOR RELATIONSHIP/COMPANY AUTHOR RELATIONSHIP/COMPANY Jeon, Jae-Han �������������������������������������� Disclosed no conflict of interest. Ke, Bilun ����������������������������������������������� Disclosed no conflict of interest. Jeon, Justin Y. �������������������������������������� Disclosed no conflict of interest. Keady, Joyce ���������������������������������������� Disclosed no conflict of interest. Jeong, Kyung Hwan ����������������������������� Disclosed no conflict of interest. Keçik, Onur ������������������������������������������� Disclosed no conflict of interest. Jessen, Niels ��������������������������������������� Disclosed no conflict of interest. Keenan, Hillary A. �������������������������������� Disclosed no conflict of interest. Ji, Linong ���������������������������������������������� Consultant: Bayer HealthCare, Bristol-Myers Squibb Kefaloyianni, Eirini ������������������������������� Disclosed no conflict of interest. Company, Eli Lilly and Company, Merck & Co., Inc., Keith-Hynes, Patrick ����������������������������� Disclosed no conflict of interest. Novartis Corporation, Novo Nordisk Inc., Roche USA, Kelkar, Rohini ��������������������������������������� Disclosed no conflict of interest. Sanofi U.S.;Research Support: Roche USA, Sanofi U.S. Kelley, David E. ������������������������������������ Employee: Merck & Co., Inc. Jia, Weiping ����������������������������������������� Disclosed no conflict of interest. Kelly, Ronan P. �������������������������������������� Employee: Eli Lilly and Company; Stock/Shareholder: Eli Jiang, Hui ��������������������������������������������� Disclosed no conflict of interest. Lilly and Company. Jiang, Jenny ����������������������������������������� Disclosed no conflict of interest. Kemnitz, Joseph W. ����������������������������� Disclosed no conflict of interest. Jianjun, Liu ������������������������������������������� Disclosed no conflict of interest. Kemppainen, Kaisa M. ������������������������� Disclosed no conflict of interest. Jiao, Ping ��������������������������������������������� Disclosed no conflict of interest. Kennedy, Christopher ��������������������������� Disclosed no conflict of interest. Jin, Shi ������������������������������������������������� Disclosed no conflict of interest. Kern, Philip A. �������������������������������������� Disclosed no conflict of interest. Jo, Young-II ������������������������������������������ Disclosed no conflict of interest. Kernan, Kelly ���������������������������������������� Disclosed no conflict of interest. Joglekar, Charudatta ���������������������������� Disclosed no conflict of interest. Kerr, Peter G. ���������������������������������������� Advisory Panel: Fresenius, Amgen Inc. Johnson, Jennal L. ������������������������������� Employee: Eli Lilly and Company. Kerr-Conte, Julie ���������������������������������� Disclosed no conflict of interest. Johnson, Matthew L. ��������������������������� Disclosed no conflict of interest. Kesireddy, Veena ���������������������������������� Disclosed no conflict of interest. Johnson, William D. ���������������������������� Disclosed no conflict of interest. Khai Koon, Heng ���������������������������������� Disclosed no conflict of interest. Johnston, Stephen ������������������������������� Employee: Truven Health Analytics. Khazaezadeh, Nina ������������������������������ Disclosed no conflict of interest. Jones, Dean P. �������������������������������������� Disclosed no conflict of interest. Khedkar, Aditya ������������������������������������ Disclosed no conflict of interest. Jose, Aimee ����������������������������������������� Disclosed no conflict of interest. Khowaja, Ameer ���������������������������������� Research Support: Eli Lilly and Company. Joshi, Shashank R. ������������������������������� Consultant: Bayer Zydus Pharma, Zydus Cadila; Speaker’s Kibbey, Richard G. �������������������������������� Disclosed no conflict of interest. Bureau: Abbott, Emcure, Franco Indian, Johnson & Kiens, Bente ����������������������������������������� Disclosed no conflict of interest. Johnson, Marico, MSD, Novartis, Novo Nordisk, PHFI, Kil, Siyoen �������������������������������������������� Disclosed no conflict of interest. Ranbaxy, Roche, Sanofi, USV. Kim, Bong-Jo ���������������������������������������� Disclosed no conflict of interest. Joshi, Suyog ����������������������������������������� Disclosed no conflict of interest. Kim, Dong-II ����������������������������������������� Disclosed no conflict of interest. Joshipura, Kaumudi J. ������������������������� Disclosed no conflict of interest. Kim, Dong-Wook ���������������������������������� Disclosed no conflict of interest. Jouvet, Nathalie ���������������������������������� Disclosed no conflict of interest. Kim, Doo Man �������������������������������������� Disclosed no conflict of interest. Juarez-Comboni, Sonia C. �������������������� Disclosed no conflict of interest. Kim, In Joo ������������������������������������������� Disclosed no conflict of interest. Judd, Robert L. ������������������������������������� Disclosed no conflict of interest. Kim, Jae Bum ��������������������������������������� Disclosed no conflict of interest. Jung, II-Hoon ���������������������������������������� Disclosed no conflict of interest. Kim, Jihye �������������������������������������������� Disclosed no conflict of interest. Jung, Yun-Seung ���������������������������������� Disclosed no conflict of interest. Kim, Ji-Young ��������������������������������������� Disclosed no conflict of interest. Jurczak, Michael J. ������������������������������ Disclosed no conflict of interest. Kim, Jongoh ����������������������������������������� Disclosed no conflict of interest.

AUTHOR D I SCLOSURE Justice, Anne E. ����������������������������������� Disclosed no conflict of interest. Kim, Joon Young ���������������������������������� Disclosed no conflict of interest. Kabadi, Udaya M. �������������������������������� Advisory Panel: Sanofi U.S.;Speaker’s Bureau: Sanofi U.S. Kim, Jung Seok ������������������������������������ Disclosed no conflict of interest. Kabra, Uma D. �������������������������������������� Disclosed no conflict of interest. Kim, Mi-Kyung ������������������������������������� Disclosed no conflict of interest. Kadener, Sebastian ������������������������������ Disclosed no conflict of interest. Kim, Nam-Ho ���������������������������������������� Disclosed no conflict of interest. Kady, Jamie ������������������������������������������ Disclosed no conflict of interest. Kim, Nam-Kyu �������������������������������������� Disclosed no conflict of interest. Kahn, Barbara B. ���������������������������������� Disclosed no conflict of interest. Kim, Nan Hee ��������������������������������������� Disclosed no conflict of interest. Kahn, C. Ronald ������������������������������������ Disclosed no conflict of interest. Kim, Pankyung �������������������������������������� Disclosed no conflict of interest. Kahn, Jonathan ������������������������������������ Disclosed no conflict of interest. Kim, Sin Gon ���������������������������������������� Disclosed no conflict of interest. Kalsekar, Iftekhar ��������������������������������� Employee: AstraZeneca Pharmaceuticals LP. Kim, Soohyun Park ������������������������������� Disclosed no conflict of interest. Kamenov, Zdravko �������������������������������� Disclosed no conflict of interest. Kim, Sung Gyun ������������������������������������ Disclosed no conflict of interest. Kandror, Konstantin V. �������������������������� Disclosed no conflict of interest. Kim, Sung-Woo ������������������������������������ Disclosed no conflict of interest. Kane, Penelope ������������������������������������ Disclosed no conflict of interest. Kim, Tae Hyoung ���������������������������������� Disclosed no conflict of interest. Kaneko, Shizuka ����������������������������������� Advisory Panel: Astellas Pharma US, Inc., Novo Nordisk Kim, Tae Joon ��������������������������������������� Disclosed no conflict of interest. Inc., Taisho Pharmaceutical Co., Ltd., Takeda Kim, Wook �������������������������������������������� Disclosed no conflict of interest. Pharmaceutical Company Limited; Speaker’s Bureau: Kim, Yong-Seong ���������������������������������� Disclosed no conflict of interest. Astellas Pharma US, Inc., AstraZeneca, Bristol-Myers Kim, Young Jin ������������������������������������� Disclosed no conflict of interest. Squibb, Eli Lilly Japan K.K., Johnson & Johnson, Kim, Young-Bum ����������������������������������� Disclosed no conflict of interest. Mitsubishi Tanabe Pharma Corporation, Novartis Kim, Yun Kyoung ���������������������������������� Disclosed no conflict of interest. Pharmaceuticals Corporation, Novo Nordisk Inc., Kimple, Michelle E. ������������������������������ Disclosed no conflict of interest. Sumimoto Dainippon Pharma Co., Ltd., Taisho King, George L. ������������������������������������� Disclosed no conflict of interest. Pharmaceutical Co., Ltd., Takeda Pharmaceutical King, Timothy ��������������������������������������� Disclosed no conflict of interest. Company Limited. Kingwell, Bronwyn A. �������������������������� Disclosed no conflict of interest. Kaneto, Hideaki ������������������������������������ Research Support: Astellas Pharma US, Inc., AstraZeneca Kircher, Robert �������������������������������������� Employee: Dose Safety Inc.; Stock/Shareholder: Dose Pharmaceuticals LP, Boehringer Ingelheim Safety Inc. Pharmaceuticals, Inc., Daiichi-Sankyo Co., Ltd., Eli Klisch, Theresa ������������������������������������� Disclosed no conflict of interest. Lilly Japan K.K., Kissei Pharmaceutical Co., Ltd., Knadler, Mary P. ����������������������������������� Employee: Eli Lilly and Company; Stock/Shareholder: Eli Kowa Pharmaceuticals, Merck Sharp & Dohme, Lilly and Company. Mitsubishi Tanabe Pharma Corporation, Novartis Knoblauch, Nicholas W. ����������������������� Disclosed no conflict of interest. Pharmaceuticals Corporation, Novo Nordisk Inc., Ono Knop, Filip K. ���������������������������������������� Consultant: AstraZeneca Pharmaceuticals LP, Boehringer Pharmaceutical Co., Ltd., Sanofi U.S., Shionogi Inc., Ingelheim Pharmaceuticals, Inc., Bristol-Myers Squibb Takeda Pharmaceutical Company Limited. Company, Eli Lilly and Company, Gilead, Merck Sharp Kang, Dong-Woo ���������������������������������� Disclosed no conflict of interest. & Dohme, Novo Nordisk A/S, Sanofi U.S., Zealand Kang, Jahoon ��������������������������������������� Disclosed no conflict of interest. Pharma A/S; Research Support: Novo Nordisk A/S, Kang, Kyung Koo ���������������������������������� Disclosed no conflict of interest. Sanofi U.S. Kang, Shin-Wook ��������������������������������� Disclosed no conflict of interest. Knutsen, Chad �������������������������������������� Employee: Pacific Diabetes Technologies, Inc.;Stock/ Karaderi, Tugce ������������������������������������ Disclosed no conflict of interest. Shareholder: Pacific Diabetes Technologies, Inc. Karaliota, Sevasti ��������������������������������� Disclosed no conflict of interest. Ko, Yi-An ���������������������������������������������� Disclosed no conflict of interest. Karalis, Katia ���������������������������������������� Disclosed no conflict of interest. Kobiernicki, Frances ����������������������������� Disclosed no conflict of interest. Karsdal, Morten ����������������������������������� Stock/Shareholder: Nordic Bioscience. Kodella, Elisavet ���������������������������������� Disclosed no conflict of interest. Kasid, Natasha ������������������������������������� Disclosed no conflict of interest. Kodella, Kostantia �������������������������������� Disclosed no conflict of interest. Kattah, William ������������������������������������ Disclosed no conflict of interest. Koistenen, Heikki ��������������������������������� Disclosed no conflict of interest. Katz, Laurence B. ��������������������������������� Employee: LifeScan, Inc. Kokovay, Erzsebet �������������������������������� Disclosed no conflict of interest. Kaufholz, Melanie �������������������������������� Disclosed no conflict of interest. Kolar, Matthew J. �������������������������������� Disclosed no conflict of interest. Kaufman, Francine ������������������������������� Employee: Medtronic MiniMed, Inc.; Stock/Shareholder: Kondegowda, Nagesha G. ������������������� Disclosed no conflict of interest. Medtronic, Inc. Konishi, Masahiro �������������������������������� Disclosed no conflict of interest. Kawaguchi, Yasushi ����������������������������� Disclosed no conflict of interest. Konopka, Adam R. �������������������������������� Disclosed no conflict of interest. Kawaguchi, Yoshiya ����������������������������� Disclosed no conflict of interest. Kooy, Adriaan ��������������������������������������� Disclosed no conflict of interest. Kawamoto, Manabu ���������������������������� Disclosed no conflict of interest. Koratkar, Revati ������������������������������������ Disclosed no conflict of interest. Kazakos, Kyriakos �������������������������������� Disclosed no conflict of interest. Korhonen, Pasi ������������������������������������� Employee: Takeda Development Centre Europe.

LB104 AUTHOR RELATIONSHIP/COMPANY AUTHOR RELATIONSHIP/COMPANY Kornfeind, Ellyn ������������������������������������ Disclosed no conflict of interest. Lau, Raymond G. ���������������������������������� Disclosed no conflict of interest. Koroscil, Thomas M. ���������������������������� Disclosed no conflict of interest. Lau, Winston ���������������������������������������� Disclosed no conflict of interest. Krasner, Alan ���������������������������������������� Employee: Biodel Inc.; Stock/Shareholder: Biodel Inc. Lautsch, Norman ���������������������������������� Disclosed no conflict of interest. Kraus, Morey ���������������������������������������� Disclosed no conflict of interest. Lavalle-González, Fernando J. ������������� Advisory Panel: AstraZeneca, Boehringer Ingelheim, Eli Kretzler, Matthias ��������������������������������� Consultant: Abbvie, AstraZeneca Pharmaceuticals LP, Lilly, Janssen, Novo Nordisk, Sanofi;Board Member: Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly AstraZeneca, Boehringer Ingelheim, Janssen, Novo and Company, Novo Nordisk Inc., Pfizer Inc.;Research Nordisk, Sanofi;Research Support: Boehringer Support: Abbvie, AstraZeneca Pharmaceuticals LP, Ingelheim, Janssen, Novo Nordisk, Sanofi;Speaker’s Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly Bureau: AstraZeneca, Boehringer Ingelheim, Eli Lilly, and Company, Novo Nordisk Inc., Pfizer Inc. Janssen, MSD, Novo Nordisk, Sanofi. Krischer, Jeffrey P. �������������������������������� Disclosed no conflict of interest. Lavin, Philip T. �������������������������������������� Research Support: ZS Pharma, Inc.; Stock/Shareholder: ZS Krishnaswamy, Kamala ������������������������ Disclosed no conflict of interest. Pharma, Inc. Kronenberg, Florian ������������������������������ Disclosed no conflict of interest. Layden, Brian T. ������������������������������������ Disclosed no conflict of interest. Ku, Bon Jeong �������������������������������������� Disclosed no conflict of interest. Le, Yun-Zheng ��������������������������������������� Disclosed no conflict of interest. Kuang, Lin �������������������������������������������� Disclosed no conflict of interest. Leach, Jake ������������������������������������������ Employee: Dexcom, Inc. Kubo, Fumiyo ���������������������������������������� Research Support: Astellas Pharma US, Inc., AstraZeneca Leber, Alexander ���������������������������������� Disclosed no conflict of interest. Pharmaceuticals LP, Boehringer Ingelheim Leber, Stacey ���������������������������������������� Disclosed no conflict of interest. Pharmaceuticals, Inc., Bristol-Myers Squibb Company, Lee, Douglas S. ������������������������������������ Employee: Pfizer Inc.;Stock/Shareholder: Pfizer Inc. Daiichi-Sankyo Co., Ltd., Eli Lilly Japan K.K., Lee, Hong Kyu �������������������������������������� Disclosed no conflict of interest. Johnson & Johnson, Kissei Pharmaceutical Co., Ltd., Lee, In-Kyu ������������������������������������������� Disclosed no conflict of interest. Merck Sharp & Dohme, Mitsubishi Tanabe Pharma Lee, Jennifer ���������������������������������������� Disclosed no conflict of interest. Corporation, Novartis Corporation, Novo Nordisk Inc., Lee, Jimmy Tsz-Hang ��������������������������� Disclosed no conflict of interest. Ono Pharmaceutical Co., Ltd., Sanofi U.S., Sumimoto Lee, Jisoo ��������������������������������������������� Employee: Boehringer Ingelheim Pharma GmbH & Co. KG. Dainippon Pharma Co., Ltd., Takeda Pharmaceutical Lee, Junga �������������������������������������������� Disclosed no conflict of interest. Company Limited. Lee, Jung-Hun �������������������������������������� Disclosed no conflict of interest. Kudva, Yogish C. ���������������������������������� Disclosed no conflict of interest. Lee, Kwan-Hoo ������������������������������������� Disclosed no conflict of interest. Kuhadiya, Nitesh D. ����������������������������� Disclosed no conflict of interest. Lee, Mi Kyung �������������������������������������� Disclosed no conflict of interest. Kuliawat, Regina ���������������������������������� Disclosed no conflict of interest. Lee, Tsz-Hang ��������������������������������������� Disclosed no conflict of interest. Kulkarni, Rohit N. ��������������������������������� Disclosed no conflict of interest. Lee, Woohyung ������������������������������������ Disclosed no conflict of interest. Kumar, Ashish �������������������������������������� Disclosed no conflict of interest. Leech, Colin ������������������������������������������ Disclosed no conflict of interest. Kumar, Satish ��������������������������������������� Disclosed no conflict of interest. Lehman, Donna M. ������������������������������� Disclosed no conflict of interest. Kumar, Sudhesh ����������������������������������� Disclosed no conflict of interest. Leiter, Lawrence A. ������������������������������ Research Support: AstraZeneca Pharmaceuticals LP. Kumar, Sunil ����������������������������������������� Disclosed no conflict of interest. Leng, Jiyan ������������������������������������������� Disclosed no conflict of interest. Kumareswaran, Kavita ������������������������� Speaker’s Bureau: Astra Zeneca, Eli Lilly, Medtronic, Inc., Leng, Song ������������������������������������������� Disclosed no conflict of interest.

MSD, Sanofi U.S., Takeda. Lentucci, Claudia ���������������������������������� Disclosed no conflict of interest. AUTHOR D I SCLOSURE Künzli, Nino ������������������������������������������ Disclosed no conflict of interest. Leonardi, Anthony �������������������������������� Disclosed no conflict of interest. Kurmi, Kiran ����������������������������������������� Disclosed no conflict of interest. Lerakis, Stamatios ������������������������������� Disclosed no conflict of interest. Kurtz, Natalie ��������������������������������������� Employee: Medtronic MiniMed, Inc.; Stock/Shareholder: Lernmark, Åke �������������������������������������� Disclosed no conflict of interest. Medtronic, Inc. Lettre, Guillaume ��������������������������������� Disclosed no conflict of interest. Kusmartseva, Irina ������������������������������� Disclosed no conflict of interest. Levenson, Amy E. ��������������������������������� Disclosed no conflict of interest. Kutoh, Eiji ��������������������������������������������� Disclosed no conflict of interest. Levin, Philip A. ������������������������������������� Advisory Panel: Novo Nordisk Inc., Sanofi U.S.; Kwak, Eunhwa ������������������������������������� Disclosed no conflict of interest. Consultant: Novo Nordisk Inc., Sanofi U.S.;Research Kwon, Se Chang ����������������������������������� Disclosed no conflict of interest. Support: , LLC., Eli Lilly and Kyoong, Andrew ����������������������������������� Disclosed no conflict of interest. Company, Novo Nordisk Inc., Sanofi U.S.;Speaker’s Kyrgios, Ioannis ������������������������������������ Disclosed no conflict of interest. Bureau: Amylin Pharmaceuticals, LLC., Boehringer La Ronde-Richard, Ann-Marie ������������� Disclosed no conflict of interest. Ingelheim Pharmaceuticals, Inc., Eli Lilly and LaBell, Elizabeth S. ������������������������������ Employee: Eli Lilly and Company; Stock/Shareholder: Eli Company, GlaxoSmithKline, Novo Nordisk Inc. Lilly and Company. Levy, Brian L. ���������������������������������������� Employee: LifeScan, Inc. Laca, Jose �������������������������������������������� Disclosed no conflict of interest. Li, Bin ��������������������������������������������������� Disclosed no conflict of interest. Lacadie, Cheryl ������������������������������������� Disclosed no conflict of interest. Li, Fenfen ���������������������������������������������� Disclosed no conflict of interest. Lacombe, Julie ������������������������������������� Disclosed no conflict of interest. Li, GuoDong ������������������������������������������ Disclosed no conflict of interest. Laffel, Lori M. ��������������������������������������� Advisory Panel: Animas Corporation, AstraZeneca, Li, Hui ��������������������������������������������������� Disclosed no conflict of interest. Boehringer Ingelheim Pharmaceuticals, Inc., Bristol- Li, Ji ������������������������������������������������������ Disclosed no conflict of interest. Myers Squibb, Dexcom, Inc., Eli Lilly and Company, Li, Liwu ������������������������������������������������� Disclosed no conflict of interest. Johnson & Johnson, LifeScan, Inc., Menarini Group, Li, Nina ������������������������������������������������� Employee: Merck & Co., Inc. Novo Nordisk Inc., Oshadi Drug Administration, Li, Qin ��������������������������������������������������� Disclosed no conflict of interest. Roche Diagnostics, Sanofi U.S.;Consultant: Animas Li, Ruifeng �������������������������������������������� Disclosed no conflict of interest. Corporation, AstraZeneca, Boehringer Ingelheim Li, Wangen ������������������������������������������� Disclosed no conflict of interest. Pharmaceuticals, Inc., Bristol-Myers Squibb, Dexcom, Li, Wenjing ������������������������������������������� Disclosed no conflict of interest. Inc., Eli Lilly and Company, Johnson & Johnson, Li, Xingwang ���������������������������������������� Disclosed no conflict of interest. LifeScan, Inc., Menarini Group, Novo Nordisk Inc., Li, Xuhang �������������������������������������������� Disclosed no conflict of interest. Oshadi Drug Administration, Roche Diagnostics, Sanofi Li, Zihao ������������������������������������������������ Disclosed no conflict of interest. U.S.; Research Support: Bayer HealthCare, Boehringer Liang, Weiqiang ����������������������������������� Disclosed no conflict of interest. Ingelheim Pharmaceuticals, Inc., Dexcom, Inc. Liao, Yi-Chun ���������������������������������������� Disclosed no conflict of interest. Lage, Adrianne ������������������������������������� Disclosed no conflict of interest. Liao, Yunfei ������������������������������������������� Disclosed no conflict of interest. Lagerstedt, Jens ���������������������������������� Disclosed no conflict of interest. Lichliter, Jason ������������������������������������� Disclosed no conflict of interest. Lakhani, Rohan ������������������������������������� Disclosed no conflict of interest. Liew, Chong Wee ��������������������������������� Disclosed no conflict of interest. Lakka, Timo ������������������������������������������ Disclosed no conflict of interest. Lightwood, Dan ������������������������������������ Employee: UCB Pharma. Lakshmi, Mudigere N. �������������������������� Disclosed no conflict of interest. Lim, Sai Kiang �������������������������������������� Disclosed no conflict of interest. Lam, Eric Chen Quin ����������������������������� Employee: Eli Lilly and Company. Lin, Daniel J. ���������������������������������������� Disclosed no conflict of interest. Lam, Karen Siu-Ling ����������������������������� Disclosed no conflict of interest. Lin, Dongping ��������������������������������������� Disclosed no conflict of interest. Lam, Meghan ��������������������������������������� Disclosed no conflict of interest. Lin, Su Fan �������������������������������������������� Disclosed no conflict of interest. Lammert, Eckhard �������������������������������� Other Relationship: Author persue the patent application Lin, Yung-Chieh ������������������������������������ Disclosed no conflict of interest. WO 2013/029762 A1. Lincoff, A. Michael ������������������������������� Disclosed no conflict of interest. Langlais, Paul R. ����������������������������������� Disclosed no conflict of interest. Lindberg, Iris ���������������������������������������� Disclosed no conflict of interest. Lanza, Ian ��������������������������������������������� Disclosed no conflict of interest. Linder, Marie ���������������������������������������� Research Support: Centre for Pharmacoepidemiology (CPE) Lao, Julie ���������������������������������������������� Employee: Merck & Co., Inc. at Karolinska Institute has contracts with several Larco, Nancy C. ������������������������������������ Disclosed no conflict of interest. pharmaceutical companies and performs research for Larco, Philippe �������������������������������������� Disclosed no conflict of interest. them through research grants. Larrivee, Sandra ����������������������������������� Disclosed no conflict of interest. Lindgren, Cecilia M. ����������������������������� Disclosed no conflict of interest. Larsen, Peter ���������������������������������������� Disclosed no conflict of interest. Lingvay, Ildiko ��������������������������������������� Consultant: AstraZeneca Pharmaceuticals LP, Novo Lassance Gomes, Luciana �������������������� Disclosed no conflict of interest. Nordisk Inc.; Other Relationship: Sanofi U.S., Editorial.; Lassman, Michael E. ���������������������������� Employee: Merck & Co., Inc. Research Support: GID, Novo Nordisk Inc., Pfizer Inc.

LB105 AUTHOR RELATIONSHIP/COMPANY AUTHOR RELATIONSHIP/COMPANY Linnebjerg, Helle ���������������������������������� Employee: Eli Lilly and Company; Stock/Shareholder: Eli Matheson, Don ������������������������������������ Employee: Dose Safety Inc.; Stock/Shareholder: Dose Lilly and Company. Safety Inc. Lious, Daniel ���������������������������������������� Disclosed no conflict of interest. Mathieu, Chantal ��������������������������������� Advisory Panel: AstraZeneca Pharmaceuticals LP, Liu, Ching-Ti ����������������������������������������� Disclosed no conflict of interest. Boehringer Ingelheim Pharmaceuticals, Inc., Bristol- Liu, Dongmin ���������������������������������������� Disclosed no conflict of interest. Myers Squibb Company, Eli Lilly and Company, Liu, Franklin ������������������������������������������ Employee: Merck & Co., Inc. Hanmi, Johnson & Johnson, MannKind Corporation, Liu, Hangsheng ������������������������������������ Disclosed no conflict of interest. Merck Sharp & Dohme, Novartis Pharmaceuticals Liu, Jia �������������������������������������������������� Disclosed no conflict of interest. Corporation, Novo Nordisk Inc., Pfizer Inc., Sanofi Liu, Jiajun ��������������������������������������������� Employee: Eli Lilly and Company; Stock/Shareholder: Eli U.S.; Speaker’s Bureau: AstraZeneca Pharmaceuticals Lilly and Company. LP, Eli Lilly and Company, Merck Sharp & Dohme, Liu, Quan ���������������������������������������������� Disclosed no conflict of interest. Novartis Pharmaceuticals Corporation, Novo Nordisk Liu, Ying ������������������������������������������������ Disclosed no conflict of interest. Inc., Sanofi U.S. Liu, Yuanhang ��������������������������������������� Disclosed no conflict of interest. Matsuoka, Takaaki ������������������������������� Research Support: Astellas Pharma US, Inc., AstraZeneca Liu, Yujia ����������������������������������������������� Disclosed no conflict of interest. Pharmaceuticals LP, Boehringer Ingelheim Lizárraga-Mollinedo, Esther ����������������� Disclosed no conflict of interest. Pharmaceuticals, Inc., Daiichi-Sankyo Co., Ltd., Eli Lizarzaburu, Juan C. ����������������������������� Disclosed no conflict of interest. Lilly Japan K.K., Kissei Pharmaceutical Co., Ltd., Lo, K. Sin ���������������������������������������������� Disclosed no conflict of interest. Kowa Pharmaceuticals, Merck Sharp & Dohme, Loh, Margaret �������������������������������������� Disclosed no conflict of interest. Mitsubishi Tanabe Pharma Corporation, Novartis Loh, Yik Wen ���������������������������������������� Disclosed no conflict of interest. Pharmaceuticals Corporation, Novo Nordisk Inc., Ono Lombard, Julian H. ������������������������������� Disclosed no conflict of interest. Pharmaceutical Co., Ltd., Sanofi U.S., Shionogi Inc., Loos, Ruth J.F. �������������������������������������� Disclosed no conflict of interest. Takeda Pharmaceutical Company Limited. Lopez, Claudia �������������������������������������� Disclosed no conflict of interest. Matsushita, Kanae ������������������������������� Disclosed no conflict of interest. Lopez-Gutierrez, Joel ��������������������������� Disclosed no conflict of interest. Matteucci, Elena ���������������������������������� Disclosed no conflict of interest. Lu, Brian ����������������������������������������������� Disclosed no conflict of interest. Mauceri, Joseph ���������������������������������� Disclosed no conflict of interest. Lu, Christine ����������������������������������������� Disclosed no conflict of interest. Mauseth, Richard ��������������������������������� Employee: Dose Safety Inc.; Stock/Shareholder: Dose Lu, Meng ���������������������������������������������� Disclosed no conflict of interest. Safety Inc. Lu, Qi ���������������������������������������������������� Disclosed no conflict of interest. Mazzone, Theodore ������������������������������ Disclosed no conflict of interest. Lu, Yang ������������������������������������������������ Disclosed no conflict of interest. McCarthy, Mark I. �������������������������������� Disclosed no conflict of interest. Lu, Yingchang ��������������������������������������� Disclosed no conflict of interest. McDaniel, Kristen �������������������������������� Disclosed no conflict of interest. Lu, Yingli ����������������������������������������������� Disclosed no conflict of interest. Mcdonald, Molly ���������������������������������� Disclosed no conflict of interest. Lu, Yongke �������������������������������������������� Disclosed no conflict of interest. McElrtah, Thomas F. ����������������������������� Disclosed no conflict of interest. Lubree, Himangi ����������������������������������� Disclosed no conflict of interest. McEwen, Laura N. ������������������������������� Disclosed no conflict of interest. Lucas, Anthony ������������������������������������� Disclosed no conflict of interest. McGuire, Darren K. ������������������������������ Disclosed no conflict of interest. Lulo, James ������������������������������������������ Disclosed no conflict of interest. McKenney, Sarah ��������������������������������� Research Support: Medtronic MiniMed, Inc.

AUTHOR D I SCLOSURE Lund, Asger ������������������������������������������ Disclosed no conflict of interest. McLaughlin, Kerry A. ��������������������������� Disclosed no conflict of interest. Lundqvist, Kristin ��������������������������������� Disclosed no conflict of interest. McTigue, Kathleen M. ������������������������� Disclosed no conflict of interest. Luo, Jing ����������������������������������������������� Disclosed no conflict of interest. Meah, Farah ����������������������������������������� Disclosed no conflict of interest. Luo, Oscar �������������������������������������������� Disclosed no conflict of interest. Medina-Gomez, M. Carolina ���������������� Disclosed no conflict of interest. Luque-Fernandez, Miguel A. ���������������� Disclosed no conflict of interest. Mehta, Aditya �������������������������������������� Disclosed no conflict of interest. Lv, Tiantian ������������������������������������������� Disclosed no conflict of interest. Mehta, Cyrus ���������������������������������������� Disclosed no conflict of interest. Ly, Trang T. �������������������������������������������� Disclosed no conflict of interest. Mehta, Ravindra L. ������������������������������� Advisory Panel: Abbvie, AM Pharma, Ardea, Eli Lilly and Lynes, Mattew D. ��������������������������������� Disclosed no conflict of interest. Company; Consultant: Astellas Pharma US, Baxter, Lyv, Fuping �������������������������������������������� Disclosed no conflict of interest. CSL Behring, Inc., Eli Lilly and Company, Ferring Ma, Jian-Xing �������������������������������������� Disclosed no conflict of interest. Research, GlaxoSmithKline, Isis Pharmaceuticals, Inc., Ma, Tony ����������������������������������������������� Employee: Eisai Inc. Sanofi-Aventis, Sova;Research Support: International Ma, Xiaotang ��������������������������������������� Disclosed no conflict of interest. Safety Adverse Events Consortium, Thrasos Maarouf, Omar H. �������������������������������� Disclosed no conflict of interest. Therapeutics; Stock/Shareholder: Astute Inc. MacDonald, Patrick E. �������������������������� Disclosed no conflict of interest. Mei, Yong ��������������������������������������������� Disclosed no conflict of interest. Machida, Yui ���������������������������������������� Disclosed no conflict of interest. Meijer, Rick I. ��������������������������������������� Disclosed no conflict of interest. Macias, William L. ������������������������������� Employee: Eli Lilly and Company; Stock/Shareholder: Eli Meikle, Peter J. ������������������������������������ Disclosed no conflict of interest. Lilly and Company. Meinicke, Thomas �������������������������������� Employee: Boehringer Ingelheim GmbH. MacIsaac, Richard J. ��������������������������� Disclosed no conflict of interest. Meissner, Thomas �������������������������������� Other Relationship: Author persue the patent application Madiraju, Anila K. �������������������������������� Disclosed no conflict of interest. WO 2013/029762 A1. Madura II, James A. ���������������������������� Disclosed no conflict of interest. Meister, Gunter ������������������������������������ Disclosed no conflict of interest. Magyar, Kendra ������������������������������������ Disclosed no conflict of interest. Melissinos, Michail ����������������������������� Disclosed no conflict of interest. Maheshwari, Pradeep K. ��������������������� Disclosed no conflict of interest. Mellbin, Linda G. ���������������������������������� Research Support: MSD, Sanofi Aventis. Mahesula, Swetha ������������������������������� Disclosed no conflict of interest. Mendivil, Carlos O. ������������������������������ Disclosed no conflict of interest. Majak, Maila ���������������������������������������� Employee: EPID Research performs financially supported Menegaz, Danusa �������������������������������� Disclosed no conflict of interest. studies for several pharmaceutical companies Meng, Shu �������������������������������������������� Disclosed no conflict of interest. including Takeda Development Centre Europe. Meng, Ying ������������������������������������������� Disclosed no conflict of interest. Makdissi, Antoine �������������������������������� Disclosed no conflict of interest. Menon, Venu ���������������������������������������� Disclosed no conflict of interest. Malik, Vasanti S. ���������������������������������� Disclosed no conflict of interest. Menon, Vinod ��������������������������������������� Disclosed no conflict of interest. Mallikarjuna, Shwetha ������������������������ Disclosed no conflict of interest. Merino-Trigo, Ana �������������������������������� Employee: Sanofi. Manan, Jyotika ������������������������������������ Disclosed no conflict of interest. Merton, Kate ���������������������������������������� Employee: Janssen Research & Development, LLC. Mandarino, Lawrence J. ���������������������� Disclosed no conflict of interest. Meunier, Clemence ������������������������������ Disclosed no conflict of interest. Manganiello, Vincent Manganiello ����� Disclosed no conflict of interest. Miao, Ji ������������������������������������������������ Disclosed no conflict of interest. Maniatis, Nikolas ��������������������������������� Disclosed no conflict of interest. Michels, Aaron W. ������������������������������� Disclosed no conflict of interest. Manning Fox, Jocelyn E. ���������������������� Disclosed no conflict of interest. Milani, Massimo ���������������������������������� Employee: Isdin. Mansmann, Ulrich �������������������������������� Disclosed no conflict of interest. Milaszewski, Kerry ������������������������������� Consultant: Eli Lilly and Company. Manson, JoAnn E. �������������������������������� Other Relationship: Pfizer Inc. Milhem, Tyler ��������������������������������������� Employee: Pacific Diabetes Technologies, Inc.;Stock/ Maratos Flier, Eleftheria ���������������������� Advisory Panel: Novo Nordisk Inc., Sanofi. Shareholder: Pacific Diabetes Technologies, Inc. Marcinak, John ������������������������������������ Disclosed no conflict of interest. Min, Ae-Kyung ������������������������������������� Disclosed no conflict of interest. Marquard, Jan ������������������������������������� Other Relationship: Author persue the patent application Min, Jihee �������������������������������������������� Disclosed no conflict of interest. WO 2013/029762 A1. Min, Kyung Wan ���������������������������������� Disclosed no conflict of interest. Marquez, Eladio ����������������������������������� Disclosed no conflict of interest. Min, So Yun ������������������������������������������ Disclosed no conflict of interest. Martin, Brittany ������������������������������������ Disclosed no conflict of interest. Minium, Judi ���������������������������������������� Disclosed no conflict of interest. Martin, Holly R. ������������������������������������ Employee: Eli Lilly and Company. Mintz, James ��������������������������������������� Disclosed no conflict of interest. Martin, Jennifer A. ������������������������������ Employee: Eli Lilly and Company; Stock/Shareholder: Eli Mirmira, Raghavendra G. ��������������������� Disclosed no conflict of interest. Lilly and Company. Misha’l, Aly A. ������������������������������������� Disclosed no conflict of interest. Maruthur, Nisa M. �������������������������������� Disclosed no conflict of interest. Mitrovich, Connor �������������������������������� Disclosed no conflict of interest. Mather, Kieren J. ��������������������������������� Consultant: Boehringer Ingelheim GmbH, Sanofi U.S.; Miura, Junnosuke �������������������������������� Disclosed no conflict of interest. Research Support: Abbott, Boehringer Ingelheim Co., Ltd, Miyashita, Kazuyuki ����������������������������� Research Support: Astellas Pharma US, Inc., AstraZeneca Merck & Co., Inc., Nippon, Novo Nordisk A/S, Sanofi U.S. Pharmaceuticals LP, Boehringer Ingelheim

LB106 AUTHOR RELATIONSHIP/COMPANY AUTHOR RELATIONSHIP/COMPANY Pharmaceuticals, Inc., Bristol-Myers Squibb Company, Neale, Helen ���������������������������������������� Employee: UCB Pharma. Daiichi-Sankyo Co., Ltd., Eli Lilly Japan K.K., Johnson Neergaard, Jesper S. ��������������������������� Disclosed no conflict of interest. & Johnson, Kissei Pharmaceutical Co., Merck Sharp Nelson, Scott M. ���������������������������������� Advisory Panel: Roche Diagnostics; Research Support: & Dohme, Mitsubishi Tanabe Pharma Corporation, Roche Diagnostics; Speaker’s Bureau: Roche Novartis Pharmaceuticals Corporation, Novo Nordisk Diagnostics. Inc.,Ltd., Ono Pharmaceutical Co., Ltd., Sanofi U.S., Neuman, Joshua C. ������������������������������ Disclosed no conflict of interest. Sumimoto Dainippon Pharma Co., Ltd., Takeda Nhan, Trinh ������������������������������������������� Disclosed no conflict of interest. Pharmaceutical Company Limited. Nicholls, Stephen ��������������������������������� Disclosed no conflict of interest. Miyatsuka, Takeshi ������������������������������ Research Support: Astellas Pharma US, Inc., AstraZeneca Nie, Xiaomin ���������������������������������������� Disclosed no conflict of interest. Pharmaceuticals LP, Boehringer Ingelheim Nie, Yaohui ������������������������������������������� Disclosed no conflict of interest. Pharmaceuticals, Inc., Bristol-Myers Squibb Company, Nissen, Steven E. ��������������������������������� Disclosed no conflict of interest. Daiichi-Sankyo Co., Ltd., Dainippon Pharma Co., Niu, Jianmin ����������������������������������������� Disclosed no conflict of interest. Ltd., Eli Lilly Japan K.K, Johnson & Johnson, Kissei Nobrega, Marcelo A. ��������������������������� Disclosed no conflict of interest. Pharmaceutical Co., Ltd., Merck Sharp & Dohme, Noel, Guillaume ����������������������������������� Disclosed no conflict of interest. Mitsubishi Tanabe Pharma Corporation, Novartis Nordén, Kristina ����������������������������������� Disclosed no conflict of interest. Pharmaceuticals Corporation, Novo Nordisk Inc., Ono Norman-Burgdolf, Heather L. ��������������� Disclosed no conflict of interest. Pharmaceutical Co., Sanofi U.S., Sumimoto, Ltd., North, Kari E. ���������������������������������������� Disclosed no conflict of interest. Takeda Pharmaceutical Company Limited. North, Paula E. ������������������������������������� Disclosed no conflict of interest. Mizuno, Ken ����������������������������������������� Employee: Kowa Pharmaceuticals. Norton, Luke ����������������������������������������� Disclosed no conflict of interest. Mlynarchik, Andrew ����������������������������� Disclosed no conflict of interest. Nowlan, Molly ������������������������������������� Disclosed no conflict of interest. Mlynarski, Wojciech ���������������������������� Disclosed no conflict of interest. Nunlee-Bland, Gail ������������������������������� Disclosed no conflict of interest. Modi, Devangi �������������������������������������� Disclosed no conflict of interest. Nunoue, Tomokazu ������������������������������� Disclosed no conflict of interest. Moerman, Ericka ���������������������������������� Disclosed no conflict of interest. Obrosova, Irina G. �������������������������������� Disclosed no conflict of interest. Mohammad Moradi, Shayan ��������������� Disclosed no conflict of interest. Odede, Geofrey ������������������������������������ Employee: UCB Pharma. Mohan, Viswanathan ��������������������������� Disclosed no conflict of interest. Ogawa, Daisuke ����������������������������������� Disclosed no conflict of interest. Mohanasundaram, Daisy ��������������������� Disclosed no conflict of interest. Oh, Byung-Chul ������������������������������������ Disclosed no conflict of interest. Mohlke, Karen L. ���������������������������������� Disclosed no conflict of interest. Oh, Kook-Hwan ������������������������������������ Disclosed no conflict of interest. Mohseni, Mahshid ������������������������������� Disclosed no conflict of interest. Oh, Kyoung-Jin ������������������������������������� Disclosed no conflict of interest. Moisidou, Maria ���������������������������������� Disclosed no conflict of interest. Oh, Minsuk ������������������������������������������� Disclosed no conflict of interest. Molina, Judith T. ���������������������������������� Disclosed no conflict of interest. Ohta, Masayuki ������������������������������������ Employee: Kowa Pharmaceuticals. Mondesir, Debbie ��������������������������������� Disclosed no conflict of interest. Okada, Junichi ������������������������������������� Disclosed no conflict of interest. Moon, Sanghoon ���������������������������������� Disclosed no conflict of interest. Okada, Shuichi ������������������������������������� Disclosed no conflict of interest. Moore, Adrian �������������������������������������� Employee: UCB Pharma. O’Neal, David ��������������������������������������� Disclosed no conflict of interest. Moore, Robert �������������������������������������� Disclosed no conflict of interest. O’Rahilly, Stephen �������������������������������� Disclosed no conflict of interest.

Mora, Edwin ����������������������������������������� Disclosed no conflict of interest. Orchard, Trevor J. ��������������������������������� Disclosed no conflict of interest. AUTHOR D I SCLOSURE Moreno-Ruiz, Francisco J. ������������������� Disclosed no conflict of interest. Ordelheide, Anna-Maria ���������������������� Disclosed no conflict of interest. Morgan, Diana ������������������������������������� Disclosed no conflict of interest. Orduz, Arturo ���������������������������������������� Disclosed no conflict of interest. Morley, Thomas S. ������������������������������� Disclosed no conflict of interest. O’Reilly, Eilis J. ������������������������������������ Disclosed no conflict of interest. Morris, Andrew P. ��������������������������������� Disclosed no conflict of interest. Oropeza, Daniel ������������������������������������ Disclosed no conflict of interest. Morris, Heather L. �������������������������������� Disclosed no conflict of interest. Orr, Gregory ������������������������������������������ Disclosed no conflict of interest. Morris, Kristin �������������������������������������� Employee: Pacific Diabetes Technologies, Inc.;Stock/ Oruk, Guzide Gonca ������������������������������ Disclosed no conflict of interest. Shareholder: Pacific Diabetes Technologies, Inc. Osakai, Aya ������������������������������������������ Disclosed no conflict of interest. Morrow, Linda �������������������������������������� Employee: Profil Institute for Clinical Research, Inc.; Osawa, Mari ���������������������������������������� Disclosed no conflict of interest. Stock/Shareholder: Profil Institute for Clinical Osborne, Timothy ��������������������������������� Disclosed no conflict of interest. Research, Inc. Osborne, William ��������������������������������� Disclosed no conflict of interest. Morton-Eggleston, Emma B. ���������������� Disclosed no conflict of interest. Osei, Kwame ���������������������������������������� Consultant: Merck & Co., Inc.; Research Support: Mosser, Rockann ���������������������������������� Disclosed no conflict of interest. AstraZeneca Pharmaceuticals LP. Mounayar, Marwan ������������������������������ Disclosed no conflict of interest. Osganian, Stavroula ����������������������������� Disclosed no conflict of interest. Mudaliar, Sunder ���������������������������������� Advisory Panel: AstraZeneca Pharmaceuticals LP; Østergaard, Jakob A. ��������������������������� Disclosed no conflict of interest. Consultant: AstraZeneca Pharmaceuticals LP; O-Sullivan, InSug ��������������������������������� Disclosed no conflict of interest. Research Support: AstraZeneca Pharmaceuticals Oteng-Ntim, Eugene ���������������������������� Disclosed no conflict of interest. LP, Cebix, Inc., Intarcia Therapeutics, Inc., Janssen Otter, Silke �������������������������������������������� Disclosed no conflict of interest. Research & Development LLC; Speaker’s Bureau: Otto, Michael ��������������������������������������� Disclosed no conflict of interest. AstraZeneca Pharmaceuticals LP. Ouwens, Margriet �������������������������������� Disclosed no conflict of interest. Mudgett, John ������������������������������������� Employee: Merck & Co., Inc. Owen, Neville �������������������������������������� Disclosed no conflict of interest. Muise, Eric ������������������������������������������� Employee: Merck & Co., Inc. Pachanski, Michele ������������������������������ Disclosed no conflict of interest. Mullapudi, Kamesh ������������������������������ Disclosed no conflict of interest. Packham, David K. ������������������������������� Consultant: Nephrogenex, ZN Pharma. Mullen, Deborah M. ����������������������������� Disclosed no conflict of interest. Palaia, Thomas ������������������������������������� Disclosed no conflict of interest. Muniyappa, Ranganath ������������������������ Disclosed no conflict of interest. Pallardo, Felipe ������������������������������������ Disclosed no conflict of interest. Munk, Ole L. ����������������������������������������� Disclosed no conflict of interest. Pallavi, Puttrevana M. �������������������������� Disclosed no conflict of interest. Muñoz, Oscar ��������������������������������������� Disclosed no conflict of interest. Pan, Kewu �������������������������������������������� Disclosed no conflict of interest. Munoz-Gomez, Miguel ������������������������� Disclosed no conflict of interest. Pandey, Varun K. ���������������������������������� Disclosed no conflict of interest. Munoz-Torres, Francisco ���������������������� Disclosed no conflict of interest. Pankratz, Nathan ���������������������������������� Disclosed no conflict of interest. Murakami, Kazutoshi ��������������������������� Disclosed no conflict of interest. Panlasigui, Neil ������������������������������������ Disclosed no conflict of interest. Murakami, Kentaro ������������������������������ Employee: Kowa Pharmaceuticals. Parenty, Geraldine �������������������������������� Disclosed no conflict of interest. Murthy, Narasimha ������������������������������ Disclosed no conflict of interest. Pargal, Summi �������������������������������������� Disclosed no conflict of interest. Mynatt, Randall L. �������������������������������� Research Support: American Diabetes Association. Parikh, Lisa ������������������������������������������� Disclosed no conflict of interest. Na, Ki-Ryang ���������������������������������������� Disclosed no conflict of interest. Parikh, Neha ����������������������������������������� Employee: Medtronic MiniMed, Inc. Nagarajan, Lakshmipriya ��������������������� Disclosed no conflict of interest. Park, Anna �������������������������������������������� Disclosed no conflict of interest. Nagel, Friederike ���������������������������������� Employee: Boehringer Ingelheim Pharma GmbH & Co. KG. Park, Hyoungchun �������������������������������� Disclosed no conflict of interest. Naik, Sarita ������������������������������������������ Disclosed no conflict of interest. Park, Ji-Hye ������������������������������������������ Disclosed no conflict of interest. Nair, K. Sreekumaran ��������������������������� Disclosed no conflict of interest. Park, Keun-Gyu ������������������������������������� Disclosed no conflict of interest. Nakamura, Katherine ��������������������������� Employee: Dexcom, Inc. Park, So Hyun ��������������������������������������� Disclosed no conflict of interest. Nakamura, Naoto ��������������������������������� Disclosed no conflict of interest. Park, Sun-Hee �������������������������������������� Disclosed no conflict of interest. Nakamura, Yumiko ������������������������������� Disclosed no conflict of interest. Park, Tae Sun ���������������������������������������� Disclosed no conflict of interest. Nakatsuka, Atsuko ������������������������������� Disclosed no conflict of interest. Park, Tae-Joon �������������������������������������� Disclosed no conflict of interest. Nam, Minwoo �������������������������������������� Disclosed no conflict of interest. Park, Yousung ��������������������������������������� Disclosed no conflict of interest. Narayan, K.M. Venkat �������������������������� Disclosed no conflict of interest. Parker, Stephen ������������������������������������ Disclosed no conflict of interest. Narisu, Narisu �������������������������������������� Disclosed no conflict of interest. Parker, Stephen C.J. ����������������������������� Disclosed no conflict of interest. Nasr, Gamela ���������������������������������������� Disclosed no conflict of interest. Parkin, Christopher G. �������������������������� Consultant: Animas Corporation, Asante Solutions, Inc., Nassar, Wael F. ������������������������������������ Disclosed no conflict of interest. CeQur SA, Dexcom, Inc., Roche Diagnostics, Sanofi U.S. Nawrocki, Andrea �������������������������������� Employee: Merck & Co., Inc. Parson, Henri ���������������������������������������� Disclosed no conflict of interest. Neal, Adam S. �������������������������������������� Disclosed no conflict of interest. Parthasarathy, Vijayalaksmi ����������������� Disclosed no conflict of interest.

LB107 AUTHOR RELATIONSHIP/COMPANY AUTHOR RELATIONSHIP/COMPANY Pascual, Michael ���������������������������������� Disclosed no conflict of interest. Quek, Jonathan Caleb �������������������������� Disclosed no conflict of interest. Pasko, Dorota ��������������������������������������� Disclosed no conflict of interest. Queniat, Gurvan ����������������������������������� Disclosed no conflict of interest. Pasquarello, Cindy ������������������������������� Disclosed no conflict of interest. Quinn, Lauretta T. ��������������������������������� Disclosed no conflict of interest. Pasquel, Francisco J. ��������������������������� Disclosed no conflict of interest. Qunibi, Wajeh �������������������������������������� Other Relationship: UpToDate; Research Support: ZS Patel, Nashita �������������������������������������� Disclosed no conflict of interest. Pharma, Inc. Patel, Niraja ����������������������������������������� Disclosed no conflict of interest. Quon, Michael J. ���������������������������������� Disclosed no conflict of interest. Patel, Pankaj ���������������������������������������� Employee: Cadila Healthcare Ltd. Quyyumi, Arshed A. ����������������������������� Disclosed no conflict of interest. Patiño, Jorge E. ������������������������������������ Disclosed no conflict of interest. Radford, Elizabeth J. ���������������������������� Disclosed no conflict of interest. Patti, Mary-Elizabeth ��������������������������� Consultant: Defined Health, Diasome, Foodminds, LLC; Radovick, Sally ������������������������������������� Disclosed no conflict of interest. Research Support: American Diabetes Association, Ragolia, Louis ��������������������������������������� Disclosed no conflict of interest. Ajinomoto Group, National Institute of Diabetes Rahbar, Samuel ������������������������������������ Disclosed no conflict of interest. and Digestive and Kidney Diseases, Janssen Rajagopalan, Sujit �������������������������������� Disclosed no conflict of interest. Pharmaceutical Companies of Johnson & Johnson, Ramasamy, Boominathan �������������������� Disclosed no conflict of interest. MedImmune, Nuclea, Sanofi U.S. Rameh, Lucia E. ������������������������������������ Disclosed no conflict of interest. Pattou, François ����������������������������������� Disclosed no conflict of interest. Randeva, Harpal S. ������������������������������ Disclosed no conflict of interest. Paumelle, Réjane ��������������������������������� Disclosed no conflict of interest. Ranetti, Aurelian Emil �������������������������� Advisory Panel: National Ethical Commission for the Pears, Skye ������������������������������������������� Disclosed no conflict of interest. drug’s clinical study; Research Support: Eli Lilly and Peng, Jinghua �������������������������������������� Disclosed no conflict of interest. Company, Pfizer Inc., Servier;Speaker’s Bureau: Pereira, Mark A. ����������������������������������� Disclosed no conflict of interest. Abbott, Alfa Wasserman, Eli Lilly and Company. Perissi, Valentina ��������������������������������� Disclosed no conflict of interest. Ranjani, Harish ������������������������������������� Disclosed no conflict of interest. Peroni, Odile D. ������������������������������������ Disclosed no conflict of interest. Rao, Ranganatha ���������������������������������� Disclosed no conflict of interest. Perron, Gabrielle ���������������������������������� Disclosed no conflict of interest. Raphael, Frederica ������������������������������� Disclosed no conflict of interest. Perry, Rachel J. ������������������������������������ Disclosed no conflict of interest. Rask-Madsen, Christian ����������������������� Disclosed no conflict of interest. Pery, Billy ���������������������������������������������� Employee: LabStyle Innovations, Ltd. Rasmussen, Henrik S. �������������������������� Employee: ZS Pharma, Inc.; Stock/Shareholder: ZS Pessin, Jeffrey E. ��������������������������������� Disclosed no conflict of interest. Pharma, Inc. Petersen, Kitt F. ������������������������������������ Disclosed no conflict of interest. Rathjen, Thomas ���������������������������������� Disclosed no conflict of interest. Petri, Renata T. ������������������������������������� Disclosed no conflict of interest. Raverdy, Violeta ����������������������������������� Disclosed no conflict of interest. Petrocchi-Passeri, Pamela ������������������� Disclosed no conflict of interest. Ravishankar, Aarthi ������������������������������ Disclosed no conflict of interest. Pettus, Jeremy H. ��������������������������������� Advisory Panel: Sanofi U.S, Tandem Diabetes Care, Inc.; Ravussin, Eric ��������������������������������������� Advisory Panel: Genentech, Inc., Novo Nordisk Inc. Consultant: Sanofi U.S.;Speaker’s Bureau: Dexcom, Raymond, Ralph H. ������������������������������� Stock/Shareholder: Bristol-Myers Squibb Company. Inc., Johnson & Johnson. Raz, Itamar ������������������������������������������� Research Support: AstraZeneca Pharmaceuticals LP. Pfeffer, Sébastien ��������������������������������� Disclosed no conflict of interest. Read, Linda ������������������������������������������ Disclosed no conflict of interest. Pichotta, Philip ������������������������������������� Employee: Biodel Inc.; Stock/Shareholder: Biodel Inc. Reagan, Louise A. �������������������������������� Disclosed no conflict of interest. Picklesimer, Amy ���������������������������������� Disclosed no conflict of interest. Reaven, Peter D. ���������������������������������� Disclosed no conflict of interest.

AUTHOR D I SCLOSURE Piecuch, Emaly ������������������������������������� Disclosed no conflict of interest. Reddy, Narendra L. ������������������������������� Disclosed no conflict of interest. Pihoker, Cate ���������������������������������������� Disclosed no conflict of interest. Reddy, Ravi ������������������������������������������� Disclosed no conflict of interest. Pilegaard, Henriette ����������������������������� Disclosed no conflict of interest. Redman, Leanne M. ����������������������������� Disclosed no conflict of interest. Pillai, Sreekumar G. ����������������������������� Employee: Eli Lilly and Company. Reers, Christina ������������������������������������ Disclosed no conflict of interest. Pinney, Sara E. ������������������������������������� Disclosed no conflict of interest. Rees, Gwyn ������������������������������������������ Disclosed no conflict of interest. Piron, Matthew ������������������������������������ Disclosed no conflict of interest. Regner, Kevin R. ����������������������������������� Disclosed no conflict of interest. Piston, David W. ����������������������������������� Disclosed no conflict of interest. Reik, Wolf ��������������������������������������������� Disclosed no conflict of interest. Pitale, Ameya ��������������������������������������� Disclosed no conflict of interest. Reiser, Jochen �������������������������������������� Other Relationship: Co-founders of TRISAQ, a Pittas, Anastassios G. �������������������������� Disclosed no conflict of interest. biopharmaceutical company aimed to develop new Pober, David ����������������������������������������� Disclosed no conflict of interest. therapies for kidney disease. Poitout, Vincent ������������������������������������ Disclosed no conflict of interest. Renström, Frida ������������������������������������ Disclosed no conflict of interest. Polidori, David �������������������������������������� Employee: Janssen Research & Development LLC. Resalat, Navid �������������������������������������� Disclosed no conflict of interest. Pollin, Toni I. ����������������������������������������� Disclosed no conflict of interest. Rewers, Arleta ������������������������������������� Disclosed no conflict of interest. Polonsky, William H. ���������������������������� Advisory Panel: Novo Nordisk, RocheSanofi, Sanofi; Rewers, Marian ����������������������������������� Disclosed no conflict of interest. Consultant: Abbott, Boehringer Ingelheim, Dexcom, Reynolds, Vincent L. ����������������������������� Employee: Eli Lilly and Company; Stock/Shareholder: Eli Eli Lilly, Novo Nordisk, Roche, Sanofi. Lilly and Company. Polsky, Sarit ������������������������������������������ Disclosed no conflict of interest. Rho, Jun Gi ������������������������������������������� Disclosed no conflict of interest. Pongratz, Rebecca L. ���������������������������� Disclosed no conflict of interest. Ricchiuto, Piero ������������������������������������ Disclosed no conflict of interest. Poole, Lucinda A. ��������������������������������� Disclosed no conflict of interest. Richardson, Carolyn C. ������������������������� Disclosed no conflict of interest. Popoola, Orishebawo B. ����������������������� Disclosed no conflict of interest. Richter, Erik A. �������������������������������������� Disclosed no conflict of interest. Popova, Dora ���������������������������������������� Disclosed no conflict of interest. Ridderstrale, Martin ����������������������������� Employee: Steno Diabetes Center A/S; Speaker’s Bureau: Porceban, Matheus ������������������������������ Disclosed no conflict of interest. Boehringer Ingelheim GmbH, Eli Lilly and Company, Porksen, Niels �������������������������������������� Employee: Eli Lilly and Company; Stock/Shareholder: Eli GlaxoSmithKline, Johnson & Johnson, Medtronic, Lilly and Company. Inc., Merck & Co., Inc., Novartis, Novo Nordisk A/S, Possenti, Roberta ��������������������������������� Disclosed no conflict of interest. Roche Diagnostics, Sanofi-Aventis. Poston, Lucilla �������������������������������������� Research Support: Abbott Nutrition. Riggs, Arthur ���������������������������������������� Disclosed no conflict of interest. Pouwer, Frans ��������������������������������������� Disclosed no conflict of interest. Rivera, Alba D. ������������������������������������� Disclosed no conflict of interest. Poveda, Alaitz �������������������������������������� Disclosed no conflict of interest. Robertson, R. Paul �������������������������������� Disclosed no conflict of interest. Poy, Matthew N. ���������������������������������� Disclosed no conflict of interest. Robinson, Matthew M. ������������������������ Disclosed no conflict of interest. Prakash, Prashant K. ���������������������������� Disclosed no conflict of interest. Robson, Stephen C. ������������������������������ Disclosed no conflict of interest. Pratley, Richard E. �������������������������������� Disclosed no conflict of interest. Rocha, Hermano A.L. ��������������������������� Disclosed no conflict of interest. Predmore, Zachary ������������������������������� Disclosed no conflict of interest. Rocha, Milagros ����������������������������������� Disclosed no conflict of interest. Preiser, Nicholas ���������������������������������� Disclosed no conflict of interest. Rochat, Thierry ������������������������������������� Disclosed no conflict of interest. Preston, Kyle ���������������������������������������� Disclosed no conflict of interest. Rodriguez, Carlos G. ����������������������������� Employee: Merck & Co., Inc. Previs, Stephen ������������������������������������ Employee: Merck & Co., Inc. Rodriguez, Henry ���������������������������������� Disclosed no conflict of interest. Previs, Steve ���������������������������������������� Disclosed no conflict of interest. Rodriguez-Cañete, Alberto ������������������� Disclosed no conflict of interest. Price, David A. �������������������������������������� Employee: Dexcom, Inc. Rodriguez-Pacheco, Francisca ������������� Disclosed no conflict of interest. Prince, Melvin J. ���������������������������������� Employee: Eli Lilly and Company; Stock/Shareholder: Eli Roger, George W. ��������������������������������� Disclosed no conflict of interest. Lilly and Company. Rojas-Rodriguez, Raziel ����������������������� Disclosed no conflict of interest. Priyadarshini, Medha ��������������������������� Disclosed no conflict of interest. Rollins, Derrick K. ��������������������������������� Disclosed no conflict of interest. Probst-Hensch, Nicole ������������������������� Disclosed no conflict of interest. Rondon, Martin ������������������������������������ Disclosed no conflict of interest. Pu, Xiaoqi ��������������������������������������������� Disclosed no conflict of interest. Rosenblit, Paul D. ��������������������������������� Advisory Panel: Eli Lilly and CompanyJanssen; Research Puckrein, Gary A. ���������������������������������� Disclosed no conflict of interest. Support: Abbott, Amgen Inc., Dexcom, Inc., Eli Puppala, Sobha ������������������������������������ Disclosed no conflict of interest. Lilly and Company, MannKind Corporation, Merck, Puri, Vishwajeet ����������������������������������� Disclosed no conflict of interest. Novo Nordisk Inc., Orexigen Therapeutics, Inc., Pyun, Bo-Jeong ������������������������������������ Disclosed no conflict of interest. Pfizer Inc.;Speaker’s Bureau: Abbott, AstraZeneca, Qi, Ling ������������������������������������������������� Disclosed no conflict of interest. GlaxoSmithKline, Janssen, KOWA, Merck, Novo Qi, Lu ���������������������������������������������������� Disclosed no conflict of interest. Nordisk Inc., Takeda, Pfizer Inc. Qiu, Rong ���������������������������������������������� Employee: Janssen Research & Development, LLC. Rosenkilde, Mette M. �������������������������� Disclosed no conflict of interest.

LB108 AUTHOR RELATIONSHIP/COMPANY AUTHOR RELATIONSHIP/COMPANY Rosenstock, Julio ��������������������������������� Advisory Panel: Boehringer Ingelheim, Bristol-Myers Schreiber, Stefanie ������������������������������� Disclosed no conflict of interest. Squibb, GlaxoSmithKline, Johnson & Johnson, Schulz, Christina-Alexandra ����������������� Disclosed no conflict of interest. Lexicon, Roche; Consultant: Boehringer Ingelheim, Schurmann, Claudia ����������������������������� Disclosed no conflict of interest. Bristol-Myers Squibb, GlaxoSmithKline, Johnson Schwede, Frank ������������������������������������ Disclosed no conflict of interest. & Johnson, Lexicon, Roche; Research Support: Scirica, Benjamin M. ���������������������������� Research Support: AstraZeneca Pharmaceuticals LP. AstraZeneca, Boehringer Ingelheim, Bristol-Myers Scott, Donald ��������������������������������������� Disclosed no conflict of interest. Squibb, GlaxoSmithKline, Johnson & Johnson, Scott, Laura ������������������������������������������ Disclosed no conflict of interest. Lexicon, Pfizer, Roche. Scott, Robert A. ������������������������������������ Disclosed no conflict of interest. Rosman, Paul M. ���������������������������������� Advisory Panel: LabStyle Innovations Ltd; Consultant: Screaton, Robert A. ������������������������������ Disclosed no conflict of interest. LabStyle Innovations Ltd; Research Support: Sczelecki, Sarah ����������������������������������� Disclosed no conflict of interest. LabStuke Innovations Ltd; Speaker’s Bureau: LabStyle Seed, Paul T. ����������������������������������������� Disclosed no conflict of interest. Innovations Ltd. Seely, Ellen W. ������������������������������������� Disclosed no conflict of interest. Ross-Degnan, Dennis ��������������������������� Disclosed no conflict of interest. Segal, Jodi ������������������������������������������� Disclosed no conflict of interest. Rossi, Luca ������������������������������������������� Disclosed no conflict of interest. Segal, Karen R. ������������������������������������ Employee: Mesoblast Inc. Rother, Kristina I. ���������������������������������� Disclosed no conflict of interest. Seielstad, Mark ������������������������������������ Disclosed no conflict of interest. Rountree, Austin ���������������������������������� Disclosed no conflict of interest. Sekar, Sakthivel ������������������������������������ Disclosed no conflict of interest. Roust, Lori R. ���������������������������������������� Disclosed no conflict of interest. Selbach, Matthias �������������������������������� Disclosed no conflict of interest. Rovira-Llopis, Susana �������������������������� Disclosed no conflict of interest. Seo, Dongju ������������������������������������������ Disclosed no conflict of interest. Roy, Anirban ����������������������������������������� Employee: Medtronic, Inc.; Stock/Shareholder: Medtronic, Seo, Ji A. ���������������������������������������������� Disclosed no conflict of interest. Inc. Seo, Ji Hye ������������������������������������������� Disclosed no conflict of interest. Roy-Duval, Christine ���������������������������� Employee: Sanofi;Stock/Shareholder: Sanofi. Seramani, Sankar ��������������������������������� Disclosed no conflict of interest. Ruan, Yijun ������������������������������������������� Disclosed no conflict of interest. Sereika, Susan M. �������������������������������� Disclosed no conflict of interest. Rubio-Puchol, Olalla ����������������������������� Disclosed no conflict of interest. Serné, Erik H. ��������������������������������������� Disclosed no conflict of interest. Ruetten, Hartmut ��������������������������������� Employee: Sanofi U.S.;Stock/Shareholder: Sanofi U.S. Serpas, Lilian ��������������������������������������� Disclosed no conflict of interest. Ruiz, Tiffany ������������������������������������������ Disclosed no conflict of interest. Sesso, Howard D. �������������������������������� Research Support: Pfizer Inc. Russell, Steven J. �������������������������������� Advisory Panel: Tandem Diabetes Care, Inc.; Consultant: Sever, Sanja ����������������������������������������� Other Relationship: Co-founder of TRISAQ, a Medtronic, Inc., Sanofi U.S.;Other Relationship: biopharmaceutical company aimed to develop new Abbott Diabetes Care, Dexcom, Inc., Eli Lilly and therapies for kidney disease. Company, Insulet Corporation, Medtronic, Inc., Sanofi Severini, Cinzia ������������������������������������ Disclosed no conflict of interest. U.S., Tandem Diabetes Care, Inc.; Research Support: Sha, Haibo �������������������������������������������� Disclosed no conflict of interest. Abbott Diabetes Care, Inc. Shah, Chirag P. ������������������������������������� Consultant: Regeneron Pharmaceuticals, Inc. Rutkowski, Joseph M. ������������������������� Disclosed no conflict of interest. Shah, Kaanan ��������������������������������������� Disclosed no conflict of interest. Ryan, Alexander J. ������������������������������� Disclosed no conflict of interest. Shah, Neha ������������������������������������������ Disclosed no conflict of interest. Rydén, Lars ������������������������������������������� Consultant: Astra Zeneca, Bristol-Myers Squibb Company, Shah, Parag ������������������������������������������ Disclosed no conflict of interest.

Hoffman-La Roche Limited; Research Support: Astra Shah, Viral �������������������������������������������� Disclosed no conflict of interest. AUTHOR D I SCLOSURE Zeneca, Hoffman-La Roche Limited. Shamsi, Farnaz ������������������������������������� Disclosed no conflict of interest. Sacks, Frank M. ������������������������������������ Disclosed no conflict of interest. Shanahan, William ������������������������������ Employee: Arena Pharmaceuticals. Sackstein, Robert ��������������������������������� Disclosed no conflict of interest. Shang, Jin �������������������������������������������� Employee: Merck & Co., Inc. Saghatelian, Alan �������������������������������� Disclosed no conflict of interest. Shankar, Sudha S. �������������������������������� Employee: Eli Lilly and Company; Stock/Shareholder: Eli Saito, Tsugumichi ��������������������������������� Disclosed no conflict of interest. Lilly and Company. Sakaguchi, Masaji ������������������������������� Disclosed no conflict of interest. Shanmugham, Satya ���������������������������� Disclosed no conflict of interest. Sakai, Shinobu ������������������������������������� Disclosed no conflict of interest. Shao, Yimin ������������������������������������������ Disclosed no conflict of interest. Sakimura, Kenji ������������������������������������ Disclosed no conflict of interest. Sharifi, Amin ���������������������������������������� Disclosed no conflict of interest. Sakuma, Toshie ������������������������������������ Disclosed no conflict of interest. Sharma, Naveen ���������������������������������� Disclosed no conflict of interest. Saleh, Farrah ���������������������������������������� Disclosed no conflict of interest. Sharma, Pragya ������������������������������������ Disclosed no conflict of interest. Sales, Vicencia M. ������������������������������� Disclosed no conflict of interest. Shaw, Collin ����������������������������������������� Disclosed no conflict of interest. Salomon, Arthur ����������������������������������� Disclosed no conflict of interest. She, Jin-Xiong �������������������������������������� Disclosed no conflict of interest. Salsali, Afshin �������������������������������������� Employee: Boehringer Ingelheim GmbH. Shebani, Zachariah ������������������������������ Disclosed no conflict of interest. Samocha-Bonet, Dorit �������������������������� Disclosed no conflict of interest. Sheehan, John ������������������������������������� Employee: AstraZeneca Pharmaceuticals LP. Samovski, Dmitri ���������������������������������� Disclosed no conflict of interest. Shehata, Kristal ����������������������������������� Disclosed no conflict of interest. Samuel, Varman T. ������������������������������� Disclosed no conflict of interest. Shepherd, Peter ����������������������������������� Disclosed no conflict of interest. Sanchez, Rosalia ���������������������������������� Disclosed no conflict of interest. Sherwin, Robert S. ������������������������������� Advisory Panel: AstraZeneca Pharmaceuticals LP; Sandall, Jane ��������������������������������������� Disclosed no conflict of interest. Consultant: Bristol-Myers Squibb Company, Eli Lilly Sanders, Thomas A.B. �������������������������� Advisory Panel: Global Dairy Platform, Heinz PLC, and Company, McKinsey & Company, Merck & Co., Malaysian Palm Oil Board; Consultant: Natural Inc., Novartis Pharmaceuticals Corporation; Other Hydration Council. Relationship: MannKind Corporation, Merck & Co., Santos, Rosa Ferreira ��������������������������� Disclosed no conflict of interest. Inc., Novartis Pharmaceuticals Corporation; Research Saremi, Aramesh ��������������������������������� Disclosed no conflict of interest. Support: Merck & Co., Inc. Sasaki, Shugo �������������������������������������� Research Support: Astellas Pharma US, Inc., AstraZeneca Shi, Hang ���������������������������������������������� Research Support: NuSirt Biopharma. Pharmaceuticals LP, Boehringer Ingelheim Shibusawa, Ryo ����������������������������������� Disclosed no conflict of interest. Pharmaceuticals, Inc., Bristol-Myers Squibb Company, Shimo, Naoki ���������������������������������������� Research Support: Astellas Pharma US, Inc., AstraZeneca Daiichi-Sankyo Co., Ltd., Eli Lilly Japan K.K., Pharmaceuticals LP, Boehringer Ingelheim Johnson & Johnson, Kissei Pharmaceutical Co., Ltd., Pharmaceuticals, Inc., Bristol-Myers Squibb Company, Merck Sharp & Dohme, Mitsubishi Tanabe Pharma Daiichi-Sankyo Co., Ltd., Eli Lilly and Company, Corporation, Novartis Pharmaceuticals Corporation, Johnson & Johnson, Kissei Pharmaceutical Co., Ltd., Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd., Merck Sharp & Dohme, Mitsubishi Tanabe Pharma Sanofi U.S., Sumimoto Dainippon Pharma Co., Ltd., Corporation, Novartis Pharmaceuticals Corporation, Takeda Pharmaceutical Company Limited. Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd., Sathyanarayana, Padma ���������������������� Disclosed no conflict of interest. Sanofi U.S., Sumimoto Dainippon Pharma Co., Ltd., Satin-Smith, Marta ������������������������������ Disclosed no conflict of interest. Takeda Pharmaceutical Company Limited. Sattar, Naveed ������������������������������������� Consultant: AstraZeneca, Boehringer Ingelheim GmbH, Shimoda, Yoko ������������������������������������� Disclosed no conflict of interest. Bristol-Myers Squibb, Sanofi U.S. Shimomura, Iichiro ������������������������������� Research Support: Astellas Pharma US, Inc., AstraZeneca Savage, Peter ��������������������������������������� Disclosed no conflict of interest. Pharmaceuticals LP, Boehringer Ingelheim Sawicki, Konrad T. �������������������������������� Disclosed no conflict of interest. Pharmaceuticals, Inc., Daiichi-Sankyo Co., Ltd., Eli Scalia, Rosario ������������������������������������� Disclosed no conflict of interest. Lilly Japan K.K., Kissei Pharmaceutical Co., Ltd., Schade, David S. ���������������������������������� Disclosed no conflict of interest. Kowa Pharmaceuticals, Merck Sharp & Dohme, Schalkwijk, Casper G. �������������������������� Disclosed no conflict of interest. Mitsubishi Tanabe Pharma Corporation, Novartis Schatz, Desmond ��������������������������������� Disclosed no conflict of interest. Pharmaceuticals Corporation, Novo Nordisk A/S, Ono Scherer, Philipp ������������������������������������ Disclosed no conflict of interest. Pharmaceutical Co., Ltd., Sanofi U.S., Shionogi Inc., Schindler, Christian ������������������������������ Disclosed no conflict of interest. Takeda Pharmaceutical Company Limited. Schliess, Freimut ���������������������������������� Disclosed no conflict of interest. Shin, Jeong Jae ����������������������������������� Disclosed no conflict of interest. Schneider, Martin ��������������������������������� Disclosed no conflict of interest. Shin, Myung ����������������������������������������� Employee: Merck & Co., Inc. Schönke, Milena ���������������������������������� Disclosed no conflict of interest. Shon, Ho Sang ������������������������������������� Disclosed no conflict of interest.

LB109 AUTHOR RELATIONSHIP/COMPANY AUTHOR RELATIONSHIP/COMPANY Short, Kevin R. ������������������������������������� Disclosed no conflict of interest. Suh, Kyung-Shin ����������������������������������� Disclosed no conflict of interest. Shulman, Gerald I. ������������������������������� Disclosed no conflict of interest. Sumner, Anne ��������������������������������������� Disclosed no conflict of interest. Shungin, Dmitry ����������������������������������� Disclosed no conflict of interest. Sun, Chenglin ��������������������������������������� Disclosed no conflict of interest. Shyong, Tai E. ��������������������������������������� Disclosed no conflict of interest. Sun, Li-Ping ������������������������������������������ Disclosed no conflict of interest. Siddiqui, Uzma Mohammad ����������������� Disclosed no conflict of interest. Sun, Qi �������������������������������������������������� Disclosed no conflict of interest. Siegle, Greg J. ������������������������������������� Disclosed no conflict of interest. Sun, Wanqing ��������������������������������������� Disclosed no conflict of interest. Sievers, Felix ���������������������������������������� Disclosed no conflict of interest. Sun, Xiao Jian �������������������������������������� Disclosed no conflict of interest. Sigrist, Kirsten ������������������������������������� Disclosed no conflict of interest. Sundaresan, Sinju �������������������������������� Disclosed no conflict of interest. Silk, Maria E. ���������������������������������������� Employee: Eli Lilly and Company; Stock/Shareholder: Eli Sundelin, Elias ������������������������������������� Disclosed no conflict of interest. Lilly and Company. Super, Dennis ��������������������������������������� Disclosed no conflict of interest. Silvia, Maria Elizabeth Rossi ��������������� Disclosed no conflict of interest. Sury, Matthias �������������������������������������� Disclosed no conflict of interest. Sim, Thuan Kai Jelvin �������������������������� Disclosed no conflict of interest. Svendsen, Berit ������������������������������������ Disclosed no conflict of interest. Simell, Olli G. ��������������������������������������� Disclosed no conflict of interest. Sweet, Ian �������������������������������������������� Disclosed no conflict of interest. Siminerio, Linda ����������������������������������� Disclosed no conflict of interest. Syed, Ismail ������������������������������������������ Disclosed no conflict of interest. Simmons, Rebecca A. �������������������������� Disclosed no conflict of interest. Synold, Timothy ������������������������������������ Disclosed no conflict of interest. Sims, Emily K. �������������������������������������� Disclosed no conflict of interest. Szanto, Ildiko ���������������������������������������� Disclosed no conflict of interest. Singh, Avinainder ��������������������������������� Disclosed no conflict of interest. Tabatabai, Niloofar M. ������������������������� Disclosed no conflict of interest. Singh, Bhupinder ���������������������������������� Employee: ZS Pharma, Inc.; Stock/Shareholder: ZS Tahara, Yumiko ������������������������������������� Disclosed no conflict of interest. Pharma, Inc. Tailleux, Anne ��������������������������������������� Disclosed no conflict of interest. Singh, Kiran Pal ������������������������������������ Disclosed no conflict of interest. Taitel, Michael ������������������������������������� Disclosed no conflict of interest. Singh, Maneet ������������������������������������� Disclosed no conflict of interest. Takahara, Mitsuyoshi ��������������������������� Research Support: Astellas Pharma US, Inc., Boston Singh, Sasha ���������������������������������������� Disclosed no conflict of interest. Scientific Corporation, Johnson & Johnson, Singhal, Jyotsana �������������������������������� Disclosed no conflict of interest. Mitsubishi Tanabe Pharma Corporation, Novartis Singhal, Sharad S. ������������������������������� Disclosed no conflict of interest. Pharmaceuticals Corporation, Otsuka Pharmaceutical Sinha, Manasi �������������������������������������� Disclosed no conflict of interest. Co., Ltd., Sanofi U.S., Takeda Pharmaceutical Sinha, Rajita ����������������������������������������� Disclosed no conflict of interest. Company Limited. Sinha, Vikram P. ������������������������������������ Employee: MacroGenics, Inc. Takahashi, Yusuke �������������������������������� Disclosed no conflict of interest. Sivapalaratnam, Sutesh S. ������������������ Disclosed no conflict of interest. Takaike, Hiroko ������������������������������������� Disclosed no conflict of interest. Sjöstrand, Annika ��������������������������������� Disclosed no conflict of interest. Tam, Charmaine ����������������������������������� Disclosed no conflict of interest. Skerrett, Donna ������������������������������������ Employee: Mesoblast Inc. Tamanini, Filippo ���������������������������������� Disclosed no conflict of interest. Skjøth, Trine V. �������������������������������������� Employee: Novo Nordisk A/S; Stock/Shareholder: Novo Tan, Ruo-Ding ��������������������������������������� Consultant: Intarcia Therapeutics, Inc. Nordisk A/S. Tanenberg, Robert J. ���������������������������� Disclosed no conflict of interest. Skokos, Dimitris ����������������������������������� Disclosed no conflict of interest. Tang, Cheng Cai ����������������������������������� Employee: Eli Lilly and Company. Sleeman, Mark ������������������������������������� Disclosed no conflict of interest. Tang, Huilin ������������������������������������������ Disclosed no conflict of interest.

AUTHOR D I SCLOSURE Smith, Brian ����������������������������������������� Disclosed no conflict of interest. Tang, Yuefeng ��������������������������������������� Disclosed no conflict of interest. Smith, Steven R. ���������������������������������� Disclosed no conflict of interest. Tantawi, Hyam R. ��������������������������������� Disclosed no conflict of interest. Smulders, Yvo M. ��������������������������������� Disclosed no conflict of interest. Tattikota, Sudhir Gopal ������������������������ Disclosed no conflict of interest. Sohler, Nancy ��������������������������������������� Disclosed no conflict of interest. Taylor, Ann �������������������������������������������� Employee: Novartis Pharmaceuticals Corporation. Sohn, Hae-Young ��������������������������������� Disclosed no conflict of interest. Taylor, D. Leland ����������������������������������� Disclosed no conflict of interest. Solhjou, Zhabiz ������������������������������������� Disclosed no conflict of interest. Taylor, Hugh S. ������������������������������������� Disclosed no conflict of interest. Somesh, Baggavalli P. �������������������������� Disclosed no conflict of interest. Teague, April ���������������������������������������� Disclosed no conflict of interest. Son, Jee Woong ����������������������������������� Disclosed no conflict of interest. Temprosa, Marinella ���������������������������� Disclosed no conflict of interest. Son, Moon-Ho �������������������������������������� Disclosed no conflict of interest. Tennagels, Norbert ������������������������������� Employee: Sanofi-Aventis Deutschland GmbH. Song, Dae-Kyu ������������������������������������� Disclosed no conflict of interest. Tersey, Sarah ���������������������������������������� Disclosed no conflict of interest. Song, Yiqing ����������������������������������������� Disclosed no conflict of interest. Thaker, Vidhu ���������������������������������������� Disclosed no conflict of interest. Sontheimer, Alexandra ������������������������� Disclosed no conflict of interest. Theisen, Daniel ������������������������������������ Disclosed no conflict of interest. Sorrenson, Brie ������������������������������������ Disclosed no conflict of interest. Theiss, Hans D. ������������������������������������ Disclosed no conflict of interest. Sosenko, Jay M. ���������������������������������� Disclosed no conflict of interest. Theoharis, Stamatis ����������������������������� Disclosed no conflict of interest. Souhami, Elisabeth ������������������������������ Employee: Sanofi;Stock/Shareholder: Sanofi. Thevenet, Julien ���������������������������������� Disclosed no conflict of interest. Soumerai, Stephen ������������������������������ Disclosed no conflict of interest. Thibodeau, Asa ������������������������������������ Disclosed no conflict of interest. Southam, Lorraine �������������������������������� Disclosed no conflict of interest. Thiel, Steffen ��������������������������������������� Disclosed no conflict of interest. Souza, Sandra C. ���������������������������������� Employee: Merck & Co., Inc. Thombare, Aparna ������������������������������� Disclosed no conflict of interest. Sowers, James R. �������������������������������� Disclosed no conflict of interest. Thompson, David M. ���������������������������� Disclosed no conflict of interest. Sparre-Ulrich, Alexander H. ����������������� Disclosed no conflict of interest. Thompson, Michael ����������������������������� Disclosed no conflict of interest. Speight, Jane ��������������������������������������� Disclosed no conflict of interest. Tian, Suyan ������������������������������������������� Disclosed no conflict of interest. Sperling, Laurence S. ��������������������������� Disclosed no conflict of interest. Tinahones, Francisco J. ������������������������ Advisory Panel: AstraZeneca Pharmaceuticals LP, Spiegelman, Donna ������������������������������ Disclosed no conflict of interest. Boehringer Ingelheim Pharmaceuticals, Inc., Bristol- Spirakis, Ruth ��������������������������������������� Disclosed no conflict of interest. Myers Squibb Company, Eli Lilly and Company, Staels, Bart ������������������������������������������ Disclosed no conflict of interest. GlaxoSmithKline, Hoffman LaRoche, Merck, Merck Staimez, Lisa R. ������������������������������������ Disclosed no conflict of interest. Sharp & Dohme Limited, Novartis Pharmaceuticals Stansfield, Brain ����������������������������������� Disclosed no conflict of interest. Corporation, Novo Nordisk, Inc., Sanofi;Consultant: Staten, Myrlene ����������������������������������� Disclosed no conflict of interest. AstraZeneca Pharmaceuticals LP, Boehringer Stefanovski, Darko ������������������������������� Disclosed no conflict of interest. Ingelheim Pharmaceuticals, Inc., Bristol-Myers Squibb Steinbeck, Gerhard ������������������������������ Disclosed no conflict of interest. Company, Eli Lilly and Company, GlaxoSmithKline, Stella, Peter ����������������������������������������� Employee: Sanofi. Hoffman LaRoche, Merck, Merck Sharp & Dohme Stephens, Ella �������������������������������������� Disclosed no conflict of interest. Limited, Novartis Pharmaceuticals Corporation, Novo Stephens, Jacqueline M. ��������������������� Disclosed no conflict of interest. Nordisk, Inc., Sanofi;Research Support: AstraZeneca Stepp, David W. ����������������������������������� Disclosed no conflict of interest. Pharmaceuticals LP, Boehringer Ingelheim Stier, Christine K. ��������������������������������� Disclosed no conflict of interest. Pharmaceuticals, Inc., Bristol-Myers Squibb Company, Stirban, Alin ����������������������������������������� Disclosed no conflict of interest. Eli Lilly and Company, GlaxoSmithKline, Hoffman Stirrups, Kathy ������������������������������������� Disclosed no conflict of interest. LaRoche, Merck, Merck Sharp & Dohme Limited, Stitzel, Michael L. �������������������������������� Disclosed no conflict of interest. Novartis Pharmaceuticals Corporation, Novo Nordisk, Stolz, Daiana ���������������������������������������� Disclosed no conflict of interest. Inc., Sanofi. Stram, Daniel O. ����������������������������������� Disclosed no conflict of interest. Tinsley, Liane ���������������������������������������� Disclosed no conflict of interest. Straznicky, Nora ����������������������������������� Disclosed no conflict of interest. Tique, Claudia R. ���������������������������������� Disclosed no conflict of interest. Stringham, Heather ������������������������������ Disclosed no conflict of interest. Tobacman, Joanne K. ��������������������������� Disclosed no conflict of interest. Strongman, Helen �������������������������������� Employee: Clinical Practice Research Datalink Group Tomokazu, Nunoue ������������������������������� Disclosed no conflict of interest. performs financially supported studies for several Tong, Jenny ������������������������������������������ Disclosed no conflict of interest. pharmaceutical companies including Takeda Tonks, Katherine ����������������������������������� Disclosed no conflict of interest. Development Centre Europe. Tonne, Jason M. ����������������������������������� Disclosed no conflict of interest. Su, Xiong ���������������������������������������������� Disclosed no conflict of interest. Toppari, Jorma ������������������������������������� Disclosed no conflict of interest. Suarez-Cuervo, Catalina ���������������������� Disclosed no conflict of interest. Torres, Jason M. ���������������������������������� Disclosed no conflict of interest. Subkhangulova, Aygul �������������������������� Disclosed no conflict of interest. Torres, Lizardo �������������������������������������� Disclosed no conflict of interest.

LB110 AUTHOR RELATIONSHIP/COMPANY AUTHOR RELATIONSHIP/COMPANY Toschi, Elena ���������������������������������������� Disclosed no conflict of interest. Ingelheim Pharmaceuticals, Inc., Bristol-Myers Toumilehto, Jaakko ������������������������������ Disclosed no conflict of interest. Squibb Company, Eli Lilly and Company, Merck Trautmann, Michael ����������������������������� Disclosed no conflict of interest. Sharp & Dohme, Novartis AG, Novo Nordisk A/S, Trawley, Steve �������������������������������������� Disclosed no conflict of interest. Sanofi Pasteur SA, Takeda Pharmaceutical Company Trevino, Michelle B. ����������������������������� Disclosed no conflict of interest. Limited, Zealand Pharma A/S; Speaker’s Bureau: Tripaldi, Juliet R. ���������������������������������� Disclosed no conflict of interest. AstraZeneca Pharmaceuticals LP, Boehringer Tripathy, Devjit T. ���������������������������������� Disclosed no conflict of interest. Ingelheim Pharmaceuticals, Inc., Bristol-Myers Squibb Triplett, Eric W. ������������������������������������� Disclosed no conflict of interest. Company, Eli Lilly and Company, Merck Sharp & Tryggestad, Jeanie B. ��������������������������� Disclosed no conflict of interest. Dohme, Novo Nordisk A/S, Sanofi Pasteur SA, Takeda Tsachalina, Theofaneia ������������������������ Disclosed no conflict of interest. Pharmaceutical Company Limited, Zealand Pharma Tsai, Katherine ������������������������������������� Employee: MedImmune, LLC. A/S. Tschöp, Matthias ���������������������������������� Disclosed no conflict of interest. Vinik, Aaron I. ��������������������������������������� Advisory Panel: Merck Sharp & Dohme, Pfizer Inc.; Tseng, Eva �������������������������������������������� Disclosed no conflict of interest. Consultant: Isis Pharmaceuticals, Inc., Merck Sharp Tseng, Yu-Hua �������������������������������������� Disclosed no conflict of interest. & Dohme, NeuroMetrix, Inc., Pamlab-A Nestle Tu, Weiping ������������������������������������������ Disclosed no conflict of interest. Health Science Company, Pfizer Inc.;Research Tumlin, James A. ���������������������������������� Advisory Panel: Eli Lilly and Company; Consultant: Eli Support: American Diabetes Association, Impeto Lilly and Company; Research Support: Eli Lilly and Medical, Ipsen Bioscience, Inc., Intarcia Therapeutics, Company, Genkyotex, Gilead, Janssen Pharmaceutical Inc., National Institutes of Health, Novo Nordisk Companies of Johnson & Johnson, Mallinckrodt Inc., Sanofi U.S., ViroMed Laboratories Inc., VM Pharmaceuticals. Biopharma, Pfizer Inc.;Speaker’s Bureau: Merck Sharp Tung, Gregory ��������������������������������������� Disclosed no conflict of interest. & Dohme, Pamlab-A Nestle Health Science Company. Tuomilehto, Jaakko ������������������������������ Disclosed no conflict of interest. Vishwanath, Anu ���������������������������������� Disclosed no conflict of interest. Turcot, Valerie �������������������������������������� Disclosed no conflict of interest. Viswanathan, Prabhakar ���������������������� Disclosed no conflict of interest. Tuttle, Edward �������������������������������������� Consultant: Intarcia Therapeutics, Inc. von Eckardstein, Arnold ����������������������� Disclosed no conflict of interest. Tuttle, Katherine ����������������������������������� Consultant: Amgen Inc., Eli Lilly and Company, NOXXON von Meyenn, Ferdinand ����������������������� Disclosed no conflict of interest. Pharma AG. von Oettingen, Julia ����������������������������� Disclosed no conflict of interest. Tütüncüoglu, Aliye P. ���������������������������� Disclosed no conflict of interest. von Ziegler, Franz ��������������������������������� Disclosed no conflict of interest. Ucar, Duygu ������������������������������������������ Disclosed no conflict of interest. Voskanyan, Gayane ������������������������������ Employee: Medtronic MiniMed, Inc.; Stock/Shareholder: Uchigata, Yasuko ��������������������������������� Disclosed no conflict of interest. Medtronic, Inc. Uddén Hemmingsson, Joanna ������������� Advisory Panel: Novo Nordisk A/S, Sanofi U.S.;Other Wada, Asuka ���������������������������������������� Disclosed no conflict of interest. Relationship: Novo Nordisk A/S, Sanofi U.S.; Wada, Jun �������������������������������������������� Disclosed no conflict of interest. Research Support: InfoCare. Walker, Tomas �������������������������������������� Employee: Dexcom, Inc. Umpierrez, Guillermo E. ����������������������� Consultant: Boehringer Ingelheim Pharmaceuticals, Inc., Walter, Mary F. ������������������������������������� Disclosed no conflict of interest. Merck Sharp & Dohme, Novo Nordisk Inc., Regeneron Wanders, Desiree �������������������������������� Disclosed no conflict of interest.

Pharmaceuticals, Inc., Sanofi U.S.;Research Support: Wang, Aihua ���������������������������������������� Disclosed no conflict of interest. AUTHOR D I SCLOSURE Boehringer Ingelheim Pharmaceuticals, Inc., Merck Wang, Bingshun ����������������������������������� Disclosed no conflict of interest. Sharp & Dohme, National Institutes of Health, Novo Wang, Fang ������������������������������������������ Disclosed no conflict of interest. Nordisk Inc., Regeneron Pharmaceuticals, Inc., Sanofi Wang, Fei ��������������������������������������������� Disclosed no conflict of interest. U.S. Wang, Guang ��������������������������������������� Disclosed no conflict of interest. Üner, Aykut G. �������������������������������������� Disclosed no conflict of interest. Wang, Guixia ���������������������������������������� Disclosed no conflict of interest. Unterman, Terry G. ������������������������������� Disclosed no conflict of interest. Wang, Haiyan ��������������������������������������� Disclosed no conflict of interest. Uppal, Karan ���������������������������������������� Disclosed no conflict of interest. Wang, Hongliang ��������������������������������� Disclosed no conflict of interest. Uribe-Bruce, Liliana ����������������������������� Employee: Profil Institute for Clinical Research, Inc. Wang, Liangsu ������������������������������������� Employee: Merck & Co., Inc. Uribe-Wiechers, Ana C. ����������������������� Disclosed no conflict of interest. Wang, Lu ���������������������������������������������� Disclosed no conflict of interest. Vaidya, Anand �������������������������������������� Disclosed no conflict of interest. Wang, Ningjian ������������������������������������ Disclosed no conflict of interest. Valdes, Jorge ��������������������������������������� Employee: Dexcom, Inc. Wang, Pin-Wen ������������������������������������ Employee: Genentech, Inc. Valdes, Sergio �������������������������������������� Disclosed no conflict of interest. Wang, Renwei �������������������������������������� Disclosed no conflict of interest. Valera, Jose ����������������������������������������� Disclosed no conflict of interest. Wang, Sheng-Ping ������������������������������� Employee: Merck & Co., Inc. van Hinsbergh, Victor W.M. ����������������� Disclosed no conflict of interest. Wang, Shuxia ��������������������������������������� Disclosed no conflict of interest. van Poelgeest, Erik M. ������������������������� Disclosed no conflict of interest. Wang, Tiange ��������������������������������������� Disclosed no conflict of interest. van Polanen, Nynke ����������������������������� Disclosed no conflict of interest. Wang, Tiansheng ��������������������������������� Disclosed no conflict of interest. VanderHeiden, Anna ���������������������������� Disclosed no conflict of interest. Wang, Wang ���������������������������������������� Disclosed no conflict of interest. Vanhoutte, Jonathan ���������������������������� Disclosed no conflict of interest. Wang, Wei ������������������������������������������� Disclosed no conflict of interest. Vantyghem, Marie Christine ���������������� Disclosed no conflict of interest. Wang, Xiaojin ��������������������������������������� Disclosed no conflict of interest. Vargas, Gabriela ����������������������������������� Disclosed no conflict of interest. Wang, Xiaolin ��������������������������������������� Disclosed no conflict of interest. Vasavada, Rupangi C. �������������������������� Disclosed no conflict of interest. Wang, Xinye ����������������������������������������� Disclosed no conflict of interest. Vassileva, Maria T. ������������������������������� Disclosed no conflict of interest. Wang, Ying ������������������������������������������� Disclosed no conflict of interest. Vasudevan, Sudha �������������������������������� Disclosed no conflict of interest. Ward, Glenn M. ������������������������������������ Disclosed no conflict of interest. Vazquez-Pedreño, Luis ������������������������� Disclosed no conflict of interest. Ward, W. Kenneth �������������������������������� Advisory Panel: Xeris Pharmaceuticals, Inc.; Employee: Vehik, Kendra ��������������������������������������� Disclosed no conflict of interest. Pacific Diabetes Technologies, Inc.;Stock/ Vella, Adrian ����������������������������������������� Consultant: Bristol-Myers Squibb Company, Genentech, Shareholder: Pacific Diabetes Technologies, Inc. Inc., Novartis Pharmaceuticals Corporation, Sanofi Wardecki, Marek ���������������������������������� Employee: Sanofi;Stock/Shareholder: Sanofi. U.S., XOMA Corporation; Research Support: BioKier, Warden, Charles ���������������������������������� Disclosed no conflict of interest. Daiichi-Sankyo Co., Ltd., GI Dynamics, Inc., Merck & Wardle, Jane ���������������������������������������� Disclosed no conflict of interest. Co., Inc., Novartis Pharmaceuticals Corporation. Warren, Graham ����������������������������������� Employee: LifeScan, Inc. Vellanki, Priyathama ���������������������������� Disclosed no conflict of interest. Watada, Hirotaka ��������������������������������� Research Support: Astellas Pharma US, Inc., AstraZeneca Vendelbo, Mikkel H. ����������������������������� Disclosed no conflict of interest. Pharmaceuticals LP, Boehringer Ingelheim Venkataranganna, Marikunte V. ����������� Disclosed no conflict of interest. Pharmaceuticals, Inc., Daiichi-Sankyo Co., Ltd., Vento, Flor �������������������������������������������� Disclosed no conflict of interest. Eli Lilly Japan K.K., Johnson & Johnson, Kissei Verma, Mahesh Kumar ������������������������ Disclosed no conflict of interest. Pharmaceutical Co., Ltd., Merck Sharp & Dohme, Veyrat-Durebex, Christelle ������������������� Disclosed no conflict of interest. Mitsubishi Tanabe Pharma Corporation, Novartis Victor, Victor M. ����������������������������������� Disclosed no conflict of interest. Pharmaceuticals Corporation, Novo Nordisk Inc., Vikentieva, Elena ���������������������������������� Disclosed no conflict of interest. Ono Pharmaceutical Co., Ltd., Sanofi U.S., Takeda Villa, Stephanie R. �������������������������������� Disclosed no conflict of interest. Pharmaceutical Company Limited. Villanes, Sofia �������������������������������������� Disclosed no conflict of interest. Watanabe, Eiko ������������������������������������ Disclosed no conflict of interest. VIllena, Lorena ������������������������������������� Disclosed no conflict of interest. Watanabe, Richard M. ������������������������� Disclosed no conflict of interest. Vilsbøll, Tina ����������������������������������������� Advisory Panel: AstraZeneca Pharmaceuticals LP, Watson, Karol E. ���������������������������������� Disclosed no conflict of interest. Boehringer Ingelheim Pharmaceuticals, Inc., Webb, Seamus ������������������������������������� Disclosed no conflict of interest. Bristol-Myers Squibb Company, Eli Lilly and Weber, Mary Beth �������������������������������� Disclosed no conflict of interest. Company, GI Dynamics, Inc., Merck Sharp & Dohme, Wedick, Nicole M. ������������������������������� Disclosed no conflict of interest. Novo Nordisk A/S, Sanofi Pasteur SA, Takeda Weindruch, Richard ������������������������������ Disclosed no conflict of interest. Pharmaceutical Company Limited; Consultant: Weintraub, Daniel S. ���������������������������� Disclosed no conflict of interest. AstraZeneca Pharmaceuticals LP, Boehringer Weintraub, Neal L. ������������������������������� Disclosed no conflict of interest.

LB111 AUTHOR RELATIONSHIP/COMPANY AUTHOR RELATIONSHIP/COMPANY Welch, Ryan ����������������������������������������� Disclosed no conflict of interest. Lilly Japan K.K., Johnson & Johnson, Kissei Welters, Alena ������������������������������������� Disclosed no conflict of interest. Pharmaceutical Co., Ltd., Merck Sharp & Dohme, Wen, Xiaoquan ������������������������������������� Disclosed no conflict of interest. Mitsubishi Tanabe Pharma Corporation, Novartis Weng, Jianping ������������������������������������ Disclosed no conflict of interest. Pharmaceuticals Corporation, Novo Nordisk Inc., Wentzell, Katherine ����������������������������� Disclosed no conflict of interest. Ono Pharmaceutical Co., Ltd., Sanofi U.S., Sumimoto West, Shauna ��������������������������������������� Employee: UCB Pharma. Dainippon Pharma Co., Ltd., Takeda Pharmaceutical Westcott, Gregory P. ���������������������������� Disclosed no conflict of interest. Company Limited. Wharam, James F. ������������������������������� Disclosed no conflict of interest. Yamanaka, Hisashi ������������������������������� Disclosed no conflict of interest. Wheeler, Heather E. ����������������������������� Disclosed no conflict of interest. Yamazaki, Masahiro ����������������������������� Disclosed no conflict of interest. Wheeler, Michael B. ���������������������������� Disclosed no conflict of interest. Yan, Jing-He ����������������������������������������� Employee: Novartis Pharmaceuticals Corporation. Whelan, Mary �������������������������������������� Disclosed no conflict of interest. Yang, Alex �������������������������������������������� Consultant: ZS Pharma, Inc.; Stock/Shareholder: ZS White, Ariel ������������������������������������������ Disclosed no conflict of interest. Pharma, Inc. White, Ursula ��������������������������������������� Disclosed no conflict of interest. Yang, Hyuk In ��������������������������������������� Disclosed no conflict of interest. Whitlock, Kathryn B. ���������������������������� Disclosed no conflict of interest. Yang, Jae Sung ������������������������������������ Disclosed no conflict of interest. Whitworth, Melissa K. ������������������������� Disclosed no conflict of interest. Yang, Juhong ��������������������������������������� Disclosed no conflict of interest. Willett, Walter C. ��������������������������������� Disclosed no conflict of interest. Yang, Lu ������������������������������������������������ Disclosed no conflict of interest. Williams, Michelle ������������������������������� Disclosed no conflict of interest. Yang, Shaojuan ������������������������������������ Disclosed no conflict of interest. Williams, Rachael �������������������������������� Employee: Clinical Practice Research Datalink Group Yang, Wenying ������������������������������������� Disclosed no conflict of interest. performs financially supported studies for several Yang, Xiaodong ������������������������������������ Employee: Merck & Co., Inc. pharmaceutical companies including Takeda Yao, Li ��������������������������������������������������� Disclosed no conflict of interest. Development Centre Europe. Yap, Chui Sun ��������������������������������������� Disclosed no conflict of interest. Williamson, Donald A. ������������������������� Disclosed no conflict of interest. Yasuda, Tetsuyuki ��������������������������������� Disclosed no conflict of interest. Willnow, Thomas ��������������������������������� Disclosed no conflict of interest. Ye, Jenny ���������������������������������������������� Employee: Sanofi;Stock/Shareholder: Sanofi. Wilson, Lisa ����������������������������������������� Disclosed no conflict of interest. Ye, Jianping ����������������������������������������� Disclosed no conflict of interest. Wiltshire, Esko ������������������������������������� Disclosed no conflict of interest. Yeo, Kwee Poo ������������������������������������� Employee: Eli Lilly and Company. Winkler, Thomas W. ����������������������������� Disclosed no conflict of interest. Yepes, Carlos Augusto ������������������������� Speaker’s Bureau: Eli Lilly and Company, Medtronic Winters, Alexandra H. ������������������������� Disclosed no conflict of interest. MiniMed, Inc., Novo Nordisk Inc. Wisherd, Chris ������������������������������������� Disclosed no conflict of interest. Yerges-Armstrong, Laura ��������������������� Disclosed no conflict of interest. Wnendt, Stephan ��������������������������������� Disclosed no conflict of interest. Yiew, Kan Hui ��������������������������������������� Disclosed no conflict of interest. Woerdeman, Jorn �������������������������������� Disclosed no conflict of interest. Yi-Frazier, Joyce P. �������������������������������� Disclosed no conflict of interest. Woerle, Hans J. ����������������������������������� Employee: Boehringer Ingelheim GmbH. Yik Ying, Teo ����������������������������������������� Disclosed no conflict of interest. Wohlfart, Paulus ���������������������������������� Employee: Sanofi-Aventis Deutschland GmbH. Yilmaz, Hamiyet ����������������������������������� Disclosed no conflict of interest. Wojtaszewski, Jørgen F.P. �������������������� Disclosed no conflict of interest. Ying, Wei ���������������������������������������������� Disclosed no conflict of interest. Wolford, Brooke ����������������������������������� Disclosed no conflict of interest. Yogeshwari, Sivakumaran ������������������� Disclosed no conflict of interest.

AUTHOR D I SCLOSURE Wondisford, Fredric E. �������������������������� Disclosed no conflict of interest. Yoo, Hye Jin ����������������������������������������� Disclosed no conflict of interest. Wong, Chi-Ming ����������������������������������� Disclosed no conflict of interest. Yoon, Sun Ae ���������������������������������������� Disclosed no conflict of interest. Wood, Teresa ��������������������������������������� Disclosed no conflict of interest. Yore, Mark M. �������������������������������������� Disclosed no conflict of interest. Woon Puay, Koh ����������������������������������� Disclosed no conflict of interest. Yorek, Mark A. ������������������������������������� Disclosed no conflict of interest. Wouters, Kristiaan ������������������������������� Disclosed no conflict of interest. Young, Edwin ��������������������������������������� Disclosed no conflict of interest. Wright, Kathryn F. �������������������������������� Stock/Shareholder: Pfizer Inc. Young, Kristin L. ����������������������������������� Disclosed no conflict of interest. Wronkowitz, Nina �������������������������������� Disclosed no conflict of interest. Yu, Ji Hee ��������������������������������������������� Disclosed no conflict of interest. Wu, Bin ������������������������������������������������� Disclosed no conflict of interest. Yuan, Geheng ��������������������������������������� Disclosed no conflict of interest. Wu, Di �������������������������������������������������� Employee: Medtronic MiniMed, Inc. Yuan, Jian-Min ������������������������������������� Disclosed no conflict of interest. Wu, Hongyu ������������������������������������������ Disclosed no conflict of interest. Yun, Nari ����������������������������������������������� Disclosed no conflict of interest. Wu, Jimmy ������������������������������������������� Disclosed no conflict of interest. Zaharieva, Emanuela ��������������������������� Disclosed no conflict of interest. Wu, Jun ������������������������������������������������ Disclosed no conflict of interest. Zangeneh, Farhad �������������������������������� Disclosed no conflict of interest. Wu, Xiwei ��������������������������������������������� Disclosed no conflict of interest. Zavolan, Mihaela ��������������������������������� Disclosed no conflict of interest. Wu, Yan ������������������������������������������������ Disclosed no conflict of interest. Zeller, Cordula �������������������������������������� Employee: Boehringer Ingelheim GmbH. Wunderlich, F. Thomas ������������������������� Disclosed no conflict of interest. Zemel, Michael B. �������������������������������� Board Member: NuSirt Biopharma; Employee: NuSirt Xia, Fangzhen ��������������������������������������� Disclosed no conflict of interest. Biopharma; Stock/Shareholder: NuSirt Bopharma. Xia, Jonathan ��������������������������������������� Disclosed no conflict of interest. Zeng, Yanmei ��������������������������������������� Disclosed no conflict of interest. Xiao, Xianchao ������������������������������������� Disclosed no conflict of interest. Zera, Chloe ������������������������������������������� Disclosed no conflict of interest. Xu, Aimin ���������������������������������������������� Disclosed no conflict of interest. Zevallos, Juan C. ���������������������������������� Disclosed no conflict of interest. Xu, Haiyan �������������������������������������������� Disclosed no conflict of interest. Zhang, Dongming ��������������������������������� Disclosed no conflict of interest. Xu, Jing ������������������������������������������������ Disclosed no conflict of interest. Zhang, Fang ������������������������������������������ Disclosed no conflict of interest. Xu, Liou ������������������������������������������������ Disclosed no conflict of interest. Zhang, Huiliang ������������������������������������ Disclosed no conflict of interest. Xu, Ping ������������������������������������������������ Disclosed no conflict of interest. Zhang, Jinping ������������������������������������� Disclosed no conflict of interest. Xu, Shanshan ��������������������������������������� Disclosed no conflict of interest. Zhang, Junqing ������������������������������������ Disclosed no conflict of interest. Xu, Yuan ����������������������������������������������� Disclosed no conflict of interest. Zhang, Ming ����������������������������������������� Disclosed no conflict of interest. Xue, Bingzhong ������������������������������������ Research Support: NuSirt Biopharma. Zhang, Puhong ������������������������������������� Disclosed no conflict of interest. Xue, Ruidan ������������������������������������������ Disclosed no conflict of interest. Zhang, Quanjiang ��������������������������������� Disclosed no conflict of interest. Xue, Yaoming ��������������������������������������� Disclosed no conflict of interest. Zhang, Shu ������������������������������������������� Employee: Boehringer Ingelheim Pharmaceuticals, Inc. Xuhong, Hou ����������������������������������������� Disclosed no conflict of interest. Zhang, Tong ������������������������������������������ Disclosed no conflict of interest. Yaghootkar, Hanieh ������������������������������ Disclosed no conflict of interest. Zhang, Wenwei ������������������������������������ Disclosed no conflict of interest. Yajnik, Chittaranjan ������������������������������ Disclosed no conflict of interest. Zhang, Xi ���������������������������������������������� Disclosed no conflict of interest. Yajnik, Pallavi ��������������������������������������� Disclosed no conflict of interest. Zhang, Yiyi �������������������������������������������� Disclosed no conflict of interest. Yale, Jean-François ������������������������������ Advisory Panel: Abbott, AstraZeneca, Bayer, Boehringer Zhao, Peng ������������������������������������������� Disclosed no conflict of interest. Ingelheim, Eli Lilly, Janssen, Medtronic, Merck, Novo Zhao, Tieyun ����������������������������������������� Disclosed no conflict of interest. Nordisk, Sanofi;Research Support: AstraZeneca, Zhao, Zhiyun ����������������������������������������� Disclosed no conflict of interest. Boehringer Ingelheim, Eli Lilly, Janssen, Medtronic, Zhen, Wei ��������������������������������������������� Disclosed no conflict of interest. Merck, Novo Nordisk, Sanofi;Speaker’s Bureau: Zheng, Yan ������������������������������������������� Disclosed no conflict of interest. Abbott, AstraZeneca, Bayer, Boehringer Ingelheim, Zheng, Yang ����������������������������������������� Disclosed no conflict of interest. Eli Lilly, Janssen, Medtronic, Merck, Novo Nordisk, Zhong, Xueyu ��������������������������������������� Disclosed no conflict of interest. Sanofi. Zhou, Beiyan ���������������������������������������� Disclosed no conflict of interest. Yamabi, Masaki ����������������������������������� Employee: Kowa Pharmaceuticals. Zhou, Haihong �������������������������������������� Employee: Merck & Co., Inc. Yamada, Eijiro �������������������������������������� Disclosed no conflict of interest. Zhou, Joanna ��������������������������������������� Disclosed no conflict of interest. Yamada, Iwao �������������������������������������� Employee: Kowa Pharmaceuticals. Zhou, Junwen �������������������������������������� Disclosed no conflict of interest. Yamada, Masanobu ����������������������������� Disclosed no conflict of interest. Zhu, Beibei ������������������������������������������� Disclosed no conflict of interest. Yamaguchi, Satoshi ����������������������������� Disclosed no conflict of interest. Zhu, Chaoxia ���������������������������������������� Disclosed no conflict of interest. Yamamoto, Yuichi �������������������������������� Research Support: Astellas Pharma US, Inc., Zhu, Chunfang �������������������������������������� Disclosed no conflict of interest. AstraZeneca Pharmaceuticals LP, Boehringer Zhu, Meili ��������������������������������������������� Disclosed no conflict of interest. Ingelheim Pharmaceuticals, Inc., Bristol-Myers Zhu, Yingmin ���������������������������������������� Disclosed no conflict of interest. Squibb Company, Daiichi-Sankyo Co., Ltd., Eli Ziegler, Anette-Gabriele ����������������������� Disclosed no conflict of interest.

LB112 AUTHOR RELATIONSHIP/COMPANY AUTHOR RELATIONSHIP/COMPANY Ziegler, Thomas R. �������������������������������� Consultant: Abbott, Baxter; Research Support: Abbott, Zinzen, Robert P. ����������������������������������� Disclosed no conflict of interest. National Institutes of Health. Zubatov, Yelena ������������������������������������ Disclosed no conflict of interest. Zinman, Bernard ����������������������������������� Disclosed no conflict of interest. AUTHOR D I SCLOSURE

LB113