Late Breaking Abstracts

June 2016 | Volume 65 | Suppl. 1A | www.diabetes.org/diabetes

Late Breaking Abstracts LB1–LB88

Subject Index LB89–LB91

Abstract Author Index LB92–LB101

Abstract Author Disclosure Information LB102–LB117

scientificsessions.diabetes.org

ComLatepli catBreaiokingns—Hy Abstractspoglycemia

Complications—Hypoglycemia 3-LB Hypothalamic Glucose Transport Kinetics in Experimentally Induced Hypoglycemia-associated Autonomic Failure (HAAF) in Humans 1-LB AMIR MOHEET, ELIZABETH R. SEAQUIST, PIERRE-GILLES HENRY, JAMES JOERS, The Role of NPY in Adrenal Function during Recurrent Hypogly- ANJALI KUMAR, DINESH DEELCHAND, MELISSA TERPSTRA, KRISTINE KUBISIAK, cemia LYNN EBERLY, GULIN OZ, Minneapolis, MN YUNBING MA, QIAN WANG, MATTHEW D. WHIM, New Orleans, LA The hypothalamus is thought to play a critical role in glucose sensing and The counter regulatory response (CRR) is a hormonal and neuroendo- regulating counterregulatory hormone response to hypoglycemia (HG). The crine mechanism essential in restoring blood glucose levels following POSTERS mechanisms responsible for the development of HAAF remain uncertain, Complications hypoglycemia. In type 1 diabetes, the CRR is often impaired and restora- but some suggest that increased glucose transport may contribute. Here we Acute and Chronic tion of euglycemia is critically dependent on epinephrine release from the tested the hypothesis that hypothalamic glucose transport will be upregu- adrenal glands. Following recurrent episodes of hypoglycemia, common lated in healthy volunteers preconditioned with recurrent HG to induce HAAF in the diabetic state, the ability to evoke epinephrine release becomes compared to preconditioning with euglycemia (EU). progressively worse. The reasons are not clear but could involve central In these experiments we employed a standard experimental model of HAAF or peripheral mechanisms (e.g., an adrenal impairment of epinephrine syn- in humans. For preconditioning, subjects underwent 2 hyperinsulinemic EU or thesis or release). HG clamp studies on day 1 and a 3rd on day 2. Hypothalamic glucose transport To examine this issue we quantified the adrenal expression of tyrosine kinetics were assessed on day 2 after the 3rd preconditioning clamp by measur- hydroxylase (TH; the rate limiting enzyme for catecholamine synthesis) in ing hypothalamic glucose concentrations using ¹H MRS at 3 tesla over a ~1 hour (i) control mice; (ii) mice exposed once to insulin-induced hypoglycemia period during which blood glucose was experimentally increased from 95 mg/dl (IIH, blood glucose < 60 mg/dL) and (iii) mice subjected to three episodes to one of 3 target hyperglycemic levels (200, 300 or 400 mg/dl). ¹H MR spectra of IIH. We first confirmed that the hypoglycemia-induced rise in urine epi- were collected from a 10 x 12 x 13 mm³ hypothalamic voxel. Metabolites were nephrine levels was blunted after recurrent IIH. Quantification of adrenal quantified using LCModel. Mathematical modeling was used to calculate maxi- TH-ir showed that single IIH resulted in an increase in TH expression, while mum transport rate/cerebral metabolic rate of glucose (Tmax/CMRglc). this effect was blunted after recurrent IIH. In contrast, the adrenal levels 11 subjects (9M/2F, age 30±8 yrs) completed the EU pre-conditioning studies, of neuropeptide Y (NPY), an adrenal co-transmitter that inhibits TH expres- of whom 7 subjects (6M/1F, age 27±3 yrs) also completed the HG pre-condition- sion via Y1 receptors (Wang et al, 2013), were increased after single and ing studies and had successful induction of HAAF. There was no significant dif- recurrent IIH. The levels of TH were quantified in NPY knockout mice and ference in Tmax/CMRglc in subjects exposed to recurrent HG with HAAF (1.749 were now elevated after both single and recurrent IIH. The removal of NPY ± 0.143) compared to control subjects exposed to EU (1.619 ± 0.098; p=0.45). also rescued the typical attenuation in epinephrine release after recurrent In conclusion, in healthy subjects exposure to recurrent HG with induction IIH. Electrophysiological and optogenetic studies revealed no differences of HAAF did not result in upregulation of hypothalamic glucose transport. in chromaffin cell secretory capacity in wild type mice after IIH challenges. Supported By: National Institutes of Health (2R01NS35192); National Center for No impairment was observed for hepatic glucose production after recur- Advancing Translational Sciences (UL1TR000114) rent IIH, indicating the CRR downstream of the adrenal was intact. These results suggest recurrent hypoglycemia-induced CRR failure involves a peripheral defect in adrenal signaling that is due to an activity- and neuro- 4-LB peptide Y-dependent inhibition of TH synthesis. Seven-Year Outcome Data from a Computer-guided Inpatient Glu- Supported By: National Institutes of Health (DK080441, DK098134) cose Management System ROBERT J. TANENBERG, SANDRA HARDEE, CAITLIN ROTHERMEL, Greenville, NC, Vashon, WA 2-LB Inpatient hyperglycemia (HG) and hypoglycemia (HO) independently predict Fasting-induced Activation of Sympathetic Plasticity Limits morbidity and mortality. Blood glucose (BG) management via protocol-driven Hypoglycemia insulin (I) administration improves patient outcomes. Algorithmically based MANQI WANG, MATTHEW D. WHIM, New Orleans, LA computerized systems optimize the timing of BG checks and I dosing. A rise in epinephrine secretion from adrenal chromaffin cells is a key A retrospective observational study (1/2009-12/2015) evaluated the impact event in the sympathetic nervous system response to fasting and contrib- of EndoTool® (ET) computer-guided BG management system in intensive care utes to the counter-regulatory response (CRR) that opposes hypoglycemia. units at a 900-bed tertiary care teaching hospital. Patients assigned to ET How this sympathetic response is regulated during fasting is not clear. To had an indication for IV I infusion, including uncontrolled diabetes, stress HG, address this question we studied sympatho-adrenal activity in mice that and/or post-operative BG levels >140 mg/dL. We evaluated time to achieve were fed ad lib or fasted for 1 day. Fasting increased urine epinephrine but BG control in patients with HG and HO incidence. did not alter the blood glucose level, indicating that the CRR could main- Data were available for all treated patients; over 7 years, 492,078 readings tain euglycemia during fasting. Neuropeptide Y (NPY) which is co-released were obtained from 16,850 patients. ET brought HG patients’ BG to 180 mg/ with the catecholamines from neuroendocrine chromaffin cells appears to ≤ dL within 1.5-2.3 h. Minimal HO was observed, with only 0.93% of values regulate this sympatho-adrenal response because fasting did not increase <70 mg/dL and 0.03% <40mg/dL. HO showed year-on-year decreases (Figure); urine epinephrine levels in NPY knockout (NPY k/o) mice and the mice were ANOVA analysis of the percentage of BG values <70 mg/dL found a significant hypoglycemic. I.p. injection of epinephrine in fasted NPY k/o mice restored reduction in frequency, from 1.04% in 2009 to 0.05% in 2015 (P<0.0001). This euglycemia. To determine how the loss of NPY prevented epinephrine study confirms that computerized IV I administration improves inpatient BG release we assessed transmission at the preganglionic chromaffin cell → control while minimizing HO. synapse. Using acute adrenal slices, synaptic transmission was quantified by measuring evoked excitatory postsynaptic currents (EPSCs) in chromaf- Figure. Percentage of Patient Glucose Values <70 mg/dL with EndoTool: 2009 fin cells. Fasting increased the amplitude of the evoked EPSC monitored to 2015. in chromaffin cells from wild type (wt) mice. In contrast, the amplitude of the evoked EPSC was decreased in the fasted NPY k/o animals compared to fed littermates. Fasting also led to a decrease in the paired-pulse ratio (PPR) in wt animals, but to an increase in NPY k/o mice, suggesting the involvement of a presynaptic component. Furthermore, pharmacological inhibition of Y5 receptors blocked the fasting-induced increase in synaptic plasticity and epinephrine release in wt mice, resulting in hypoglycemia. We conclude that an NPY-dependent modulation of the preganglionic → chromaffin cell synapse promotes the release of epinephrine that is required to maintain euglycemia during fasting. Supported By: National Institutes of Health (DK080441, DK098134)

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LB1 Complications—Macrovascular—Atherosclerotic Cardiovascular Disease and Human Diabetes

Complications—Macrovascular— cant reduction in the risk of AMI (HR 0.80, 95% CI 0.65-0.99, P=0.04), CVA (HR Atherosclerotic Cardiovascular Disease and 0.82, 95% CI 0.74-0.91, P=0.0001), overall mortality (HR 0.48, 95% CI 0.41-0.57, Human Diabetes P<0.0001, and the composite outcome (HR 0.82, 95% CI 0.74-0.91, P=0.0002). In this analysis from a large U.S. integrated health system, GLP-1RA exposure was found to be associated with a reduction in the risk of cardiovascular events 5-LB observed and overall mortality among patients with T2D, after adjusting for

POSTERS Advanced Glycation End Products, Oxidation Products, and Devel- potential confounders. These results support the use of GLP-1RAs in the man- Complications opment of Atherosclerosis in the Veterans Affairs Diabetes Trial

Acute and Chronic agement of T2D. Conclusions regarding overall safety should be balanced by (VADT) results from prospectively designed cardiovascular outcomes studies. ARAMESH SAREMI, SCOTT K. HOWELL, PAUL J. BEISSWENGER, PETER D. Supported By: Novo Nordisk Inc. REAVEN, Phoenix, AZ, Lebanon, NH To determine whether plasma levels of advanced glycation end-products (AGEs) and oxidation products (OXs) play a role in the development atheroscle- 7-LB rosis in type 2 diabetes, we measured plasma levels of AGEs: methylglyoxal Endoplasmic Reticulum Stress and Autophagy Are Impaired in Epi- hydroimidazolone (MGHI), carboxymethyl lysine (CML), carboxyethyl lysine cardial Adipose Tissue from Heart Failure Patients With and Without (CEL), 3-deoxyglucosone hydroimidazolone (3DGH), and glyoxal hydroimida- Diabetes zolone (GHI), and OXs: 2-aminoadipic acid (2-AAA), and methionine sulfoxide EUGENIA CARVALHO, DANIEL ESPINOZA, MARISA LOUREIRO, MIGUEL PATRICIO, (MetSO) at baseline. After an average of 10 ± 2 years, we assessed for sub- MANUEL ANTUNES, ANA BURGEIRO, Coimbra, Portugal clinical atherosclerosis using carotid intima-media thickness (CIMT) n=398, Epicardial adipose tissue (EAT) has a major impact on cardiovascular (CV) coronary artery calcium (CAC) n=353, and abdominal aorta artery calcification health due to its direct cross-talk with cardiomyocytes. Insulin-stimulated glu- (AAC) n=345, among VADT participants. In separate risk factor adjusted multi- cose uptake and lipolysis in EAT cells is impaired. Although reported the role of variable regression models, 2-AAA and CEL predicted CAC; CML, CEL, and GHI autophagy and endoplasmic reticulum (ER) stress in CV health due to diabetes predicted AAC, and GHI predicted CIMT (Table). In conclusion, distinct AGEs (DM), its impact on EAT cells from heart failure (HF) is unknown. To unravel and OXs are associated with the development of subclinical atherosclerosis. ER stress and autophagy in EAT cells, genes expression was performed for GRP94, IRE1α, GADD153, Beclin-1, LAMP2, as well as p62. GRP94 expression Table. Multivariable Regression Models for Measures of Subclinical Athero- was highly increased in EAT compared to subcutaneous adipose (SAT). IRE1α sclerosis (b±SE) are Shown. expression was increased in EAT comparing to SAT. Significance remained in EAT between non-DM and DM patients comparing with SAT. GADD153 expression was increased in EAT comparing with SAT, in DM patients. ER stress marker expression is higher in EAT compared to SAT, in DM patients. Beclin-1 expression was highly increased in EAT compared to SAT. Significance remained between tissues in DM patients. There were also changes in the expression of LAMP2 (increase; p<0.058) and p62 (decrease; p<0.053) genes in EAT from HF patients. Beclin-1 expression is higher in EAT compared to SAT, in DM patients. These results support the differences between these two adipose tissue depots in HF patients, and show EAT as a possible therapeutic target in the cardiac microenvironment.

8-LB Statin-induced Glucose Intolerance SUN H. KIM, GERALD M. REAVEN, Stanford, CA Treatment with statins has been associated with an increase in risk for type 2 diabetes, but the mechanisms remain unclear. We conducted a cross- sectional study in men without diabetes treated with a statin (n=17) and without (n=23) and evaluated differences in insulin action, secretion and clearance. All had an insulin suppression test to measure insulin resistance and graded- Supported By: American Diabetes Association (1-06-CR-32 to P.D.R.); National glucose infusion test (GGIT) to measure insulin secretion rate and insulin Institutes of Health clearance rate (ICR). Statin treatment had no effect on insulin resistance or insulin secretion. Statin treatment was associated with significant (P<0.05) increase in ICR (1.3 ± 0.4 vs. 0.9 ± 0.3 L/min/m2) and decrease in insulin area- 6-LB under-the-curve (AUC, 947 ± 604 vs. 1557 ± 892) during the GGIT. Statin treat- Glucagon-like Peptide-1 Receptor Agonist Use and Rates of Cardio- ment was also associated with trend for increased glucose AUC (33 ± 3 vs. 31 vascular Events and Mortality in Patients with Type 2 Diabetes in a ± 4, P=0.06). Figure shows the relationship between insulin resistance and Large Integrated Health System ICR in men treated with and without a statin. Men on statins had higher ICR KEVIN M. PANTALONE, TODD M. HOBBS, BRIAN J. WELLS, SHELDON X. KONG, than expected for degree of insulin resistance. In conclusion, statin-associ- MICHAEL W. KATTAN, JONATHAN BOUCHARD, KEVIN M. CHAGIN, CHANGHONG ated glucose intolerance is accompanied by an increase in ICR. Therefore, YU, BRIAN SAKURADA, ALEX MILINOVICH, WAYNE WENG, JANINE M. BAUMAN, statins may worsen glucose tolerance by interfering with the normal compen- ROBERT S. ZIMMERMAN, Cleveland, OH, Plainsboro, NJ, Winston-Salem, NC satory decrease in insulin clearance in insulin-resistant individuals. In addition to lowering serum glucose in type 2 diabetes (T2D), GLP-1RAs have been reported to decrease appetite, induce weight loss, and decrease systolic Figure. blood pressure. The aim of this study was, using a large retrospective cohort, to assess the potential impact of GLP-1RA exposure on cardiovascular disease and mortality outcomes in patients with T2D. Patients with T2D between 2005-2015 (N=105,862) were identified in the enterprise-wide electronic health record at the Cleveland Clinic using a validated electronic phenotype. A time-dependent, Cox multiple regression analysis was used to assess the association between GLP-1RA exposure and the risk of acute myocardial infarction (AMI), stroke (CVA), overall mortality, as well as the composite of all three outcomes. The model adjusted for differences in demographics, hypertension, lab/vitals, past history of outcomes, and T2D medications. During the study period, patients who were exposed to GLP-1RA experienced statistically significantly fewer events after adjusting for other antidiabetic treatments and covariates, than those patients on antidiabetic regimens that did not include GLP-1RA. During the time of exposure, patients in the GLP-1RA cohort had a statistically signifi-

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LB2 Complications—Nephropathy—Basic and Experimental Science

Complications—Nephropathy—Basic and 11-LB Experimental Science Role of Annexin A1 in the Cardiac and Renal Dysfunction Associated with Experimental Type 1 Diabetes Mellitus 9-LB GARETH S. PURVIS, JIANMIN CHEN, DENNIS KUSTERS, CHRIS REUTELING- Renal Sinus Fat in Conjunction with Fatty Liver Could Impact Kidney SPERGER, EGLE SOLITO, CHRIS THIEMERMANN, London, United Kingdom, Maas- tricht, Netherlands

Function in Humans POSTERS

Type 1 diabetes mellitus (T1DM) is an autoimmune disease, which leads Complications DOROTHEA I. SIEGEL-AXEL, ROBERT WAGNER, JÜRGEN MACHANN, MARTINA to microvascular complications, including diabetic nephropathy and cardio- Acute and Chronic GUTHOFF, ULRIKE SCHMIDT, BIRGIT SCHREINER, PETER NAWROTH, SILVIO NAD- myopathy. Annexin A1 (ANXA1) is an endogenous anti-inflammatory peptide, ALIN, MOIN A. SALEEM, ALFRED KOENIGSRAINER, FALKO FEND, FRITZ SCHICK, which limits and resolves inflammation in a number of disease states. This ANDREAS FRITSCHE, ERWIN SCHLEICHER, HANS ULRICH HÄRING, Tübingen, Ger- study investigates whether endogenous ANXA1 plays a role in the devel- many, Heidelberg, Germany, Bristol, United Kingdom Previously we found that perivascular fat (cells) around arm arteries (PVFC) opment of the nephropathy/cardiomyopathy in experimental T1DM and if differs from other fat depots. Renal sinus fat (RSF) is a unique perivascular fat treatment with human recombinant (hr) ANXA1 attenuates nephropathy/ cardiomyopathy in T1DM. depot. To test if RSF influences obesity-related kidney disease, we analysed -/- the association between RSF and kidney function in nondiabetic subjects. To Left ventricle echocardiography in diabetic ANXA1 mice revealed a sig- study functional effects of RSF cells (RSFC) on glomerular cells, they were nificant decline in ejection fraction (EF; 57±0.9 vs. 64±0.8%) and, hence, cardiac dysfunction when compared to diabetic WT controls. Likewise diabetic cocultured with endothelial cells (EC) and podocytes (PO). RSF was quantified -/- by MRI, renal function by the estimated glomerular filtration rate (eGFR) and ANXA1 mice had elevated albumin-to-creatinine ratio (ACR; 105.9±7.9 vs. urine albumin/creatinine ratio measured in 449 subjects. Human RSF sections 76.5±6.2 mg/g) when compared to age-matched WT diabetic mice indicating were stained with HE, M1/M2 macrophage markers and CD31. Human EC or worsening proteinuria. When compared to diabetic WT-mice, mice treated PO were cocultured with RSFC. Fetuin-A (600 µg/ml) was added to study if with hrANXA1 have less cardiac (EF; 72±6.4 vs. 55±4.9%) and renal dysfunc- hepatokines aggravate obesity-related kidney diseases. After 24-72 h, mRNA tion (ACR; 76.5±6.2 vs. 53.1±3.4 mg/g) as a result of experimental T1DM. In expression and protein release were quantified. eGFR was negatively associ- diabetic WT mice, cardiac function progressively declined from week 7 to ated with RSF. In subjects with fatty liver RSF was associated with albuminu- week 13. Interesting, when diabetic WT-mice were given late treatment with ria. In vitro RSFC and PVFC growth was similar but differed from other fat cell hrANAX1 (week 7-13), the decline in cardiac function was halted (EF; 63±0.8 types. In RSFC the expression of proinflammatory factors, MCP-1 and HGF vs. 60±1 renal dysfunction was attenuated (CCL; 324±47 vs. 533±68 mg/g) was elevated. In cocultures RSFC caused a decrease of IL-6/8, MCP-1 and compared to age-matched diabetic mice. In experimental T1DM, ANXA1-/- mice display a more advanced disease TGF-β in PO, but an increase of HGF in EC. However, fetuin-A decreased HGF and stimulated IL-8, MCP-1, ICAM-1/ALCAM expression in EC and IL-6/8 in PO. state indicating that endogenous ANXA1 limits the progression of cardiac and renal dysfunction. In addition, treatment with hrANXA1 reduces the extent This was confirmed on protein level. The effects were mediated by NFκB and JNK signalling pathways. Immunostainings showed M1/M2 macrophages and of cardiac and renal dysfunction associated with T1DM. Importantly, late vascularization in RSF. The decrease in proinflammatory/adhesion molecules treatment with hrANXA1 given after significant disease (cardiac and renal dysfunction) had developed can halt further disease progression, showings and TGF-β in EC/PO and HGF increase by cocultured RSFC indicate a benign effect of RSF. However, fatty liver-derived fetuin-A induced proinflammatory, that hrANXA1 may be useful in the treatment of the secondary complications fibrotic, chemoattractive and adhesion molecules in glomerular cells reversing of T1DM. the reduced proinflammatory into an induced one. Thus, a crosstalk of fatty Supported By: British Heart Foundation liver and RSF may adversely affect renal physiology, as underlined by the association of RSF with albuminuria in subjects with high liver fat. 12-LB Supported By: German Federal Ministry of Education for Research (FKZ- Dipeptidyl Peptidase-4 Inhibition by Saxagliptin Prevents Inflamma- 01KQ0902F) tion and Renal Injury by Targeting the Nlrp3/ASC Inflammasome MANDEEP BAJAJ, YOCHAI BIRNBAUM, JINQIAO QIAN, YUMEI YE, Houston, TX, 10-LB Kumming, China, Galveston, TX Glucagon like peptide-1 (GLP-1) receptor activation delays the progres- Iron Accelerates the Progression of Diabetic Nephropathy by Acti- sion of diabetic nephropathy (DN) in rodents. The NOD-like receptor 3 (Nlrp3) vating Renin-Angiotensin System inflammasome plays an important role in DN. Dipeptidyl peptidase-4 inhibi- KAPIL CHAUDHARY, FOLAMI L. POWELL, SUDHA ANANTH, MARIAPPAN tors (DPP-4I) inhibit the degradation of endogenous GLP-1. We assessed GURUSAMY, RAJENDRA K. KARNATAK, SAURABH RANJAN, JAYA P. GNANA- whether DPP-4I attenuates diabetes-induced activation of the inflammasome PRAKASAM, Augusta, GA, Hershey, PA, Waterbury, CT Kidney iron accumulation has been reported in various chronic kidney dis- and progression of DN in mice with type 2 (T2DM), as well as type 1 (T1DM) eases (CKDs) including diabetic nephropathy (DN). Although catalytic iron diabetes. BTBR (T2DM), Akita (T1DM) and their matched nondiabetic control induced oxidative damage has been implicated in the progression of CKDs, the (WT) mice received 8-week treatment with Saxagliptin (Saxa) or vehicle. Kid- mechanism by which impaired iron metabolism alters the pathogenesis of DN ney weight and kidney/body weight ratio increased in the BTBR and Akita has never been investigated. In this study, we found increased iron accumula- mice compared to their WT mice. Saxa attenuated these changes in the BTBR, tion in the kidneys of type 1 (streptozotocin, STZ-induced) and type 2 (C57BLKS- but not in the Akita mice and had no effect in the WT mice. Serum BUN and Leprdb, db/db) diabetic mice. There was increased expression of iron regulatory creatinine significantly increased in the BTBR and Akita mice. Saxa attenu- genes in kidney tissues of STZ-induced and db/db diabetic mice compared to ated the increase in both the BTBR and Akita mice. Saxa improved glycemic the control mice. HFE, an important iron regulatory protein, senses the cellular control in the BTBR mice, but had no effect on glucose levels in the Akita and iron status and regulates iron uptake. To elucidate the mechanism by which iron WT mice. Serum CRP, TNFα, IL-1β, IL-6 and IL-18 were significantly higher in accumulation affects the progression of DN, we induced diabetes in wild type the BTBR and Akita mice than in the WT mice. Saxa attenuated the increase (WT) mice and Hfe knockout (KO) mice model of iron overload using STZ. Cortical in both the BTBR and Akita mice. Kidney and adipose protein levels of ASC1, kidney iron accumulation was 3-fold higher in diabetic Hfe KO mice compared to NLRP3, TNFα and Caspase-1 were higher in the BTBR and Akita mice than in diabetic WT mice. Albumin/creatinine ratio (ACR) was 2 fold higher in 12-week the WT mice. Saxa reduced the levels in both types of diabetic mice. Saxa STZ induced diabetic Hfe KO mice. Histologically, kidneys of 12-week diabetic attenuated diabetes-induced activation of the inflammasome and progression Hfe KO mice showed mild to moderate changes such as glomerular and tubular of DN. As Saxa did not affect glucose levels in the Akita mice, these effects basement membrane thickening and mesangial expansion, while WT diabetic are independent of glucose lowering. mice did not show any alterations. Expression of prorenin/renin was found to Supported By: American Diabetes Association (7-13-TS-04 to M.B.); AstraZeneca be significantly higher in diabetic Hfe KO mice compared to diabetic WT mice. Expression of Kidney injury molecule (KIM1), a marker for kidney damage, was 3 fold higher in diabetic Hfe KO mice compared to diabetic WT mice. Thus our data suggests that during diabetes, kidney iron accumulation induced activation of renin-angiotensin-system (RAS) potentially leads to systemic and/or intraglom- erular hypertension resulting in rapid progression of DN. Supported By: American Heart Association (14SDG20510062)

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LB3 Complications—Nephropathy—Clinical and Translational Research

Complications—Nephropathy—Clinical and 15-LB Translational Research The Association of Prevalent Macroalbuminuria with Levels of Sphingolipids and Glycosphingolipids at the End of the DCCT Study 13-LB NATHANIEL L. BAKER, KELLY J. HUNT, RICHARD L. KLEIN, SAMAR M. HAMMAD, COL4A3 Missense Variant Associated with Diabetic Nephropathy GABRIEL VIRELLA, MARIA F. LOPES-VIRELLA, THE DCCT/EDIC GROUP OF INVESTI- GATORS, Charleston, SC

POSTERS (DN) Is Also Associated with Glomerular Basement Membrane Width

Complications There is mounting evidence that sphingolipid metabolism is altered in (GBMW) in People with Type 1 Diabetes (T1D)

Acute and Chronic diabetes and specific sphingolipids are associated with the development of CHEN DI LIAO, ANDREW D. PATERSON, S. MICHAEL MAUER, M. LUIZA CAR- complications. We measured sphingolipids (ceramides, sphingomyelins) and AMORI, LINDA T. HIRAKI, Toronto, ON, Canada, Minneapolis, MN Meta-analysis of genome-wide association studies for DN (macroalbuminu- glycosphingolipids (hexosyl and lactosyl-ceramides) in plasma obtained from ria/end-stage renal disease vs. normoalbuminuria (NA)) identified a significant 518 type 1 diabetic patients at the close out visit of Diabetes Control and association with rs55703767 (Asp326Tyr) in COL4A3, with the minor allele Complications Trial (DCCT). We compared the sphingolipid profile of patients associated with reduced risk (OR=0.79, P=2x10-9; Todd et al., ADA 2016 late who maintained normal albumin excretion rate (AER <40 mg/24 h; n=368) and breaking abstract). To determine a functional effect of this variant we studied those who developed macroalbuminuria (MA; AER>=300 mg/24 h; n=46) dur- its association with GBMW in 253 NA, normotensive, European ancestry T1D ing the DCCT study. To test cross-sectional associations between prevalent subjects from Renin-Angiotensin System Study (RASS, Mauer et al., NEJM MA and sphingolipid species we used logistic regression models where sphin- 2009) with GFR>90 ml/min/1.73m2. GBMW, measured by electron microscopy golipids/glycosphingolipids were grouped into tertiles. Those with MA during (orthogonal intercept method) in renal biopsies, at baseline and 5 yrs after DCCT were more likely to have decreased levels of various very long chain randomization to placebo, ACE inhibitor, or ARB. Treatment did not affect sphingolipids while also having increased levels of the corresponding very GBMW (Mauer et al., NEJM 2009). Genotyping was performed using both Illu- long chain glycosphingolipids. Figure 1 presents findings within each tertile mina HumanOmni1-Quad and HumanCoreExome and genotype for rs55703767 of C20 sphingolipid and glycosphingolipid species. (p<0.001). Both ceramides agreed completely; minor allele frequency = 0.2 and genotypes were in Hardy- and glycoceramides modulate insulin action but differ in tissue specificity and Weinberg Equilibrium. 53% were female; mean±SD baseline age=30±10 yrs; mechanism of action. Further basic studies are needed to determine how very long chain sphingolipids/glycosphingolipids contribute to the development of T1D duration=11±5 yrs; HbA1c=8.6±1.4%; and GBMW=480±88nm. Linear regression using additive coding of genotype, adjusting for age, T1D duration, sex and MA and nephropathy. mean HbA1c found that for each additional minor allele mean GBMW from the Figure 1. two measures was on average 23nm thinner (SE=8, p=0.006). There was no evidence of deviation from an additive genetic model. Further adjustment for population structure within Europeans, assigned treatment and study center had little effect on the genetic association (β=20nm, SE=8, p=0.02). There was no significant evidence for heterogeneity of the genetic effect by T1D duration or mean HbA1c. The effect is consistent with the minor allele protecting from DN. Coupled with the finding that thicker GBMW is a strong independent predictor of DN in NA T1D individuals (Caramori et al., JASN 2013), this provide a structural connection between the COL4A3 variant and decreased DN risk.

14-LB

Withdrawn

Supported By: National Institutes of Health; National Heart, Lung, and Blood Insti- tute (P0NID1-HL55782); National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases (R01-DK081352, R01-DK088778); JDRF (2006-49)

16-LB Metabolic Subtypes of Type 1 Diabetes, Medication Costs, and Pro- gression of Diabetic Kidney Disease during 14 Years of Follow-Up RAIJA LITHOVIUS, IIRO TOPPILA, VALMA HARJUTSALO, CAROL FORSBLOM, PER- HENRIK GROOP, VILLE-PETTERI MAKINEN, FINNISH DIABETIC NEPHROPATHY STUDY, Helsinki, Finland, Adelaide, Australia We investigated the longitudinal cost profile of prescription medicines and progression of diabetic kidney disease in previously published metabolic subtypes of type 1 diabetes (T1D). The study included T1D patients (2,059 men, 1,924 women) from the Finnish Diabetic Nephropathy Study, a national prospective cohort. Five subtypes were created in 2008 according to 28 biochemical measures that were collected between 1999 and 2007: good glycaemic control (Subtype A), high HDL-C (B), advanced kidney disease (C), metabolic syndrome (D), and low cholesterol (E). Outpatient medication records were extracted from the Social Insurance Institution starting from 1994. The primary end-points were prescription costs for i) diabetes drugs, ii) cardiovascular drugs, and iii) other drugs. Kidney disease was defined as microalbuminuria (30mg/24 h < uAER < 300mg/24h), macroalbuminuria (uAER > 300 mg/24h) or end-stage renal disease (dialysis or transplant). The secondary end-point was progression from normal uAER (incident albuminuria). The lowest total cost was observed for subtypes A (good glycemic control) and E (low cholesterol). The advanced kidney disease subtype (C) showed 3.6-fold cost and the metabolic syndrome (D) 2.4-fold cost compared to Subtype A (P < 0.001). Costs

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LB4 Complications—Nephropathy—Clinical and Translational Research

were 1.3-fold higher in men for Subtypes C (P=0.004) and D (P=0.03) compared to women. Diabetes drug costs were 1.2-fold higher for the Subtype C in both sexes (P < 0.001). A high risk for incident albuminuria (OR = 4.5, P < 0.001) was observed for the metabolic syndrome subtype (D) when compared to Subtype A. Eighteen women had the metabolic profile of advanced kidney disease (C) but normal uAER at baseline, with up to 14-fold risk for progression into albuminuria. These results highlight the role of the metabolic syndrome in T1D as POSTERS Complications

the prelude to escalating drug costs and complications. Acute and Chronic

17-LB Effects of Linagliptin on Glycemic Control and Albuminuria in Type 2 Diabetes—The MARLINA-T2D™ Trial PER-HENRIK GROOP, MARK E. COOPER, VLADO PERKOVIC, BERTHOLD HOCHER, KEIZO KANASAKI, GUNTRAM SCHERNTHANER, KUMAR SHARMA, ROBERT C. STANTON, ROBERT TOTO, JESSICA CESCUTTI, MAUD GORDAT, THOMAS MEIN- ICKE, AUDREY KOITKA-WEBER, HANS JUERGEN WOERLE, MAXIMILIAN VON EYNATTEN, Helsinki, Finland, Melbourne, Australia, Sydney, Australia, Potsdam, Ger- many, Ishikawa, Japan, Vienna, Austria, San Diego, CA, Boston, MA, Dallas, TX, Reims, Supported By: Boehringer Ingelheim France, Biberach, Germany, Ingelheim, Germany MARLINA-T2D™ (NCT01792518), a multicenter, double-blind, placebo (PBO)- controlled clinical trial, investigated glycemic and renal effects of the DPP-4 18-LB Prevalence of Diabetic Nephropathy in Ecuador, Hispanic America inhibitor linagliptin (LINA) in patients (pts) with type 2 diabetes (T2D), albu- MARIANA GUADALUPE, GRACIELA ALVAREZ, ALBERTO CALLE, AMR RADWAN, minuria and eGFR 30 mL/min/1.73m2. In total 360 pts with T2D (HbA1c 6.5- ≥ ELSA VERA, BYRON ZUÑIGA, DOLORES VERON, CLAUDIA BERTUCCIO, QINGHUA 10%) and persistent albuminuria (urinary albumin-to-creatinine-ratio [UACR] FENG, NOEMI BAUTISTA, ALICIA CERCADO, DELMA VERON, Milagro, Ecuador, 30-3000 mg/gCr) despite stable background of single renin-angiotensin sys- Guayaquil, Ecuador, Córdoba, Argentina, New Haven, CT, Seattle, WA tem blockade were randomized to LINA (n=182) or PBO (n=178) for 24 wks. Diabetic nephropathy (DN) is a life-threatening complication of type 2 dia- Primary glycemic and key secondary renal surrogate endpoints were HbA1c betes mellitus (T2DM) and its prevalence is disproportionally higher in His- and UACR change from baseline (BL) over 24 wks, respectively. Overall mean panic population. Determining the prevalence and risk factors of DN in our BL (SD) HbA1c and geometric mean (gMean) UACR were 7.8 (0.9) % and 126 community is important to advise the policy makers for adapting health strat- mg/gCr (microalbuminuria 73.7%; macroalbuminuria 20.3%), respectively. At egies aligned with our regional priorities. We conducted a prospective, obser- wk 24, PBO-adjusted mean HbA1c change from BL was -0.60% (95% CI -0.78, vational and cross-sectional study between 09/2014 and 12/2015, by enrolling -0.43; p<0.0001; Figure 1A). PBO-adjusted gMean for time weighted average 845 study subjects (99% Confidence Ievel and ±4.4% margin of error) between of % change from BL in UACR over 24 wks was -6.0% (95% CI -15.0, 3.0; NS; 21 and 70 years old, from the general population of Guayas, Ecuador, urban Figure 1B). LINA was well tolerated with a renal safety profile consistent with and rural zones. The mean age of the study group was 43.4±13.8 years, 66.2% previous clinical trials. In conclusion, LINA significantly improved glycemic of them were women and 33.6% of them resided in rural areas. We collected control without a significant effect on UACR. Whether a renoprotective effect demographic data using a structured questionnaire and measured systemic of LINA could emerge from chronic intervention in more advanced diabetic glucose, HbA1c, creatinine (cr), and microalbuminuria (µAlb) in an overnight kidney disease is currently being explored in the ongoing CARMELINA™ trial. urine sample. T2DM group was defined as subjects with physician diagnosed Figure 1. T2DM, being on insulin or oral hypoglycemic treatment, fasting plasma glucose ≥126 mg/dl or random glucose ≥200 mg/dl and/or HbA1c ≥6.5%. DN was defined as µAlb ≥30 mg/gr-cr, estimated glomerular filtration rate <60 ml/min/1.73m2 (eGFR: calculated by chronic kidney disease epidemiology col- laboration group equation), or both. Prediabetic group (PD) was defined as individuals with fasting plasma glucose between 100 and 125 mg/dl and HbA1c between 5.7 and 6.4%. Among our study population, the prevalence of DN was 8.16% (CI 95%, 6% - 10%). The prevalence of T2DM was 16.2% (CI 95%, 14% - 19%), 50% of them had DN. The percentage of unknown diagnosis of T2DM was 21.9%. The prevalence of PD was 16.3% (CI 95%, 14% - 19%). Among subjects with DN, 76.8% of them had µAlb ≥30 mg/gr-cr, 21.7% of them had eGFR <60ml/min/1.73m2, and 13% of them had both. The prevalence of DN is alarmingly high among adults of Guayas, the most populated region of Ecuador; the high prevalence of T2DM and PD display a shadowy Ecuadorean picture, DN might become still more prevalent. Supported By: Secretaria de Ciencia y Tecnologia de Ecuador, Proyecto Prometeo; Universidad Estatal de Milagro (UNEMI-OCAS-SO-27092013, 2014 Nº26 DV)

19-LB Genome-Wide Association Study Identifies Novel Loci Associated with Baseline Renal Function and the Rate of Decline in Renal Func- tion among Chinese Patients with Type 2 Diabetes RONALD C. MA, GUOZHI JIANG, CLAUDIA C. TAM, ANDREA O. LUK, HEUNG MAN LEE, CADMON K. LIM, ALICE P. KONG, XIAODAN FAN, SI LOK, TING FUNG CHAN, KEVIN Y. YIP, NELSN TANG, STEPHEN K. TSUI, WEICHUAN YU, BRIAN TOMLIN- SON, YU HUANG, HUI YAO LAN, CHEUK CHUN SZETO, WING YEE SO, JULIANA C. CHAN, THE TRANSCEND CONSORTIUM, Hong Kong, China Diabetic kidney disease is a major cause of morbidity and mortality in patients with diabetes. We utilize a trans-omic approach to exmaine the genome, epigenome and transcriptome of patients with diabetic kidney complications. We performed a nested case-control study from the Hong Kong Diabetes Registry (HKDR). eGFR was calculated according to the Chi- nese Modification of Diet in Renal Disease (MDRD) equation. Samples were genotyped using the Illumina Omni 2.5+ exome array and genotype data was

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LB5 Complications—Neuropathy

imputed using minimac (1000G phase 3v5). After standard quality control pro- non-decliners T1D patients (n=3). The quantity and quality of total mRNA were cedures, 8.02 million SNPs (MAF ≥ 0.01) were included in the final analysis. assayed on an Agilent 2100 Bioanalyzer and libraries were prepared from 100 We included 5739 subjects in the genome-wide association analysis for base- ng total mRNA per sample using the TruSeq Stranded Total RNA Library Prep line eGFR in T2DM. In addition, we performed an analysis for change in eGFR Kit with Ribo-Zero Gold (Illumina). 18 to 25 million reads were obtained per among 4372 participants from the HKDR who were free of chronic kidney dis- sample. From 436 mRNAs that were differentially expressed (p<0.05), we ease (defined as eGFR<60 ml/min/1.73m2) at baseline, and who had at least 3 are showing the top 10 genes that were increasingly up- or down-regulated

POSTERS measurements of eGFR during the follow-up period (up to 30th June 2014). For according to renal function worsening. Complications

Acute and Chronic the change in eGFR, a linear regression model of time on eGFR (least squares This study identified genes as novel potential urinary biomarkers for DRD. method) was created, and the slope of the regression line (expressed as ml/ Validation in our T1D patients cohort is ongoing to evaluate their predictive min/1.73m2/year) was used to indicate the annual eGFR decline. Association value in DRD progression. analysis was adjusted for age of diabetes onset, gender, duration of diabetes, Table. and principal components. We identified 45 SNPs with suggestive association (p<10-5 ) with baseline eGFR, with the top association signal from chromo- Gene Gene name P value Fold some 3 (MAF 0.176, Beta -5.0297, [95% CI -6.940 to -3.1195]). Analysis for the symbol change slope of eGFR change during follow-up identified 100 variants with strong CYP4F22 cytochrome P450 family 4 subfamily F member 22 0.0002 -3.78 association with eGFR slope (p<10-5 ), with the strongest association signal SLC6A3 solute carrier family 6 member 3 0.002 -2.67 from a variant on chromosome 1, (MAF 0.149, Beta -0.3426, [95% CI -0.4693 to PKD2L1 polycystin 2 like 1, transient receptor potential 0.003 3.14 -0.2158]). Our study has identified a number of novel regions associated with cation channel renal function and decline in renal function in T2D for follow-up genotyping. MAP1LC3C microtubule associated protein 1 light chain 3 gamma 0.003 2.33 Supported By: Research Grants Council of the Hong Kong Administrative Region, China (T12-402/13-N); Focused Innovations Scheme of the Chinese University of PMP22 peripheral myelin protein 22 0.004 2.33 Hong Kong CDH6 cadherin 6 0.005 3.23 HS3ST2 heparan sulfate-glucosamine 3-sulfotransferase 2 0.005 2.68 20-LB PCDHGB2 protocadherin gamma subfamily B, 2 0.008 1.93 Hemoglobin and eGFR by Diabetes Status: Effect of High Capacity LYPD3 LY6/PLAUR domain containing 3 0.009 -2.62 Oxygen Carriers ASHLEY WILLIAMS, BAQIYYAH CONWAY, Morgantown, WV GPNMB glycoprotein nmb 0.01 2.93 Chronic hypoxia is a mediator of chronic kidney disease (CKD) progression. Supported By: São Paulo Research Foundation 2015/19000-6) Diabetes (DM) induces hyperfiltration of the kidneys leading to an excess consumption and a greater need for oxygen. Though low hemoglobin (hb) is a maker of reduced kidney function, hb may also have direct salutary (via its Complications—Neuropathy oxygen carrying capacity) or detrimental (via iron induced damage) effects on the kidney. Perflurooctanonate (PFOA) is an environmental contaminant with a high oxygen carrying capacity and has been used in synthetic blood 22-LB The Slipping Slipper Sign—A Poor Man’s Test For Severe Diabetic development and harvested organ preservation. We investigated whether Peripheral Neuropathy the relationship between Hb and eGFR varies by DM and CKD status and SURUJPAL TEELUCKSINGH, KHAMA LUTCHMANSINGH, Y. SWAMY VENKATESH, whether PFOA affects this relationship. Participants were drawn from the TERENCE SEEMUNGAL, AMBIKA RAO, Saint Augustine, Trinidad and Tobago, C8 health project (n= 5296 and 49161 w/ and w/out DM, respectively, age Columbia, SC 20). eGFR was assessed using the MDRD formula. CKD defined as eGFR ≥ < The slipping slipper sign (SSS) was studied for its ability to screen for dia- 60. Adjusting for age and sex, higher Hb was inversely related to eGFR in the betic peripheral neuropathy. The SSS is present when there is an affirmative population overall (p<0.0001). Stratifying by DM status, this inverse relation- response to the question: Have you ever lost a slipper (footwear unstrapped ship remained only in those w/out DM (β = -1.05, p<0.0001 w/out DM; β = at the ankles) while walking without being aware that you have done so? 2.20, p<0.0001 w/DM). To determine whether this was due to the hypoxia We investigated the implications of a positive SSS on traditional neuropathy of CKD, we stratified by CKD status (26% and 11%, respectively, in those w/ scores, nerve conduction studies and ultrasound of the right sural nerve in 74 and w/out DM). In those w/out CKD, Hb was inversely associated w/eGFR patients with diabetes. All subjects underwent ultrasonographic and nerve regardless of DM status (all p< 0.05). However, given the presence of CKD, conduction studies of the right sural nerve by an examiner blinded to SSS Hb was positively related w/eGFR regardless of DM status (p<0.0001 for all). status and findings evaluated against demography, clinical history, anthro- Further controlling for PFOA (p<0.0001 in all four groups), the hb-eGFR rela- pometry as well as traditional clinical and autonomic neuropathic scores. The tionship disappeared in those w/DM but no CKD but remained in those w/both duration of diabetes in SSS [median (IQR) = 10.0 (4.0-20.3)] differed signifi- DM and CKD (p<0.0001). Controlling for PFOA had no effect on the hb-eGFR cantly from patients without the SSS [median (IQR) =15.0 (8.5-25.0)], p= 0.028. relationship in those w/out DM. The divergent relationship between hb and Those with SSS were more likely to have reported a higher frequency of retin- eGFR by DM may be due to increased hypoxia in DM and CKD and the greater opathy (36.8%) and cerebrovascular accidents (18.4%) compared with those presence CKD in DM. The absence of a hb-eGFR relationship in those w/DM without, (2.8% and 13.9%, respectively, p<0.05). In SSS there was markedly uncomplicated by CKD may be due to increased hypoxia in DM in general and diminished nerve conduction as evidenced by both latency (median (IQR) 0 vs. the salutary effect of the high oxygen carrying capacity of PFOA. and 2.1 (0.0-2.9)) and amplitude ([median (IQR)]= 0 vs. 4.0 (0.0-10.8)), compared with those without SSS. Similarly, maximal thickness of the right sural nerve 21-LB measured by utrasonography at the ankle 3.0 (2.3-3.4) vs. 3.5 (3.0-3.9) and RNA Sequencing of Urinary Sediment Cells from Type 1 Diabetes leg 3.4 (2.7-3.8) vs. 3.9 (3.3-4.2) were reduced, p<0.01 in. Likewise, Toronto Patients Presenting or Not Rapid Renal Function Decline Clinical Scores and Autonomic Scores were significantly different in those MARIA B. MONTEIRO, VANESSA G. FREITAS, SUELI O. SHINJO, DANIELE P. SAN- with and without SSS. There was a strong positive Spearman’s correlation TOS-BEZERRA, KARINA THIEME, MARISA PASSARELLI, UBIRATAN F. MACHADO, for both Toronto and Autonomic scores with SSS whereas nerve conduction MARCIA S. QUEIROZ, ANTONIO M. LERARIO, SUELY KAZUE MARIE, MARIA L. findings and ultrsonographic findings were strongly negatively correlated with CORREA-GIANNELLA, São Paulo, Brazil, Ann Arbor, MI the SSS, p< 0.01. The SSS when positive identifies individuals with severe Diabetic renal disease (DRD) is a major cause of end stage renal disease diabetic peripheral neuropathy and highly abnormal nerve conduction and worldwide. Recently the use of urine in the study of DRD has increased. ultrasonographic characteristics. Besides being an organ-specific sample, urine is an easily obtainable material. We conducted urine collection of type 1 diabetes (T1D) patients to identify new progression markers of DRD. We showed increased mRNA expression of the gene encoding thioredoxin interacting protein in the urinary sediment of patients with an estimated glomerular filtration rate decline > 5 mL/ min/1.73m2 after a 2-year follow-up (“decliners”) compared to “non-decliners” patients. As a next step, we performed a RNA sequencing experiment using urinary sediment of healthy controls (n=2), decliners T1D patients (n=2) and

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LB6 Complications—Retinopathy

23-LB betes rather than T2D it is unclear whether DR can similarly benefit patients Diabetes, Prediabetes, and Obesity Are the Metabolic Drivers of with frank T2D. To address this, we investigated the effects of DR on PN in Polyneuropathy HFD-fed mice injected with streptozotocin (STZ), a model described by Yorek BRIAN C. CALLAGHAN, LEILI GAO, YUFENG LI, XIANGHAI ZHOU, EVAN REYNOLDS, MS et al. (2014) which more accurately resembles a T2D phenotype. MOUSUMI BANERJEE, EVA FELDMAN, LINONG JI, Ann Arbor, MI, Beijing, China From 5 wk of age, male C57BL6/J mice were fed either a standard diet (10% Polyneuropathy is a prevalent, disabling condition, and diabetes is the kcal fat; CTRL) or a high fat diet (60% kcal fat; HF). At 12 wk a subset of HF mice were administered with low dose STZ (1x75mg/kg, 1x50mg/kg; HF-STZ). POSTERS leading cause. Prediabetes has also been implicated, but results are conflict- Complications ing. Multiple studies have shown that the metabolic syndrome is associated At 16 wk a subset of CTRL, HF and HF-STZ mice were sacrificed for baseline Acute and Chronic with polyneuropathy, but which components drive this association remains metabolic and neuropathy phenotyping. Subsequently, additional subsets of unclear. We recruited 4,001 participants from Pinggu, China to undergo meta- HF and HF-STZ mice were placed on a 10% kcal fat diet for 8 wk (HF-DR and bolic and neuropathy phenotyping. Glycemic status was determined by the HF-STZ-DR, respectively) until study conclusion at 24 wk when terminal neu- Expert Committee on the diagnosis and classification of diabetes mellitus ropathy phenotyping was performed. definition utilizing the glucose tolerance test. Polyneuropathy was defined By study conclusion HF mice exhibit signs of impaired glucose tolerance and as a Michigan Neuropathy Screening Instrument (MNSI) examination score robust PN. As predicted, HF-DR mice displayed an improved metabolic profile greater than 2. Multivariable logistic regression evaluated the association of which corresponded with improved peripheral nerve function when compared metabolic syndrome components with polyneuropathy. The mean age was to HF mice. As a consequence of STZ administration, HF-STZ mice developed 51.64+11.77 years with 50.96% women. Glycemic testing revealed 18.7% a robust hyperglycemia compared to HF mice. Despite this hyperglycemia, the had diabetes, 44.1% prediabetes, and 37.2% normoglycemia. Polyneuropathy presentation of PN was that of a similar degree to that seen in HF mice. Simi- was observed in 15.3% with diabetes, 6.3% with prediabetes, and 3.2% with lar to HF-DR mice, after 8 wk of DR HF-STZ-DR mice had significantly improved normoglycemia (p<0.001 for trend). Diabetes (OR=2.64, 95% CI 1.80-3.86) metabolic profile and PN was corrected. and weight (OR 1.09, 95% CI 1.02-1.17) were the only metabolic syndrome In conclusion, DR of HF-STZ mice can improve the metabolic profile and measures significantly associated with polyneuropathy. The polyneuropathy restore peripheral nerve function. This study supports the idea that dietary prevalence increases with worsening glycemic status. Diabetes, prediabetes, intervention is a feasible strategy in improving peripheral nerve health both and obesity are the likely metabolic drivers of polyneuropathy. in patients with pre-diabetes and T2D. Supported By: Novo Nordisk Foundation (NNF14SA0006); National Institutes of Table. Association of Metabolic Components and Polyneuropathy. Health/National Institute of Diabetes and Digestive and Kidney Diseases (1 R24 Parameter Adjusted OR (95% CI) 082841); National Institutes of Health (1 DP3 DK094292) Diabetes 2.64* (1.80, 3.86) Pre-diabetes 1.22 (0.84, 1.75) 26-LB Height 1.20* (1.05, 1.37) Demyelination and Axonal Loss in Diabetic Polyneuropathy Is Indi- unit=5cm cated by Magnetic Resonance Diffusion Tensor Imaging Weight unit=5kg 1.09* (1.02, 1.17) MICHAEL VAEGGEMOSE, MIRKO PHAM, STEFFEN RINGGAARD, H. TANKISI, NIELS EJSKJAER, PER L. POULSEN, HENNING ANDERSEN, Aarhus, Denmark, Heidelberg, SBP unit=10 mm Hg 1.03 (0.96, 1.11) Germany, Odense, Denmark Triglycerides unit=50 mg/dL 1.01 (0.96, 1.06) Hypothesis and Aim: Threefold: 1) to evaluate the use of magnetic reso- HDL unit=50 mg/dL 0.99 (0.87, 1.12) nance (MR) diffusion tensor imaging (DTI) for detecting neuropathy, 2) to demonstrate nerve lesions in patients with type 1 diabetes and 3) to describe the Supported By: National Institutes of Health (NS079417) pathophysiology of these lesions. We have previously presented data on nerve MR-volumetrics in diabetic peripheral neuropathy (ADA oral presentation). 24-LB Methods: Ten type 1 diabetic patients with polyneuropathy (+PNP), 10 type Dysregulation of MicroRNA Profile during Diabetic Wound Healing 1 diabetic patients without polyneuropathy (-PNP) and 10 healthy controls (HC) LOUISE T. DALGAARD, RIE JUUL WILLEMOES, ANJA E. SØRENSEN, RITA S. FER- were included. Diffusion tensor images were acquired to evaluate the extent REIRA, ERMELINDO C. LEAL, EUGENIA CARVALHO, Roskilde, Denmark, Coimbra, of focal lesions in the sciatic and tibial nerve using a 3 Tesla scanner. DTI frac- Portugal tional anisotropy (FA) and apparent diffusion coefficients (ADC) were calcu- Impaired wound healing is a serious diabetic complication. MicroRNAs lated. The MR scans consisted of 16 axial slices of the sciatic nerve and the (miRNAs) are dynamically regulated by environmental factors. The hypothesis tibial nerve. The presence of PNP was determined based on nerve conduction is that skin miRNAs are dysfunctional in diabetes, leading to abnormal wound studies, vibratory perception thresholds and clinical neurological examination. healing. The regulation/function of miRNAs was studied in diabetic and con- Results: FA values of the sciatic nerve were significantly lower in diabetic trol mice at days 0, 3 and 10 post wounding. Wound healing was delayed in patients with PNP compared to controls and diabetic patients without PNP, diabetic mice (p<0.01). A miRNA profile was determined for over 561 miRNAs (+PNP: 0.38 (0.25-0.43), -PNP: 0.47 (0.41-0.52), HC: 0.48 (0.41-0.59)) (median, using Taqman MicroRNA array cards. 288 different miRNAs were identified range) (p < 0.01). Furthermore, there was a difference in the ADC between with a Ct level <32, and the majority was over 1.5 fold decreased by wound- the groups, (+PNP: 1611 (1382-2220), -PNP: 1489 (1389-1599), HC: 1420 (1250- ing, and 63 were over 1.5 fold decreased in skin, whereas 41 miRNAs were 1608)) (p < 0.01). Results from the tibial nerve where equivalent. increased over 1.5 fold by wounding and 94 were increased by diabetes. Data Conclusion: This study using diffusion tensor imaging of the sciatic and tib- were filtered for predicted miRNA targets (TargetScan database) and path- ial nerve showed lower FA values and higher ADC values in diabetic patients way analysis was done using Gene-Ontology (GO) Biological Process terms. with PNP as compared to healthy controls and non-neuropathic patients. Predicted mRNAs collectively targeted by miRNAs up-regulated in diabetes Lower FA values and higher ADC may reflect less constriction of flow along the were enriched for cellular biosynthetic processes and transcription (p<0.05 nerve indicating demyelination and axonal loss in PNP. Our findings indicate a and p<0.004). Categories related to extracellular matrix were enriched in pre- possible pathophysiology for the development of diabetic PNP. dicted targets for miR-29a (p<4.0E-05). miRNA profile is markedly changed during diabetic wound healing and GO analysis suggest regulation of cellular metabolism and extracellular matrix formation. Complications—Retinopathy

25-LB 27-LB Dietary Reversal Ameliorates Peripheral Neuropathy in HFD-STZ The Hippo Pathway Is Disturbed in Rats with Diabetic Retinopathy Mice JING HAN, YAN WU, TIANTIAN LV, HONGLIANG WANG, WEI XING, Beijing, China PHILLIPE D. O’BRIEN, LUCY M. HINDER, JOHN M. HAYES, CAREY BACKUS, ELISA- The Hippo pathway has been a hot spot in recent years. It was firstly discov- BETH S. BRUNO, EVA L. FELDMAN, Ann Arbor, MI ered in Drosophila and evolutionally conserved in mammals. The Hippo path- Peripheral neuropathy (PN) is a common complication of type 2 diabetes way consists of a pair of related serine/threonine kinase: MST1/2 and Lats1/2. (T2D) for which no effective treatment currently exists. We have evidence The latter one phosphorylates YAP and TAZ, otherwise they will translocate demonstrating that PN which manifests in high fat diet (HFD)-fed mice can be into nuclear and interact with transcriptional factors TEAD. The Hippo pathway completely corrected through a paradigm of dietary reversal (DR). As HFD-fed is first described as a regulator of tissue growth by controlling cell proliferation mice more closely represent a model of impaired glucose tolerance/predia- and apoptosis, then recognized to be associated with cancer development. But

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LB7 Complications—Retinopathy

whether this signaling pathway plays a role in diabetic retinopathy (DR) is not Markov model to undertake CUA. The risk component was modelled using defined. So in this experiment, we aim to examine the changes of proteins of the current distribution of RDR which provided the relative costs and quality the Hippo pathway in retina of diabetic model, and then clarify the character adjusted life years (QALY) estimates for delayed screening. Transition and risk taken by this signaling pathway in DR. The diabetes was established in rats by were individually modelled for T1DM and T2DM. All estimates are based on intraperitoneal injection of streptozocin (STZ). According to previous studies, a 20 year time horizon. DR was set up in STZ induced rats after 32 weeks. So the retinas of rats were Data from 2,286 and 36,202 persons with T1DM and T2DM respectively

POSTERS removed to assess the alterations of the proteins of the Hippo pathway at that were analysed. HbA was the strongest predictor of the risk of progression to

Complications 1c

Acute and Chronic time. The distribution and expression of P-MST1/2 and P-YAP were detected RDR. At HbA1c values (at the time of screening) of 6.5, 8.0 and 9.5% the cohort by immunohistochemistry. In addition, the levels of Lats1, TAZ and TEAD were of persons with T1DM were estimated to lose a QALY for a cost saving to measured by Western blot. The results showed that compared with normal screening of £17,846, £5,891 and £15 respectively. The cohort of persons with control rats, P-MST1/2 level in inner plexiform layer and P-YAP in photorecep- T2DM for the same HbA1c level saved screening £73,199, £35,613 and £16,843 tor layers decreased in diabetic rats’ retinas. Moreover, the rats displayed a for each QALY lost. The cost saving for one QALY lost is over 6 times higher significant increase in Lats, TAZ and TEAD in 32 weeks of diabetes. Our results for T2DM compared to T1DM at a HbA1c 8%. demonstrate that the activity and expression levels of the Hippo pathway are Trading off QALYs lost versus NHS savings in relation to existing notions disturbed in the course of DR and it suggests that this signaling pathway is of value for money and the distinct difference in the risk of progression to involved in the development of DR. But in the end we have to point out that RDR between persons with T1DM and T2DM suggests that extending screen- our evidence is correlative and clear links between mutation events in Hippo ing intervals in persons with T2DM is cost effective based on CUA. This is in pathway and progression of DR are needed if we attempt to reveal the function marked contrast to those with T1DM in whom based on this evidence annual of Hippo pathway in DR. screening remains justified. Supported By: Health and Care Research Wales 28-LB Bariatric Surgery Reduces the Long-Term Incidence of Retinopa- 30-LB thy and Nephropathy in Obese Patients with Screen Detected and Diabetic Macular Edema Identified by Optical Coherence Tomogra- Known Type 2 Diabetes (T2D) phy (OCT) Screening during Diabetes Primary Care Visits BJÖRN CARLSSON, MARKKU PELTONEN, KAJSA SJÖHOLM, LENA CARLSSON, JENNIFER K. SUN, RUTH S. WEINSTOCK, MARK WARREN, MARCEL B. TWA- Mölndal, Sweden, Helsinki, Finland, Gothenburg, Sweden HIRWA, JOSHUA I. BARZILAY, MADHU K. MOHAN, TRACI CLEMONS, DME FOUND Bariatric surgery often causes diabetes remission in obese patients, espe- STUDY GROUP, Boston, MA, Syracuse, NY, Greenville, NC, Edinburg, TX, Duluth, GA, cially in newly diagnosed diabetes. We have previously reported that it also Lanham, MD, Rockville, MD reduces the incidence of overall macrovascular and microvascular complica- Diabetic macular edema (DME) from abnormal vascular permeability is a tions in the Swedish Obese Subjects (SOS) study, a prospective controlled major cause of vision loss from diabetes, often beginning without symptoms. trial comparing bariatric surgery and usual care. We have now analyzed the Advances in treatment have improved visual outcomes in DME, but many effects of bariatric surgery on retinopathy, nephropathy and neuropathy, patients do not receive timely eye screening to identify DME and permit them traced in nationwide registers, in SOS patients with screen detected T2D to seek treatment to preserve vision. Early identification of DME and prompt (n=246) and established T2D (n=357, mean duration 5.2 years) followed for up referral to retina specialists could reduce DME-related vision loss. To address to 26 years. Bariatric surgery reduced the incidence of retinopathy in patients this issue, we performed a multicenter, prospective clinical study to deter- with screen detected T2D [incidence rate 6.3 and 19.2 per 1000 person years mine whether point-of-care, undilated optical coherence tomography (OCT) in the surgery and control groups, respectively; HR=0.27 (0.15-0.50), p<0.001] retinal imaging combined with an OCT-guided referral algorithm at diabetes and established T2D [incidence rate 25.9 and 46.9 per 1000 person years in the primary care visits facilitates retina specialist care for patients with DME. surgery and control groups, respectively; HR=0.51 (0.37-0.70), p<0.001]. The Patients with A1c > 10% or diabetes duration > 10 years were enrolled. Need incidence of nephropathy was also reduced by bariatric surgery in both sub- for referral was determined based on OCT retinal thickness parameters and groups [screen detected T2D: incidence rate 3.8 and 9.7 per 1000 person years image quality alone. Across 9 sites, 382 adults with type 1 or 2 diabetes were in the surgery and control groups, respectively; HR=0.37 (0.17-0.81), p=0.012; enrolled and underwent OCT. Baseline characteristics were: mean±SD age established T2D: incidence rate 18.8 and 9.6 per 1000 person years in the 54±14 yrs, A1c 9.1±1.9%, diabetes duration 19±11 yrs; 36% type 1 diabetes; surgery and control groups, respectively; HR=0.48 (0.30-0.77), p=0.002]. Com- 65% Caucasian and 50% female. In this cohort, 77% reported a previous eye plications affecting nerves were few and there was no difference in incidence examination of which only 62% were dilated; 11% were undilated and 27% did between the surgery and control groups [screen detected T2D: incidence rate not recall dilation status. After OCT, 42 participants (11%) were referred for 2.1 and 3.3 per 1000 person years in the surgery and control groups, respec- retinal evaluation based on central-involved retinal thickening (N=27), thick- tively, p=0.322; established T2D: incidence rate 4.3 and 6.8 per 1000 person ening threatening the retinal center (N=12) or low OCT signal (N=3) suggestive years in the surgery and control groups, respectively, p=0.206]. We conclude of possible ocular pathology. Only 7 (16%) of these patients had previously that bariatric surgery is associated with reduced long-term incidence of com- been seen by a retina specialist. These data suggest that identification of plications affecting eyes and kidneys both in patients with screen detected patients at risk for vision loss from DME using OCT is feasible within the dia- T2D and established T2D. betes primary care setting, finding pathology that warrants further referral in Supported By: National Institute of Diabetes and Digestive and Kidney Diseases nearly 10%. OCT screening may thus enable improved detection of disease, (R01DK105948); Swedish Research Council; Swedish Federal Government; Swedish thereby potentially improving access to care and visual outcomes in patients Diabetes Foundation with diabetes. Supported By: JDRFI (17-2012-371); Genentech 29-LB Economic and Patient Impact of Biennial Screening for Diabetic 31-LB Retinopathy Predicting Visual Acuity Response to Anti-VEGF DME Therapy in Pro- REBECCA L. THOMAS, THOMAS G. WINFIELD, STEPHEN D. LUZIO, RAJESH PETER, tocol I: A Post-hoc Analysis of Outcomes in Patients with Limited and FRANK D. DUNSTAN, PIPPA ANDERSON, DAVID R. OWENS, Swansea, United King- Intermediate Response at 12 Weeks dom, Cardiff, United Kingdom VICTOR H. GONZALEZ, McAllen, TX This study examined the economic and patient benefits based on cost utility Purpose: Early prediction of anti-VEGF response may facilitate timely con- analysis (CUA) of extending screening from annual to biennial in persons with- sideration of additional therapies, for patients unlikely to achieve optimal out diabetic retinopathy (DR) at last screening in persons with type 1 (T1DM) BCVA response over time. This analysis assessed long-term BCVA outcomes and type 2 diabetes (T2DM) attending a National DR Screening Service in at years 1-3, in patients with limited or intermediate BCVA response to ranibi- Wales (DRSSW), UK. zumab at week 12. Data from DRSSW and Primary Care were linked using secure anonymised Methods: A post-hoc analysis of the DRCRnet Protocol I data was con- information linkage. This allowed DR results to be analysed along with other ducted that included DME patients randomized to ranibizumab+deferred or putative risk factors (HbA1c, known duration and current treatment of diabe- prompt laser. Patients were stratified by observed BCVA response at week 12 tes, blood pressure, gender and smoking status). Weibull regression analysis into three cohorts: <5 letters, 5-9 letters, and ≥10 letters improvement. Visual was used to estimate transition risks (risk of progression to referable DR, acuity outcomes, measured by mean BCVA change from baseline (CFB) and RDR) within the screening pathway which then populated a time varying proportion of ≥10-letter gainers at 1 and 3 years, were evaluated.

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LB8 Diabetic Dyslipidemia

Results: 340 patients met inclusion criteria. At week 12, 135 (39.7%) was consistent with a decrease in conversion of labelled citrate into hepatic patients showed limited early response (<5 letters improvement), 79 (23.2%) lipids. DIO mice treated with the same dose also showed a complete reversal patients had intermediate early response (5-9 letters improvement), and 126 of glucose intolerance following an OGTT. This was also associated with a (37.1%) patients had strong early response (≥10 letters improvement). Differ- modest reduction in plasma glucose concentrations. In summary, we intro- ences in mean BCVA CFB at week 12 (-0.3, +6.9 and +15.2; p<0.001) remained duce a novel, potent and selective inhibitor of NaCT, which reduces hepatic evident at week 52 (+2.8, +8.2 and +16.5, p<0.001) and week 156 (+3.0, +8.2 lipid production and plasma glucose following an OGTT. and +13.8; p<0.001). Controlling for potential confounders, a significant asso- POSTERS Complications ciation remained between BCVA response at week 12 and BCVA response at 34-LB Acute and Chronic weeks 52 and 156 (p<0.001 for both). The majority of limited and intermediate Increased Electronegative LDL in Type 2 Diabetes Promotes Cardiac early responders (77.0% and 55.7%) failed to gain ≥10 letters from baseline by Dysfunction through Inducing Endothelial Hyperpermeability week 52, with mean BCVA CFB at week 156 for these patients of 1.2 and 4.8 AN SHENG LEE, WEI YU CHEN, CHIN HU LAI, TZU YU HSU, CHU HUANG CHEN, letters, respectively. Moreover, among intermediate early responders, 27.8% Taipei, Taiwan, Taichung, Taiwan, Houston, TX regressed to <5 letters improved from baseline by week 156. L5, the most electronegative low-density lipoprotein (LDL) subfractions (L1- Conclusion: Long-term BCVA response to ranibizumab in DME can be pre- L5), is increased in patients with type 2 diabetes. Although L5 can induce dicted after 12 weeks. endothelial dysfunction via lectin-like oxidized LDL receptor-1 (LOX-1), whether it could exacerbate cardiac function by inducing endothelial hyperpermeabil- 32-LB ity is unclear. We injected C57/BL6 mice with human L5 or L1 for 4 weeks. Impact of the IRIS-EHR Integration on Engagement and Efficiency in a The heart from L5 but not L1 mice showed strong staining for DiI-labeled LDL, Teleretinal Examination Program for Diabetic Retinopathy and the endothelium from L5 mice showed expression changes in adherens BRIAN REED, YVONNE CHU, CHRISTINA WENG, KELLEY CARROLL, JAMES CAMP- junction proteins. This means L5 may penetrate microvessel into heart by in BELL, SUNIL GUPTA, JONATHAN STEVENSON, Houston, TX, Pensacola, FL ducing coronary hyperpermeability. We then examined the cardiac effect of Telemedicine solutions for eye exams have become increasingly prevalent L5 by analyzing pressure-volume loop data. Preload-independent parameters in the management of diabetic patient populations. As more primary care showed both systolic and diastolic dysfunction in L5-treated mice. Moreover, physicians (PCPs) adopt this approach to complete the diabetic eye exam, premature ventricular contractions occurred in 1 of 4 L5-injected mice. The integration into the everyday work flow is critical in driving its sustainability. cardiac dysfunction caused by L5 was not seen in LOX-1-/- mice. To further The IRIS teleretinal exam platform consists of a non-dilated fundus camera, clarify the underlying mechanisms, isolated myocytes were used to examine cloud-based reading center, and secure Internet-based transfer portal. In the electrophysiologic effect of L5 by patch clamp and calcium image system. October 2015, the Harris Health System (HHS, Houston, TX) integrated their It showed action potential prolongation and calcium overload in L5 but not previously-standalone IRIS teleretinal examination program with their cur- L1-treated mice. To our knowledge, this is the first study to show that a natu- rent EHR, Epic. To assess the outcomes post-EHR integration, we conducted rally occurring human LDL subfraction can directly induce cardiac contractile a survey of providers and technicians to identify and evaluate perception in and conductive dysfunction. terms of efficiency, engagement, and patient access compared to that prior to Figure. integration. According to the survey, 86% of PCP respondents reported that the IRIS-EHR integration increased access for their patients receiving diabetic retinal exams. After the Epic integration, 69% of PCP respondents reported a decrease in the time it took to obtain results of a patient’s scan. 75% of technicians reported a 4-fold decrease in the amount of time spent manually uploading results after the integration. 83% of PCP respondents considered the IRIS reports to be helpful for managing diabetic patients, and over 77% of respondents were satisfied with the efficiency of the integrated product. Post-integration, patient examination volume increased 49.4% compared to same period prior year. Based on the results of this survey, the integration of the IRIS teleretinal examination program with an EHR system led to increased utilization as well as higher physician engagement and the perception of decreased operational time and effort.

Diabetic Dyslipidemia

33-LB Discovery of Novel Inhibitors of the Sodium-Coupled Citrate Trans- porter (SLC13A5) MATTHEW GORGOGLIONE, KIM HUARD, JESSICA JONES, JANICE BROWN, KEITH RICCARDI, NICHOLAS VERA, CECILE VERNOCHET, JEFFREY PFEFFERKORN, DEREK Supported By: Ministry of Science and Technology of Taiwan (MOST-104-2320- ERION, Cambridge, MA, Groton, CT B-715-009-MY3, MOST-103-2314-B-715-008); Mackay Medical College (1021A06, Citrate is a critical regulatory metabolic intermediate as it facilitates the 1031B14, 1041B08) assimilation of glycolysis and lipid synthesis. Inhibition of hepatic citrate uptake by blocking the sodium-coupled citrate transporter (NaCT or SLC13A5) 35-LB has been suggested as a potential therapeutic intervention to treat metabolic MEDI4166: A PCSK9 Ab-GLP-1 Fusion Molecule that Elicits Robust disease. A virtual search of Pfizer’s compound library for structures similar to Antidiabetic and Antihyperlipidemic Effects In Rodents and Nonhu- the transporter’s preferred substrate citrate was conducted and 500 com- man Primates pounds were selected for testing in a HEK-293-derived stable cell line over- JAMES L. TREVASKIS, ARTHUR T. SUCKOW, TIM HUMMER, MATTHIEU expressing SLC13a5 (HEKNaCT). This led to the discovery of 2 (PF-06649298), a CHODORGE, ANTHONY CELESTE, DAVID HORNIGOLD, JACQUI NAYLOR, LESLEY dicarboxylate which inhibited 50% of the citrate uptake from the media into JENKINSON, MICHAEL FEIGH, DAVID FAIRMAN, BALAJI AGORAM, CHARLES LEE, the cell (at 0.80 µM). Using a tritiated analog of 2, we observed a competitive STEVEN COATS, JOSEPH GRIMSBY, CRISTINA RONDINONE, ANISH KONKAR, interaction between citrate and 2 with increasing concentrations of citrate, North Bethesda, MD, Cambridge, United Kingdom, Ann Arbor, MI, Copenhagen, Den- suggesting a common binding site on NaCT. To test the inhibitory effects in a mark natural environment, we used cryopreserved human hepatocytes (CHH) and Type 2 diabetes (T2D) is a chronic metabolic disease characterized by observed inhibition of citrate uptake, albeit with a significant shift in potency hyperglycemia and increased cardiovascular (CV) risk. Achieving robust glyce- (0.41 µM in HEKNaCT vs. 16.2 µM in CHH). To test the effects of 2 in vivo steady mic control and significantly reducing CV risk are twin goals that are the cor- state intravenous infusion of 2 in rats demonstrated significant uptake of nerstone of therapy in type 2 diabetic subjects. MEDI4166 is a genetic fusion compound in liver and kidney, as opposed to plasma. Livers of mice dosed molecule comprising a GLP-1 analog linked to an anti-proprotein convertase with 250 mg/kg showed a 33% reduction in labelled citrate uptake, which subtilisin/kexin type 9 (PCSK9) antibody. MEDI4166 has been engineered to

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LB9 Diabetic Dyslipidemia

provide optimal glycemic control and PCSK9 suppression in one molecule. 37-LB Potency at the GLP-1 receptor has been modulated to provide optimum phar- One-Year Post-marketing Surveillance Study of Saroglitazar in macological benefit while potentially minimizing GLP-1-induced side effects at Patients with Diabetic Dyslipidemia exposures necessary to efficiently suppress PCSK9. MEDI4166 fully activated ANUJ MAHESHWARI, BANSHI SABOO, NARSINGH VERMA, Lucknow, India, GLP-1 receptors expressed in CHO cells relative to native GLP-1, and was Ahmedabad, India able to restore LDL uptake by HepG2 cells treated with recombinant PCSK9. Saroglitazar is the world’s first approved dual PPAR α/γ agonist. It is cur- POSTERS MEDI4166 (1 or 10 mg/kg) administered subcutaneously (sc) into diet-induced Complications rently approved in India for the treatment of hypertriglyceridemia in type 2

Acute and Chronic obese (DIO) mice reduced blood glucose levels up to 7 days following a single diabetes not controlled with statin. This was a post-marketing surveillance injection. The effects of the higher dose on glucose lasted up to 14 days post- study conducted with the objective to evaluate the safety and efficacy of saro- dosing. Repeated once-weekly (QW) dosing with MEDI4166 (3, 10 or 30 mg/ glitazar 4mg once daily. Total 106 patients with diabetic dyslipidemia were kg, sc) for 26 days reduced body weight and fat mass in a dose-dependent included in this study. The mean age of study population was 54.82 years and manner in DIO mice. In addition, MEDI4166 significantly reduced blood glucose 66% participants were male. At baseline, all patients were on stable doses at all doses investigated. Repeated QW administration of MEDI4166 (3, 10 or of Metformin and 99% patients were on statin therapy. The mean baseline 30 mg/kg, sc) for 4 weeks in diabetic db/db mice dose-dependently reduced triglycerides (TG) and Non-HDL cholesterol were 252.69 mg/dl and 164.35 4 h fasted blood glucose levels. In addition, a single dose of MEDI4166 (10 mg/ mg/dl respectively. All patients were prescribed saroglitazar 4mg once daily kg, sc) administered to cynomolgus monkeys produced a decrease in LDL-C without changing the doses of on-going statin therapy. At 12 months follow- that correlated with a MEDI4166-mediated decrease in free PCSK9 levels in up, the TG was reduced from 252.69 mg/dL to 161.55 mg/dL (p<0.0001) and serum. Based on these results, MEDI4166 is being developed for the treat- non HDL-C level was reduced from 164.35 mg/dL to 107.02 mg/dL (p<0.0001). ment of T2D in patients who require control of blood glucose and LDL-C. Mean HbA1c was also significantly reduced from 8.17% at baseline to 6.77% after 1 year saroglitazar therapy in combination with other antidiabetic medi- 36-LB cations (p<0.0001). No major adverse event reported during 12 month follow- Apolipoproteins C-I and C-II Isoforms and Plasma Lipids in Type 2 up. Saroglitazar treatment was found to be weight neutral. Saroglitazar is a Diabetes potential add on therapeutic option for the treatment of hypertriglyceridemia JURAJ KOSKA, OLGICA TRENCHEVSKA, HUSSEIN YASSINE, SHRIPAD SINARI, in type 2 diabetes not controlled with statin alone. DEAN BILLHEIMER, RANDALL NELSON, DOBRIN NEDELKOV, PETER D. REAVEN, Table. Change in Lipid Parameters at 6- and 12-Months Follow-up. Values are Phoenix, AZ, Tempe, AZ, Los Angeles, CA, Tucson, AZ in Mean ± SD. Apolipoproteins (apo) C-I and C-II modulate production and clearance of Parameters Baseline 6-month 12-month *P triglyceride (TG) rich lipoproteins, and HDL cholesterol metabolism. In blood follow-up* follow-up* value they appear as major full-length apoC-I and apoC-II, and minor forms lacking 2 TG (mg/dL) 252.69±58.32 192.54±35.84 161.55±34.27 <0.0001 (apoC-I2) and 6 (apoC-II6) N-terminal amino acids. The role of apoC-I and apoC- II isoform distribution in diabetes dyslipidemia is largely unknown. LDL-C (mg/dL) 165.737±49.69 135.20±37.81 110.45±29.62 <0.0001 Relative abundance of apoC-I and apoC-II proteoforms (by mass spectrom- VLDL-C (mg/dL) 57.71±11.87 50.12±9.07 45.07±7.99 <0.0001 etry immunoassay) and plasma lipids were measured at baseline and after 9 Total cholesterol (mg/dL) 223.82±33.93 181.45±27.01 152.39±24.11 <0.0001 month of the RACED substudy of the VADT. non HDL-C (mg/dL) 164.35±33.98 129.07±27.36 107.02±24.37 <0.0001 At baseline, mean relative abundances of apoC-I2 and apoC-II6 were 29 ± SD 4% and 8.3 ± 2.6% respectively. Higher apoC-I2/C-I ratio was associated with lower TG and higher total LDL (tLDL), LDL2 (larger) and LDL3 (smaller). Higher apoC-II6/C-II was associated with lower TG and LDL4 (smallest), and higher 38-LB total cholesterol (TC), HDL, tLDL, LDL1 (largest) and LDL2 (Table). Opposite Relationship between ANGPTL3 and HDL Components and ApoC-I2/C-I and apoC-II6/C-II were increased after 9 months of both stan- Function in Nondiabetic Controls and Type 2 Diabetic Patients dard and intensive glucose lowering therapy. Changes in apoC-I2/C-I corre- LONG YAN YANG, DONG ZHAO, NING ZHANG, SHA SHA YUAN, ZONG WEI WANG, lated inversely with changes in TG and LDL4, and positively with changes JIA NAN LANG, YINGMEI FENG, Beijing, China in HDL, LDL1 and LDL2. Changes in apoC-II6/C-II correlated inversely with Type 2 diabetic patients (T2DM) are always accompanied with decreased changes in TG and LDL4, and positively with changes in TC, HDL, tLDL, LDL1, serum level of high-density lipoprotein-cholesterol (HDL-c), altered HDL LDL2 and LDL3 (Table). composition and HDL dysfunction. Angiopoietin-like protein 3 (ANGPTL3) is Our data indicate that apoC-I and apoC-II isoform distribution may modify exclusively produced by hepatocytes and secreted into circulation. ANGPTL3 lipid metabolism in type 2 diabetes. regulates lipid metabolism through inhibiting lipoprotein lipase activity. It is reported that ANGPTL3 was correlated positively with HDL-c. However, Table. Spearman Correlation between apoC-I and apoC-II Distribution (Minor- no study has studied its correlation with other HDL components and func- to-Major Isoform Ratios), and Plasma Lipids and LDL Subclasses. tion in T2DM. To address this question, 299 nondiabetic subjects and 300 T2DM patients were analyzed in the study. We demonstrated that plasma level of ANGPTL3 was significantly lower in female T2DM patients than female controls despite no change in male groups. By single correlation analysis, ANGPTL3 level was positively associated with apoA-I concentration in HDL in female controls and T2DM subjects. Negatively correlation was detected between ANGPTL3 level and serum amyloid A (SAA) in HDL fraction in female controls but not in female T2DM subjects. Consequently, positive association between ANGPTL3 and the percentage of cholesterol efflux was observed in female controls but diminished in female T2DM patients. When taking cofounding factors including age, body mass index, mean arterial blood pressure and drug use, positive correlation between ANGPTL3 and apoA-I or the percentage of cholesterol efflux in female controls was higher than female T2DM patients (controls: apoA-I: r=0.582, p<0.001; cholesterol efflux: r=0.304, p=0.050; T2DM: apoA-I: r=0.192, p=0.019; cholesterol efflux: r=-0.196, p=-0.197). In conclusion, plasma level of ANGPL3 was positively correlated with apoA-I and HDL function in female controls. However, it was abrogated in female T2DM patients. ***p<0.001, **p<0.01, *p<0.05. Supported By: National Natural Science Foundation of China (81470566) Supported By: American Diabetes Association (1-06-CR-32 to P.D.R.); National Institutes of Health (R24-DK090958)

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LB10 Foot Care—Lower Extremities

39-LB expression was reduced in late phase of diabetes than in corresponding con- The Role of Glucagon Signaling in Lipid Homeostasis trol. Whereas, expression of CD 36, which facilitates fatty acid uptake, is VIJAY MORE, SANTHOSH SATAPATI, RAJESH PATEL, YING CHEN, YING QIAN, seen to be unchanged in late phase of diabetes. This indicates that beta oxi- STEPHEN PREVIS, LIANGSU WANG, LI PING SUN, PAUL CARRINGTON, Kenilworth, dation is lowered in later phases of diabetes irrespective of fatty acid uptake. NJ Also a decrease in expression of Sirtuin 3, the deacetylase that regulates Hyperglucagonemia is well recognized phenomenon which contributes to ACADL activity, is observed in late phase diabetic mice, while an increase was observed in early phase. In order to analyze cardiac mitochondrial oxy- POSTERS hyperglycemia in patients with type 2 diabetes. Previously, efforts have been Complications directed to evaluate glucagon antagonism as a probable remedy to diabetic gen consumption we performed high-resolution respirometry (HRR). It was Acute and Chronic hyperglycemia. Findings from glucagon receptor (GCGR) deficient mice also observed that succinate dehydrogenase (SDH) activity was high in late phase support the therapeutic approaches for preventing glucagon actions. Despite of diabetes than their respective controls. This result corroborates with the beneficial effects on glucose lowering, antagonizing glucagon action wors- observed increased expression of cardiac SDH in late phase diabetic mice. ens dyslipidemia. These findings suggest a key role of glucagon in maintain- Other OXPHOS proteins, complex I and IV were also shown to be increased in ing lipid homeostasis. Here, we demonstrate the role of glucagon in whole late stage of diabetes whereas complexes III and V levels were low. Reduced body lipid homeostasis and the mechanism through which glucagon regulates complex V activity will lead to decreased production of ATP in late stage hepatic lipid balance. Chow or high fat diet fed mice were fasted for 2 hrs diabetic heart and thus the coupling efficiency may be reduced facilitating and treated with either vehicle or GCGR agonist. After 6 hrs post-treatment, progression of cardiac dysfunction. serum parameters were measured. Cholesterol and palmitate synthesis was Supported By: Council of Scientific and Industrial Research; India Department of assessed in the mice using deuterium oxide tracer quantitation. Messen- Science and Technology; India Science and Engineering Research Board; Depart- ger RNA and protein expression of GCGR and key lipogenic enzymes were ment of Science and Technology, India detected by RT-PCR and western blot, respectively. Consistent with previous data, six hours post injection, GCGR agonist significantly increased serum NEFA, glycerol and β-hydroxybutyrate in chow fed mice suggesting increased Foot Care—Lower Extremities lipolysis and fatty acid oxidation. However, agonist treatment has no effect in DIO mice. This difference in glucagon responsiveness was accompanied by 42-LB unchanged GCGR expression between lean and DIO mouse livers. GCGR ago- A New Broad-Specificity Topical Antibiotic Class to Treat Diabetic nist significantly attenuated cholesterol synthesis in both lean and DIO mice, Foot Infections which was accompanied by increased phosphorylation of Hmgcr in liver. Our CHRISTOPHER MCMASTER, Halifax, NS, Canada preliminary data demonstrates that acute dosing of GCGR agonist increases Diabetic foot ulcer infection (DFIs) account for 25% of diabetes costs to the lipolysis in lean mice, however, DIO mice are resistant to this effect. Mecha- community and 50% of the duration of in-patient hospital stays for patients nistic elucidation of glucagon impact on lipogenesis is in progress. with diabetes. Current treatments for DFIs have limited success, with many patients experiencing increasing severity of disease despite receiving the 40-LB standard of care, often resulting in loss of a limb or extremity. My lab has Efficacy and Safety of Saroglitazar in Indian Diabetics—Two-Year developed a library of 752 compounds comprising a novel antibiotic class for Data topical administration that possess unique physicochemical properties and SHASHANK R. JOSHI, RUBY SOUND, BANSHI D. SABOO, Mumbai, India, Ahmeda- broad spectrum activity that aim to substantially increase the efficacy of DFI bad, India treatment. Using the gold standard animal model of Stage 2 DFI, we demon- Saroglitazar is a dual PPAR alpha/gamma agonist available in India for more strated that as a 1% cream our lead molecules decreased bacterial load by than 2 years. Patients were evaluated for efficacy and safety of Saroglitazar 98-99% and substantially increased wound healing. We next compared our (4 mg). A total of 108 patients were followed over 24 months with a mean candidate molecule with mupirocin (Bactroban®) the market leader for topi- duration of diabetes of 9.3 years. The demographic profile was mean age of cal infections, in the gold standard DFI animal model. Each animal contained 61 years, mean BMI 28 kg/m2. 64.8% patients were male and 45.36% were on four wounds and was treated with our candidate, mupirocin, and negative Statin therapy and all patients were on Metformin therapy. 71.28% patients controls. Each compound was used at 2%, the normal dose for mupirocin. also had a second agent for diabetes treatment at baseline. The baseline Hb1c Our candidate molecule demonstrated substantially improved wound healing levels were 8.8% and Tryglycerides were 351 mg/dl. Two years of Saroglitazar as assessed by increased epithelialization (217% vs. -33%), granulation (53% lead to a significant absolute reduction of 0.7% in glycosylated Hb in patients. vs. 0%), and angiogenesis (44% vs. 0%) versus mupirocin, as well as 99.9% There was a significant improvement in Fasting and Post-prandial plasma glu- clearance of the bacterial load from the infection. In addition, we performed a cose. Addition of 4 mg Saroglitazar led to 41% reduction (P < 0.001) in Tryg- survey of 123 clinical isolates of the bacteria normally found in Stage 2 DFIs, lycerides, LDL-C (12%), Total cholesterol (16.3%) and non HDL-C (28%). Renal, Staphylococcus, Streptomyces, and Enterococcus (including drug resistant hepatic, cardiac functions which were monitored every 3 months and no seri- strains), and our candidate compound demonstrated MICs of clinical utility vs. ous adverse events were seen. No edema or weight gain was also reported. all 123 clinical isolates vs. only 67 for mupirocin. We are proceeding through Saroglitazar is a novel treatment agent in type 2 DM with dyslipidemia and preclinical trials with the expectation that administration of our new topical has long term glycemic and lipid control with a two years safety profile. antibiotic class at Stage 2 DFI, in addition to standard of care, will substan- Supported By: Zydus Cadila tially increase the efficacy of DFI treatment. Supported By: Canadian Institutes of Health Research 41-LB Augmented Mitochondrial Complex II Activity and Low Expression 43-LB of Long-Chain Acyl CoA Dehydrogenase in Prolonged Untreated Is Wound Dressing Stressful in Neuropathic Patients with Diabetic Type 2 Diabetes Foot Ulcers? Objective Monitoring of Physiological Stress Response NANDINI RAVIKUMAR JAYAKUMARI, RAJI SASIKALA RAJENDRAN, ANAND during a Wound Clinic Visit CHELLAPPAN REGHUVARAN, SULFATH THOTTUNGAL PARAMBIL, HARIKRISH- JAVAD RAZJOUYAN, GURTEJ S. GREWAL, TALAL K. TALAL, DAVID ARMSTRONG, NAN VIJAYAKUMAR SREELATHA, JAYAKUMAR KARUNAKARAN, SRINIVAS BIJAN NAJAFI, Houston, TX, Doha, Qatar, Tucson, AZ GOPALA, Thiruvananthapuram, India Poor wound healing and infection are important contributors to amputation Increased incidence of cardiac complications is associated with type 2 in diabetic foot ulcers (DFU). One important risk factor for increased severity diabetes mellitus (T2DM) and these are in part due to altered mitochondrial and susceptibility to infection and slowed wound healing is chronic stress. metabolism. High circulating free fatty acids in T2DM provide enhanced The aim of the study was to monitor physiological stress in patients with DFU supply of fatty acids in mitochondria leading to a prooxidative environment. during a wound clinic visit. In this study, physiological stress was monitored Although there is increased supply, fatty acid oxidation can become limited in 35 patients (Age: 59.3 ± 8.3 years) with DFU including pre-wound dressing in diabetic cardiac mitochondria. In order to analyze the long-term effect (preWD) and wound dressing (WD) periods. Uni-channel electrocardiogram of untreated diabetes on mitochondrial metabolism, we induced T2DM in data was recorded using a wearable patch attached to subject’s chest. Fluc- C57BL/6 mice by using streptozotocin (100 mg/kg) and nicotinamde (120mg/ tuation in stress during clinic visit was quantified by tracking changes in stan- kg) and animals were euthanized for heart after 2 weeks (early phase) and 10 dard deviation (SDNN) of normalized R-to-R intervals (NRR). Moderate and weeks (late phase) of hyperglycemia. Cardiac expression of long chain acyl high-stress periods were identified when SDNN was in the range of 60–85% CoA dehydrogenase (ACADL) was high in early phase of diabetes, while its and below 60% of baseline SDNN (from preWD), respectively. Vegal tone as

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LB11 LateDi abetesBreaking Ed uAcatbstractsion

indicator of relief from stress were quantified by root mean squared of suc- Table. Diabetes Distress. cessive of NRR (RMSSD), power of high frequency component of NRR (HF%), Variable Overall Overall No Test P and the ratio of low frequency to the high frequency components (LF/HF). On Diabetes Diabetes value average, during clinical visit moderate and high stress episodes occurred for Distress Distress 29.6 ± 16.6% and 45.5 ± 21.6% of the time respectively. There were trending (n=42) (n=178) differences between preWD and WD RMSSD (-12%, p =0.058). Significant Age (years) [M(SD)] 61.8 (11.9) 66.4 (13.2) t= 2.05 0.042

reductions in HF% (-46%, p = 0.043) and LF/HF (2.3 folds, p =0.022) were observed during WD compared to preWD, indicating significant increase in Years of DM [M(SD)] 18.5 (13.1) 14.2 (9.4) t= -2.01 0.050 stress in response to WD. This study confirms that WD is highly stressful A1c (%)[M(SD)] 8.8 (2.3) 7.6 (1.8) t= -3.09 0.003 despite lack of foot sensation in majority of patients with DFU. Previous stud- Emotional Burden subscale [n(%)] 41 (98) 39 (22) X2 (1, N=139) = 84.17 <0.001 ies suggest that high stress may negatively impact wound healing outcomes. Physician Distress subscale [n(%)] 9 (21) 5 (3) X2 (1, N=173) = 19.77 <0.001 Further studies are warrant to confirm association between stress during 2 wound clinic visit and wounds healing outcomes. Future study is recom- Regimen Distress subscale [n(%)] 36 (86) 27 (15) X (1, N=151) =82.75 <0.001 mended to examine whether stress management during WD may enhance Interpersonal distress subscale [n(%)] 20 (48) 10 (6) X2 (1, N=168)= 50.90 <0.001 wound healing outcomes.

POSTERS Supported By: Qatar National Research Foundation (NPRP 4-1026-3–277) 46-LB Technology-Assisted Case Management (TACM) in Low-Income, Diabetes Education Rural Adults with Type 2 Diabetes Behavioral M edicine, Clinical

N utrition, Education, and Exercise LEONARD E. EGEDE, JONI S. WILLIAMS, DELIA C. VORONCA, REBECCA R. KNAPP, 44-LB JYOTIKA FERNANDES, Charleston, SC From Hospital to Home: Aiding in Patient Transitions through Educa- Introduction: Low income and rural adults with diabetes have poorer access tion for Obese Older Adults with Type 2 Diabetes Mellitus and outcomes. Case management with home telemonitoring is a viable strat- CHRISTINA R. WHITEHOUSE, DAVID A. HOROWITZ, Philadelphia, PA egy for care. We evaluated the efficacy of nurse case management with home Type 2 diabetes mellitus (T2DM) is a leading cause of morbidity and mor- telemonitoring and supervised medication titration in low-income rural adults tality contributing to rising healthcare costs, especially among older adults. with poorly controlled diabetes. Incorporating a transitional care intervention that includes diabetes self-man- Methods: We randomized adults from federally qualified health centers in agement education (DSME) and home visits can assist in achieving positive rural south Carolina with baseline hemoglobin A1c (HbA1c) ≥8% to technol- health outcomes for individuals with diabetes. This study was a secondary ogy assisted case management (TACM) or usual care (UC). The TACM group data analysis of a hospital quality improvement intervention. The purpose of received a 2-in-1 blood pressure and blood glucose device that uploads to this study was to investigate differences in outcomes of a transitional care a secure server and asked to test daily. Nurses reviewed the readings and educational intervention comprised of inpatient DSME or a combination of titrated medications every 2 weeks based on average readings using an ADA both inpatient DSME and home care for patients with T2DM, aged 60 years of and JNC guided algorithm approved by primary care providers at the study age or older, who had a BMI ≥ 30 kg/m2. The outcomes of interest were rehos- clinics. An internist and an endocrinologist supervised the nurses. UC group pitalization rates and HbA1c levels for up to one year post hospital discharge received usual care. Participants were assessed at baseline, 3 months, and 6 and health related quality of life (HRQoL) scores for up to 30 days post hospital months. The primary outcome was HbA1c at 6 months post-randomization. discharge. There was a statistically significant decrease in rehospitalization Results: We assigned 113 participants to either TACM (54 [48%]) or UC (59 rates at 90 days for the hospital-based DSME plus home care group (10%) [52%]). There were, 87 (77%) patients at 3 month and 85 (75%) at 6 month compared to hospital-based DSME only (20%) and control group (26.7%), with complete measurements. Based on intent-to-treat population after mul- p<.05. There was a statistically significant decrease of HbA1c levels for both tiple imputation, the analysis of covariance with baseline HbA1c as covariate intervention groups over time; however, HbA1c levels returned to baseline showed that HbA1c at 6 months for TACM was significantly lower compared for the intervention group without home care. HbA1c levels for the hospital- to UC (-0.99, p=0.024). Longitudinal mixed effects analysis suggested the rate based DSME plus home care group remained lower than baseline suggest- of decline in HbA1c over time for TACM was significantly faster compared ing that continued education in the home added a protective effect for lower to UC (-0.16, p=0.038). Results based on per-protocol population (85 [75%] HbA1c levels. There was a positive trend toward improved HRQoL scores from subjects) were similar. baseline to 30 day post hospital discharge for the intervention groups; how- Conclusions: A combined technology-assisted and nurse case management ever, this was not statistically significant. The findings of this study support intervention in low income patients with poorly controlled T2DM is effec- the relationship of an educational intervention and obese elders’ ability to tive compared to usual care. This finding suggests that TACM provides a better manage their diabetes to improve glycemic control and avoid hospital novel approach to diabetes care in under-resourced, primary care settings for readmission. patients with limited income and resources. Supported By: U.S. Department of Defense (W81XWH-10-2-0057) 45-LB Diabetes Distress in Type 2 Diabetes Hospitalized Patients 47-LB LORI M. LEMOINE, WASEEM GAZALE, AHMAD ZAYED, NOORI DHALIWAL, KAREN YES (Youth Empowering Skills)—A Stepping Stone for Diabetes Self- RICE, New Orleans, LA Care and Empowering Young Adults with Type 1 Diabetes There is limited evidence about diabetes distress levels in the type 2 hos- RAHILA S. BHATTI, SHIOBHAN PENDER, MARIE JONES, STEPHANIE SINGHAM, pitalized patient. The purpose of this study was to assess diabetes distress PENNY JACKSON, WILLIAM HADFIELD, TOM ANTEBI, SIMON CHAPMAN, STEPH- (DD) in inpatients admitted to a quaternary facility with type 2 diabetes mel- ANIE LAMB, ANGUS FORBES, DULMINI KARIYAWASAM, Worthing, United King- litus (DM). Subjects >18 years, English literate, on insulin or sulfonylurea at dom, London, United Kingdom home were consented. A 17-item Diabetes Distress Scale (DDS17) with 4 Aim of our programme was to co-develop and co-deliver a novel interven- subscales (Emotional burden, Physician distress, Regimen distress, Interper- tion using simulation based experiential learning principles to improve diabe- sonal distress) was administered to a sample of 220 patients. Sample char- tes knowledge, quality of life, problem solving skills and confidence. A youth acteristics were compared using independent t-tests. Chi-square tested DD worker helped to engage adolescents with YES programme. Focus group work subscale comparisons and linear regression tested a model of demographic helped identify curriculum topics for the programme that were important to characteristics, admit A1c, and DD. Subjects with DD (N=42) were signifi- young people. The programme ran over 3 days and was delivered using expe- cantly younger, had longer history of DM, and higher A1c than those with riential learning styles, including simulations and peer-led sessions. N=15. no DD (N=172). Subjects with DD had significantly greater scores across all Mean age 17 ± 1.60 (SD). 53% (n=8) male. Mean HbA1c 1 year before 11.3± four subscales; however, those with no DD reported emotional burden and 2.8, duration of diabetes 7.1 (1-16) years. N=1 (CSII), n=10 (basal bolus insu- regimen distress. A1c (p<0.010) and length of DM (p<0.050) were significant lin) and n=4 (mixed insulin). There was 1.5% reduction in HbA1c (Pre-course independent predictors of DD. Results identify opportunities for future post- 11.3 ±2.8 versus Post-course 9.8 ± 2.5) at 6 months (p <0.02). Semi-structured discharge program development that should target strategies to reduce DD, interviews were conducted 6 weeks after the course. One patient said “I’ve especially emotional burden and regimen distress in patients with elevated really enjoyed the course especially the acting part. It made me realize how A1c and long history of DM. the doctors, nurses and my mum would feel looking after a patient with dia-

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LB12 LateDi abetesBreaking Ed uAcatbstractsion

betes-something I’ve always taken for granted and never really have put into The purpose of this study is to determine how effective the diabetes educa- consideration.” There has been a significant improvement in glycaemic control tion program at Diabetes Care Pharmacy (DCP) is based on A1c levels post- pre and post YES participation. Data on hospital attendance rates, unplanned completion of the program. In this IRB-approved study, we gathered patients hospital admissions rates are collected and long term data will be collected previously enrolled in the diabetes education program using the pharmacy’s to assess whether HbA1c improvements are sustained. Office Ally® and ARKRAY’s ARKCare® software. We electronically collected Figure. Pre- and Post YES Course HbA1c. A1c levels at baseline, 6 months, 12 months, and 24 months post program ® ®

completion using LabCorp and Quest Diagnostics . Follow-up calls were performed on patients with A1c > 7% to assess for the lack of glycemic control and to screen for improvements for the program. Of 311 patients enrolled, 81 patients fit the inclusion criteria. The average baseline A1c was 8.27%. After 6, 12, and 24 months of completing the program, the average A1c decreased by 1.30%, 1.21%, and 0.86% respectively (p<0.05). A total of 63 patients (77%) achieved a decrease in A1c at the 6 months mark and 51 patients maintained a decrease in A1c from baseline at the 24 month mark and of those 37 remained in control with an A1c <7%. Based on patient phone interviews, the most common reason why they were unable to effectively control their diabetes was POSTERS due personal hardships. The data from this study shows that DCP’s diabetes education program is effective in managing diabetes. However, the average decrease in A1c lessened as time progressed. This trend suggests that follow- up measures are necessary to maintain glycemic control. Behavioral M edicine, Clinical N utrition, Education, and Exercise Supported By: Diabetes Modernisation Initiative 50-LB 48-LB Diabetes Distress and A1c Improvements in a Pharmacist Diabetes Low-Cost, Systematized, Data-Driven DSME/DSMS Improves Glyce- Education Program mic Control in Insulinised Type 2 Diabetes (T2D) SARAH G. IMERSHEIN, HALEH ARMIAN, ALY HASSAN BAYOUMI, SARAH DAVID G. SEGAL, Johannesburg, South Africa TURKISTANI, MELINDA D. MARYNIUK, San Francisco, CA, Boston, MA, Jeddah, This retrospective study presents real world results from 408 insulinized Saudi Arabia T2D patients managed on the Guidepost Diabetes Self Management Edu- Diabetes distress is associated with higher A1c and other risk factors. Jos- cation/Support (DSME/S) program. DSME is the process of facilitating the lin Diabetes Center partnered with Nahdi Medical Company, a large retail knowledge, skill, and ability necessary for diabetes self-care. DSMS refers to pharmacy in the Kingdom of Saudi Arabia (KSA) to develop a pharmacist-led the support that is required for implementing and sustaining coping skills and education program. Pharmacists delivered up to four 1:1 counseling sessions behaviors needed to self-manage on an ongoing basis. Patients received peri- over 2-4 months focused on diabetes medicines, lab tests, glucose monitor- odic telephonic structured DSME consultations in a Motivational Interviewing ing, and doctor visits. setting to identify barriers to health, deliver targeted education and evalu- Customers with diabetes (n=1039) were assessed using the 2-question Dia- ate understanding while developing patient-specific goals. Self-monitoring betes Distress Scale (DDS) and a subset provided baseline A1c results (n=583) of blood glucose (SMBG) data captured in custom software according to a from their doctors or clinical lab. Customers had high levels of distress at structured testing protocol was used by the educator to identify patterns for baseline (81.3% scoring ≥2 on the 6-point DDS). diet, exercise and medication adjustment. DSMS was enhanced by incorpo- There were 720 (69.3%) customers who returned for follow-up over rating a customer relationship management approach, bringing structure to a 15 months and demonstrated significant improvement in distress. Mean A1c typically unstructured process, improving compliance and allowing tracking of also improved significantly from 8.22 to 7.27 (-0.95, p<0.05, n=257) though patient progress. At the end of the 6 month treatment period, the occurrence limited to results obtained from doctors (Table 1). of pre-meal SMBG readings above 11mmol/L had reduced by 35%. DSME/S Change in mean DDS was significant after controlling for duration, gender, delivered via the Guidepost system shows that systematized individual care treatment, baseline and change in A1c, and A1c awareness (understanding is possible at scale and can result in improved glycemic control and patient of A1c values). Only long duration diabetes (≥10 years, B=-0.519), lack of A1c satisfaction at low cost. awareness (B=0.460), and improvement in A1c (B=0.146) contributed significantly to the model. These accounted for 8.4% of differences in change in Figure. Pre-Meal Control by Month on Program. mean DDS (p<0.05). Pharmacist-led education in a retail setting may be effective at improving diabetes distress and A1c in in KSA. Table 1. Demographics and Change in Outcomes. Demographics % Female 15.2 Longer duration diabetes (≥10 years) 34.3 Insulin treatment 19.6 Change in Outcomes Baseline Follow-up Chi Sq or t-test p % High DDS (≥2) 81.3 35.3 <0.05 Mean DDS 2.80 1.62 <0.05 Paired Mean A1c (n=257) 8.22 7.27 <0.05 Supported By: Joslin Diabetes Center

51-LB Family Planning Vigilance in Women with Type 1 Diabetes (T1D): A 49-LB More Comprehensive Approach than Just Assessing Birth Control The Effects of Diabetes Education on Glycemic Control at Diabetes (BC) Care Partners SUSAN M. SEREIKA, ANDREA RODGERS FISCHL, PATRICIA SCHMITT, DOROTHY J. TONY SONG, LINDA HOANG, JENNIFER CHUA, KELLEY SONG, GINGER FARIAS, BECKER, DENISE C. CHARRON-PROCHOWNIK, Pittsburgh, PA AMANDA CORVERA, West Covina, CA Unplanned pregnancies in women with diabetes could cause maternal and Proper diabetes treatment and management can prevent or delay the onset fetal complications. While all women of child-bearing age should be vigilant of complications, such as heart or kidney disease. Diabetes education helps using effective BC all of the time when avoiding a pregnancy, women with patients understand the disease process to better manage their diabetes. diabetes who are planning a pregnancy should also be vigilant in obtaining

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LB13 Late BreaExkingerc iAsebstracts

preconception counseling (PC) prior to pregnancy. The purpose of this second- 53-LB ary analysis was to describe a more comprehensive assessment of women’s An On-line Support Tool for Type 1 Diabetes that Reduces Exercise- reproductive health called family planning vigilance (FPV) [e.g., received pre- related Hypoglycaemia including Nocturnal Episodes conception counseling (PC), frequency and methods of BC] in adult women AGATA K. PIOTROWICZ, MARGARET J. MCGILL, JANE OVERLAND, LYNDA MOLY- with T1D. Retrospective data were used from a long-term cohort study of NEAUX, STEPHEN M. TWIGG, Sydney, Australia adult women with T1D who were re-contacted having participated previ- Hypoglycemia related to exercise, especially that occurring nocturnally, is

ously as an adolescent in a PC intervention study. A matched group of women a challenge in type 1 diabetes. An online exercise tool (ExT1D) was tested with T1D who did not receive PC as teens were also recruited. All completed to determine whether hypoglycemia related to exercise can be reduced, online questionnaires regarding BC and family planning behaviors at intake with this report focusing on nocturnal episodes. Adults with T1DM (n=32) and semi-annually to 18 months. Participants (N=102) were aged 18 to 38 exercising ≥60min/wk commenced a 6 wk randomised controlled trial, in years (mean=23.7, SD=4.5), 97% Caucasian, 82% had some college, 26% the Intervention (Int.), or Control (Con.) usual care arms, then with partial were married, 29% had >1 biological children and had T1D on average 14.1 cross-over of Con. into Int. for another 6 wk. In each Int. time period study years (SD=6.7, range: 0-30). Many (69%) were aware of PC; however, only subjects utilized the tool, ExT1D. Exercise-related hypoglycemia (ErH) was 22% (n=22) reported having ever received PC and care. Most women (78%) pre-defined as CGMS levels <4.0 mM occurring within 24 hr of exercise. Two had been sexually active [mean age of sexual debut=18.2 years; range: 14-28]. fear of hypoglycaemia surveys, HFS-II-Worry and FH-15, were completed at POSTERS Of these, only 52% were vigilant using BC every time they had sex. The most baseline and after intervention. Subjects were 50% M, aged 35.8±9.5 yrs frequently used BC methods included birth control pills (BCPs) (62%), condoms (mean±SD), diabetes duration 12.3±9.9 yrs, BMI 24.2±2.6 kg/m², with base- (63%), and withdrawal (33%). Most (59%) relied on a single BC method. Of line exercise-related hypoglycemia number 4.3±4.1, per 6 days, median HbA1c those using combination BC methods (n=29, 41%), 22 (76%) used BCPs and 7.1% (ICR 6.4-7.7) NGSP units, and fructosamine 347μM (297- 438). In the RCT, Behavioral M edicine, Clinical condoms. Only 9% were FPV using combination BC methods all the time and N utrition, Education, and Exercise for all ErH, in Int. vs. Con., the RCT showed a 50% reduction (NS) in median receiving PC. Of those sexually active, more than half were non-vigilant with ErH number and similar reduction in ErH duration. In all subjects, compared BC and a fraction received PC. Educational efforts are needed to enhance with their own baseline, predefined secondary end-point analysis showed comprehensive FPV in women of child-bearing age who have T1D. longitudinal reductions in ErH number (by 43%, p=0.044) and ErH duration (by 71%, p=0.015), observed after Int. In post-hoc analysis participants with the longest per episode durations of nocturnal ErH (n=15), had significant Exercise reductions in hypoglycemia following Int., by 98%, p=0.001. These nocturnal hypoglycemia reductions were associated with lower scores for fear of hypo- 52-LB glycemia that interfere with leisure activities (FH-15), p=0.014. In contrast, Effects of Short-Term Exercise Training on Adipokine Concentration fructosamine and HbA1c levels were unchanged from baseline (not shown). and White Adipose Tissue Beiging This study shows the tool ExT1D can improve exercise-related hypoglycemia ROELAND J. MIDDELBEEK, PIRYANKA MOTIANI, JIA ZHENG, KIRSI A. VIRTANEN, including nocturnal events and thus it can aid adults with type 1 diabetes to KUMAIL K. MOTIANI, JOONAS J. ESKELINEN, ANNA M. SAVOLAINEN, JUKKA exercise more safely. KEMPPAINEN, PIRJO NUUTILA, KARI K. KALLIOKOSKI, JARNA C. HANNUKAINEN, Supported By: JDRF Australia; University of Sydney LAURIE J. GOODYEAR, Boston, MA, Turku, Finland Exercise training improves whole-body glucose homeostasis through 54-LB effects largely attributed to skeletal muscle adaptations; however, exercise Voluntary Exercise Training Improves Metabolic Symptoms via Sup- also affects adipose tissue. We tested whether a two-week medium (MIT) pression of Hypothalamic Apoptosis or high intensity training (HIT) program regulates adipokine concentration. TOMOKO MATSUBARA, BRENTON T. LAING, KHOA DO, HU HUANG, Greenville, In addition, we investigated if short-term training induces expression of the NC brown adipocyte marker uncoupling protein 1 (UCP1) in subcutaneous white Exercise training improves metabolic function via the central nervous sys- adipose tissue (scWAT), commonly in rodents referred to as beiging. Healthy tem. POMC neurons in the hypothalamus are considered to play a key role in men (n=26, age=48±5 y, BMI=26.1±2.4, VO2peak=34.2±4.1 ml/kg/min) were high fat diet-induced obesity and exercise-induced metabolic improvements. randomized to HIT and MIT groups. Subjects performed 6 HIT (6x30 sec all out However, the mechanisms of exercise training-induced improvements of cycle ergometer sprints with 4min of recovery between sprints) or 6 MIT ses- metabolic function have not been fully understood. C57BL6 male mice were sions (40-60 min ergometer cycling at 60% VO2peak). Blood and periumbilical divided into 3 groups: normal chow diet, high fat diet, and high fat diet with scWAT biopsies were taken before the intervention and 48 h after the last voluntary running wheel exercise training. Metabolic phenotypes were evalu- training session. Adipokine concentration was assessed by ELISA, and UCP1 ated by using magnetic resonance imaging, the Comprehensive Lab Animal expression by immunohistochemistry. We found that both training protocols Monitoring System, glucose/insulin tolerance tests. Immunohistochemistry similarly increased VO2peak and whole body insulin sensitivity, and decreased was used to identify pro-opiomelanocortin (POMC) neurons in hypothalamus. visceral fat (P<0.05). There were no changes in leptin, NGF, IL-8, HGF, and TUNEL assays were performed to detect hypothalamic apoptosis. Hypotha- TNF-α with either training mode. However, HIT, but not MIT significantly lamic gene expressions were evaluated by real-time PCR. Twelve weeks of reduced IL-6, an adipokine with both pro- and anti-inflammatory actions. voluntary exercise training reduced weight gain and adiposity induced by a In contrast, only MIT increased monocyte chemotactic protein 1 (MCP1), a high fat diet. Exercise training increased energy expenditure. Insulin sensitiv- chemokine possibly mediating crosstalk between adipose tissue and skeletal ity was also enhanced by exercise training. Furthermore, high fat diet sig- muscle and that may stimulate macrophage recruitment into adipose tissue. nificantly decreased the POMC neuronal populations, and this decrease was Neither HIT nor MIT significantly increased UCP1 expression in scWAT. In con- restored by exercise training. Exercise training rescued high fat diet induced clusion, short-term HIT and MIT training are not sufficient to induce scWAT hypothalamic neuronal apoptosis. High fat diet increased IKK-beta and cas- beiging, and HIT and MIT training have unique effects on adipokine concen- pase-9 gene expression in the hypothalamus. Exercise training decreased the trations. These exercise-induced changes in circulating adipokines may play impact of high fat diet through a reduction in IKK-beta and caspase-9 gene a role in tissue cross-talk, and suggest that exercise modality regulates adi- expression. The data suggests that voluntary exercise training improves pokine responses to physical activity. metabolic symptoms, in part through suppression of hypothalamic neuronal Supported By: European Foundation for the Study of Diabetes; Emil Aaltonen apoptosis and inflammation. Foundation; Hospital District of Southwest Finland; Orion Research Foundation; Supported By: Japan Society for the Promotion of Science Finnish Diabetes Foundation; Academy of Finland; Ministry of Education of the State of Finland; Paavo Nurmi Foundation; Novo Nordisk Foundation; National Institutes 55-LB of Health (R01-DK099511 to L.J.G.), 5P30DK36836, T32-DK-07260-038 (to R.J.M.); Can Regular Exercise Reverse Modification in Skeletal Muscle Joslin Diabetes Center Induced by High-Fat Diet and Decreased Insulin Secretion? JULIA M. SANTOS, SANDRA A. BENITE-RIBEIRO, MARCOS L. MORELI, DANIEL BARTOLI, DENISE OLIVEIRA, Jatai, Brazil Regular exercise improves lipid profile and increases skeletal muscle glucose uptake, which, in most cases, inhibit type 2 diabetes (DM2) development. In skeletal muscle of DM2 increase in oxidative stress seems to precede insulin resistance and mitochondria dysfunction and changes in mitochondrial

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LB14 Late BreaExkingerc iAsebstracts

DNA (mtDNA) seem to be involved with this process. Thus, the aim of this more likely to be older, female and obese. These patients had normal cardiac study was to verify the effects of endurance exercise on mtDNA and oxida- function but had impaired muscle microvascular responses during exercise tive stress in high-fat fed animals treated with a low dose of streptozotocin when compared to T2D with normal exercise capacity (Table). In conclusion, (STZ). Wistar rats were fed a diet containing 60% higher fat during all experi- impaired muscle microvascular responses to exercise are significantly associ- mental procedures weeks and at day 14 a single injection of STZ (25mg/kg) ated with functional incapacity in T2D. Whether microvascular impairments was administrated (HF + STZ group). Control rats received standard food and are due to functional and/or structural adaptations require further investiga- rd citrate buffer injection. At 3 week, half of animals of each group, animals tion. This study highlights the importance of the microcirculation in skeletal of control and HF+STZ groups performed 6 weeks of swimming 5 days/week muscle as a new therapeutic target for treating exercise intolerance in T2D. with increasing duration until reaching 60 minutes, while the other half of Table. Cardiac and Muscle Microvascular Responses to Exercise. animals group remained in a sedentary condition. 8-isoprostane, an oxidative stress marker and mtDNA copy number was quantified insoleus muscle. DM2 Reduced exercise Normal exercise capacity capacity risk factors such as visceral fat weight and plasma VLDL, were also assessed. Compared to control rats, HF+STZ increased visceral fat weight and VLDL by VO2 (ml/kg/min) 21.6 ± 0.5* 32.3 ± 0.7 ~30-50%. Beside, levels of 8-isoprostane were increased by 40% and mtDNA Ejection Fraction (%) 74.3 ± 1.0 74.1 ± 0.7 copy number by 3-fold in skeletal muscle of HF+STZ animals when compared LV filling pressure (e/E’) 10.2 ± 0.4 9.4 ± 0.2 to control groups. Endurance exercise attenuated the increase in VLDL in exer- POSTERS Cardiac Output (L/min) 7.7 ± 0.3 8.7 ± 0.3 cised HF+STZ animals when compared to sedentary HF+STZ animals, while no difference was verified at 8-isoprostane levels, mtDNA copy number and Muscle Microvascular blood volume (VI) 28.4 ± 1.9* 32.0 ± 1.0 visceral fat. Thus, in DM2 mtDNA copy number increases in skeletal muscle Muscle microvascular flow velocity (1/sec) 0.11 ± 0.01* 0.13 ± 0.01 as a response to increased in oxidative stress. Changes in lipid profile induced Behavioral M edicine, Clinical Muscle microvascular blood flow (VI/sec) 3.22 ± 0.28* 4.17 ± 0.26 N utrition, Education, and Exercise by high fat diet and insufficient insulin secretion appears to be improved by endurance exercise in a mechanism independent of oxidative stress generation and mtDNA copy number in skeletal muscle. Supported By: Conselho Nacional de Desenvolvimento Científico e Tecnológico 58-LB Ischemia Reperfusion Injury following Aerobic and Resistance Exer- (301744/2014-9) cise Training in Moderately Hyperglycemic T1DM Rats MATTHEW W. MCDONALD, MAO JIANG, MICHELLE S. DOTZERT, MICHAEL R. 56-LB MURRAY, J. ZACHARY NICKELS, EARL G. NOBLE, C.W. JAMES MELLING, London, A Single Session of Exercise Initiates Adaptive Responses in Adi- ON, Canada pose Tissue that May Lead to Improvements in Inflammation and Adi- Intensive insulin therapy (IIT) and exercise are treatment options for cardio- pose Tissue Vascularization vascular disease in populations with type 1 diabetes mellitus (T1DM); however, DOUGLAS W. VAN PELT, LISA M. GUTH, JEFFREY F. HOROWITZ, Ann Arbor, MI both increase the risk of hypoglycemia. Our group has shown that moderate Adipose tissue (AT) inflammation, fibrosis, and insufficient vascularization hyperglycemia with conservative insulin therapy (CIT) combined with high are associated with poor metabolic outcomes in overweight and obese adults. intensity aerobic exercise can reduce the risk of exercise-induced hypoglyce- The purpose of this study was to examine the effects of acute exercise on mia and provide cardiovascular benefits (CB). While increased recovery from markers of macrophage inflammatory status, extracellular matrix composi- ischemia-reperfusion (IR) injury and increased cardioprotective Hsp70 expres- tion, and angiogenesis in subcutaneous AT and inflammatory markers in sion are evident with this treatment strategy, it is unknown how these CB peripheral blood mononuclear cells (PBMC). Six overweight to obese adults compare to IIT alone. The purpose of the present study was to determine if IIT 2 (BMI: 28.2±1.6 kg/m ) performed 1hr of aerobic exercise at ~65% VO2peak. in T1DM rats elicits larger CB compared to the use of CIT and regular exercise, Subcutaneous abdominal AT biopsy samples were obtained before and 1hr as determined by recovery from IR injury. Male Sprague-Dawley rats were after exercise; fasting blood samples were also obtained before and immedi- divided into non-T1DM control (C; n=8), IIT (n=8; 4-9mM blood glucose) and CIT ately after exercise for PBMC isolation. Based on our specific a priori hypoth- (n= 32; 9-15mM blood glucose) groups. Subsequently, CIT were assigned (n=8) eses for the direction of difference in AT inflammatory gene expression, we to sedentary (CIT), high intensity aerobic exercise (HE), resistance exercise used one-tailed Student’s t-tests to compare basal and post-exercise samples. (RE) and combination exercise (CE) groups. T1DM was induced with strepto- mRNA expression of CD11C (marker of pro-inflammatory M1 macrophage) was zotocin and blood glucose was adjusted with subcutaneous insulin pellets. HE lower after exercise, while expression of CD206 (marker of anti-inflamma- occurred on a treadmill (27m/min; 1hr), RE performed weighted vertical ladder tory M2 macrophage) was elevated (both p<0.05). Exercise also increased climbs, and CE alternated daily between HE and RE. Exercise occurred 5 days/ mRNA expression of VEGF (p<0.05), which is considered the master regula- wk for 12 wks. IIT resulted in similar recovery from IR injury as C (p>0.05), tor of angiogenesis. Exercise did not significantly affect expression of col- and reduced left ventricular end-diastolic pressure compared to CIT (p<0.05). lagen VI (COL6A1; marker of AT fibrosis linked with the development of insulin Further, IIT displayed similar recovery from IR compared to all exercise modali- resistance) but collagen I (COL1A1) expression was elevated after exercise ties, although CE resulted in increased rate of developed pressure compared (p<0.05). In PBMCs, exercise significantly reduced mRNA expression of the to all groups (p<0.05). Further, while IIT had higher cardiac Hsp70 protein pro-inflammatory factor, TNFA. Together, our findings suggest each session of among non-exercised (C, CIT, IIT) rats, HE had the largest amount of cardiac exercise initiates changes in gene expression that may lead to improvements Hsp70 protein (p<0.05). These findings suggest that CIT paired with regular in systemic and adipose tissue inflammation and adipose tissue vasculariza- exercise results in similar CB as IIT alone. tion. Supported By: Natural Sciences and Engineering Council of Canada (RGPGP- Supported By: R01 DK077966, T32 DK10135702 2015-00059)

57-LB 59-LB Exercise Intolerance in Type 2 Diabetes: Heart Failure with Pre- Basal Systemic Fatty Acid Mobilization Is Higher in Exercise-Trained served Ejection Fraction or Impaired Microvascular Flow in Skeletal vs. Untrained Obese Adults Muscle? LISA M. GUTH, DOUGLAS W. VAN PELT, JEFFREY F. HOROWITZ, Ann Arbor, MI MICHELLE A. KESKE, JULIAN W. SACRE, THOMAS H. MARWICK, Hobart, Australia, It has been reported that resting fatty acid rate of appearance in plasma Melbourne, Australia (FA Ra) is two- to three-fold greater in lean, well-trained endurance athletes People with type 2 diabetes (T2D) often have impaired functional (exercise) compared with lean, sedentary controls. In obesity, however, resting FA Ra is capacity. The balance between central (e.g., cardiac) vs. peripheral mechanisms already very high - and this elevated FA Ra is commonly linked with the devel- is not well characterised. We aimed to determine the contribution of skeletal opment of several metabolic health complications, including insulin resistance. muscle microvascular dysfunction to exercise intolerance in T2D. 88 people The effect of endurance exercise training on FA Ra in obesity is not clear. The with T2D underwent exercise stress testing on a treadmill - 26 with reduced purpose of this study was to determine the effect of habitual exercise on rest- exercise capacity and 62 with normal exercise capacity. Peak VO2 was deter- ing FA Ra in overweight/obese individuals. Basal palmitate rate of appearance mined using standard cardiopulmonary stress equipment. Left ventricular (LV) in plasma (Palm Ra) was measured using stable isotope tracer methods in 7 function (by echocardiography) and thigh muscle microvascular (by contrast- overweight/obese habitual exercisers (TRAINED; VO2peak=32±2 ml/kg/min) enhanced ultrasound) responses were performed at rest and immediately and 8 overweight/obese sedentary controls (UNTRAINED; VO2peak=21±2 ml/ after treadmill exercise testing. T2D with impaired exercise capacity were kg/min; p<0.01 vs. TRAINED). TRAINED and UNTRAINED groups did not differ

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LB15 LateNu Btrreaitikingon—C Albstractsinical

in BMI (31.3±1.1 vs. 33.7±1.2 kg/m2), body mass (87.5±4.5 vs. 89.2±4.4 kg), or factors. Medications did not change in the study. Compared to baseline, A1c body composition (39±3 vs. 43±3% body fat). When measured 3 days after the decreased significantly more in the tDNA group (-0.8 ± 0.1%, p < 0.001) than TRAINED subjects’ most recent exercise session, resting Palm Ra was 50% the SC group (-0.2 ± 0.1%; p = 0.046). Fasting plasma glucose decreased sig- greater than UNTRAINED (4.8±0.6 vs. 3.2±0.4 umol/kg FM/min, p<0.05). How- nificantly in the tDNA group (-0.7 ± 0.3 mmoL, p = 0.006) but unchanged in SC ever, when measured the day after an acute session of endurance exercise (1 group (0.1 ± 0.3 mmoL, p = 0.7). Body weight decreased significantly more in h at 50% VO2peak), resting Palm Ra decreased by ~15% in TRAINED (p<0.01), the tDNA group (-3.9 ± 0.2 kg, p < 0.001) than the SC group (-0.6 ± 0.2 kg, p =

whereas Palm Ra was not altered the day after acute exercise in UNTRAINED 0.012). Both systolic and diastolic blood pressure decreased significantly in the (p>0.05). We conclude that similar to previous findings in lean endurance ath- tDNA group (-9.5 ± 1.5 and -4.0 ± 1.1 mmHg, respectively, p < 0.001 for both) letes, resting fatty acid mobilization is higher in trained vs. untrained obese but unchanged in the SC group (-1.0 ± 1.8 and -1.1 ± 1.1 mmHg, respectively, adults, especially when the trained subjects abstain from exercise for 3 days. p > 0.05 for both). Lipid profile did not change in both groups. We conclude However, exercising regularly (i.e., every 1-2 days) may help maintain resting that lifestyle intervention that includes MNT and physical activity following fatty acid mobilization at lower levels. a customized transcultural Diabetes Nutrition Algorithm significantly reduces Supported By: National Institutes of Health (T32DK10135702) A1c, body weight, and blood pressure. Similar approaches in other countries are warranted. Supported By: Abbott Nutrition Malaysia POSTERS Nutrition—Clinical 62-LB 60-LB Food Order Has a Significant Impact on Postprandial Glucose and

Behavioral M edicine, Clinical Effect of Red Grape Cells, a High Resveratrol Polyphenols Complex, Insulin Excursions

N utrition, Education, and Exercise on Glycemic Control, HbA1c, and Clock Gene mRNA Expression in ALPANA P. SHUKLA, ANTHONY CASPER, JESELIN ANDONO, SAMIR TOUHAMY, Type 2 Diabetes CATHERINE THOMAS, REKHA KUMAR, LEON IGEL, LOUIS J. ARONNE, New York, NY JULIO WAINSTEIN, OREN FROY, ZOHAR LANDAU, YOSEFA BAR-DAYAN, MONA In a previous pilot study using a typical Western meal, we demonstrated BOAZ, TALI GANZ, MIRIAM MENAGED, YOHEVED HAGAY, MALKIT AZACHI, DAN- that ingestion of protein and vegetables before carbohydrate leads to lower IELA JAKUBOWICZ, Holon, Israel, Rehovot, Israel postprandial glucose and insulin excursions up to 120 min compared to eating Disrupted clock genes (CG) mRNA expression in white blood cells (WBC) is carbohydrate first in a meal. In this follow up study, we seek to examine the associated with T2D. Resveratrol, a natural polyphenol, exerts potent modu- effect of food order on postprandial plasma glucose and insulin excursions in latory effects on CG expression and recently has been linked with glycemic the setting of three commonly followed meal patterns with extended follow- regulation. The effects of Red Grape Cells (RGC), a resveratrol polyphenol up to 180 min. 7 overweight/obese subjects (BMI 25-40kg/m2) with type 2 complex, on glycemic control and CG (Bmal1, Clock, Per2, Cry1 and Rev-erbα), diabetes (HbA1c ≤ 8%) on Metformin were studied using a within subject mRNA expression have never been explored in T2D. To study the impact of crossover design. After a 12 hour fast, subjects were randomly assigned to RGC supplementation (S) on HbA1c, plasma glucose, insulin, C-peptide and CG consume an isocaloric meal with the same composition on 3 separate days mRNA expression in WBC, 33 T2D participants aged 63.7±7.1 yrs, BMI 30.28 ± in one of the following food orders: carbohydrate (bread) followed 10 minutes 4.58 kg/m2 and HbA1c 7.76 ± 0.78% were randomized to 12 weeks to either S later by protein (chicken) and vegetables, protein and vegetables followed with RGC 1000 mg daily or placebo (PLA). All patients underwent at baseline at 10 minutes later by carbohydrate or all meal components eaten together as the end of study a meal test (520Kc, 29,4 g protein; 50.2 g CH; 44.7 g fat). After a sandwich. Blood was sampled for measurement of glucose and insulin at 12 weeks, greater reduction of HbA1c was observed in RGC - 0.55 ± 0.05% baseline and at 30 min intervals upto 180 min after the meal. The incremental (from 7.85 ±1.01 to 7.30 ± 0.75, p=0.0353) vs. PLA- 0.16±0.15% (from 7.67± areas under the curve for glucose (iAUC 0-180) were similar, though the car- 0.55 to 7.51 ± 0.52, p=0.2334). The reduction of HbA1c was 29% greater with bohydrate first pattern demonstrated greater glycemic variability with higher RGC vs. PLA. Within a sub-group with higher HbA1c at baseline (7.5 to 10.1%) peak at 60 min and lower nadir at 180 min. The average incremental glucose the reduction of HbA1c was - 1.21% with RGC and -0.39% in PLA (p<0.0247). peak following ingestion of protein and vegetables first was 51% and 45% Compared to PLA, the AUC (0-240 min) for plasma glucose and insulin showed lower compared to eating carbohydrate first or eating all meal components non-significant (NS) changes, while C-peptide had more reduction by 27.2% together as a sandwich respectively. The iAUC 0-180 for plasma insulin was with RGC vs. PLA (p=0.0409). As a result the estimated insulin sensitivity cal- significantly lower when vegetables and protein were consumed first fol- culated from fasting glucose and C-peptide was increased by 40.6% with RGC lowed by carbohydrate compared to other meal conditions. Food order has a vs. PLA (p<0.0137). Postprandial mRNA expression of the clock genes showed significant impact on postprandial glucose and insulin excursions and may be NS changes in the transcription factors Bmal1 and Clock while the repressor an effective strategy to attenuate postprandial glucose spikes and glycemic genes Per2, Cry1 and Rev-erbα, were significantly depressed (p<0.05) with variability in patients with type 2 diabetes with implications for improving RGC vs. PLA. In conclusion, 12-week S of RGC in T2D reduced HbA1c, improved insulin sensitivity. insulin sensitivity and significantly influenced the CG expression. New studies Supported By: Louis and Rachel Rudin Foundation (UL1 TR000457) are needed, to elucidate the best dosage and whether RGC might be useful as adjuvant for achieving glycemic control in T2D. 63-LB The Effect of Nopal on Blood Glucose Response in Individuals with 61-LB First-Degree Relative with T2DM Transcultural Diabetes-specificN utrition Algorithm (tDNA) Improves VIDAL T. MIRELES, BETH C. SENNE-DUFF, San Antonio, TX Glycemic Control, Body Weight, and Blood Pressure in Overweight/ Nopal or prickly pear cactus has traditionally been included in south- Obese Type 2 Diabetes Patients in Primary Care Practice: Malaysian western U.S., Native American and indigenous Mexican diets. Nopal’s use Application as a remedy for hyperglycemia secondary to diabetes, has long been a point WINNIE S. CHEE, HARVINDER KILCHARAN SINGH, OSAMA HAMDY, JEFFREY I. of contention as there is a scarcity of studies in both healthy and diabetic MECHANICK, ANKUR BARUA, VERNA LEE, SITI ZUBAIDAH MOHD ALI, ZANARIAH individuals. This study evaluated the effects of nopal on postprandial [BG] in HUSSEIN, Kuala Lumpur, Malaysia, Boston, MA, New York, NY, Seremban, Malaysia, individuals at risk of type 2 diabetes mellitus (T2DM) by virtue of having a 1st Putrajaya, Malaysia degree blood relation with a diagnosis of T2DM. An experimental crossover Transcultural Diabetes Nutrition Algorithm (tDNA) was developed by an study was conducted with healthy participants (N = 14). Potential participants international group of independent diabetes and nutrition experts and cultur- were excluded if they had an ADA type 2 diabetes risk test score greater than ally customized by local experts in several countries. tDNA aims at guiding 5, a casual BG (CBG) greater than or equal to 140 mg/dL, a FBG greater than primary care providers to recommend lifestyle intervention based on initial or equal to 100 mg/dL, or conditions and/or medications that could alter BG risk evaluation. We tested the tDNA model in a primary care setting in Malay- responses. Direct blood relations to those participating were excluded. Sub- sia where type 2 diabetes (T2D) affects 20.8% of its adult population. We jects ingested a test meal containing 100 g nopal or 100 g zucchini in a ground randomized 230 patients with overweight/obesity and T2D, not treated with beef stew containing 41 g of carbohydrate. After 20 to 30 min, subjects drank insulin and with HbA1c >7%, to either the Malaysian tDNA model or to stan- a carbonated orange flavored solution containing 75 g of carbohydrate. Sub- dard diabetes care (SC) for 6 months. Patients in the tDNA group followed sequently, researchers performed capillary BG monitoring for 180 min at 30 medical nutrition therapy (MNT), consisting of natural foods, a diabetes- min intervals. Incremental area under the curve (iAUC) was integrated manu- specific formula, and increased physical activity according to the algorithm ally using the trapezoidal method. Data was analyzed using paired t-tests. No based on initial body weight, A1c, exercise capacity and cardiovascular risk significant differences were observed in iAUC between the zucchini (5538 +

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LB16 PsychosocLate Bireaal, kingBeha viAbstractsoral Medicine

600 mg/dL/min) and nopal (5318 +963 mg/dL/min) treatments, p =0.80. Fur- complicated by dietary, cultural and social practices. Lack of knowledge, poor thermore, there was no significant difference between the observed peaks access to medical care and immigration further hindered diabetes control. for zucchini (163.5 + 8.5 mg/dL) and nopal (161.4 +10.3 mg/dL), p = 0.78. We This is the first IP study that has examined beliefs and practices of AI with conclude that consuming a meal including nopal compared to zuchinni does type 2 diabetes in the U.S. Findings from this study will be used to develop not improve post pradial glycemic response in individuals at risk of T2DM by culturally and gender specific interventions to increase early awareness, 1st degree blood relation. screening and diabetes management in this group.

Supported By: University of the Incarnate Word 66-LB 64-LB Development and Validation of the Type 1 and Type 2 Diabetes Stigma Accuracy in Carbohydrate Counting (CC) and Measures of Glycemic Assessment Scales Control in Patients with Type 1 Diabetes (T1D) JESSICA L. BROWNE, ADRIANA D. VENTURA, KYLIE MOSELY, JANE SPEIGHT, THOMAS W. DONNER, MAUREEN SEEL, SARAH LONGENECKER, Baltimore, MD Melbourne, Australia In patients with T1D, it is unclear how accuracy of CC impacts HbA1c, glyce- We aimed to develop and validate two self-report measures to assess per- mic variability (GV), and frequency of hypoglycemia (% Hypo). Adult patients ceived and experienced diabetes stigma among adults with type 1 (T1DM) with T1D (N=57) were asked about CC methods and to estimate the amount in and type 2 diabetes (T2DM). For each measure, an item pool was drafted grams (g) of carbohydrates (Carbs) of 20 pictured foods. based on: a) qualitative interviews with adults with diabetes (T1DM: N=27, POSTERS The survey was scored by the absolute difference (Abs Diff) in the amount T2DM: N=25), and b) content from other stigma scales. A 5-point response of Carbs estimated versus the actual Carb content. The Abs Diff of Carb esti- scale (strongly disagree-strongly agree) was used. Twenty-five adults (T1DM:

mates was calculated for single foods, combination foods, and low, medium n=12, T2DM: n=13) completed the draft measures and took part in cognitive Behavioral M edicine, Clinical and high Carb foods, and then correlated with HbA1c, GV [SD of all BG read- debriefing interviews. Based on participant feedback, the T1DM measure was N utrition, Education, and Exercise ings from CGMs (N=24) or BG meters (N=33)], and % Hypo (BG < 70 mg/dL). reduced from 46 to 41 items, and the T2DM measure was reduced from 57 Mean values for all patients: age 46 years, HbA1c 7.8%, and duration of to 48 items. diabetes 26 years; 81% were on insulin pumps and 42% on a CGM. The Mean A total of 2,342 respondents (T1DM: n=1,078, T2DM: n=1,264) completed (SD) Abs diff in Carb estimates (g) for 10 single foods (total Carb 271 g) = 69.0 surveys including the new stigma measures and validated scales. Using prin- (33), 10 combination foods (total Carb 453 g) = 160 (63), 8 low Carb foods (total cipal components analysis, both scales were reduced to 19 items. Unforced Carb 126 g) = 61.9 (52), 7 medium Carb foods (total Carb 245 g) = 60.1 (27), and three-factor and forced one-factor solutions with satisfactory Cronbach’s 5 high Carb foods (total Carb 353 g) = 100 (46). alpha supported the calculation of subscale and scale total scores (Table 1). Significant correlations were observed between accuracy of CC of single Satisfactory concurrent, convergent (all correlations medium-large) and dis- foods with GV and HbA1c, and medium Carb foods with GV and HbA1c. No criminant validity (all correlations small-negligible) were demonstrated for correlation between accuracy of CC and % Hypo was observed. Improvement both scales. in accuracy of CC may improve glycemic control through lower HbA1c and The novel type 1 and type 2 diabetes Stigma Assessment Scales (DSAS-1 less GV. and DSAS-2) are reliable and valid measures of perceived/experienced diabe- Table. Accuracy in Carbohydrate Counting (CC) and Measures of Glycemic tes stigma, and are now available to facilitate research in this field. Control in Patients with T1D. Table 1. Subscale Details for the DSAS-1 and DSAS-2. HbA1c GV % Hypo Scale name Subscale name Number Factor loading Subscale Total Single Foods Abs Diff 0.383# 0.313* 0.068 of items range α α Combinations Foods Abs Diff 0.239 0.189 -0.031 DSAS-1 Treated Differently 6 0.63-0.89 0.89 Low Carb Foods 0.177 0.223 -0.001 Blame and Judgement 6 0.45-0.89 0.88 0.93 Medium Carb Foods 0.290** 0.346+ -0.051 Affective Responses 7 0.59-0.92 0.89 Large Carb Foods 0.146 0.068 0.077 DSAS-2 Treated Differently 6 0.51-0.74 0.88 * P=0.02, + P=0.01, # P<0.01, ** P=0.03. Blame and Judgement 7 0.63-0.82 0.90 0.95 Internalised Stigma 6 0.56-0.82 0.90 Supported By: Diabetes Australia Psychosocial, Behavioral Medicine 67-LB 65-LB What Is the Course of Depression Symptoms in Type 2 Diabetes? Diabetes Beliefs and Practices among First-Generation Asian Indi- Risk Factors and Outcomes of 6-Year Depression Trajectories Using ans in the U.S. Latent Curve Growth Analysis RUPINDER DEOL, LISA THOMPSON, KEVIN CHUN, CATHERINE CHESLA, San Fran- STEPHANIE R. WHITWORTH, DAVID G. BRUCE, ROMOLA S. BUCKS, TIMOTHY cisco, CA DAVIS, WENDY A. DAVIS, TIMOTHY C. SKINNER, SERGIO S. STARKSTEIN, Perth, One in six Asian Indians (AI) is diagnosed with type 2 diabetes and the prev- Australia, Fremantle, Australia, Darwin, Australia alence rate is 29%. Although culturally distinct issues have been anticipated, Routine monitoring of depression in type 2 diabetes has been recom- few studies have examined AI beliefs and practices regarding diabetes. The mended, yet the longitudinal course of depression symptoms in this popula- purpose of this study was to understand cultural commonalities and differ- tion remains unclear. This study aimed to describe trajectories of depression ences in illness management in AIs. The overall goal was to provide an inter- symptom severity over 6-years, and to identify predictors and outcomes of pretive account of causal factors; daily activities and challenges; cultural and these trajectories. A community-dwelling cohort of 1,201 individuals with social practices that impacted type 2 diabetes in AI. Interpretive phenomenol- type 2 diabetes were recruited to the Fremantle Diabetes Study-Phase II ogy (IP) guided the research design and analysis. In-depth narratives about (FDS2) from 2008-2011, and administered the PHQ-9 yearly for 6-years to health beliefs and practices were gathered through open-ended interviews. assess depression symptoms. Glycemic control, self-management behaviour A sample of 12 adult participants (50% female) between the ages of 40-79, and health-related quality of life (HRQoL) were measured at baseline and at first generation AI with type 2 diabetes, low income with average duration of subsequent 2-year intervals. Latent curve growth analysis was used to iden- U.S. residency of 20 years were recruited. Each participant was interviewed tify depression symptom trajectories and associated diabetes outcomes, and twice to learn about cause, culturally specific practices, supports and barriers logistic regression models determined predictors of group membership. Three to illness understanding and management. The high prevalence of diabetes distinct trajectories of depression symptoms were identified: persistently low in AI led participants to express a sense of inevitability for developing the depression symptoms (No Depression Problem, 84.6%), a gradual worsening disease. Participants suggested that social and environmental causes out- then slight improvement in symptoms (Recurrent Depression - Low Start, weighed hereditary causes for their diabetes although beliefs were gender- 7.8%), and a pattern of gradually improving symptoms which then relapsed specific. Female participants named stressors that disrupted family harmony, (Recurrent Depression - High Start, 7.6%). Younger age, being unmarried, a overwhelming family responsibility, and a lack of communication with their lifetime history of depression, and poorer mental and physical HRQoL, sig- physicians as contributing to their diabetes. Male participants suggested that nificantly predicted membership of both depression groups. In turn, recurrent employment stresses and poor diet were causal. Diabetes management was

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LB17 PsychosocLate Bireaal, kingBeha viAbstractsoral Medicine

depression was associated with significantly higher BMI and HbA1c over time. treatment group on mean A1c value at study end (difference between telemedi- A sub-set of individuals with type 2 diabetes are at high risk of depression cine and same room = -0.82, p-value = 0.0061, 95% CI = -1.405, -0.241). symptoms that remain recurrent over time. Regular screening for depression Conclusions: Telemedicine delivered BAT was superior to same room in in primary care may better identify individuals at risk of a later relapse/pro- achieving lower A1c. This finding suggests that BAT delivered via telemedicine gression in symptoms. Younger individuals with a history of depression and is a viable treatment option for depression in adults with diabetes. poorer mental and physical HRQoL may benefit most from early and inten- Supported By: U.S. Department of Veterans Affairs (IIR-04-421)

sive intervention to buffer the effect of depression on long-term health outcomes. 70-LB Supported By: National Health and Medical Research Council (513781) Psychometric Validation of the Novel Glucose Monitoring Experi- ences Questionnaire (GME-Q) among Adults with Type 1 Diabetes 68-LB JANE SPEIGHT, ELIZABETH HOLMES-TRUSCOTT, STUART A. LITTLE, JAMES A. Impact of the Gather mHealth Diabetes Platform on A1c and Treat- SHAW, Melbourne, Australia, Newcastle, United Kingdom ment Adherence in a 3-Site Randomized Trial in India The Glucose Monitoring Experiences Questionnaire (GME-Q) was designed NORA J. KLEINMAN, AVANI SHAH, SANJIV SHAH, SANJEEV PHATAK, VIJAY to elicit users’ evaluations of their current glucose monitoring method (includ- VISWANATHAN, Hong Kong, China, Mumbai, India, Ahmedabad, India, Chennai, ing finger prick and continuous glucose monitoring (CGM) devices). Item POSTERS India development was informed by literature review as well as exploratory and India has an estimated 69.2 million people with diabetes and a prevalence cognitive debriefing interviews with 17 adults (9 women) with type 1 diabetes of 8.7%. There is mounting evidence on the benefits of telemedicine for diabe- (T1D), aged (mean±SD) 48±10 years. A conceptual framework was proposed

Behavioral M edicine, Clinical tes care, but limited information on mobile health (mHealth) in the developing including three potential domains (effectiveness, convenience, intrusiveness

N utrition, Education, and Exercise world. This study assessed the impact of the Gather mHealth diabetes plat- of monitoring method) assessed with 25 items (9 negatively worded), and a form on patient outcomes, behavior, and satisfaction. In an open-label, paral- single, overview item asking about the extent to which “my current method lel study, 90 people aged 18-65, with type 2 diabetes and an A1c between of monitoring suits me well.” The GME-Q was included in the “YourSAY: Glu- 7.5% and 12.5% were randomly assigned 1:1 to mHealth or usual care for 6 cose Monitoring” Australian online survey. A total of 592 eligible adults (aged months at 3 sites in India. All received free visits, lab tests, travel fees, and ≥18 years) with T1D, not currently using CGM, participated: 64% women, blood glucose (BG) strips and lancets. Intervention participants also received mean±SD age 44±15 years, diabetes duration 22±14 years, 42% using insu- the free mHealth app and a stipend for mobile phone data. Demographic, clini- lin pump therapy, median (IQR) number of glucose checks on a typical day cal, and patient-reported outcome data were collected at baseline, 3 months, was 6 (4,7). Complete GME-Q data were available for 578 (98%) participants, and 6 months. The primary outcome was change in A1c from baseline to 6 suggesting acceptability of the questionnaire. After deletion of 3 redundant months. Mean age was 48.4 years (SD ±9.2), 30% were female, and 25.6% items, principal components analysis supported a 22-item questionnaire with had a university education or higher. There was a mean A1c decrease of 1.5% three domains (Effectiveness (9 items); Intrusiveness (6 items); Convenience in the intervention mHealth group (n=41; 9.4% to 7.9%) and 0.8% in the usual (7 items)), accounting for 55% of variance, and displaying good internal consis- care group (n=39; 9.1% to 8.2%), a statistically significant difference (p=0.02; tency reliability (α=0.83-0.88). The domains correlated significantly (r=0.44- 95% CI: 0.1-1.37). Significantly more participants with the intervention than 0.66, p<0.001) with the single, overview item, together explaining 51% of the the control improved their medication adherence from baseline (39.0% vs. total variance in the single item score. Psychometric validation supports the 12.8%; p=0.026) and increased the frequency of their BG testing each week 22-item GME-Q, which provides an acceptable, valid and reliable measure of (39.0% vs. 10.3%; p=0.01). No other outcomes were significantly different experiences of current method of glucose monitoring. Future research needs between groups. At 6 months, 75% of participants were actively using the to determine the predictive validity of the GME-Q and explore psychometric app. Over 80% of intervention participants were “very satisfied” or “satisfied” properties among adults using CGM devices. with all app components. Those using the mHealth app had more significant A1c declines than usual care. Given the burden of diabetes in the developing 71-LB world, this tool could be utilized to expand access to quality chronic disease Pilot Study of a Novel Measure of Diabetes-specific Risk-Taking care, enhance compliance, and ultimately reduce painful and costly negative Behaviors and Health Outcomes in Older Adolescents with Type 1 outcomes. Diabetes (T1D) Supported By: Gather Health RACHEL M. WASSERMAN, BARBARA J. ANDERSON, DAVID D. SCHWARTZ, Hous- ton, TX 69-LB Glycemic control for youth with T1D is often at its worst in adolescence, Effect of Psychotherapy for Depression via Telemedicine on Glyce- while general risk-taking behaviors (e.g., smoking, binge drinking) are often at mic Control in Adults with Type 2 Diabetes: Subgroup Analysis of a their highest. Youth who engage in general risk-taking may also take risks Randomized Clinical Trial with diabetes care, but diabetes-specificrisk-taking (e.g., going 24 hours with- LEONARD E. EGEDE, REBEKAH J. WALKER, ELIZABETH H. PAYNE, REBECCA G. out checking blood glucose, or drinking alcohol with no plan to check blood KNAPP, RON ACIERNO, CHRIS FRUEH, Charleston, SC glucose overnight) has not been empirically assessed. The aim of the current Introduction: Depression is associated with poor outcomes in adults with study was to determine associations between diabetes-specific risk-taking, diabetes. We evaluated the impact of telemedicine delivered behavior activa- general risk-taking, and important health outcomes (A1c, DKA, and severe tion treatment (BAT) on glycemic control in a subgroup of older adults with hypoglycemia) in youth with T1D. Thirty adolescents with T1D (age 15-19, diabetes who participated in an RCT for depression. 60% female, M A1c=8.7±1.4%, and 33% on insulin pumps) completed a new Methods: We randomized older adults from a VA medical center with major measure, the Diabetes-Specific Risk-Taking Inventory (DSRI), in which they depression to same room or telemedicine group. Each group received 8 weekly reported how often they engaged in 34 behaviors that placed them at risk for sessions of BAT. For the subgroup analysis, we identified subjects with type 2 acute problems or poor glycemic control. Participants also completed 9 risk- diabetes and obtained hemoglobin A1c (A1c) at baseline and 12 months follow taking items from the Risk-Taking and Self-Harm Inventory for Adolescents up. We used mixed effects longitudinal models (MEM) to compare mean A1c (RTSHI-A), a measure of general risk-taking. Reliability was good for DSRI and between telemedicine and same room patients. The model included treat- RTSHI-A (α=.92, α =.85, respectively). Mean A1c over the previous year was ment, time, and an interaction term. We used MEM to estimate model-derived obtained by chart review; DKA and hypoglycemic events over the last 3 years mean A1c by treatment group at baseline and study end. were obtained by interview with the teen and parent. Results indicated a Results: We screened 780 patients and randomly assigned 120 [50%] to positive correlation between general and diabetes-specific risk-taking r( =.42, telemedicine and 121 [50%] to same room. In primary analysis, telemedicine p<.05), and between diabetes-specific risk-taking and A1c over the last year was non-inferior to same room in terms of treatment response for depression. (r=.58, p<.01). General risk-taking was associated with DKA (r=.46, p<.05), but We included 90 subjects in the subgroup analysis (43 in telemedicine and 47 in not with mean A1c or severe hypoglycemia. Diabetes-specific risk-taking is an same room). Both groups were not significantly different at baseline for demo- important new concept that adds to our understanding of behaviors that may graphics, depression, anxiety and A1c levels (telemedicine 6.9 vs. same room contribute to poor glycemic control in adolescents. Screening for diabetes- 7.3, p=0.189). Baseline mean A1c for telemedicine group was 6.9 and remained specific risk-taking may help identify patients at-risk for poor glycemic control at 6.9 at 12 months, whereas baseline mean A1c for the same room group was and provide an actionable target for preventive interventions. 7.3 and increased to 7.7 at 12 months. The longitudinal trajectories of model- Supported By: National Institute of Diabetes and Digestive and Kidney Diseases derived mean A1c values indicated that there was a significant main effect of (5K12DK097696 to B.J.A.)

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LB18 PsychosocLate Bireaal, kingBeha viAbstractsoral Medicine

72-LB 74-LB Social Networks in Type 2 Diabetes Management: Systematic Review Diabetes Distress and Poor Coping Influences Diet and Eating Behav- and Meta-analysis of Randomized Trials ior in Young Adults with Type 1 Diabetes (T1DM) GABRIELA SPENCER BONILLA, RENE RODRIGUEZ-GUTIERREZ, OSCAR J. PONCE, VIVIEN CAMILLE PAEZ, LAURETTA T. QUINN, PAMELA MARTYN-NEMETH, Chi- PATRICIA J. ERWIN, VICTOR M. MONTORI, Rochester, MN, Lima, Peru cago, IL Living with type 2 diabetes does not need to be faced alone; social net- The major focus of T1DM management is the achievement of glycemic con- works play an important role in health management and offer a potential trol to reduce diabetes complications. Unhealthy dietary patterns and weight locus of intervention. This review evaluates randomized trials testing the control behaviors are known to adversely affect glycemic control. Psycho- effect of interventions that include patients’ pre-existing social networks in logical factors influence these eating behaviors in the nondiabetic population. the management of T2DM on social support, glucose control and quality of life Little is known about the association of psychological factors with dietary and versus any comparator. We excluded trials in which social network ties were weight control behaviors in young adults with T1DM. Thus, a cross-sectional, constructed by the intervention. We performed a search of Ovid MEDLINE, descriptive correlational study was conducted to examine the associations Ovid EBM Reviews, Cochrane Central Register of Controlled Trials, EMBASE, among dietary patterns, weight control behaviors, and psychological char- PsycINFO, and CINAHL through January 2016. The search was supplemented acteristics of young adults with T1DM. The subjects included 23 males and by hand searching relevant identified references. Risk of bias was assessed females (56.5% female), 18-45 years diagnosed with T1DM for a minimum of using the Cochrane Risk of Bias Tool. two years. Questionnaires were used to collect demographic, health, dietary POSTERS We included 14 trials (1837 participants). The body of evidence retrieved and weight control behaviors, and psychological characteristics (diabetes was at unclear to low risk of bias, but was inconsistent and poorly reported distress and coping). Measured height and weight, A1c, and fasting triglycer- with regard to participants, interventions, comparators and outcomes. Inter- ides were obtained. Two unique eating patterns emerged. Unhealthy dietary Behavioral M edicine, Clinical

ventions resulted in increased social support (6 trials, 775 participants; SMD patterns (e.g., meal irregularity, snacking, fast food intake) were related to N utrition, Education, and Exercise 0.86 [95% CI, 0.33 to 1.39], I2=91%). Pooled estimates of effect for HbA1c greater diabetes regimen distress (r= .707, p= .003), higher triglycerides (r= showed a statistically significant improvement when measured at 2-4 months .642, p= .013), and greater dietary fat intake (r= .583, p= .011). Unhealthy after baseline (5 trials, 477 participants; MD -0.23 [95% CI, -0.35 to -0.12], weight control behaviors (e.g., skipping insulin, excessive exercising, fasting) I2=0%) but not at longest follow-up, which ranged from 3-24 months (12 tri- were related to higher BMI (r= .558, p= .007), lower dietary fat intake (r= -.503, als, 1507 participants; MD -0.03 [95% CI, -0.38 to 0.33], I2=93%). Five trials p= .017), greater dietary restraint (r= .685, p= .001), and more avoidant coping reported quality of life outcomes, 2 of which reported global scores that when (r= .490, p= .024). Females were more likely to participate in unhealthy weight pooled, showed a non-statistically significant improvement (282 participants; control behaviors, and avoidant coping, whereas males were more likely to SMD 0.62 [95% CI, -0.13 to 1.37], I2=91%). engage in unhealthy dietary patterns, and report more diabetes regimen dis- Emerging literature finds promising effects of social network interventions tress. Results indicate that in males diabetes distress influenced their dietary as an alternative to self-management support to improve diabetes outcomes. patterns, whereas in females poor coping was associated with unhealthy Larger, rigorously conducted and reported trials, with longer follow-up are weight control behaviors. needed to improve the reliability of this evidence and its findings. Supported By: University of Illinois at Chicago College of Nursing PROSPERO registration: CRD42016036117. Supported By: National Center for Advancing Translational Science (TL1 TR000137 75-LB to G.S.B.) Diabetes Alert Dogs (DADs) vs. Technology: Patient Experiences and Perceived Accuracy 73-LB JACLYN A. SHEPARD, JESSE H. GRABMAN, ANAND V. TRIPATHI, LINDA A. GONDER- Smoking Practices and Perceptions of Health Risks in Tobacco Use FREDERICK, Charlottesville, VA among Adolescents and Young Adults with Type 1 Diabetes The use of DADs as a method for blood glucose (BG) monitoring is rising. KATHRYN M. MIN, KRISTIN SIKES, STUART A. WEINZIMER, JODIE M. AMBRO- However, little is known about the reasons patients with type 1 diabetes SINO, West Hartford, CT, New Haven, CT (T1D) decide to use alternatives to current BG monitoring technology in their Besides the well-known negative health effects of tobacco use, smoking self-management. The present study was a preliminary investigation into undermines type 1 diabetes (T1D) management and accelerates diabetes- patient experiences with and beliefs about DAD use and continuous glucose related complications in adults. Less is known about smoking practices and monitoring (CGM). health risk perceptions in youth. The purpose of this pilot study is to investi- A group of 9 adults with T1D (age 22-43 years; 7 female; median A1c=7.2%) gate the smoking practices, awareness of health risks specific to diabetes, and 8 parents of youth with T1D (youth age 8-17 years; 4 female; median motivation to stop smoking, and readiness to learn about resources in youth A1c=8.0%) who owned DADs completed questionnaires assessing prior expe- with T1D and their parents. Adolescents and young adults (n=97) with T1D rience with CGM and beliefs about DAD performance. (mean age=17.9 yrs + 2.7) who were attending routine clinic visits at a pedi- All adults and the majority of parents (6/8) reported previous use and dis- atric diabetes clinic, and for minors, their parents (n=68) each anonymously continuation of CGM. For adults, inaccuracy, burden of use, and financial rea- completed a 12-item questionnaire prior to their appointment. Upon comple- sons were cited as primary reasons for discontinuation, while parents cited tion, participants were offered a flyer with general and diabetes-specific inaccuracy and burden of use for the child. Regarding reasons for obtaining a health risk information and smoking cessation resources. Results indicate DAD, problems related to severe hypoglycemia and hypoglycemia unaware- that nearly 15% of youth and 18% of parents endorsed smoking at least one ness was a prevalent theme reported by adults. Parents reported obtaining a tobacco product (including e-cigarettes) in their lifetime, while 4% of youth DAD to provide them with a sense of security, especially overnight, regard- and 18% of their parents admitted to current smoking practices. Of the 4 youth ing their child’s BG fluctuations and to promote increased autonomy for their who currently smoke, 3 were motivated to quit but only 2 were interested in child. All adults and the majority of parents (7/8) believed their DADs are more cessation resources. While the majority of youth (86%) and parents (62%) accurate than current diabetes technology, reporting that DADs could detect accurately identified at least one general health risk to smoking, fewer youth BGs outside a median target range of 4.4 mmol/L - 9.7 mmol/L and 4.7 mmol/L (14%) and parents (24%) accurately identified specific diabetes-related risks. -11.1 mmol/L, respectively. Only 2% of youth and 8% of parents showed interest in general smoking- Based on this preliminary study, it appears that many individuals who obtain related resources. Those who currently smoked indicated little knowledge DADs have previously used, but ultimately discontinued, CGM. Overall, DAD about the diabetes-specific risks. The diabetes-specific deleterious effects of owners tend to believe that their DADs are more accurate than current diabe- smoking are not recognized by the majority of youth with diabetes and their tes technology and offer perceived benefits related to low BG detection and parents. Diabetes providers are well-positioned to educate adolescents with peace of mind, including nighttime monitoring for children and their parents. T1D and their parents on the added risks that smoking presents to diabetes Larger trials with a focus on objective accuracy measurements are needed. management, for both prevention and cessation interventions. Supported By: National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases (1R21DK099697-01)

ADA-Supported Research For author disclosure information, see page LB102.

LB19 Clinical Therapeutics/NewLate Tech Breanolokinggy— AbstractsGlucose Monitoring and Sensing

Clinical Therapeutics/New Technology— 78-LB Glucose Monitoring and Sensing Critically Ill Patients: Accuracy of Different Methods of Measuring Blood Glucose 76-LB MARIA C. FAINGOLD, OSVALDO FRETES, MELANIE ROSMARIN, EVELYN BLANC, Performance of the GLUCOCARD® Shine in Alternative Site Testing NOELIA SFORZA, JOHANNA ROSENFARB, ROMINA CLEMENTE, SANTIAGO FRID, against the ISO 15197: 2013 Accuracy Criteria ANA FERNANDEZ, NATALIA MEO GUZMAN, JIMENA SANTAMARIA, SILVIA SCARAZZINI, ALDANA ANTONACCI, VERONICA VILLANUEVA, MIRTA GURF- JULIE WALKER, DANIELLE MAHER, PATRICIA GILL, JOHN GLEISNER, Minneapolis, INKIEL, CARLA MUSSO, Buenos Aires, Argentina MN Blood Glucose Monitoring Systems (BGMS) are important tools used in the Blood glucose meters (BGMs) were originally designed and approved for management of diabetes mellitus. Proper management of diabetes leads to self-monitoring by patients with diabetes. However, scientific associations the prevention of micro and macrovascular complications. It is important that have alerted that using them is not recommended in critically ill patients, who an adequate blood drop is produced when evaluating a blood glucose read- frequently have impaired perfusion and peripheral edema, conditions that ing. Fingersticks are the most widely accepted method for obtaining a blood may interfere with accuracy of the methods. The alternatives to BGM testing drop; however, there are situations where Alternative Site Testing (AST) may are more difficult to work with, because they are slower, more expensive, be desirable. The ISO (International Organization for Standardization) 15197: and/or riskier for patients. 2013 is an accepted standard for the accuracy of BGMS. The accuracy bound- The aim of this study was to compare the accuracy of whole blood (WB) aries of ISO 15197: 2013 require 95% of BGM results to be within ±15mg/dL (Gas analyzer) and Point-of-Care (POC) glucose measurements with its gold standard that is the glucokinase method, in critically ill patients admitted to

of the reference analyzer at glucose concentrations <100mg/dL and within our intensive care unit. ±15% of the reference analyzer at glucose concentrations ≥100mg/dL. Fur- thermore, 99% of all results are required to be within the A and B zones of A hundred finger sticks measurements and peripheral blood samples were the Consensus Error Grid. The objective of this study is to determine if the obtained from 70 patients (median age 71 years), between August 2015 and GLUCOCARD® Shine provides results that are within the accuracy boundaries January 2016. Finger sticks (Accu-Check Performa, Roche device) and periph- of the ISO 15197: 2013 Standard when performed on an alternate site (palm). eral blood samples were obtained from each patient at the same time by ® highly trained professionals. Peripheral blood sample was measured by the

POSTERS AST was performed by confirmed diabetics (n=23) on one lot of GLUCOCARD Therapeutics Shine at the ARKRAY Factory, Inc. in Minneapolis, MN. Reference values were gas analyzer method (WB), and plasma was sent to the central lab to be ana- Clinical Diabetes/ obtained using the YSI Model 2300 Analyzer. The data was analyzed against lyzed by the glucokinase method. the accuracy boundaries of the ISO 15197: 2013 Standard and the percentage According to ISO requirements there was a significantly lower number of dis- of the results in the A plus B zones of the Consensus Error Grid. 100% of cordant cases in WB measurements vs. POC (3% vs. 22%, respectively, p<0.001). the results <100mg/dL (2/2) were within ±15mg/dL of the YSI and 95.2% of Clinical concordance analysis revealed a better agreement between whole blood glucose and glucokinase (Kappa=0.84) than with POC (Kappa=0.57). the results ≥100mg/dL (20/21) fell within the ±15% of the YSI. All data were within the A and B zones of the Consensus Error Grid. The overall bias to YSI In our experience WB measurements were more accurate than the POC. was +1.5% and the correlation coefficient was (r) = 0.96, which demonstrate a Our results based in a high number of elderly patients, especially prone to be strong linear relationship between GLUCOCARD® Shine and the YSI reference fragile are in accordance with the available literature in general population. method. The data acquired on the GLUCOCARD® Shine by users through AST BGM steel needs to be validated for its use in critically ill patients. was within the accuracy boundaries of the ISO 15197: 2013 Standard. 79-LB 77-LB The Use of Dexcom G4 Continuous Glucose Monitoring in Diabetes 72-h Glucose Monitoring Profile in Mild Gestational Diabetes Mel- NHP Research litus: How Different from Healthy Pregnancies? YIN LIANG, BINGDI WANG, GUOFENG SUN, WEI QIAO, WEIWEI YE, JIQIU QIAO, ZHEN PANG, XIAOLI WANG, YONG FU XIAO, JEAN WHALEY, KEITH T. DEMAREST, ANTONIO RIBEIRO-OLIVEIRA, MARINA CARREIRO, Belo Horizonte, Brazil This study aimed to evaluate the glucose profiles of gestational diabetes YIXIN (JIM) WANG, Spring House, PA, Taicang, China (GDM) patients with 72-hours of continuous glucose monitoring (CGM) either The Nonhuman Primate (NHP) is a highly valuable model for diabetes before (GDM1) or after (GDM2) dietary counseling, comparing them with research and drug discovery. The Dexcom G4 Continuous Glucose Monitoring nondiabetic (NDM) controls. We performed CGM (Medtronic MiniMed) on (CGM) System is approved by the FDA for 24-hr real time interstitial glucose 22 GDM patients; 11 before and 11 after dietary counseling and compared readings every 5 min in diabetic patients. This study tested the CGM in cyno- them to 11 healthy controls. Several physiological and clinical characteristics molgus monkeys to evaluate if this method enabled novel insights in a diabe- of the glucose profiles were compared across the groups for: pooled measure- tes-related study, compared with the classical glucometer method. CGM was ments and hourly comparisons; exposure as evaluated by area under curve applied in male cyno monkeys (age from 9 - 23 years old, 5 euglycemic and 5 of medians, variability as evaluated by amplitudes, standard deviations and diabetic) for 7 days, to collect baseline glucose profile, as well as glucose lev- interquartile ranges; specific time points and intervals between meals; time els during oral glucose tolerance test (oGTT), intravenous glucose tolerance to peak and peak values after meals; and percentage of time with results test (ivGTT) and meal tolerance test (MTT). Our results showed that, compared with euglycemic monkeys, the basal glucose profile in diabetic monkeys <60mg/dl, 60-140mg/dl and >140mg/dl. Most women (81,8%) in the GDM groups had fasting glucose <95mg/dl, suggesting mild GDM. Variability, glu- exhibited large variation, not only among 5 monkeys with the average 24hr cose levels 1 and 2 hours after breakfast and dinner, peak values after din- glucose level coefficient of variation (CV%) value of 27.6±3.0%, but also in the ner and glucose levels between breakfast and lunch, were all significantly same monkey (24 hr CV% value is 38.2%). The CGM also revealed the impact higher in GDM1 than NDM (p<0.05 for all comparisons). The GDM2 results of stress on glucose levels when diabetic monkeys were moved from cage to were similar to NDM in all aforementioned comparisons (p>0.05). Both GDM monkey chair (average 60 min glucose levels increased from 176.4±10.2 to groups spent more time with glucose levels above 140mg/dl when compared 221.4±9.8 mg/dL, P<0.05). To avoid this stress impact, we conducted a pilot to the NDM group (p<0.05). No differences among the groups were found for: MTT (banana plus sugar feeding) while monkeys were moving freely in the pooled measurements and hourly comparisons, exposure, nocturnal, fasting, cage. Our preliminary results showed that, under natural conditions, glucose between lunch and dinner and before meals, as well as after lunch (p>0.05 levels during MTT showed (1) a low baseline (176.8±12.1 mg/dL at 0 min before for all). The main differences between the mild GDM1 group and healthy con- MTT vs. 216.4±13.8 mg/dL at 0 min before oGTT, P<0.05); and (2) reduced trols were related to glucose variability and excursions above 140mg/dl, while variation among tested monkeys (the average CV% for the 0-60 min was glucose exposure was similar. Glucose levels after breakfast and dinner also 12.0±0.6% vs. 19.7±1.3% in OGTT, P<0.05). However, some CGM limitations discerned the GDM1 group. Dietary counseling was able to keep glucose lev- were observed: (1) reduced accuracy if monkey glucose level was at ~40 mg/ els to those of healthy patients. dL, (2) 10-15 min delay of peak value during ivGTT, and (3) data points missing when glucose level was > 400 mg/dL. Our data show that compared with the Supported By: Brazilian National Council for Scientific and Technological Devel- glucometer method, the CGM can provide additional important information opment for diabetes mechanistic research and drug discovery.

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LB20 Clinical Therapeutics/NewLate Tech Breanolokinggy— AbstractsGlucose Monitoring and Sensing

80-LB 82-LB Examining the Preliminary Efficacy of a Diabetes Care Support Pro- Feasibility of a Decision Support System to Reduce Glucose Variabil- gram Facilitated by Cellular-Enabled Glucose Meters ity in Type 1 Diabetes (T1D) DANIEL J. AMANTE, MAURA E. FOX, DAVID M. HARLAN, MICHAEL J. THOMP- MARC D. BRETON, STACEY ANDERSON, STEPHEN PATEK, DANIEL R. CHERNAV- SON, Worcester, MA VSKY, JESSICA ROBIC, DAYU LV, LAURA KOLLAR, BORIS P. KOVATCHEV, Char- We report preliminary results evaluating physiological and patient- lottesville, VA reported efficacy of the Get In Touch-Phase 2 study (GIT-2). GIT-2 utilized Glucose variability (GV) is a major indicator of glucose control in T1D and cellular-enabled glucose meters to facilitate a diabetes care support program is associated with diabetes complications. We have designed a smartphone- delivered by Certified Diabetes Educators (CDEs) in a 12-month randomized based decision support system (DSS) to help T1D patients reduce GV. controlled cross-over trial. Participants with type 2 diabetes and two Hemo- The UVa DSS consists in 3 modules: automated treatment optimization; globin A1c (A1c) recordings >8.5% in the preceding year were randomized to pre-exercise advisor; and CGM based bolus calculator. Advice is given upon receive the intervention or to the control group for the first 6 months of the user request. study, followed by crossover of treatment groups for the final 6 months of the Eleven T1D subjects on insulin pump completed a randomized crossover study. Participants had A1c labs done at study enrollment, and 3, 6, 9, and 12 trial, consisting of two identical 48 h outpatient admissions (usual care vs. DSS) months post-enrollment. Patient-reported outcomes were collected via paper separated by 4 weeks; both presented a variety of challenges: meals with survey at baseline, 6 months (treatment crossover), and 12 months (study high/low carbohydrates, proteins, and fats; and 3x15min exercise each morn- completion). We show preliminary results from the first 6-months of the study ing. Subject used a blinded Dexcom G4 and followed standard pump therapy; (up to treatment group crossover). devices were downloaded prior to each admit, personalizing DSS to each sub- The average age of the study population was 56.7 years and was 52.5% jects. When using DSS, all insulin adjustments were computed automatically female (n=63). Mean baseline A1c levels were 10.3% for the intervention group and blinded to the subject (no training effect). (n=60) and 10.0% for the control group (n=60). Differences in mean change in Glucose (BG) control was assessed using blinded CGM. The study was a A1c % for the intervention group (m=1.13, SD=1.5) compared to the control safety/feasibility study, and was not powered for statistical significance, thus group (m=0.71, SD=1.4) approached statistical significance (p=0.07). Partici- effect size is reported. Main outcomes are presented in Figure 1. Effect sizes pants receiving the intervention reported a significantly greater improvement ranged between 0.4 and 0.5. POSTERS in treatment satisfaction (m=12.9) compared to the control group (m=10.7) This pilot study clearly demonstrated the feasibility of our treatment cen- Therapeutics

(p<0.05). We found no differences in change of diabetes empowerment tric, smartphone-based, decision support systems in T1D, and showed mod- Clinical Diabetes/ between treatments groups. erately high effect sizes for both BG and GV control; DSS extension to MDI Utilizing cellular-enabled glucose meters to deliver additional support from is ongoing. a team of CDEs can result in short-term benefits for patients with poorly- Figure 1. controlled diabetes. It will be important to evaluate the efficacy of this type of technology-facilitated care assistance over a longer period of time with a greater number of patients. It will also be important to evaluate effects on provider beliefs, behavior, and work flow.

81-LB Usability of a New Blood Glucose Monitoring System (BGMS) with a Mobile App TIMOTHY S. BAILEY, TRENT DAVIS, JANE WALLACE, SCOTT PARDO, ROBERT MORIN, Escondido, CA, Parsippany, NJ The Contour® Next ONE BGMS features an easy-to-use wireless-enabled blood glucose (BG) meter that links to a mobile device via Bluetooth® con- nectivity. This BGMS syncs with the Contour™ Diabetes app on a smartphone or tablet. The app in this study allows users to view graphs of their BG test results, view trends, and use a built-in bolus calculator. Previous studies demonstrated the accuracy of the BGMS in laboratory and clinical settings. This clinical study assessed the usability of the BGMS with the app. Subjects with type 1 or type 2 diabetes on insulin therapy were enrolled at a clinical site. At Visit #1, subjects were instructed to use the BGMS and app at home for 3 weeks. At Visit #2, 43 subjects completed the study by answering questionnaires about their experiences, wherein 95.4% of subjects were able to sync their meter results to the app, 89.7% of subjects were able to initiate and use the bolus calculator, and 95.4% of subjects were able to access and interpret the BG displays. Each subject completed an average of 4 BG tests per day Supported By: National Institutes of Health (R01DK051562) (on average, 83 total BG tests per subject). Subjects recorded meal markers in 32% of BG tests, whereas 72.1% of subjects recorded insulin doses, and 83-LB 46.5% of subjects used the bolus calculator (on average, 14 total uses per sub- In-Hospital Stabilisation of Blood-Sugar Control Using an Insulin ject). The BG value range was 20-601 mg/dL (1.1-33.4 mmol/L), with a mean of Balanced Infusion System (Admetsys): Clinical Results from FDA- 168 mg/dL (9.3 mmol/L). Statistically significant average decreases in HbA1c approved Clinical Studies in 43 Diabetes Patients (8.04% to 7.78%) and fructosamine (332 to 312 μmol/L) levels were observed NASSEH HASHEMI, TIM VALK, DAVID KLONOFF, KIM HOULIND, NIELS EJSKJAER, from Visit #1 to Visit #2 (P <0.0001). No significant changes in weight, BMI, Aalborg, Denmark, Orlando, FL, San Mateo, CA, Kolding, Denmark, Odense, Denmark or total daily insulin were observed. Syncing to the app was viewed as reli- Hypothesis and Aim: Threefold: 1) to assess clinical applicability in normal- able by 95% of subjects and accurate by 100% of subjects. BG displays were ization and continued stability of glucose levels, 2) to demonstrate system viewed as understandable by 98% of subjects. In conclusion, the study shows safety and performance under extraordinary circumstances and 3) to validate the ease-of-use of the new BGMS and app in the hands of subjects with dia- performance over prolonged periods of time. betes. Further studies with a larger population and a longer duration could Methods: Admetsys is a first-of-its-kind artificial pancreas for hospital care, be performed to confirm various clinical benefits of using the app with the leveraging adaptive learning algorithms and counterbalancing treatment of system. insulin and glucose. Study treatment (pulsatile infusions of insulin and/or Supported By: Bayer HealthCare glucose was delivered intravenously. Stabilisation, stress and extended trial protocols were carried out. Each successive protocol using a more refined version of the system’s physical components - first automated sensing, then high-precision syringe pumps and finally integrated power management. 43 clinically well characterized patients. All studies were FDA-approved.

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LB21 Clinical TherapeLate uBtreaicsking/New A Tbstractsechnology—Insulins

Results: 97% of all patients reached control between 80-125 mg/dL, mean Clinical Therapeutics/New Technology— time to normoglycemia was 2.5 hours and there was 0% Hypoglycemia Insulins < 70 mg/dL. Once brought to normoglycemic levels, and unless intentionally destabilized, blood glucoses remained ideal. Normoglycemia was preserved through 43.8% of attempts to destabilize. Overall we found a consistent, 86-LB effective normalization of glucose irrespective of initial level, a strong perfor- Follow-up Study of 2 Years on Efficacy Comparison of Combination mance in maintaining and restoring control during endogenous and exogenous Therapy of Exenatide and Insulin Pump and Short-Term Insulin Pump stress events and absence of hypoglycemia. Overall reduced variability and in the Treatment of Patients with Newly Diagnosed Obesity Type 2 increasingly precise glucose control. Diabetes Mellitus Conclusions: A strong system performance in bringing abnormal glucoses YANJUN WANG, YAN CHEN, JIAXIN WANG, CHUN ZHANG, SHUJIE ZHAO, HAID- under control in hospitalized diabetes patients, in restoring control under ONG LI, YING ZHAO, Changchun, China stressfull conditions and in avoiding hypoglycaemia. Our data constitute the Objective: Clinical observation of combination therapy of Exenatide and basis for planned closed-loop clinical trials in hospitalized diabetes patients insulin pump on obesity type 2 diabetes mellitus (T2DM) in a real-world set- undergoing major surgery. ting in China. Supported By: Admetsys Methods: Review 357 patients with T2DM in endocrine Department of the second hospital of Jilin University, 183 cases in Exenatide combined with insulin pump therapy group (GLP-1+CSII), and 174 cases in CSII therapy group. 84-LB Follow-up the changes of general and biochemical indexes of 357 patients Glucommander™ Outpatient, a Cloud-based Insulin Management

after 4, 12, 24, 36, 48 and 96 weeks from discharged from hospital. Solution Adjusted Insulin Doses and Achieved 2.7% Drop in A1c Per- Results: GLP-1+CSII group at each time point of pairwise comparison is centage Points also validated changes in 3 months had significant treatment effectiveness JOHN G. CLARKE, BRUCE W. BODE, Atlanta, GA (P < 0.001), FPG, 2hPG and HbAlC% was reduced (FPG, 2hPG and HbAlC% ™ This study examines the performance of Glucommander Outpatient, a was reduced (from 10.50±3.250 to 7.16±1.009, P<0.001; from 14.60±4.521 to cloud-based diabetes management program for titrating basal-bolus insulin 8.39±1.403, P<0.001; from 9.10±2.068 to 7.41±1.17, P<0.001), the indexed tends dosing, for patients using a cellular-enabled glucose meter. 31 patients with

POSTERS to be stable and had no statistical significance in 6 months (P > 0.05).

Therapeutics ™ type 1 and type 2 diabetes were treated for 12 weeks with Glucommander Conclusion: Compared with insulin therapy separately, exenatide united Clinical Diabetes/ Outpatient, which provided periodic and personalized insulin dose titration CSII treatment for newly diagnosed obesity T2DM can significantly improved recommendations to a healthcare professional, based on an automated analy- glucose and lipid control, gain weight loss, improve glycated hemoglobin, sis of a patient’s aggregated SMBG glucose data. The healthcare professional reduce the dose of insulin and had better restoration of insulin resistance. then communicated the new insulin doses to the patient via secure HIPPA text messages or email. Glucommander decreased the frequency of titration Figure. Trend of Index Changes in GLP-1+CSII and CSII Groups During Follow-up. adjustments as patient’s glucoses improved, or increased the frequency of adjustments if a patient’s glucose control worsened. Outcomes measured 1.) Pre- and post-treatment A1c 2.) Mild Hypoglycemia 40-70 mg/dL 3.) Severe Hypoglycemia <40 mg/dL 4.) Patient Satisfaction. Baseline mean A1c at initiation was 10.4% and mean A1c at the end of 12 weeks was 7.7% (P<0.00004). 7,940 BG tests were recorded, mild hypoglycemia (40-70 mg/dl) was reported in 1.6% of BGs, and there were no episodes of major hypoglycemia (< 40 mg/ dl). Patient satisfaction survey results indicated that 96% of patients would recommend the service to family and friends. Glucommander™ Outpatient is an effective decision support tool to assist providers to safely titrate insulin with very low rates of hypoglycemia.

85-LB Time Effects of the Exercise Test on Glucose Variability among Patients with Type 1 Diabetes HANJONG PARK, YOO MI JEONG, CHANG PARK, LAURIE QUINN, Seoul, Republic of Korea, Chicago, IL Exercise stress test has been known as a well-validated test for diagnostic and prognostic of cardio-vascular disease in diabetic population. However, the specific time effects on glucose variability after the test was not explored and it was difficult to manifest time-specific interventions for glycemic control due to mostly used cross-sectional data in the previous research. Therefore, the current study is aimed to examine the hourly glucose variability after the Supported By: Jilin Province Science and Technology Department exercise stress test with real-time data. Data were collected from 15 young T1DM adults aged 19 to 33 years (6 males and 9 females). The average duration of diabetes was 11.4 years (SD = 6.6) and the average of HbA1c is 7.8% (SD = 1.6). With hourly longitudinal data, subgroup analyses (stress test day versus non-stress test day) were conducted using generalized estimating equation to examine time effects of exercise stress test on glucose variability (i.e., hourly mean glucose and hourly standard deviation [SD] of glucose) with controlling for demographics (e.g., age, gender, diabetes years) and hourly data regarding the amount of insulin (basal and meal bolus), carbohydrate, and energy expenditure. Compared with the non-stress day, hourly mean glucose tended to decrease for several hours after the test and was decreased most significantly 7 hours after the test. Hourly SD of glucose changed most significantly 6 hours after the stress test and the widest variation was shown 12 hours after the test. On the non-stress test day, hourly mean glucose values were generally higher and SD of glucose was much wider over the day than those on the stress test day. Findings of the study contribute to the current understandings of post-effect of exercise stress test in terms of real time among young adults with T1DM. As having high insulin sensitivity can be a marker for hypoglycemia, adjustment of insulin dosage may be needed even long time after the stress test. Supported By: JDRF

ADA-Supported Research For author disclosure information, see page LB102.

LB22 Clinical TherapeLate uBtreaicsking/New A Tbstractsechnology—Insulins

87-LB change was -1.0 kg for 1 wk vs. -2.0 kg for 2 wk titration. Rates of severe or SWITCH 1: Reduced Hypoglycemia with Insulin Degludec (IDeg) vs. blood glucose-confirmed symptomatic hypoglycemia were low in both arms: Insulin Glargine (IGlar), Both U100, in Patients with T1D at High Risk 0.16 events/patient-year of exposure (PYE) for 1 wk and 0.76 events/PYE for 2 of Hypoglycemia: A Randomized, Double-Blind, Crossover Trial wk titration. Mean IDegLira dose at 32 wks was 41 dose steps (41 U IDeg/1.48 WENDY S. LANE, TIMOTHY S. BAILEY, GREGG GERETY, JANUSZ GUMPRECHT, mg Lira) for both arms. The safety profile of IDegLira was consistent with ATHENA PHILIS-TSIMIKAS, CHARLOTTE T. HANSEN, THOR S. NIELSEN, MARK L. previous findings; both titration algorithms were well tolerated. In conclusion, WARREN, Asheville, NC, Escondido, CA, Albany, NY, Zabrze, Poland, San Diego, CA, a pragmatic titration algorithm with 1 wk adjustments based on 2 PG readings Søborg, Denmark, Greenville, NC resulted in a similar safety and glycemic efficacy profile to that with 2 wk A 64-wk, double-blind, treat-to-target crossover trial randomized 501 adjustments based on 3 preceding PG values in insulin-naïve pts. adults with T1D and ≥1 factor associated with increased risk of developing Table. hypoglycemia to once-daily IDeg or IGlar, both with mealtime insulin aspart for 32 wk (16-wk titration, 16-wk maintenance), followed by crossover to IGlar or IDeg. Primary objective was to confirm non-inferiority in the number of severe (requiring 3rd-party aid, all externally adjudicated) or BG confirmed (<56 mg/dL) symptomatic hypoglycemic episodes during the maintenance periods. Treatment with IDeg vs. IGlar resulted in significantly lower rates of severe or BG-confirmed symptomatic hypoglycemia, severe or BG-confirmed symptomatic nocturnal hypoglycemia (00:01-05:59), and severe hypoglycemia for maintenance and total treatment periods (Figure). IDeg was superior to IGlar regarding a lower proportion of patients experiencing severe hypoglycemia during maintenance and total treatment periods. A1c non-inferiority of IDeg vs. IGlar was confirmed in both treatment periods (means, wk 32: 6.95 vs. 6.92%; wk 64: 6.95 vs. 6.97%). Adverse event rates were similar for IDeg vs. IGlar. In this T1D population, IDeg significantly reduced the rates and pro- POSTERS portions of severe hypoglycemia and the rates of BG-confirmed symptomatic Therapeutics overall and nocturnal hypoglycemia vs. IGlar. Clinical Diabetes/ Figure.

Supported By: Novo Nordisk Inc.

89-LB Withdrawn

Supported By: Novo Nordisk Inc.

88-LB Safety and Efficacy ofI nsulin Degludec/Liraglutide (IDegLira) Titrated Once Weekly (1 Wk) vs. Twice Weekly (2 Wk) in Patients (pts) with T2D Uncontrolled on Oral Antidiabetic Drugs: DUAL VI Study STEWART B. HARRIS, GYOZO KOCSIS, RUDOLF PRAGER, TERRY RIDGE, KEVAL CHANDARANA, NATALIE HALLADIN, SERGE A. JABBOUR, London, ON, Canada, Budapest, Hungary, Vienna, Austria, Indianapolis, IN, Søborg, Denmark, Philadelphia, PA In this 32-wk, open-label, non-inferiority trial, insulin-naïve pts uncontrolled on Metformin ± pioglitazone were randomized 1:1 to receive IDegLira, titrated either 1 wk based on the mean of 2 pre-breakfast plasma glucose (PG) readings (n=210) or 2 wk based on the mean of 3 pre-breakfast PG readings (i.e., 6 readings/wk, as for DUAL I-V trials; n=210). Mean A1c decreased from baseline (8.2%/8.1%) to 6.1% with IDegLira titrated 1 wk and 6.0% titrated 2 wk; non-inferiority by <0.3% was confirmed (estimated treatment difference: 0.12 [-0.04; 0.28]) (Table). Similar proportions of pts achieved A1c and composite endpoints in each arm. Mean fasting PG was similar after 32 wks. Weight

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LB23 Clinical TherapeLate uBtreaicsking/New A Tbstractsechnology—Insulins

90-LB were greater for windows extended beyond 05:59 h (Figure). Risk of ≥1 con- SWITCH 2: Reduced Hypoglycemia with Insulin Degludec (IDeg) vs. firmed ≤( 70 mg/dL) or severe event was lower for Gla-300 vs. Gla-100 using Insulin Glargine (IGlar), Both U100, in Patients with T2D at High Risk the predefined and broader windows. Corresponding annualized rates were of Hypoglycemia: A Randomized, Double-Blind, Crossover Trial also lower with Gla-300 for all windows (predefined 41%, 22:00-05:59 h 34%, CAROL H. WYSHAM, ANUJ BHARGAVA, LOUIS B. CHAYKIN, RAYMOND DE LA 00:00-07:59 h 30%, 22:00 h to prebreakfast SMPG 29% lower). A similar pat- ROSA, YEHUDA HANDELSMAN, LONE N. TROELSEN, KAJSA KVIST, PAUL NOR- tern of lower risk for Gla-300 vs. Gla-100 was seen with other hypoglycemia WOOD, Spokane, WA, Des Moines, IA, Bradenton, FL, Paducah, KY, Tarzana, CA, types. Søborg, Denmark, Fresno, CA Summary: Nocturnal hypoglycemia risk was consistently lower for Gla-300 In this 2x 32-week, double-blind, treat-to-target crossover trial, adults vs. Gla-100 irrespective of hypoglycemia definition or nocturnal window. (n=721) with T2D were randomized 1:1 to once-daily IDeg/IGlar followed by Figure. Relative Risks and Rate Ratios of Hypoglycemia by Different Noctur- crossover to IGlar/IDeg. Each treatment period comprised a 16-week titra- nal Windows for Gla-300 vs. Gla-100—Patient-level Meta-analyses of EDI- tion and 16-week maintenance period. Patients included were previously TION 2, EDITION 3, and EDITION JP 2 Clinical Trials Over 6 Months. treated with basal insulin ± oral antidiabetic drugs excluding sulfonylurea/ meglitinides, and at increased risk of developing hypoglycemia based on pre- trial risk factors. The primary endpoint was the number of severe (requiring third-party assistance and external adjudication) or blood glucose-confirmed (<56 mg/dL) symptomatic hypoglycemic events in the maintenance periods. Treatment with IDeg resulted in significantly lower rates of severe or confirmed symptomatic hypoglycemia and severe or confirmed symptomatic nocturnal hypoglycemia (occurring 00:01-05:59) vs. IGlar (Figure). The proportion of patients experiencing severe hypoglycemia in the maintenance periods was 1.6% for IDeg vs. 2.4% for IGlar (NS). Severe hypoglycemia rates were significantly lower with IDeg vs. IGlar in the total treatment period. A1c reductions with IDeg were non-inferior to IGlar. Adverse event rates were similar. POSTERS

Therapeutics Compared to IGlar, IDeg resulted in a consistent reduction in hypoglycemia in

Clinical Diabetes/ T2D patients at high risk of hypoglycemia. Figure.

Supported By: Sanofi (NCT01499095, NCT01676220, NCT01689142)

92-LB Improvement in Quality of Life after Initiation of Basal Insulin Ther- apy: Results from the ORBIT Study PUHONG ZHANG, DONGSHAN ZHU, XIAN LI, JIACHAO JI, YUQIAN BAO, YANG- FENG WU, WEIPING JIA, SATISH K. GARG, LINONG JI, Beijing, China, Shanghai, China, Aurora, CO To determine the effects on quality of life after initiating basal insulin (BI) in real world. Patients with type 2 diabetes mellitus (T2DM) uncontrolled (HbA1c and age; 7%) on oral hypoglycemic agents were enrolled from 209 hospitals of eight geographic regions of China. Type and dose of BI to initiate was at physician’s discretion. Health-related quality of life (HRQoL) was assessed at baseline and 6 months using the EuroQol-5 dimensions 3 levels (EQ-5D-3L) questionnaire. 12358 patients who kept using BI during 6 months was used for analysis. HbA1c decreased from 9.5% to 7.4% after 6 months. The reported HRQoL measured by the EQ-5D visual analogue scale (VAS) score increased by 5.6 (p < 0.001) from 76.6 to 82.3, and EQ-5D index score increased by 0.02 (p < 0.001) from 0.95 to 0.97 during 6 months. Statistically significant improvement was found in all five dimensions, with the percentages of patients Supported By: Novo Nordisk Inc. reporting no problem pain/discomfort and anxiety/depression increased most (82.5% to 91.8% and 85.3% to 95.4%, respectively). More dose titration, more 91-LB dose increase, more HbA1c reduction and long-acting BI analogues were Wider Windows for Evaluating Nocturnal Hypoglycemia Capture associated with VAS score improvement when controlling for age, rural/urban More Events and Confirm Lower Nocturnal Hypoglycemia Risk with area, baseline HbA1c and changes on staple food consumption and physical Insulin Glargine 300 U/mL (Gla-300) vs. 100 U/mL (Gla-100) in T2DM activity, etc. (Table 1). We conclude that initiation of BI therapy in real-life was GEREMIA B. BOLLI, CAROL H. WYSHAM, MILES FISHER, SOAZIG CHEVALIER, associated with improved HRQoL in patients with T2DM. ANNA CALI, BRUNO LEROY, MATTHEW C. RIDDLE, Perugia, Italy, Spokane, WA, Glasgow, United Kingdom, Paris, France, Portland, OR The EDITION clinical trials in T2DM show comparable glycemic control with less nocturnal (00:00-05:59 h) and anytime (24 h) hypoglycemia for Gla-300 vs. Gla-100. However, the predefined nocturnal window may not capture all clinically relevant hypoglycemic events during the true fasting period (i.e., late evening to prebreakfast). Post hoc patient-level meta-analyses of pooled 6-month data from EDITION 2, EDITION 3 and EDITION JP 2 (N=1922; Table) compared hypoglycemia using predefined (00:00-05:59 h) and broader nocturnal windows (22:00-05:59 h, 00:00-07:59 h, 22:00 h to prebreakfast SMPG). Total numbers of events were consistently greatest for 22:00 h to prebreakfast SMPG vs. other windows, and absolute differences (favoring Gla-300)

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LB24 Clinical TherapeLate uBtreaicsking/New A Tbstractsechnology—Insulins

Table 1. Stepwise Multivariate Linear Regression for Change in EQ-5D VAS 94-LB Scorea. Similar Glucose Control, Postprandial Glucose Excursions, and Safety in People with T1DM Using SAR342434 or Insulin Lispro in Combination with Insulin Glargine (GLA100): SORELLA 1 Study SATISH K. GARG, KARIN WERNICKE-PANTEN, MARIA ROJESKI, SUZANNE PIERRE, KRYSTYNA JEDYNASTY, Aurora, CO, Frankfurt, Germany, Bridgewater, NJ, Paris, France, Warsaw, Poland SAR342434 (SAR) was developed as rapid-acting follow-on insulin to Humalog® (U100; LIS) with similar PK/PD between the two insulins in a phase I clamp study. This phase 3 study compared efficacy and safety of SAR and LIS in people with T1DM using GLA100 (Lantus®) as basal insulin. In this 6 month randomized, controlled, open-label study, 507 people were randomized (1:1) to a multiple daily injection regimen of SAR or LIS while using once daily GLA100. SAR or LIS dose was adjusted to achieve a 2-hr postprandial glucose of 120-160 mg/dL, while avoiding hypoglycemia. The recommended target for fasting and pre-prandial glucose was 80-130 mg/dL. Primary endpoint was HbA1c change (non-inferiority margin of 0.3%) from baseline to week 26 (tested for non-inferiority of SAR versus LIS) with secondary endpoints including 7-point self-monitored plasma glucose profiles. SAR was non-inferior to LIS for change in HbA1c, with similar post-prandial glucose excursions and insulin dosages (Figure). There was no difference in the % people reporting hypoglycemia (severe hypoglycemia: SAR 7.9%; LIS 7.5%; Figure). Safety profiles (adverse events, hypersensitivity events and injection site reactions) were similar for SAR and LIS. We conclude, SAR342434 was POSTERS

as effective and well-tolerated as insulin lispro in people with T1DM. Therapeutics

Figure. Clinical Diabetes/

Supported By: Sanofi China

93-LB A Pragmatic Self-Titration 1 Unit/day (INSIGHT) Algorithm for Insulin Glargine 300 U/ml (GLA-300) Is Safe and Effective JEAN-FRANÇOIS YALE, STEWART B. HARRIS, LORI BERARD, MÉLANIE GROLEAU, PASHA JAVADI, JOHN STEWART, Montreal, QC, Canada, London, ON, Canada, Win- nipeg, MB, Canada, Laval, QC, Canada Supported By: Sanofi New basal insulin GLA-300 provides a flat and prolonged PK/PD profile with a comparable glycemic control and less hypoglycemia vs. glargine 100 U/mL 95-LB (GLA-100). In the phase III EDITION trials, insulin was titrated by the HCP based Reduced Hypoglycemia and Comparable Efficacy with Insulin on the median of the last 3 fasting prebreakfast SMPGs. Titration was done Glargine 300 U/mL (Gla-300) vs. Insulin Glargine 100 U/mL (Gla-100) once weekly, no more often than every 3 days. However, with GLA-100, the in Subjects with T2D Achieving Different Levels of Prebreakfast INSIGHT pragmatic 1U/day self-titration protocol is widely used in Canada. SMPG The objective of this 12-week, randomized pilot study (NCT02401243) was to TIMOTHY REID, OLA ODUGBESAN, JASVINDER GILL, ELENA NIKONOVA, JASON compare safety and efficacy of two titration algorithms, INSIGHT and EDI- CHAO, TIMOTHY S. BAILEY, Janesville, WI, Lawrenceville, GA, Bridgewater, NJ, Mor- TION, for GLA-300 in T2DM patients (insulin-naïve or on basal insulin ± OAD) ristown, NJ, Escondido, CA mainly in a primary care setting. Baseline characteristics of the 212 patients This post-hoc analysis of a patient population previously treated with basal randomized in the study were similar: age 62.3 years, BMI 34.2 kg/m2, A1c insulin (EDITION 2), investigated the clinical outcomes according to pre-break- 8.4%, insulin naïve 37.0%, prior basal insulin dose 57.2 U. Comparable num- fast SMPG level achievement (protocol defined [SMPG < 100mg/dL] or ADA ber of patients in each titration group reached primary endpoint of a fasting recommendation [< 130mg/dL]). SMPG 5.6 mmol/L without nocturnal (0:00-6:00 h) hypoglycemia (confirmed: ≤ 403 Gla-300-treated and 405 Gla-100-treated subjects were analyzed; SMPG 3.9 mmol/L or symptomatic or severe) at 12 weeks (INSIGHT algo- ≤ mean age 57 and 58 years, 46% and 45% male, baseline A1c 8.3% and 8.2%, rithm 22.8%; EDITION 20.6%). No between treatment differences in number FPG 147 and 141 mg/dL, respectively. Achievement of pre-breakfast SMPG, of severe hypoglycemia were noted (1 INSIGHT algorithm vs. 3 EDITION). The A1c change, proportion of subjects reaching A1c < 7.0%, and hypoglycemia percentages of patients achieving A1c 7% was 28.7% (INSIGHT algorithm) ≤ rates were assessed at 6 months. vs. 28.4% (EDITION) with a similar mean A1c (SD) of 7.6% (0.9) at week 12. Comparable proportions of Gla-300 and Gla-100-treated subjects reached Similar number of patients experienced nocturnal hypoglycemia (INSIGHT both SMPG levels, with greater A1c reduction in those reaching SMPG levels algorithm 28.7%; EDITION 27.5%). Mean (SD) insulin dose at week 12 was in both treatment groups (Table). Across all hypoglycemia definitions, event comparable in both titration algorithms (INSIGHT algorithm 67.0 U (37.8); EDI- rates were generally lower in Gla-300-treated subjects reaching SMPG < 130 TION 70.0 U (43.1)). Change in weight from baseline was also similar (INSIGHT mg/dL and those not reaching SMPG < 100 or < 130 mg/dL; event rates for any algorithm 0.41 kg (3.3); EDITION 0.15 kg (2.4)). No between groups differences nocturnal hypoglycemia were significantly lower in Gla-300-treated subjects in adverse events were noted. In conclusion, application of a self-titration of 1 regardless of SMPG level achievement (Table). There were no differences in U/day algorithm with GLA-300 is safe, effective and comparable to the previ- severe hypoglycemia rates. ously tested EDITION algorithm. Supported By: Sanofi Canada

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LB25 Clinical TherapeLate uBtreaicsking/New A Tbstractsechnology—Insulins

Irrespective of pre-breakfast SMPG level achievement, comparable effi- through co-expression of glucokinase (Gck) and insulin (Ins) by adeno-associated cacy and less hypoglycemia were observed with Gla-300 versus Gla-100 in viral vectors of serotype 1 (AAV1), increasing glucose uptake and correcting this T2D population. hyperglycaemia in diabetic mice and dogs. Here we demonstrate sustained cor- Table. Glycemic Control and Hypoglycemia in Subjects Reaching and Not rection of diabetes for 8 years in diabetic dogs previously treated with a single Reaching Pre-Breakfast SMPG Levels. administration of AAV1 vectors encoding for Ins and Gck. Dogs showed normalization of fasting glycaemia, recovery of body weight, reduced fructosamine Gla-300 Gla-100 P value (n = 403) (n = 405) levels and increased insulin and C-peptide circulating levels throughout the observation period. This was associated with long-term survival without occur- Pre-breakfast SMPG < 100 mg/dL rence of secondary diabetic complications or adverse events for 8 years after Number of subjects, n (%) 113 (28) 138 (34) 0.07 AAV-mediated gene transfer. Vector genome biodistribution analysis confirmed A1c change from baseline, % -1.0 (0.10) -0.9 (0.08) 0.39a that most of the detectable vector was present in genetically engineered mus- A1c < 7.0%, n (%) 48 (42.5) 54 (39.1) 0.70b cles, which showed normal muscle morphology. Accordingly, Ins and Gck trans- gene expression was specifically detected in skeletal muscle of treated dogs. c Overall hypoglycemia*, events/patient-year 20.1 22.0 0.02 Our data represent the first demonstration of long-term correction of diabetes in Any nocturnal hypoglycemia†, events/patient-year 2.7 4.6 < 0.05c a large animal model using gene transfer. This study also confirms the long-term Documented symptomatic hypoglycemia‡, events/patient-year 9.5 8.4 0.03c safety of the AAV-mediated overexpression of Ins and Gck for the treatment of Documented symptomatic nocturnal hypoglycemia§, events/ 1.9 2.4 0.09 diabetes, laying the foundation for the clinical translation of this approach to patient-year veterinary medicine and to human patients in the future. Supported By: Ministerio de Economía y Competitividad, Plan Nacional I+D+I Pre-breakfast SMPG 100 mg/dL ≥ (SAF2011-24698, SAF 2014-54866-R) Number of subjects, n (%) 290 (72) 267 (66) 0.07 A1c change from baseline, % -0.6 (0.06) -0.5 (0.05) 0.46a 97-LB The Approach to Euglycemia Prior to Clamp Study Determines Phar- A1c < 7.0%, n (%) 70 (24.1) 65 (24.3) 1.00b macodynamics of s.c. Injected Insulin in Type 1 Diabetes Mellitus Overall hypoglycemia, events/patient-year 12.0 17.4 < 0.05c POSTERS CARMINE G. FANELLI, FRANCESCA PORCELLATI, PAOLA LUCIDI, ANNA MARINELLI Therapeutics Any nocturnal hypoglycemia†, events/patient-year 1.7 3.6 < 0.05c ANDREOLI, PATRIZIA CIOLI, PAOLA CANDELORO, GEREMIA B. BOLLI, Perugia, Italy Clinical Diabetes/ Documented symptomatic hypoglycemia‡, events/patient-year 5.7 8.0 < 0.05c Aim of the present study was to establish the importance of physiological approach to achieve euglycemia in T1DM subjects at 0 time vs. rapid correc- Documented symptomatic nocturnal hypoglycemia§, events/ 1.0 2.3 < 0.05c patient-year tion of hyperglycemia in the 4 hours prior to clamp. 11 T1DM subjects were studied twice (random, 2-4 week interval) in a clamp study (0.35 U/kg s.c. Pre-breakfast SMPG < 130 mg/dL injection at 20.00 h). Last NPH was day before the clamp, last meal was day Number of subjects, n (%) 297 (74) 320 (79) 0.08 of clamp (12.00 h) with s.c. rapid-acting I analogue (RAIA). On one occasion, A1c change from baseline, % -0.9 (0.06) -0.8 (0.05) 0.18a the noon RAIA dose was optimized to aim at 2 h postprandial plasma glucose A1c < 7.0%, n (%) 108 (36.4) 107 (33.4) 0.55b (PP-PG) 100-120 mg/dl (study 1). On the other, the same standard meal was eaten with no guidance to PP-PG. At 16.00 h subjects initiated i.v. infusion of c Overall hypoglycemia, events/patient-year 15.4 19.9 < 0.05 I and/or glucose (G), as needed, to reach target PG 100 mg/dl by 18.00 h, and Any nocturnal hypoglycemia†, events/patient-year 2.2 4.1 < 0.05c keep it until 20.00 h (s.c. injection of NPH for the clamp). PG, I infusion rate Documented symptomatic hypoglycemia‡, events/patient-year 7.0 8.1 < 0.05c (IIR) and G infusion rate (GIR) from 16.00-20.00 h are given in Table (7 out of Documented symptomatic nocturnal hypoglycemia§, events/ 1.4 2.2 < 0.05c 11 subjects). patient-year Table. Pre-breakfast SMPG ≥ 130 mg/dL Time of day (h) 16.00 17.00 18.00 19.00 20.00 Number of subjects, n (%) 106 (26) 85 (21) 0.08 Relative time (h) -4 -3 -2 -1 0 A1c change from baseline, % -0.3 (0.12) -0.3 (0.10) 0.90a PG (mg/dl) b Study 1 115±6 108±8 102±3 99±2 99±4 A1c < 7.0%, n (%) 10 (9.4) 12 (4.1) 0.50 Study 2 174±20 159±19 136±20 112±15 98±4 c Overall hypoglycemia, events/patient-year 11.3 15.3 < 0.05 IIR (mU/Kg/min) Any nocturnal hypoglycemia†, events/patient-year 1.2 3.5 < 0.05c Study 1 0 0.15±0.04 0.09±0.06 0.04±0.01 0.06±0.01 Documented symptomatic hypoglycemia‡, events/patient-year 5.9 8.3 < 0.05c Study 2 0 0.51±0.16 0.47±0.17 0.32±0.14 0.19±0.05 Documented symptomatic nocturnal hypoglycemia§, events/ 0.9 2.6 < 0.05c GIR (mg/Kg/min) patient-year Study 1 0 0 0 0 0 Study 2 0 0 0 0.21±0.28 0.52±0.20 Data represent mean (standard error) unless specified otherwise. Efficacy data based on mITT population, hypoglycemia data based on safety population. Results: End of action (time PG >118 mg/dl) was greater in study 2 vs. study a b c P values from one-way ANOVA, Fisher exact test, Poisson modelling. 1 (15.6±2.8 vs. 13.8±2.6 h, p<0.05) and GIR was also greater in study 2 vs. *Overall hypoglycemia was any hypoglycemia event recorded; †Hypoglycemia occurring between 00:00 and 05:59; ‡ Documented symptomatic hypoglycemia study 1 (1734±1243 and 1149±1159 mg/kg) [p<0.05, AUC(GIR 0-end of study)]. ≤70 mg/dL at any time of day; §Documented symptomatic hypoglycemia ≤70 Conclusions: Acute correction of hyperglycemia with large i.v. I dose to rap- mg/dL occurring between 00:00 and 05:59. idly obtain euglycemia prior to clamp study, is followed by increased in insulin Supported By: Sanofi U.S. action which may persist for several hours thus altering PD of s.c. injected I.

96-LB 98-LB Long-Term Correction of Diabetes in Dogs after Single Intramuscular Once-Weekly Basal Insulin PE0139 Displays a Sustained Reduc- Administration of Adeno-associated Viral Vectors Encoding for Insu- tion in Fasting Glucose and Average Daily Glucose following Once- lin and Glucokinase Weekly Dosing for 6 Weeks VERONICA JIMENEZ, MARIA L. JAEN, LAIA VILÀ, JORDI RODO, MIQUEL GAR- RON BRAZG, JOANN MALATESTA, LYNNE GEORGOPOULOS, SUE ARNOLD, WIL- CIA, IVET ELIAS, LUCA MAGGIONI, XAVIER LEON, SERGIO MUÑOZ, IRIS GRIFOLL, LIAM KRAMER, LEON SHI, POUL STRANGE, Renton, WA, Malvern, PA, North Poto- DAVID CALLEJAS, EDUARD AYUSO, TURA FERRE, VIRGINIA HAURIGOT, FATIMA mac, MD, Princeton Junction, NJ BOSCH, Bellaterra, Spain PE0139 is a fusion protein comprising mature human insulin at the N-ter- Diabetes is a chronic disease for which there is no cure and is associated minus and a repeating polymeric elastin-like-polypeptide at the C-terminus, with severe secondary complications, caused largely by poor glycaemic con- expressed in E. coli. Subjects had T2DM with HbA1c ≥ 7.5% to <11.0%, on a trol. Treatment with exogenous insulin fails to prevent these complications stable regimen of non-insulin antidiabetic therapy for 3 months prior to entry. completely, leading to significant morbidity and mortality. We previously dem- Eight subjects (6 active; 2 placebo) were randomized sequentially in Cohort onstrated that it is possible to generate a “glucose sensor” in skeletal muscle 1 and 13 subjects (9 active; 4 placebo) in subsequent cohorts. Subjects were

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LB26 Clinical TherapeuticsLate/New Brea Techkingnolo Abstractsgy—Insulin Delivery Systems

dosed once weekly for 6 weeks and followed for 28 days after the last dose Table. Sensor Glucose (SG) and Insulin Use. for safety, pharmacokinetics and evaluation of glycemic control. No dose lim- Parameter All 24 Hours 10:00PM to 7:00AM iting toxicities or SAEs were reported. Hypoglycemic events (≤ 70 mg/dL with (mean±SD, (median)) (mean±SD, (median)) or without symptoms) were reported in 33% of placebo subjects, and 17% and Baseline HCL Period p Baseline HCL Period p 44% of PE0139 subjects receiving 0.4 and 0.8 mg/kg, respectively. Related TEAEs occurring in > 5% of subjects were confined to mild/moderate injection SG, mg/dL 150.2±22.7 150.8±13.7 0.644 148.8±25.1 147.5±14.1 0.380 (150.1) (149.9) (146.9) (146.3) site erythema. PE0139 demonstrated dose-related increases in mean serum concentrations with statistically significant dose dependent decreases in SG>180 mg/dL (%) 27.4±13.7% 24.5±9.2% <.001 26.9±15.2% 21.6±9.9% <.001 mean average daily glucose change from baseline compared to placebo at (26.7%) (24.1%) (26.4%) (20.6%) week 6 (Figure 1) with no indication of a larger mean glucose day to day vari- 70 < SG ≤ 180 mg/dL (%) 66.7±12.2% 72.2±8.8% <.001 66.8±14.0% 75.3±9.8% <.001 ability during the week in the active groups compared to placebo. PE0139 was (67.8%) (73.4%) (67.0%) (76.4%) well tolerated and displays a glucose profile supporting once weekly dosing. SG ≤70 mg/dL (%) 5.9±4.1% 3.3± 2.0% <.001 6.4±5.3% 3.1±2.2% <.001 Figure 1. Placebo (N=5) Adjusted Mean (±SEM) Change from Baseline1 in (5.25%) (2.9%) (5.3%) (2.6%) Average Daily Glucose2 (mg/dL) Following 6 Weeks of Once Weekly Dosing SG ≤50 mg/dL (%) 1.0±1.1% 0.6±0.6% <.001 1.1±1.5% 0.6±0.7% <.001 with PE0139 in Subjects with T2DM. (0.6%) (0.4%) (0.6%) (0.5%) Total daily insulin dose (U) 47.5±22.7 50.9±26.7 <.001 (43.9) (44.1) Supported By: Medtronic

100-LB Technosphere Insulin Inhalation Powder (TI) Displays Earlier Onset and Shorter Duration than Insulin Lispro (Lispro)

ROBERT A. BAUGHMAN, TIM HEISE, MARSHALL L. GRANT, PHILIPPE GROSJEAN, POSTERS LAURENT PERRIN, YOUSSEF HIJAZI, BRITTA GOEBEL, RAPHAEL DAHMEN, Dan- Therapeutics bury, CT, Neuss, Germany, Paris, France, Frankfurt, Germany Clinical Diabetes/ The dose-response curve of TI (4, 12, and 48 U doses) was compared to that of Lispro (8, 30, and 90 U doses) in a cross-over hyperinsulinemic, euglycemic clamp with 30 T1DM patients. Key parameters: PD - onset, time to 50% max GIR (T50%-GIRmax), max effect (GIRmax), duration (T100% of GIR-AUC0-end), total effect (GIR-AUC0-end). PK - max insulin conc (INS-Cmax), time of max conc (Tmax) and exposure (INS-AUClast). Table. Pharmacodynamic Response [Mean (SD)]. Insulin - Dose “Onset” GIR “Duration” T GIR-AUC Clinical Therapeutics/New Technology— max 100% 0-end T50%-GIRmax (mg/min) of GIR-AUCend (g) Insulin Delivery Systems (min) (hr) TI- 4 U 15.6 (10.2) 182 (84.9) 1.83 (1.03) 8.8 (5.7) 99-LB TI - 12 U 21.4 (7.10) 491 (218) 3.13 (1.30) 32.1 (14.9) Pivotal Trial of a Hybrid Closed-Loop System in Type 1 Diabetes (T1D) RICHARD BERGENSTAL, BRUCE BUCKINGHAM, SATISH GARG, STUART WEINZ- TI - 48 U 18.9 (3.32) 905 (236) 6.43 (2.23) 131.2 (37.5) IMER, RONALD BRAZG, JACOB ILANY, BRUCE BODE, TIMOTHY BAILEY, STACEY M. ANDERSON, ROBERT SLOVER, JOHN SHIN, SCOTT LEE, FRANCINE R. KAUF- MAN, Minneapolis, MN, Palo Alto, CA, Aurora, CO, New Haven, CT, Renton, WA, Lispro - 8 U 52.4 (16.6) 423 (198) 5.03 (1.30) 59.7 (29.7) Ramat Gan, Israel, Atlanta, GA, Escondido, CA, Charlottesville, VA, Northridge, CA A hybrid closed-loop (HCL) insulin delivery system was evaluated to estab- Lispro - 30 U 51.3 (17.1) 898 (243) 7.24 (1.39) 191.9 (55.6) lish its safety for unsupervised use in patients ≥14 years. The system included the Medtronic MiniMed 670G pump, 4th-generation sensors, and a control Lispro - 90 U 44.5 (11.2) 1194 (273) 9.78 (1.98) 372.7 (85.5) algorithm. Patients calibrated the sensor periodically and gave mealtime and correction boluses as needed. A 2-wk run-in (baseline) phase was followed by a 3-mo study phase of HCL at home and supervised hotel settings for 5 Table. Key Pharmacokinetics Parameters. nights followed by an optional continued-access program. Data were avail- Insulin - Dose Cmax (μIU/mL) Tmax (min) AUClast (μU·hr/mL) able from 124 patients with T1D (55 male) with mean (±SD) age, 37.8±16.46 yr [mean (SD)] (median) [mean (SD)] (30 age ≤21) and duration of diabetes 21.7±13.65 yr. Sensor glucose (SG) and TI - 4 U 43.9 (21.2) 10 59.5 (66.2) A1c values from baseline and study phases were compared. HCL mode was used for a median 87.2% (IQR, 75.0% to 91.7%) of the time after first start. TI - 12 U 123 (67.2) 15 150 (124) There were higher percentages of SG 71-180 mg/dL, lower percentages of SG TI - 48 U 597 (259) 20 673 (340) ≤70 mg/dL, and lower percentages of SG ≤50 mg/dL during 24 hours and at Lispro - 8 U 62.9 (19.1) 68 210 (65.2) night (p<.001 for each) in the study phase compared to baseline (Table). Mean Lispro - 30 U 167 (48.3) 75 543 (158) A1c decreased from 7.4±0.9% to 6.9±0.6% (p<.001). SG variability measured by coefficient of variation decreased from 0.38 to 0.35 (p<.001). There was Lispro - 90 U 551 (251) 90 1760 (515) no DKA, severe hypoglycemia, or serious device-related adverse event dur- Cmax and AUC were dose proportional for TI but slightly sublinear for Lispro; ing 12,389 patient-days. At study’s end, 99 patients entered the continued- saturable GIRmax was obtained over the dose range for both insulins. Onset of access program. The HCL system was safe, acceptable, and associated with activity for TI occurred ca. 25-35 minutes earlier than for Lispro. TI duration improved glucose control during extended at-home use. of action is about 2 hours shorter than an equivalent dose of Lispro. Dose- response was almost linear up to 48U TI and 30 U Lispro.

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LB27 Clinical TherapeuticsLate/New Brea Techkingnolo Abstractsgy—Insulin Delivery Systems

101-LB 103-LB A Comparison of Glycemic Outcomes for Two Computerized Insulin Closed-Loop Control Reduces Hypoglycemia during Extended Win- Infusion Algorithms in CV Surgery Patients ter-Sport Exercise in Youth with T1D: The AP Ski Camp VALERIE GARRETT, LINDA FORNOFF, JODIE BECKER, ROBBY BOOTH, AMY HEN- DANIEL R. CHERNAVVSKY, MARK DEBOER, JESSICA ROBIC, BORIS P. KOVATCHEV, DERSON, RAYMIE MCFARLAND, Asheville, NC, Waltham, MA, Greenville, SC MARC D. BRETON, Charlottesville, VA Hyperglycemia in patients undergoing cardiovascular (CV) surgery is an Skiing represents intense, prolonged exercise with metabolic effects com- independent risk factor for increased morbidity and mortality. Studies have pounded by cold and altitude, including major risk for hypoglycemia in type 1 dia- shown that optimal glycemic management can reduce surgical complications. betes (T1D) during and after skiing. The performance of artificial pancreas (AP) There are ongoing questions as to which glycemic targets and protocols are has not been tested under these conditions. We evaluated 16 adolescents with best, and little research has been done comparing efficacy and safety for T1D (ages 11-16; 8 males) in a randomized controlled trial with the UVA AP N=8 computerized insulin infusion algorithms. vs. Sensor Augmented Pump (SAP) therapy N=8 during a 5-day ski camp includ- A retrospective evaluation was conducted comparing two computerized ing 5 hours of skiing per day. Average temperatures were -10°C, and altitude insulin infusion algorithms in postoperative CV surgery patients at a 723 ~1300 m. In addition to AP, real-time remote monitoring was used for all partici- bed hospital. The first 1755 patients used EndoTool IV (ET) and the last 219 pants. The AP system achieved significant reduction of hypoglycemia: % time <70 patients used Glucommander™ IV (GM). Capillary blood glucose (CBG) target mg/dL during skiing and hours after: AP vs. SAP: 1.6 % vs. 4.1% P= 0.008; without was adjusted from <120 with ET to <140 with GM. An observer in the unit significant change in overall glycemic control. Overnight hypoglycemia treatments completed a time motion analysis. were reduced 2-fold, 2.6 Treatment/Subject/Day (T/S/D) vs. 5.3 T/S/D P=0.04. There were no AP-related adverse events and patient evaluations of the system Efficacy and safety were compared for GM vs. ET and included 1.) % of st

and the study was overwhelmingly positive. From this 1 winter-sport study test- hyperglycemia (CBG > 180 mg/dL), 2.) % of patient days <70 and <40 mg/dL, ing AP, we concluded that our AP system performed reliably and safely in cold tem- 3.) % of CBG <70 and <40 mg/dL, 4.) % of patients <70 and <40 mg/dL. Time peratures, reducing hypoglycemia during and after intense prolonged exercise. from CBG due to IV insulin titration was measured. This setting offers a unique experience to adolescents with T1D (see Photo) and In this hospital’s CV unit, GM was more effective and safer than ET. Hyperg- also conditions for rigorous AP system testing in extreme real-life conditions. lycemia was significantly reduced with GM compared with ET. There were no severe hypoglycemia <40 mg/dL events with GM and there was a significant POSTERS

Therapeutics decrease in hypoglycemia <70 mg/dL with GM compared with ET. Nursing

Clinical Diabetes/ time from CBG due to IV insulin titration was reduced by 47% (from 19.9 minutes to 10.5 minutes) with GM compared with ET.

102-LB Within-Subject Variability of Insulin Exposure and Metabolic Activ- ity following Replicate Doses of Technosphere® Insulin Inhalation Powder (TI) in Patients with T1DM ROBERT A. BAUGHMAN, MARSHALL GRANT, LEONA PLUM-MORSCHEL, VIRGINIE ESPOSITO, ASTRID DELFOLIE, YOUSSEF HIJAZI, RAPHAEL DAHMEN, Danbury, CT, Mainz, Germany, Paris, France, Frankfurt, Germany Point estimates and 95% CIs for the variance components of key PK and PD parameters were estimated using a linear mixed-effect model with period (fixed) and subject (random) effects. In hyperinsulinemic, euglycemic clamp studies, single doses of TI were administered on 2 occasions to 22 T1DM subjects to assess within-subject variability in PK and PD. Key parameters: PD - glucose infusion rate (GIR-AUC0-end) and maximum GIR (GIRmax); PK - maximum observed serum insulin concentration (Cmax) and insulin exposure (AUClast). Table. Pharmacodynamic Response: Mean (SD). Supported By: National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases (DP3DK106826-01) Insulin - Dose Glucose disposition Maximum GIR GIRmax GIR-AUC0-end (mg) (mg/min) TI - 16 U (Period 1) 48151 (16732) 642 (231) 104-LB Real-World Use of Open Source Artificial Pancreas Systems TI - 16 U (Period 2) 52377 (20061) 596 (206) DANA M. LEWIS, SCOTT M. LEIBRAND, Seattle, WA Pharmacokinetic Parameters: mean (SD) Over a period of 6 months, over 40 patients worldwide have built Artificial Pancreas Systems (APS) with off-label use of existing insulin pumps, continuous Cmax (µU/mL) AUClast (µU·hr/mL) glucose monitors (CGM), and open source software (OpenAPS). The patients TI - 16 U (Period 1) 279 (133) 262 (91.9) have been using these systems outside of any clinical trial setting for more than TI - 16 U (Period 2) 286 (146) 265 (120) 80,000 total hours. OpenAPS is designed to be, and has been, far safer than standard pump/CGM therapy, as measured by duration of hypoglycemia and Table. Statistical Analysis (Point Estimate and 95% CI). hyperglycemia, with no reports of severe hypo or hyperglycemic events. It has Within- Total SD allowed patients and caregivers remarkable improvements in quality of life due subject SD to increased time in range, uninterrupted sleep, and peace of mind. OpenAPS users (18 respondents, 67% male/33% female, 61% adults/39% children, PD Parameter Estimate 95% CI Estimate 95% CI median 27 years old (SD 14.5 years), 15 years with diabetes (SD 11.7 years), 10 Log(GIR-AUC0-end) 0.283 (0.214 to 0.418) 0.433 (0.352 to 0.591) years on pump therapy (SD 3.6 years), 3 years on CGM (SD 2.5 years)) were sur- veyed on quantitative and qualitative measures of their experience using their Log(GIRmax) 0.271 (0.204 to 0.400) 0.418 (0.340 to 0.572) self-built APS. While using OpenAPS, self-reported outcome measures showed PK Parameter Estimate 95% CI Estimate 95% CI median HbA1c dropped from 7.1% (SD 0.8%) to 6.2% (SD 0.5%), and median Log(Cmax) 0.209 (0.161 to 0.299) 0.446 (0.355 to 0.621) percent time in range (80-180 mg/dL) increased from 58% (SD 14%) to 81% (SD

Log(AUClast) 0.162 (0.124 to 0.231) 0.412 (0.325 to 0.578) 8%). All but one respondent reported some improvement in sleep quality, and 56% reported a large improvement. Users cautioned that DIY AP implementa- In T1DM subjects receiving replicate single 16 U TI doses, the within- tions require significant effort to build and maintain, and pointed out that these subject SD was less than 21% for PK parameters and less than 28% for PD systems cannot be considered a “technological cure,” but were extremely satis- parameters. fied with the “life changing” improvements associated with using an APS. Many users reported their health care providers (HCP) as being supportive, but some expressed disappointment at lack of interest from their HCP. These experiences are instructive for what patients can expect from commercial APS when they become available, and can help HCPs be prepared to set patients’ expectations properly when discussing or recommending an APS.

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LB28 Clinical TherapeuticsLate/New Brea Techkingnolo Abstractsgy—Non-Insulin Injectables

105-LB Clinical Therapeutics/New Technology— Faster Insulin Kinetics Improves Artificial Pancreas Controller Per- Non-Insulin Injectables formance during In-Silico Simulations JOSEPH EL YOUSSEF, PETER G. JACOBS, JESSICA R. CASTLE, NAVID RESALAT, 107-LB RAVI REDDY, NICK PREISER, Portland, OR MEDI0382, a GLP-1-Glucagon Dual Agonist, Meets Safety and Toler- As faster-acting insulin analogs and formulations continue to develop, the ability Endpoints in a Single-Dose Study in Healthy Volunteers modeling of glucose response in subjects with type 1 diabetes must evolve PHILIP AMBERY, SEBASTIAN KLAMMT, MARCELLA PETRONE, WENJI PU, SHEILA to accommodate the improved kinetics. Current models of insulin action rely DICOSTANZA, LUTZ JERMUTUS, CRISTINA RONDINONE, Cambridge, United King- upon the kinetics of analogs such as aspart or lispro, which may be slower than dom, Berlin, Germany, Gaithersburg, MD newer insulins, such as BioChaperone Lispro or FiAsp. To address this issue, we Clinically significant weight loss remains a key unmet need in the manage- have conducted simulations of glucose control using a model of type 1 diabetes ment of type 2 diabetes mellitus. MEDI0382 is a novel glucagon-like peptide-1 and a bi-hormonal artificial pancreas controller (APC). Utilizing a virtual popula- (GLP-1)-glucagon dual-agonist peptide designed to facilitate glycemic control tion of 163 subjects with differing underlying insulin dynamic patterns derived and weight loss. A phase 1, randomized, blinded study was conducted in 6 from a priori parameter distributions, we implemented a 24 hour scenario that cohorts of healthy subjects in Germany. Each cohort consisted of a total of 8 includes 3 meals, in which insulin kinetics were modeled either as lispro insulin subjects, 6 of whom received a single dose of MEDI0382 at 5, 10, 30, 100, 150, (peak time to maximum plasm insulin of 35-40 minutes) or as an ultra fast-acting and 300 µg, respectively, and 2 of whom received placebo. Blood pressure, insulin (UFAI - peak time to maximum plasma insulin of 20-25 minutes). With- pulse, food intake, and adverse events were monitored over the course of the out modifications to the single hormone controller, we demonstrated improved

study (Table 1). Overall, MEDI0382 was well tolerated; vomiting, increased glycemic control as measured by reduced time spent in hypoglycemia (17.5% vs. pulse rate and blood pressure were observed at the higher doses. Prespecified 6.7%, p<0.001), reduced time in hyperglycemia (5.2% vs. 3.1%, p<0.001), and exploratory endpoints suggested that overall daily food intake and plasma reduced peak post-prandial glucose levels (206 vs. 182 mg/dl, p<0.001), without glucose levels after meal time were lower in subjects treated with MEDI0382 a significant change in insulin dose (18.2 vs. 20.0 units of basal insulin per day, at all doses than in subjects given placebo. This effect was especially notable p = 0.8). This improvement is likely to extend to bi-hormonal systems, potentially around the first meal time. A tolerability window has been established for reducing the need for glucagon. It is also important to note that these results

MEDI0382 in which multiple dosing studies can be initiated in subjects with POSTERS were obtained without parameter tuning for the faster insulin kinetics, which type 2 diabetes. Glucose lowering and food intake reduction were observed Therapeutics would likely further improve glucose control. Finally, faster insulins may reduce after administration of a single dose of MEDI0382 to healthy volunteers. Clinical Diabetes/ the significant risk of hypoglycemia as a result of physical exercise. These data demonstrate the significant benefit that faster-acting insulins can have on glu- Table 1. Results of Monitoring Over the Course of the Study. cose control using a closed-loop artificial pancreas. Dose Median pulse Blood pressure (mmHg) No. of Overall Median glucose peak Supported By: National Institutes of Health (K23 DK090133-05) (µg) (bpm) subjects daily food (mmol/L)d Peaka Maximum Diastolic Systolic with intake vomiting compared 106-LB post-dose Peak Maximum Peak Maximum After After After changeb (no. of with placebo Artificial Pancreas: Sitagliptin Lowers Postprandial Glucose post-dose post-dose episodes) (%)c breakfast lunch dinner LISA J. UNDERLAND, JENIECE TRAST, AMY DOWD, RANJITHA KATIKANENI, change change RUBINA HEPTULLA, Bronx, NY 0 72.2 11.8 77.0 8.5 134.0 12.0 0 (0) 100 7.5 5.2 7.1 Post-prandial hyperglycemia (PPG) complicates the management of type 1 5 79.7 11.3 79.5 13.0 122.0 10.5 0 (0) 100 6.2 4.9 7.0 diabetes. Sitagliptin, a dipeptidyl peptidase-4 inhibitor with a half life of 12 hours, could lower PPG. We hypothesized that Sitagliptin would decrease post- 10 72.8 12.7 71.5 8.0 124.5 9.5 0 (0) 100 5.8 5.1 6.0 prandial hyperglycemia in a closed loop system compared to insulin alone. 30 70.0 9.8 76.5 10.5 124.0 13.5 0 (0) 96 5.4 4.4 5.2 Eight subjects with type 1 diabetes underwent a double-blinded placebo 100 72.0 16.8 86.5 16.0 129.5 8.5 1 (1) 82 5.5 4.7 5.2 controlled study with 50 mg, 100 mg of Sitagliptin, and placebo as a dose 150 81.0 15.7 75.0 15.0 128.5 7.5 4 (9) 60 5.1 5.1 5.2 determination study. Then, 14 subjects with type 1 diabetes on insulin pump and good glycemic control (A1c ≤ 8.5%) were placed on an insulin only closed 300 102.0 35.5 80.0 19.0 138.5 26.0 5 (30) 23 4.7 5.1 4.9 loop system with Medtronic control tool for 24 hours with 4 scheduled meals. Abbreviation: bpm = beats per minute. a Median pulse peak is defined as Glucose and insulin concentrations were measured. Statistical analysis was the median of the maximum pulse from pre-dose to day 28. b Median pulse done using repeated measures ANOVA. maximum post-dose change is defined as the median of maximum change in pulse from pre-dose to day 28. c Overall daily food intake across breakfast, There was a statistically significant reduction with Sitagliptin 100 mg com- d pared to placebo (p<0.03) (See Figure 1). Insulin levels were lower in the group lunch and dinner. Median glucose levels were determined at approximately 1 h after breakfast, corresponding to 3.5 h after dosing; approximately 1 h after receiving Sitagliptin. The effect was more prominent in the first 2 meals of the lunch, corresponding to 7 h after dosing; and approximately 1 h after dinner, study. No difference in the incidence of hypoglycemia between the 2 groups. corresponding to 13.5 h after dosing. Use of Sitagliptin can reduce blood glucose concentrations in patients with type 1 diabetes when using closed loop system. The ease of using an oral 108-LB medication with limited side effects may improve glycemia in closed loop sys- Lixisenatide Improves Glycemic Control in Asian Patients with tem. Timing and frequency of the dose consider the half-life of Sitagliptin. Type 2 Diabetes Mellitus Who Have Poor Glycemic Control with Oral Figure 1. Glucose Analox (8 p.m.–End of the Study). Antidiabetic Drugs: An Individual Patient Data Meta-analysis HUA SHU, LINA GU, LICHUANG MEN, JUMING LU, Beijing, China, Shanghai, China We performed a meta-analysis to assess the safety and efficacy of lixisenatide as an adjunct therapy in Asian patients with type 2 diabetes mellitus (T2DM) inadequately controlled with oral antidiabetic drugs (OADs). Our meta-analysis included 5 lixisenatide Phase 3 studies from the GetGoal program. In each study, T2DM patients who had HbA1c ≥7% despite an established OAD regimen were randomized to lixisenatide or placebo for 24 weeks. Individual patient data from Asian T2DM patients in these multi-ethnic studies were extracted, amalgamated and meta-analyzed. The primary endpoint was change in glycated hemoglobin (HbA1c) from baseline to week 24. Other endpoints were change in 2‑hour postprandial glucose (PPG), fasting plasma glucose, body weight, the number (%) of patients who reached HbA1c and PPG targets, an HbA1c target of ≤7% plus a PPG target of ≤180 mg/dL and safety. Lixisenatide was superior to placebo in reducing HbA1c and PPG and significantly more patients given lixisenatide vs. placebo achieved HbA1c and PPG targets (Table). Patients given lixisenatide had a stable body weight with a Supported By: National Institutes of Health trend towards a decrease. Lixisenatide was safe. In summary, lixisenatide as

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LB29 Clinical TherapeuticsLate/New Brea Techkingnolo Abstractsgy—Non-Insulin Injectables

an adjunct therapy can significantly improve glycemic control of Asian T2DM RN909 subjects and 1 PBO subject had transaminase elevations 3 x upper patients who do not meet targets for glycemic control with an OAD regimen. limit of normal. In conclusion, single dose of RN909 significantly reduced FPG Table. Mean Differences between Lixisenatide and Placebo Groups. and HbA1c in T2D subjects on Metformin. Figure.

Supported By: Sanofi (China) Investment Co., Ltd.

109-LB +

Using Pharmacologically Programmed CD34 Cells for the Treatment of Type 1 Diabetes ROBERT TACKE, KEVIN LAI, DAVE ROBBINS, MOUFIDA BEN NASR, LISA GUERRET- TAZ, BETSY REZNER, TOM LEE, EMILY DRIVER, BLAIRE BEERS-MULROY, THUY LE, HEATHER FOSTER, CHRISTOPHER TRUONG, MOHSEN SABOURI, SARAH RAYNEL, NEWSHA SAHAF, PAOLO FIORINA, PHILIPPE A. PARONE, DANIEL SHOEMAKER, 111-LB

POSTERS San Diego, CA, Boston, MA Effect of Lixisenatide on Heart Rate: A Pooled Analysis of Eight Get- Therapeutics CD34+ cells are known to traffic to sites of inflammation via the CXCR4/ Goal Studies Clinical Diabetes/ SDF-1 axis. Additionally, CD34+ cells have been shown to possess T-cell sup- JORGE PLUTZKY, NEIL SKOLNIK, ELENA NIKONOVA, WILLIAM STAGER, RACHELE pressive activity mediated in part by the PD-L1 pathway. These properties sug- BERRIA, Boston, MA, Philadelphia, PA, Morristown, NJ, Bridgewater, NJ gest CD34+ cells might serve as potent immuno-modulatory entities for the Accelerated heart rate (HR) may be associated with increased cardiovas- treatment of autoimmune and inflammatory diseases, such as type 1 diabetes cular disease, prompting attention to possible GLP-1 receptor agonist (RA) (T1D). We have previously demonstrated that modulating, or programming, effects on this parameter. This exploratory analysis assessed HR in patients CD34+ cells with 16,16-dimethyl prostaglandin E2 (FT1050) ex vivo significantly with type 2 diabetes (T2D) from 8 Phase III trials of lixisenatide, a short-acting increases the gene expression of CXCR4 (~20-fold) and results in improved GLP-1 RA, in the GetGoal clinical program. HR (pulse) data were collected from homing and engraftment in vivo. In an effort to further enhance the homing and routine vital signs recordings prior to dosing (24 h post previous injection). immune-regulatory properties of CD34+ cells, a small molecule screen was per- Using pooled data from the 8 studies (N=3687), no significant difference was formed and we identified a combination of small molecules, dmPGE2 and dex- seen with lixisenatide vs. placebo in vital sign HR data using within-study amethasone (FT4145), that synergizes to upregulate CXCR4 mRNA by ~60-fold least squares mean difference (Table). Furthermore, data were retrospec- and PD-L1 by ~ 4-fold. Ex vivo modulation of CD34+ cells with this combination tively pooled, grouped by baseline HR (≥90, 60-89, <60 bpm) and changes enhances the capacity of CD34+ cells to traffic, and to suppress T-cell prolifera- in HR group at week 24 were analyzed (Table). The majority of lixisenatide tion and effector function, in vitro in a CXCR4-mediated migration assay. In and placebo patients experienced a change in HR of +/-5 bpm from baseline murine and humanized T1D models, FT1050-FT4145 programmed CD34+ cells to week 24. No difference in HR was seen at week 24 with lixisenatide vs. exhibit enhanced trafficking to the pancreas, as compared to vehicle-treated placebo across the baseline HR patient categories. In addition, a comprehen- cells, and a single administration of programmed cells results in a reversion sive sensitivity analysis involving regression and meta-analyses considered of hyperglycemia in NOD mice. We also show that programmed cells can pre- whether preselected predictive factors correlated with HR change from vent hyperglycemia when administered prior to disease onset in NOD mice. baseline to week 24. No significant difference was observed between the Finally, in a model of islet transplant, a single administration of programmed treatment groups. In conclusion, lixisenatide had no substantial effect on HR cells prolongs graft survival. In summary, these studies provide compelling evi- in patients with T2D, with baseline HR not serving as a predictor in most dence that FT1050-FT4145 programmed CD34+ cells have enhanced trafficking patients in these 8 studies. and immuno-modulatory properties, and can attenuate disease in models of Table. T1D and islet transplant. These results underscore the potential for ex vivo programmed CD34+ cells to be developed as a cellular immunotherapy for the treatment of autoimmunity and inflammatory diseases.

110-LB Robust Glucose and HbA1c Lowering after a Single Dose of RN909 (PF-06293620) in Type 2 Diabetes (T2D) BARRY GUMBINER, BROOKE ESTEVES, VANESSA DELL, TENSHANG JOH, PAMELA D. GARZONE, ALISON FORGIE, CHANDRASEKHAR UDATA, San Diego, CA, Cam- bridge, MA, South San Francisco, CA RN909, a humanized IgG2Δa monoclonal antibody (Mab), binds to and blocks glucagon signaling through the glucagon receptor (GR). Since T2D is associated with glucagon dysregulation, a GR antagonist may be effective in treating hyperglycemia. Because Mabs offer distinct treatment advantages compared to small molecules, an ongoing first-in-human study is being conducted to assess safety, tolerability, pharmacokinetic and pharmacodynamics of single-doses of RN909. Thirty six (27 active + 9 placebo) T2D subjects on daily Metformin (≥1500 mg) received one RN909 subcutaneous injection (0.3, 1, 3, 6 mg/kg) or placebo (PBO) and were followed for 12 weeks. In subjects treated with RN909, dose-dependent fasting plasma glucose (FPG)-lowering, durability of FPG lowering and decreased HbA1c were observed. Mean (±SD) baseline FPG and HbA1c were 175±36 mg/dL and 8.2±0.8%, respectively. FPG Supported By: Sanofi decrease at 4 weeks ranged from -21±23 to -52±12 mg/dL and overall maximal decrease ranged from -55±31 to -74±18 mg/dL in RN909 subjects. At 12 weeks, maximal HbA1c decrease was 1.5±0.9% in RN909 subjects. Four (4)

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LB30 Clinical TherapeuticsLate/New Brea Techkingnolo Abstractsgy—Non-Insulin Injectables

112-LB patients uncontrolled on Metformin ± 1 other oral antidiabetic drug [OAD], and Liraglutide Acutely Inhibits Glucagon, Lipolysis, and Ketogenesis in LixiLan-L trial, comparing iGlarLixi with Gla-100 in 736 patients uncontrolled Type 1 Diabetes on basal insulin ± 1 or 2 OADs. In both trials, only Metformin was continued MANISHA GARG, NITESH D. KUHADIYA, HUSAM GHANIM, SANAA ABUAYSHEH, upon study initiation and dosing was either optimized up to 2000 mg/d or BARRETT TORRE, JEANNE HEJNA, MANAV BATRA, ANTOINE MAKDISSI, AJAY stabilized > 1500mg/day. CHAUDHURI, PARESH DANDONA, Buffalo, NY Compared with Gla-100 or lixisenatide alone, iGlarLixi resulted in statisti- In view of the occurrence of diabetic ketoacidosis associated with the use cally significant improvement in GV profiles as indicated by the HBGI and AUC of SGLT2 inhibitors in patients with type 1 diabetes and absence of this com- metrics (see Table), without a clinically significant change in the low blood plication in patients treated with liraglutide in spite of reductions in insu- glucose index as a proxy for hypoglycemia (remaining < 1.0 for all). In addition, lin doses, we investigated the effect of liraglutide on ketogenesis. Sixteen statistically significant mean blood glucose level reductions were achieved. patients with inadequately controlled type 1 diabetes on CSII (mean age: 40 In conclusion, iGlarLixi demonstrated a cumulative decrease in GV, greater years; mean HbA1c: 7.7%) were divided into two groups of 8 patients each. than each of its components (Gla-100 and lixisenatide), in both the LixiLan-O They were maintained on their basal insulin infusion and were followed up and LixiLan-L trials. in our clinical research unit for 5 hours after an overnight fast. Eight patients Table. Patient Characteristics and Glycemic Variability Outcomes. were injected with liraglutide 1.8 mg and the other 8 were injected with Study LLO Study LLL Study placebo. The patients injected with placebo maintained their glucose and glucagon concentrations without an increase but there was a significant iGlarLixi Gla-100 Lixisenatide iGlarLixi Gla-100 increase in FFA (from 0.3 to 0.5 mM), acetoacetate (from 0.4 to 0.75 mM n=300 n=284 n=144 n=246 n=238 and β-hydoxybutyrate (from 0.22 to 0.5 mM) concentrations. In contrast, Baseline Characteristics liraglutide significantly reduced the increase in FFA, and totally prevented Age, Years 57.9 58.5 59.3 58.9 60.4 the increase in acetoacetate and β-hydroxybutyrate concentrations while suppressing glucagon concentrations as well. We conclude that liraglutide Female, % 56 53 44 57.3 52.9 suppresses glucagon (from 82 to 65 ng/L), lipolysis and ketogenesis acutely. A1c, % 8 8.1 8.2 8 8.1 These observations are relevant to the use of liraglutide in the management FPG, mg/dL 176 173 177 135 131 POSTERS of type 1 diabetes. Therapeutics Mean SMPG* Supported By: Endocrine Fellows Foundation Clinical Diabetes/ Baseline 187 183.9 187.5 165.3 161.5 113-LB Week 30 126.5 139 153.9 139.1 154.8 The Effect of Liraglutide on Dietary Lipid-induced Insulin Resistance Change vs. Baseline -60.5 -44.9 -33.7 -26.1 -6.6 in Humans P-value <0.0001 <0.0001 <0.0001 <0.0001 0.002 LIZETTE LOPEZ, JURAJ KOSKA, CAMELIA BURCIU, PETER D. REAVEN, Phoenix, AZ Mean change vs. 15.6 26.8 19.5 We previously reported short-term diets rich in saturated fatty acids (SFA) iGlarLixi blunt peripheral insulin action. As we also demonstrated that GLP-1 agonists P-value <0.0001 <0.0001 <0.0001 can suppress postprandial lipid elevations and improve microvascular function, we hypothesized that liraglutide (LIR) may inhibit SFA induced insulin HBGI* resistance (IR). Baseline 10.3 9.8 10.4 7 6.3 29 subjects with normal or mildly impaired glucose tolerance underwent a Week 30 2.0 3.4 5.1 3.7 5.7 baseline insulin suppression test (IST), which measures steady state plasma Change vs. Baseline -8.3 -6.3 -5.3 -3.3 -0.56 glucose (SSPG150-180min) and correlates well with glucose clamp measures of IR, while on a healthy diet. They were then randomized to 3 weeks of LIR P-value <0.0001 <0.0001 <0.0001 <0.0001 0.116 (titrated weekly up to 1.8 mg/day), or 3 weeks of placebo (Plac), in a cross-over Mean change vs. 2.0 3.0 2.79 design. Plasma glucose, insulin and triglycerides (TG) were measured on both iGlarLixi treatments over 8 hrs after a SFA-enriched breakfast, and ISTs conducted P-value 0.001 <0.0001 <0.0001 after 24 hrs on the SFA-enriched diet. Ten participants had subcutaneous fat AUCn* biopsies prior to ISTs and insulin-mediated vasodilation measured ex vivo in isolated arterioles. Baseline 2633 2592 2641 2355 2294 Daylong plasma glucose and TG levels were lower after LIR vs. Plac (AUC0- Week 30 1775 1973 2149 1954 2205 8hrs, mean [SD]: glucose 86 [7] vs. 94 [7]; TG 170 [73] vs. 247 [130] mg/dl per Change vs. Baseline -858 -619 -492 -401 -90 hour, p<0.001 and p<0.05 respectively). Dilation of arterioles was blunted by P-value <0.0001 <0.0001 <0.0001 <0.0001 0.004 33% on the SFA diet (on Plac, p<0.001 vs. baseline), which was largely ame- liorated by LIR (p=0.3 vs. baseline). SSPG was markedly increased by the SFA Mean change vs. 239 366 312 diet on Plac (172 [60] vs. 98 [40] mg/dl baseline, p<0.001), and was partially iGlarLixi reduced after LIR (149 mg/dl [53], p=0.06 vs. Plac). Insulin levels during the IST P-value <0.0001 <0.0001 <0.0001 were higher after LIR (even with octreotide infusion, 41 [21] vs. 31 [12] mU/l, *Based on 7-point blood self-monitored blood glucose profiles values (pre- p<0.001) which may have accounted for the reduction in SSPG after LIR. injection fasting glucose, 2 hours after breakfast, before lunch, 2 hours after In summary, a SFA-enriched diet raises daylong triglyceride levels, reduces lunch, before dinner, 2 hours after dinner, at bedtime). AUCn, area under curve microvascular function and increases IR. Short-term treatment with liraglu calculated for each subject; HBGI, high blood glucose index; SMPG, self- tide blunts the effect of SFA on the first two processes, and counteracts monitored plasma glucose. Comparisons used two sample t-tests. NTC no. LLO octreotide-induced inhibition of insulin secretion, but may not prevent diet study: NCT02058147; NTC no. LLL Study: NCT02058160. induced insulin resistance. Supported By: Sanofi U.S.

114-LB 115-LB Insulin Glargine/Lixisenatide Fixed Ratio Combination Improves Gly- Cancer Risk with Incretin-based Glucose-Lowering Medications cemic Variability in Type 2 Diabetes Compared with Placebo and Nonincretin Comparators RONNIE ARONSON, GUILLERMO E. UMPIERREZ, WILLIAM STAGER, BORIS P. MIRNA ABD EL AZIZ, MELANIE KAHLE, JURIS J. MEIER, MICHAEL A. NAUCK, KOVATCHEV, Toronto, ON, Canada, Atlanta, GA, Bridgewater, NJ, Charlottesville, VA Bochum, Germany iGlarLixi is a once-daily titratable, single injection of fixed-ratio combina- Some epidemiological data and tissue analyses after exposure to incretin- tion of insulin glargine 100 U/mL (Gla-100) and lixisenatide, and is in develop- based glucose-lowering medications (IBGLM) suggest an elevated cancer risk, ment for the treatment of type 2 diabetes. e.g., for pancreatic cancer. We performed a meta-analysis of cancer reported This post-hoc analysis compared glycemic variability (GV) as measured by in clinical studies with GLP-1 receptor agonists (GLP-1 RA; exenatide b.i.d., lira- the high blood glucose index (HBGI) and area under the curve (AUC) of patient glutide [both 1.2/1.8 mg/d, for diabetes and 3.0 mg/d, for obesity], exenatide q.w., self-monitored plasma glucose (SMPG) 7-point profile data from the phase-3, dulaglutide, and albiglutide) and DPP-4 inhibitors (DPP-4-I; sitagliptin, vildaglip- 30-week LixiLan-O trial, comparing iGlarLixi, Gla-100 and lixisenatide in 1,170 tin, saxagliptin, alogliptin, and linagliptin), all approved doses pooled, versus pla-

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LB31 Clinical TherapeLateut iBcsrea/Newking T echAbstractsnology—Oral Agents

cebo/non-incretin comparators (data from manufacturers, safety publications, to estimate the HbA1c change, controlling for baseline patient characteristics or FDA advisory committee documents). For lixisenatide, sitagliptin, saxagliptin, (age, any major diabetes complications, prior T2DM drug regimen), medication and alogliptin, data from cardio-vascular outcomes trials were also used (versus adherence (days covered by the GLP-1 or DPP-4 ≥80%), and the addition of placebo/standard of care). For GLP-1 RA, a total of 23912 patients contributed other T2DM drugs. Data was extracted from RCTs of products taken by >5% 28043.9 patient years of observation (PYO; vs. 16620 and 19933.5 with placebo/ of RW patients that investigated use of a GLP-1 or DPP-4 (11 RCTs) as a second comparators, respectively), for DPP-4I, 62869 patients contributed 89871.4 PYO line treatment. Similar to the RCTs, selected RW patients had a baseline HbA1c (vs. 56834 and 84142.4, respectively). For all IBGLM combined, the rate ratio 7-10%, were drug-treated, but did not take insulin at baseline. Patients treated for any neoplasm (any dignity) was 0.95 (95% CI 0.89-1.01). For any malignant with a GLP-1 (N=221) were younger (57 vs. 63 yrs, P<0.01) than DPP-4 patients neoplasm, it was 0.89 (0.83-0.96, p = 0.002). For colorectal adenomas, and car- (N=652), had higher baseline HbA1c (8.34 vs. 8.15%, P<0.01) and were less cinomas, the rate ratios were 1.09 (0.88-1.36) and 0.79 (0.58-1.07), respectively. adherent (29 vs. 37%, P=0.03). RW HbA1c change was similar (-0.52% GLP-1 For pancreatic carcinoma, it was 0.67 (0.45-0.99, p = 0.045). Thyroid, breast vs. -0.51% DPP-4, P=0.90). In contrast, clinical trials typically reported a larger and prostate cancer were not increased. There was no statistically significant reduction in HbA1c than these RW findings (RCT HbA1c change ranges -0.84% to difference in cancer rates between GLP-1 RA and DPP-4-I, and no significantly -1.60% for GLP-1s; -0.47% to -0.90% for DPP-4). The regression model predicts elevated risk for any single compound for any of the tumor entities examined. well (-1.04% GLP-1; -0.69% for DPP-4), with poor adherence accounting for 75% In conclusion, based on a large database of randomized, controlled, prospective of the gap between RW and predicted trial results in both drug classes. Second studies, there was no indication of an elevated cancer risk with either GLP-1 line treatments such as GLP-1s and DPP-4s suffer from poorer outcomes in RW RA or DPP-4I, while the confidence intervals for the pooled data were narrow, settings, primarily due to poor adherence, indicating an urgent need for strate- indicating a relatively precise estimate of the relative risks. gies to improve RW adherence and realize the full benefit of therapy.

Supported By: Intarcia Therapeutics, Inc. 116-LB Efficacy of Metreleptin in Patients with Type 1 Diabetes CHANDNA VASANDANI, GREGORY CLARK, BEVERLEY ADAMS-HUET, CLAUDIA Clinical Therapeutics/New Technology— QUITTNER, ABHIMANYU GARG, Dallas, TX, Buffalo Grove, IL Oral Agents Metreleptin improves hyperglycemia in markedly hypoleptinemic patients POSTERS Therapeutics with generalized lipodystrophies. Recent preclinical studies reveal leptin’s 118-LB Clinical Diabetes/ potential in restoring insulin-deficient diabetic rodents to metabolic health Changes in Hepatic Fat Are Correlated with Biomarkers Suggestive without any insulin. Therefore, in a pilot study, we investigated the efficacy and of Liver Injury but Not Fibrosis in Type 2 Diabetes Patients Treated safety of metreleptin, 0.08 mg/kg/d in 5 females and 0.04 mg/kg/d in 3 males, with a Novel Glucagon Receptor Antagonist with suboptimally-controlled T1DM. After a baseline period of 4 wk, metre- SUDHA S. SHANKAR, MICHELLE X. ZHANG, SUMAN DUVVURU, KATHLEEN M. leptin was given subcutaneously twice daily for 20 wk (0-12 wk with insulin KELLY-BORUFF, NELSON CONCEPCION, JR., NAGA CHALASANI, THOMAS A. at stable doses and 12-20 wk with 50% lower basal insulin dose with further HARDY, CRISTINA B. GUZMAN, Indianapolis, IN, Toronto, ON, Canada adjustment based on self-monitored blood glucose), followed by off therapy LY2409021 (LY), a novel oral glucagon-receptor antagonist, has shown period of 4 wk. Metreleptin therapy did not lower hemoglobin A1c significantly significant glucose lowering effects in type 2 diabetes (T2D). These effects compared to baseline value with a median [range] difference of -0.15% [-0.70, were accompanied by an increase in hepatic fat fraction (HFF) at 6 months, 0.20], and -0.10% [-0.40, 0.50] at 12 and 20 wk, respectively (Table 1). Fur- assessed by repeat magnetic resonance imaging measurements in a Phase thermore, metreleptin therapy did not improve fasting plasma glucose; mean 2 trial of 174 T2D patients (Table). The relationship between changes in HFF blood glucose from glucometer, 1,5-anhydroglucitol (Table 1) or 24 hr profiles and various noninvasive markers suggestive of liver injury and fibrosis in this of plasma glucose, glucagon and free fatty acids. Metreleptin reduced median patient cohort was evaluated (Table). The increase in absolute HFF with LY weight by 2.6 [-1, 8.7] and 3.0 kg [1, 12.9] (p=0.003) and daily insulin dose by was significantly (p<.005) and robustly correlated with changes in serum ala- 12.1% [-0.6, 32.8] and 15.4% [-4.7, 42.6] at wk 12 and 20 (p=0.006), respectively. nine aminotransferase (ALT) and keratin 18 (K18) fragments (M30 and M65) We conclude that metreleptin was not efficacious in improving glycemic con- and nonalcoholic fatty liver disease (NAFLD) Liver Fat Score, while no correla- trol in T1DM although it reduced body weight and daily insulin dose modestly. tions were observed with Enhanced Liver Fibrosis or NAFLD Fibrosis scores. Table 1. Metabolic Variables as Mean (SD) or Median [Minimum and In contrast, the correlations with placebo were fewer and less robust (ALT, Maximum] *p<0.05 vs. Wk 0. Liver Fat Score, p<.05), while no notable correlations were seen with sita- Variables Baseline Metreleptin Metreleptin Off Metreleptin Omnibus gliptin. These novel data demonstrate a strong correlation between hepatic (wk 0) (wk 12) (wk 20) (wk 24) P value fat accumulation and Liver Fat Score as well as circulating markers of hepatic Weight (kg) 70.7 (5.9) 68.1 (6.9)* 66 (8)* 67.8 (7)* 0.003 injury, such as ALT and K18 fragments, in the context of clinically relevant glucagon-receptor antagonism in T2D patients. The increase in hepatic fat Leptin (ng/mL) 22 [6-34] 39 [7-172]* 49 [6-371]* 27 [6-134]* 0.049 was not associated with noninvasive measures of hepatic fibrosis. Insulin dose (U/d) 45.9 (11.5) 40.1 (12.3)* 39.4 (11)* 44.0 (11) 0.006 Table. Correlation between Absolute Hepatic Fat Fraction Change and HbA1c (%) 7.6 (0.4) 7.4 (0.5) 7.7 (0.3) 7.6 (0.6) 0.48 Changes in Selected Biomarkers after 6 Months of Treatment. Fasting plasma glucose 159 (69) 151 (36) 116 (56) 131 (40) 0.68 (mg/dL) Capillary blood glucose 172 (29) 168 (22) 176 (19) 177 (21) 0.44 meter mean (mg/dL) 1,5-anhydroglucitol (ug/mL) 4.6 (3.2) 5.2 (3) 3.7 (.09) 3.3 (0.7) 0.59 Supported By: JDRFI; Amylin Pharmaceuticals, Inc.; Aegerion Pharmaceuticals

117-LB Differences in T2DM Therapy Outcomes in Trials vs. the Real-World (RW): Identifying the Impact of Poor Adherence GINGER S. CARLS, EDWARD TUTTLE, RUO DING TAN, JOHNNY HUYNH, JOHN YEE, STEVEN V. EDELMAN, WILLIAM H. POLONSKY, Menlo Park, CA, Boston, MA, San Diego, CA, Del Mar, CA We assessed the RW HbA1c change in patients initiating second line diabetes drugs, the gap between RW and randomized controlled trial (RCT) efficacy, and factors accounting for these differences. This retrospective cohort study used a large U.S. integrated EMR-administrative claims database to identify adult T2DM patients who initiated a glucagon-like peptide-1 receptor agonist (GLP-1) or a dipeptidyl peptidase-4 inhibitor (DPP-4). HbA1c change was calculated for patients with an HbA1c at drug initiation (-90, + 14 days) and a second HbA1c 1 year (±90 days) after drug initiation. Multivariate regression was used

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LB32 Clinical TherapeLateut iBcsrea/Newking T echAbstractsnology—Oral Agents

119-LB 121-LB DS-8500a, a Novel GPR119 Agonist, Showed Significant Glucose Lanthionine Synthetase C-like 2 (LANCL2)-dependent Mechanisms Lowering Effect and Was Well Tolerated in Patients with Type 2 Dia- of Glycemic Control by Abscisic Acid betes Mellitus ELENA ZOCCHI, RAQUEL HONTECILLAS, ADRIA CARBO, SANTINA BRUZZONE, NOBUYA INAGAKI, HUBERT S. CHOU, SHUJI TSUKIYAMA, TAKUO WASHIO, NOAH PHILIPSON, LAURA STURLA, JOSEP BASSAGANYA-RIERA, Genova, Italy, KAZUHITO SHIOSAKAI, YASUHIKO NAKATSUKA, TAKASHI TAGUCHI, Kyoto, Blacksburg, VA Japan, Edison, NJ, Buckinghamshire, United Kingdom, Tokyo, Japan Prediabetes, metabolic syndrome (MS) and diabetes are serious health con- DS-8500a is a novel agonist of the G-protein coupled receptor 119 (GPR119) ditions that increasingly afflict the majority of the U.S. population. Lanthion- expressed in pancreatic beta cells and intestinal L cells in humans. It is being ine synthetase C-like 2 (LANCL2) has been identified as the molecular target developed as a treatment for type 2 diabetes mellitus (T2DM). The objective of abscisic acid (ABA) for glycemic control. Plasma and tissue ABA levels of this study was to evaluate the efficacy, safety and tolerability of DS-8500a originate from two sources: 1) dietary origin from plants, and 2) endogenous as monotherapy in patients with T2DM. synthesis. The plasma ABA pool can be depleted in diabetic individuals. Oral This was a randomized, double-blind, placebo-controlled, parallel-group, ABA administration in microgram amounts significantly reduces both glycemia multicenter study. Ninety nine Japanese T2DM subjects were randomized and insulinemia of healthy subjects undergoing an oral glucose tolerance test in a 1:1:1 ratio to receive DS-8500a 10 mg, 75 mg or placebo, administered (OGTT), indicating that ABA reduces the amount of insulin required to control orally once daily for 28 days. The primary efficacy endpoint was the change hyperglycemia. To further characterize the antidiabetic effects of low-doses from baseline in 24-hour weighted mean glucose (24hr-WMG) at Day 28. Other of ABA we used the db/db and the diet-induced obesity (DIO) mouse models endpoints included changes in fasting plasma glucose (FPG) and 2-hour post- of diabetes. In dose response studies, db/db mice were treated with oral con- prandial glucose (2hr-PPG) at Day 28. centrations of 1, 10, 40 and 200μg ABA/kg/d. Oral ABA treatment (1μg/kg/d) of Baseline characteristics were similar across the treatment groups. In genetically obese db/db mice and mice with DIO significantly reduced fasting subjects treated with either doses of DS-8500a, statistically significant and blood glucose (FBG), glucose tolerance during a GTT, and HbA1C levels. Fur- clinically relevant improvement in 24hr-WMG continued without evidence thermore, we provide mechanistic evidence in vivo that the molecular target for attenuation, and reached 19 mg/dL (P <0.001) reduction in 24hr-WMG of ABA is LANCL2 since the loss of the receptor in LANCL2-/- mice abrogated in the 75 mg group at the end for the 28-day treatment period, compared the glucose-normalizing effects of oral ABA. Mechanistically, ABA increased POSTERS with placebo. Significant reductions in FPG and 2hr-PPG were also observed, translocation of the glucose transporter GLUT4 to the plasma membrane and Therapeutics compared with placebo. In addition to the glycemic effects, clinically impor- GLUT4-dependent glucose uptake in adipocytes and myoblasts. Release from Clinical Diabetes/ tant decreases in total cholesterol (-8.4%, P<0.0001), LDL cholesterol (-7.0%, entero-endocrine cells of GLP-1, a key regulator of carbohydrate intake and P<0.05) and triglycerides (-35.9%, P<0.0001), and increases in HDL cholesterol metabolism targeted by the most recent antidiabetic drugs, is enhanced by (15.9%, P<0.0001) were evident on Day 28 in the 75 mg group, compared with ABA both in vitro and in vivo. In summary, oral ABA supplementation is emerg- placebo. Both DS-8500a doses evaluated were well tolerated. There were ing as an innovative nutritional intervention for improving glycemic control in no reports of serious adverse events (SAE), discontinuations due to AEs, or healthy individuals and prediabetic patients by activating LANCL2. hypoglycemia. In summary, DS-8500a was well tolerated, and showed significant glycemic 122-LB benefits in 24hr-WMG, FPG, 2hr-PPG and favorable changes in lipid profile Chronic Treatment with the Sulfonylurea Glyburide Reduces Amy- over 28 days of administration in Japanese patients with T2DM. loid-beta Pathology in the APPswe/PSEN1de9 Mouse Model of Alzheimer’s Disease 120-LB SHANNON L. MACAULEY, EMILY E. CAESAR, MOLLY STANLEY, THOMAS E. A Second Generation GPR40 (FFAR1) Agonist with a Unique In-vitro MAHAN, DAVID M. HOLTZMAN, St. Louis, MO Profile DemonstratesI mproved GLP-1 Secretion and Glucose Lower- Patients with type 2 diabetes (T2D) have a 2-4 fold increased risk for devel- ing in Rodents plus Glucose Benefits in Humans with Type 2 Diabe- oping Alzheimer’s Disease (AD). Hyperglycemia, hyperinsulinemia, and insulin tes resistance are hallmarks of T2D and these features are thought to exacerbate ANNE REIFEL MILLER, YANYUN CHEN, MIN SONG, CHARLIE CHANGZHI HU, clinical features of AD, such as amyloid-beta (Aβ) deposition and tau accumu- KEYUE CHEN, RICHARD W. ZINC, KEITH A. OTTO, GUEMALLI CARDONA, ANJANA lation. Therefore, we hypothesized that using the antidiabetic drug, glyburide/ PATEL LEWIS, JAYANA P. LINESWALA, STEVEN D. KAHL, XIAOSU MA, CHAH- glibenclamide, to treat metabolic dysfunction would benefit T2D and improve RZAD MONTROSE-RAFIZADEH, EDWARD JOHN PRATT, CHAFIQ HAMDOUCHI, AD pathology. Four-month-old PS1/APP mice, a mouse model of cerebral Indianapolis, IN amyloidosis, were treated systemically with glibenclamide or placebo for 3 Several GPR40 (FFAR1) agonists have been examined in clinical trials but months. At 7 months, glibenclamide treatment decreased Aβ pathology by were subsequently terminated for further development. To more clearly under 40-50%, including decreased Aβ deposition, plaque burden, and levels of stand GPR40 pharmacology, we therefore developed assays to explore the Aβ40 and Aβ42 within the cortex and hippocampus. Interestingly, there was receptor’s multiple binding sites and resulting signal transduction pathways. no difference in either microglial or astrocyte activation. With respect to A second generation GPR40 agonist, LY2922470, was identified that binds the peripheral metabolism, glibenclamide treatment caused transient hypergly- allosteric 1 site (Ki = 21 nM) resulting in potent and full agonist activity in beta cemia for 1 month. No changes in serum insulin were found, yet treated mice arrestin (EC50 = 7 nM, 139%) and IP-1 (EC50 = 9 nM, 133%) assays, and potent displayed glucose intolerance compared to controls. Possible mechanisms partial agonist activity in a calcium flux assay (EC50 = 2 nM, 51%). Further for reduced Aβ pathology in treated mice include elevated Aβ degrading studies revealed that LY2922470 has a receptor residence time of 46 minutes enzymes, altered APP processing, or accelerated Aβ clearance. Although not on GPR40 and does not cross react with closely related receptors. Compared significant, there is a trend towards decreased Aβ half-life in treated mice. to first generation molecules, this new in-vitro profile translates into better Therefore, future experiments will explore Aβ clearance mechanisms as an GLP-1 secretion in the STC-1 cell line, improved glucose lowering in an acute explanation for glibenclamide’s effects. Taken together, these data suggest ipGTT performed in lean mice (normalization of glucose levels with an ED90 of that treatment with sulfonylureas can reduce Aβ deposition in APP/PS1 mice 5 mg/kg), and improved glucose lowering during OGTTs performed in Zucker by modulating vascular KATP channel activity, suggesting a novel approach for fa/fa rats after 1 and 21 days of dosing. Therefore, LY2922470 is a potent, effi- treating AD. cacious, selective, and durable GPR40 agonist which demonstrates significant Supported By: National Institutes of Health (P01 NS080675, NSF DGE-1143954, improvements compared to first generation molecules in preclinical studies. F32 NS080320); Donors Cure LY2922470 was advanced to clinical testing and demonstrated dose proportional PK in normal healthy volunteers and significant decreases in average and fasting glucose levels in individuals with type 2 diabetes. These results suggest that a better understanding of the complicated GPR40-ligand interactions provides valuable information to identify molecules with improved preclinical profiles for clinical testing.

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LB33 Clinical TherapeLateut iBcsrea/Newking T echAbstractsnology—Oral Agents

123-LB group. In general, favorable drug effects in all dose groups were suggestive of NIP-231, a Novel, Partial Glucokinase Activator for the Treatment decreases in MMTT (AUC) and FPG even when they were not statistically sig- of Type 2 Diabetes Exerts Marked HbA1c Reduction with Protective nificant. Beneficial changes were also observed in all lipid parameters, though Effect on Beta Cells only triglycerides exhibited statistically significant differences. YUSUKE ITO, JUNJI KAMON, SHIGETADA SASAKO, TAKESHI NAITO, Saitama, Based on the results of this Phase II Proof of Concept trial, MLR-1023 repre- Japan, Tokyo, Japan, Chiba, Japan sents an important potential new therapy in the treatment of type 2 diabetes. New antidiabetic drugs are still needed by reason that existing drugs are not sufficient for beta cell protection, sustained glycemic control and no risk of 125-LB hypoglycemia. The partial glucokinase activator, NIP-231, could satisfy the need Effect of Ertugliflozin plus Sitagliptin on Glycemic Control vs. Either because it significantly reduces HbA1c in chronic treatment with protective Treatment Alone in Subjects with T2DM Inadequately Controlled effect on beta cells and less risk of hypoglycemia. NIP-231 (EC50=48 nM) given with Metformin in a single oral administration lowered glucose levels without affecting insulin ROY ELDOR, RICHARD PRATLEY, GREGORY GOLM, SUSAN HUYCK, YANPING QIU, secretion in C57BL/6 mice. Four week treatment of NIP-231 at doses higher than SHEILA SUNGA, JEREMY JOHNSON, STEVEN TERRA, JAMES MANCUSO, SAM- 3 mg/kg significantly reduced HbA1c without affecting hepatic lipid contents in UEL S. ENGEL, BRETT LAURING, Rahway, NJ, Orlando, FL, Beijing, China, Andover, high-fat diet/streptozotocin (HFD/STZ)-induced diabetic mice. NIP-231 was more MA, New London, CT efficacious than sitagliptin and Metformin at the dose comparable to clinical dose Ertugliflozin (ERTU) is an oral SGLT2 inhibitor in development for T2DM (100 mg/kg bid and 200 mg/kg bid, respectively) in HbA1c reduction. The combi- treatment. In a double-blind Phase 3 trial, subjects (n=1233) with A1c 7.5- nation therapy of NIP-231 and either Metformin or sitagliptin showed marked 11.0% on stable Metformin ≥1500 mg/day were randomized to 1 of 5 treat- additive effects. NIP-231 recovered insulin content in pancreatic beta-cells but ment groups (Table). ERTU+sitagliptin (SITA) combinations were compared Metformin did not, whereas both NIP-231 and Metformin reduced HbA1c in a with corresponding ERTU doses alone (5 or 15 mg) and SITA alone. Baseline dose-dependent manner. NIP-231 significantly lowered glucose levels even in characteristics were comparable among groups (overall mean age 55.1 yrs, HFD/STZ-induced diabetic mice exhibiting a sulfonylurea-induced secondary fail- A1c 8.6%). After 26 wks, co-administration of ERTU+SITA was significantly ure. NIP-231 could provide a prominent therapy for type 2 diabetes. more effective than ERTU or SITA alone in reducing A1c, FPG, and achiev- Figure. ing A1c <7.0%, and significantly more effective in reducing body weight and POSTERS Therapeutics systolic blood pressure vs. SITA (Table). Incidence of adverse events (AEs) was

Clinical Diabetes/ similar across groups, except for higher rates of genital mycotic infections in groups receiving ERTU vs. SITA alone (females, 4.9-7.6% vs. 1.1%; males, 2.4-4.7% vs. 0%, respectively). Urinary tract infection rates were higher with ERTU alone (but not ERTU+SITA) vs. SITA alone (range: 3.2% [SITA] to 5.6% [ERTU 15 mg]). Symptomatic hypoglycemia rates ranged from 2.4% (ERTU 5 mg) to 4.9% (ERTU 15 mg+SITA). Hypovolemia AE rates were 1.6 and 0.8% in ERTU 5 and 15 mg groups, respectively, and 0% in all other groups. Co-administration of ERTU+SITA provided more effective glycemic control vs. ERTU or SITA alone and was generally well-tolerated. Table. Summary of Key Efficacy Endpoints at Week 26. ERTU ERTU SITA ERTU ERTU 5 mg 15 mg 100 mg 5 mg + SITA 100 mg 15 mg + SITA 100 mg (n=250) (n=248) (n=247) (n=243) (n=244) Change from baseline, A1c (%) -1.0 -1.1 -1.1 -1.5 -1.5 LS mean (95% CI) (-1.2, -0.9) (-1.2, -1.0) (-1.2, -0.9) (-1.6, -1.4)† (-1.6, -1.4)† FPG (mg/dL) -35.5 -37.1 -25.9 -44.4 -48.9 (-39.8, 31.2) (-41.4, -32.8) (-30.3, -21.5) (-48.7, -40.0)† (-53.2, -44.6)† 124-LB Body weight (kg) -2.7 -3.7 -0.7 -2.5 -2.9 Clinical Proof-of-Concept for an Antidiabetic Agent with a Novel (-3.1, -2.3) (-4.2, -3.3) (-1.1, -0.2) (-3.0, -2.1)‡ (-3.4, -2.5)‡ Mechanism for Reducing Insulin Resistance FRANK GREENWAY, FELIX GUZMAN, RAUL A. TAMAYO, SIN GON KIM, ELAINE Systolic BP (mmHg) -3.9 -3.7 -0.7 -3.4 -3.7 (-5.3, -2.5) (-5.1, -2.3) (-2.1, 0.8) (-4.8, -2.0)‡ (-5.1, -2.3)‡ WATKINS, MIN KYONG MOON, SANG YOUL RHEE, MOON KYU LEE, JUAN P. § § FRIAS, JULIO ROSENSTOCK, CHOON HEE CHUNG, SEUNG HWAN LEE, BRAD- A1c <7.0% at Week 26, n (%) 66 (26.4) 79 (31.9) 83 (33.6) 127 (52.3) 120 (49.2) LEY BLOCK, BONG SOO CHA, KWAN WOO LEE, WILLIAM T. CEFALU, WAYNE L. †P≤0.002 vs. individual treatments; ‡P≤0.005 vs. SITA; §P<0.001 based on HARPER, HYEONG KYU PARK, BYUNG JOON KIM, ANDREW G. REAUME, HEE model-estimated odds ratios comparing ERTU+SITA vs. individual treatments. WON YOO, Baton Rouge, LA, Miami, FL, Seoul, Republic of Korea, Chula Vista, CA, A constrained longitudinal model was used for continuous endpoints and Los Angeles, CA, Dallas, TX, Wonju, Republic of Korea, Oviedo, FL, Suwon, Republic of logistic regression for binary endpoints. Korea, Raleigh, NC, Incheon, Republic of Korea, Exton, PA Supported By: Merck & Co., Inc./Pfizer, Inc. Despite the recent release of several new agents with different mechanisms, there remains an unmet medical need towards the treatment of underlying 126-LB insulin resistance. MLR-1023, a selective lyn kinase activator, is a repositioned Effect of Empagliflozin (EMPA) on Bone Fractures in Patients with orally bioavailable small molecule that was identified as a diabetes therapeutic. Type 2 Diabetes (T2DM) The compound was previously developed through Phase II studies for treatment SVEN KOHLER, STEFAN KASPERS, AFSHIN SALSALI, CORDULA ZELLER, HANS J. of gastric ulcers where it demonstrated good safety and tolerability in human WOERLE, Ingelheim, Germany, Ridgefield, CT, Biberach, Germany subjects. It has since been shown to improve insulin action in a variety of in Patients with T2DM have an increased risk of fractures compared with indi- vivo preclinical models without activating PPAR receptors. Importantly, unlike viduals without diabetes. Sodium glucose cotransporter 2 inhibition may alter currently available insulin sensitizers, MLR-1023 shows effects after a single the renal reabsorption of calcium and phosphate, potentially affecting bone administration and is weight neutral in chronic administration settings. metabolism. We assessed the effect of EMPA on bone fractures in patients This proof-of-concept clinical study included 130 subjects with T2DM. Subjects with T2DM using pooled placebo-controlled trial data and data from a head- were 18-75 years of age, had BMIs of 20-40 kg/m2, glycosylated HbA1c of 7-10%, to-head study versus glimepiride (GLIM; EMPA-REG H2H-SU). were either Metformin-naïve or washed off of Metformin, and were not exposed Pooled safety data were analyzed from patients who were randomized to other antidiabetic agents within the previous 6 months. Subjects were treated (1:1:1) to receive EMPA 10 mg, 25 mg or placebo (PBO) in 15 randomized, with one of four active doses (100mg qd, bid, 200mg qd, bid) of MLR-1023 or pla- Phase I–III clinical trials (including the cardiovascular outcomes trial, EMPA- cebo for 4 weeks after having 3 weeks of placebo run-in. A mixed meal tolerance REG OUTCOME), plus 4 extension studies. In EMPA-REG H2H-SU, patients test (MMTT) which was a primary endpoint was conducted at Day 1 and Day 29 received EMPA 25 mg or GLIM as add-on to Metformin for 104 weeks and and fasting plasma glucose (FPG) was monitored weekly during clinic visits. could participate in a 2-year extension. Bone fracture adverse events (AEs) Top line analysis reveals statistically significant improvements in MMTT were evaluated through a search of investigator-reported AEs and analyzed (AUC; -119.7 mg*h/dL) and FPG (-38.8 mg/dL) were found in the 100 mg qd descriptively.

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LB34 Clinical TherapeLateut iBcsrea/Newking T echAbstractsnology—Oral Agents

In the pooled analysis, 4221, 4196 and 4203 patients received EMPA 10 mg, forms and displays good tissue distribution and inhibition in mice. Treatment EMPA 25 mg and PBO, respectively, and median exposure was 698, 699 and of db/db mice with CNX-010-710 (30 mpk, bid) for 8 weeks caused significant 658 days in these groups, respectively. Bone fracture AEs were reported in 119 reduction of 17% fasting glucose (333±7 vs. 391±11 mg/dl; p<0.05 ), 16.8% fed patients (2.8%), 105 patients (2.5%) and 123 patients (2.9%) in EMPA 10 mg, glucose (440±19 vs. 514±12 mg/dl; p<0.01), 1.2% HbA1c (9.5±0.2 vs. 10.7±2; EMPA 25 mg and PBO groups, respectively. This corresponded to a rate of 1.55, p<0.01) and 19% serum triglyceride (147±6 vs. 175±4 mg/dl; p<0.05) com- 1.36 and 1.69/100 patient-years, respectively. In EMPA-REG H2H-SU, 765 and pared to control animals. A significant 60% reduction in fasting plasma insulin 780 patients received EMPA 25 mg and GLIM, respectively, and bone fracture (4.5±0.7 vs. 7.2±0.7 ng/ml; p<0.01) and calculated HOMA-IR (92±15 vs. 173±17; AEs were reported in 31 patients (4.1%) and 33 patients (4.2%) in the EMPA 25 mg p<0.001) indicated improvement in whole body insulin sensitivity. CNX-010- and GLIM groups, respectively. This corresponded to a rate of 1.28 and 1.40/100 710 caused 7.2% reduction in body weight (44.2±1.6 vs. 47.4±1.2 g) and 19% patient-years, respectively. There were no changes from baseline in calcium or reduction in subcutaneous adipose depots weight (p≤0.05) without chang- phosphate in any group in the pooled analysis or in EMPA-REG H2H-SU. ing food intake. CNX-010-710 caused a 32% increase in serum HDL-C (68±7.2 To conclude, in a pooled analysis of >12,000 patients with T2DM, EMPA vs. 101±3.6 mg/dl;p<0.001), a 56% reduction in liver triglyceride (10.57±2 vs. did not increase the risk of bone fracture compared with PBO. In a 4-year 24.12±1.5 mg/dl; p<0.001), a non-significant increase in bone weight (~10%), head-to-head study, EMPA did not increase the risk of bone fracture compared decrease in osteoclast number (19%) and 1.5 fold reduction in serum hydroxy- with GLIM. proline (p<0.01) levels in ovarectomized C57BL6/J mice on HFD. Further pres- Supported By: Boehringer Ingelheim & Eli Lilly and Company Diabetes Alliance ervation of trabecular thickness and continuity indicated significant reduction of bone resorption. In 28 days toxicity study, CNX-010-710 (100 mg/kg, bid) 127-LB did not cause any test compound-related adverse effect on clinical chemistry, Effect of Empagliflozin (EMPA) on Diabetic Ketoacidosis (DKA) in gross pathology, physiological behavior, body weight, organ weights, micro- Patients with Type 2 Diabetes (T2DM): Pooled Clinical Trial Data pathology and urinary parameters in Wistar rats. No HPA activation or adre- SØREN LUND, FERNANDO SOLIMANDO, SVEN KOHLER, CORDULA ZELLER, STE- nal hyperplasia were observed in mice. CNX-010-710 has potential to address FAN KASPERS, Ingelheim, Germany, Biberach, Germany lipid disorders and osteoporosis. Sodium glucose cotransporter 2 inhibition leads to loss of glucose in the urine and decreased insulin-to-glucagon ratio, which may lead to a shift from 129-LB POSTERS glucose to lipid oxidation and increased ketone bodies. We assessed the inci- Effects of Canagliflozin (CANA) on Serum Magnesium (Mg) in Patients Therapeutics dence of DKA with EMPA using pooled clinical trial data. with Type 2 Diabetes Mellitus (T2DM) Clinical Diabetes/ Safety data were pooled from patients with T2DM treated with EMPA 10 RICHARD E. GILBERT, CHRISTIAN MENDE, UJJWALA VIJAPURKAR, SUE SHA, mg or 25 mg in 18 randomized, Phase I-III clinical trials of 8 days’ to 4 years’ MICHAEL J. DAVIES, MEHUL DESAI, Toronto, ON, Canada, La Jolla, CA, Raritan, NJ duration (including the cardiovascular outcomes trial, EMPA-REG OUTCOME), Hypomagnesemia is an established risk factor for ventricular arrhythmia plus 6 extension studies. Based on adverse events (AEs) reported by the inves- that is also associated with T2DM and its cardiometabolic complications. tigators, DKA was assessed through a search of 3 Medical Dictionary for Reg- CANA, an SGLT2 inhibitor, has been shown to increase serum Mg without ulatory Activities (MedDRA) preferred terms (diabetic ketoacidosis; diabetic detectable changes in fractional excretion in patients with T2DM. We evalu- ketoacidotic hyperglycemic coma; ketoacidosis) and analyzed descriptively. ated the proportion of patients with low serum Mg (<1.8 mg/dL) at baseline Total exposure was 8368, 11017, and 10472 patient-years in the EMPA 10 (BL) and week 26 using pooled data from 4 placebo (PBO)-controlled studies of mg, EMPA 25 mg and comparator groups, respectively. The proportion of CANA in 2313 patients with T2DM (mean serum Mg = 1.9 mg/dL; range = 1-3 patients with any DKA AE was low in all groups and comparable between mg/dL). At BL, 18.3% of patients had Mg <1.8 mg/dL, 80.7% had Mg 1.8-2.3 groups. All patients with DKA AEs in EMPA groups recovered, except for 1 mg/dL (normal Mg), and 1.0% had Mg >2.3 mg/dL (hypermagnesemia). Patients patient (EMPA 10 mg; post-treatment AE) scheduled for hospital discharge with Mg <1.8 mg/dL were more likely to be female, white, have longer T2DM but lost to follow-up. Two patients discontinued treatment with EMPA due duration and have microvascular disease than those with Mg ≥1.8 mg/dL. At to DKA AEs. week 26, increases in serum Mg were seen with CANA 100 and 300 mg versus To conclude, in an analysis of pooled data with >19000 patient-years’ PBO in patients with BL Mg <1.8 mg/dL (17.0% and 19.0% vs. 3.9%) and Mg exposure to EMPA, the incidence of DKA was low and comparable between ≥1.8 mg/dL (4.9% and 7.0% vs. -1.4%). A greater proportion of patients with groups. BL Mg <1.8 mg/dL had Mg ≥1.8 mg/dL at week 26 with CANA 100 and 300 mg Table. versus PBO (74.1% and 80.6% vs. 28.8%; Figure). Hypomagnesemic patients treated with CANA versus PBO were 10-14 times more likely to achieve Mg Empagliflozin 10 mg Empagliflozin 25 mg Comparators ≥1.8 mg/dL. In summary, CANA treatment was associated with normalization (n=4558) (n=5520) (n=5599) of serum Mg in hypomagnesemic patients with T2DM, potentially leading to n Rate/100 n Rate/100 n Rate/100 improved cardiometabolic outcomes and reduced risk of arrhythmia. (%) patient- (%) patient- (%) patient- years years years Figure. Proportion of Patients with Baseline Serum Mg <1.8 mg/dL Who Achieved Serum Mg ≥1.8 mg/dL at Week 26. Any DKA 5 0.06 2 0.02 5 0.05 adverse event (0.1) (<0.1) (0.1) Diabetic 5 0.06 2 0.02 4 0.04 ketoacidosis (0.1) (<0.1) (0.1) Ketoacidosis 0 0 0 0 1 0.01 (<0.1) Serious DKA 5 0.06 1 0.01 4 0.04 adverse event* (0.1) (<0.1) (0.1) Data from patients treated with ≥1 dose of study drug. *Adverse events reported as serious adverse events by investigator. Supported By: Boehringer Ingelheim & Eli Lilly and Company Diabetes Alliance

128-LB Cnx-010-710, an Orally Dosable, Safe, and Pan Tissue Acting Hsd11b1 Specific Inhibitor Displays Antihyperglycemic, Antihyperlipidemic, and Antiosteoporotic Effects in Mice JAGANNATH R. MADANAHALLI, ANIL M. THARAPPEL, HARSHA KRISHNA REDDY, Supported By: Janssen Scientific Affairs, LLC GOWTHAMRAJ GUNTI, ONKARAMURTHY MALLAPPA, ANOOPRAJ RAJAPPAN, YOGANAND MOOLEMATH, ANUP O. MAMMEN, VENKATARANGANNA V. MARI- KUNTE, SOMESH P. BAGGAVALLI, Bengaluru, India CNX-010-710 is a selective small molecule inhibitor of 11-Hydroxysteroid dehydrogenase (11-HSDβ1) with IC50 of 7nM (human) and 64nM (mouse) iso-

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LB35 Clinical TherapeLateut iBcsrea/Newking T echAbstractsnology—Oral Agents

130-LB estly greater A1c reduction and weight loss, and can reduce blood pressure, Ertugliflozin Effectively Improves Glycemic Control as Monotherapy but may cause more genital infection when compared to DPP-4i. in Patients with T2DM Figure. SAMUEL DAGOGO-JACK, MELANIE DAVIES, JUAN FRIAS, GIUSEPPE DEROSA, AMANDA DAREKAR, KRISTEN FOCHT, GREGORY GOLM, JEREMY JOHNSON, DIDIER SAUR, STEVEN TERRA, Memphis, TN, Leicester, United Kingdom, Los Ange- les, CA, Pavia, Italy, Walton Oaks, United Kingdom, Collegeville, PA, Upper Gwynedd, PA, Rahway, NJ, Paris, France, Andover, MA Ertugliflozin (ERTU) is an oral SGLT2 inhibitor in development for treatment of patients with T2DM. This presents results from the efficacy endpoints at week 26 in this ongoing Phase 3, 52-week, randomized, double-blind, placebo- controlled trial, assessing the efficacy and safety of ERTU compared with placebo (PBO) in patients with T2DM and inadequate glycemic control (A1c 7.0-10.5%) on diet and exercise (N=461). Adult patients (age 56.4 ± 11.0 yrs; baseline A1c 8.21 ± 0.98%, and duration of T2DM 5.0 ± 5.1 years, mean ± SD) were randomized to receive PBO, ERTU 5 mg or ERTU 15 mg once daily in a 1:1:1 ratio. 132-LB At week 26, patients randomized to ERTU 5 mg and ERTU 15 mg had signifi-

Hospital Discharge Algorithm Based on Admission HbA1c for the cantly greater reductions in A1c, FPG, body weight, and 2-hour post-prandial Management of Patients with Type 2 Diabetes: Sitagliptin Discharge glucose (PPG) and were significantly more likely to have an A1c <7.0% when Trial compared to PBO (Table 1). The placebo-adjusted least-squares mean reduc- ROMA Y. GIANCHANDANI, PRIYATHAMA VELLANKI, FRANCISCO PASQUEL, DAN- tion in A1c was 0.99% and 1.16% for ERTU 5 mg and ERTU 15 mg, respectively. IEL J. RUBIN, KATHLEEN M. DUNGAN, ISABEL ANZOLA, PATRICIA GOMEZ, ISRAEL Compared with PBO, ERTU treatment was associated with a trend toward HODISH, JENNIFER MACDONALD, SANGEETA LATHKAR-PRADHAN, KWAME lower blood pressure.

POSTERS OSEI, ANJU JOSE, FEBA GEORGE, GUILLERMO E. UMPIERREZ, Ann Arbor, MI, Therapeutics Overall AE rates were comparable between ERTU and PBO and the rate Atlanta, GA, Decatur, GA, Philadelphia, PA, Columbus, OH Clinical Diabetes/ of serious AEs was low across groups. A higher incidence of genital mycotic Few studies have focused on the optimal management of patients with infections in females was observed in patients taking ERTU 15 mg (22.6%) type 2 diabetes (T2DM) after hospital discharge. Accordingly, we conducted a and ERTU 5 mg (16.4%) compared to PBO (7.0%); there was no increase in multicenter trial to determine the efficacy and safety of a hospital discharge the incidence of urinary tract infections with either dose of ERTU relative to algorithm based on admission HbA1c to guide outpatient therapy in 255 medi- placebo. cine and surgery patients with T2DM. Patients with HbA1c ≤7% (n= 68) were Table 1. discharged on oral antidiabetic agents (OAD) with sitagliptin/ Metformin Endpoint Analysis Ertugliflozin 5 mg Ertugliflozin 15 mg combination (Janumet®). Those with HbA1c between 7% and 9% (n= 99) Metric† vs. Placebo vs. Placebo were discharged on Metformin/sitagliptin plus glargine at 50% of the inpa- Estimate (95% CI) p-value Estimate (95% CI) p-value tient dose. Those with HbA1c >9% (n= 87) were discharged on Metformin/ sitagliptin plus glargine at 80% of the inpatient dose, or on basal bolus regi- A1c (%) Diff -0.99 (-1.22, -0.76) <0.001 -1.16 (-1.39, -0.93) <0.001 men. Duration of the study was 6 months with treatment adjusted to achieve FPG (mg/dL) Diff -34.53 (-42.76, -26.29) <0.001 -44.01 (-52.28, -35.74) <0.001 a target HbA1c level <7%. The primary outcome was change in HbA1C at 3 Body weight (kg) Diff -1.76 (-2.57, -0.95) <0.001 -2.16 (-2.98, -1.34) <0.001 and 6 months after discharge. The HbA1c on admission was 8.70±2.32% and Proportion of patients OR 3.59 (1.85, 6.95) <0.001 6.77 (3.46, 13.24) <0.001 decreased to 7.31±1.48% at 3 months and to 7.32±1.68% at 6 months (both, with A1c<7% p<0.001). The mean daily glucose at enrollment was 211.6±53.8 mg/dl and decreased to 134.33±32.5 mg/dl and 133.41±39.8 mg/dl at 3 and 6 months, 2-hour PPG (mg/dL) Diff -69.03 (-83.24, -54.83) <0.001 -67.33 (-81.73, -52.93) <0.001 respectively (both, p<0.001). Patients with HbA1c <7% had a change from SBP (mmHg) Diff -3.31 (-5.98, -0.65) 0.015* -1.71 (-4.40, 0.98) 0.213 6.27±0.48% to 6.28±0.80% and 6.22±0.99% at 3 and 6 months. Patients with DBP (mmHg) Diff -1.80 (-3.51, -0.09) 0.039* -0.37 (-2.09, 1.35) 0.669* HbA1c 7-9% had a reduction from 8.04±0.65% to 7.29±1.1% and 7.34±1.27% †Diff = Difference in least squares means based on a constrained longitudinal (both p<0.001), and those with HbA1c >9% had a reduction from 11.35±1.71 to data analysis model; OR = adjusted odds ratio. *Nominal p-values. All efficacy 7.98±1.75% and 8.02±2.01% at 3 and 6 months (both p<0.001). Mild hypogly- analyses are based on the full analysis set, excluding data after initiation of cemia (<70 mg/dl) was reported in 23.5% patients in the HbA1c <7% group, glycemic rescue therapy. 23.2% with HbA1c 7-9%, and in 26.4% of patients with HbA1c >9%. A BG<40 Supported By: Pfizer, Inc./Merck & Co., Inc. mg/dl was reported in <2% of patients on OAD or on the combination of OAD + insulin therapy. In summary, the proposed HbA1c-based hospital discharge 131-LB algorithm with sitagliptin and Metformin, with or without basal insulin, was found to be safe and effective for the management of general medicine and The Efficacy of SGLT2 Inhibitors Compared with DPP-4 Inhibitors as surgical patients with T2DM. Add-on Therapy to Metformin: A Meta-analysis Supported By: Merck & Co., Inc. BASEM M. MISHRIKY, DOYLE M. CUMMINGS, ROBERT J. TANENBERG, Greenville, NC Metformin is the cornerstone of treatment for type 2 diabetes mellitus 133-LB (T2DM). There is no consensus on the best second-line agent when Metformin The Relationship between DPP-4 Inhibition and Glycemic Variability fails. We performed a meta-analysis to explore the efficacy of SGLT2i com- in Patients with Type 2 Diabetes pared to DPP-4i as add-on therapy to Metformin. We searched MEDLINE for SE EUN PARK, BYUNG WAN LEE, JAE HYEON KIM, CHANG HEE JUNG, SEUNG randomized trials comparing SGLT2i to DPP-4i as add-on therapy to Metformin HWAN LEE, SUNGHWAN SUH, WOO JE LEE, YOUNGHWAN JANG, SUNGHO KIM, in inadequately controlled T2DM. We pooled outcomes at ≤26 weeks (w) CHEOL YOUNG PARK, Seoul, Republic of Korea together and those at ≥52 wk together. Number needed to harm (NNH) was Glycemic variability may contribute independently to diabetes complica- calculated for side effects. Six studies were included. There was a greater tions in addition to chronic sustained hyperglycemia. Although, there were reduction in hemoglobin A1c (A1c) at ≥52 wk favoring SGLT2i compared to significant differences in ability to reduce glycemic variability between DPP-4 DPP-4i, but not at ≤26 wk (Figure). There was greater weight reduction favor- inhibitors in previous studies, the exact mechanism is still unknown. The pur- ing SGLT2i (MD [95% CI] = -2.31 kg [-2.66, -1.96] at ≤26 wk and -2.45 kg [-2.83, pose of this study was to assess the relationship between glycemic variability -2.07] at ≥52 wk) compared to DPP-4i. SGLT2i treated patients had greater and DPP-4 inhibition. A multi-center, randomized, active controlled, open- reduction in systolic and diastolic blood pressure at both time points com- label, parallel design study was performed in 69 patients with HbA1c greater pared to DPP-4i. The incidence of genital infection was significantly higher than 7.5%. Subjects were randomized (1:1:1) to receive gemigliptin 50 mg qd, in the SGLT2i group compared to the DPP-4i group (RR [95% CI] = 3.43 [1.96, sitagliptin 100 mg qd, or glimepiride 2 mg qd with Metformin SR 500-1000 mg 6.02], NNH=21). Both SGLT2i and DPP-4i reduced A1c and can be considered qd for 12 weeks. All patients underwent continuous glucose monitoring (CGM) as reasonable options for add-on therapy to Metformin. SGLT2i provide mod- at baseline and after 12 weeks. CGM measurements were monitored for consecutive 4 days by using a CGM system (CGMS® System Gold™, Medtronic

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LB36 Clinical Therapeutics/New TechLatenolo Breagy—Pkinghar Abstractsmacologic Treatment of Complications

MiniMed). Activity of DPP-4 enzyme was measured at baseline and after 12 With regard to acute renal impairment/failure, only empagliflozin was signifi- weeks in all patients. Multiple regression analyses and Pearson correlation cantly associated with a reduced risk compared to placebo (OR=0.73; 95% CI, coefficient were used to test the association between changes in DPP-4 inhi- 0.61 to 0.88). Of these three SGLT2 inhibitors, dapagliflozin was associated bition and in glycemic variability. DPP-4 activity changes significantly corre- with the highest risk of composite of renal impairment/failure events while lated with changes in mean amplitude of glycemic excursions (MAGE; r=-0.30, empagliflozin was associated with the lowest risk of acute renal impairment/ p=0.032) and standard deviation (SD; r=-0.28, p=0.034) of glucose but not in failure. Our results indicate that dapagliflozin use may have potentially harm- HbA1c and fasting plasma glucose. The association with MAGE remained sig- ful effects on renal function and empagliflozin may have a protective effect nificant (p = 0.047) after adjusting for age, sex, body mass index, baseline on acute renal impairment/failure. Future safety monitoring from large well- HOMA-IR, and baseline HbA1c. A similar profile was also observed in SD of conducted RCT and real-world data is warranted. glucose. DPP-4 inhibition is associated with reduction of glycemic variability Supported By: Indiana University Health/Indiana University School of Medicine in type 2 diabetic patients. These results suggest that a more potent member in the DPP-4 inhibitors class may be considered as the optimal therapeutic options to decrease glycemic variability in type 2 diabetes patients. Clinical Therapeutics/New Technology— Supported By: LG Life Sciences Pharmacologic Treatment of Complications

134-LB 136-LB Effect of Metformin on Insulin Sensitivity in Overweight Adolescents Low-Carbohydrate Diet Reduces the Effect of Glucagon on Glucose with Type 1 Diabetes (T1D) Recovery during Mild Hypoglycemia in Patients with Type 1 Diabetes

KRISTEN J. NADEAU, KELLEE M. MILLER, MELANIE CEE-GREEN, EVA TSALIKIAN, AJENTHEN RANJAN, ISABELLE STEINECK, SIGNE SCHMIDT, CAMILLA DAMM- MICHAEL TANSEY, JULIE COFFEY, EDA CENGIZ, WILLIAM V. TAMBORLANE, FRYDENBERG, STEN MADSBAD, JENS JUUL HOLST, KIRSTEN NØRGAARD, Hvi- TAMARA S. HANNON, LARRY A. FOX, BRANDON NATHAN, INGRID LIBMAN, dovre, Denmark, Copenhagen, Denmark Aurora, CO, Tampa, FL, Iowa City, IA, New Haven, CT, Indianapolis, IN, Jacksonville, FL, Dual hormone pump treatment with insulin and glucagon reduces risk of Minneapolis, MN, Pittsburgh, PA mild hypoglycemia. However, the efficacy of glucagon to elevate plasma glu- A large randomized control trial (RCT) (N=140) of overweight youth with cose (PG) when liver glycogen stores are partly depleted is unknown. This POSTERS T1D showed no improvement in HbA1c with Metformin use over 6 months but two-way crossover randomized clinical study investigated the effect of low- Therapeutics modest decrease in total daily insulin (TDI) dose and a reduction in BMI and dose glucagon to restore PG from mild hypoglycemia in patients on high (HCD) Clinical Diabetes/ % body fat. We performed an ancillary study to the larger RCT to determine (>250 g daily) vs. low (LCD) carbohydrate diets (<50 g daily). if Metformin improves insulin sensitivity (IS) in overweight youth with T1D Ten patients with insulin pump treated type 1 diabetes (median±SD age assessed by hyperinsulinemic euglycemic clamp. Thirty seven overweight 48±10 years, HbA1c 6.9±2.7%, and BMI 24.5±1.8 kg/m2) randomly completed adolescents from 7 pediatric diabetes centers (mean age 15.7 years [range 1 week of HCD and 1 week of LCD. Each week ended with a study day, where 12-19 yrs], mean T1D duration 7.0 years [range 1-14 yrs] 54% female, 78% fasting patients received sc. insulin estimated to reduce PG to 54 mg/dl. non-Hispanic white, mean HbA1c 8.8%, mean BMI 97th%tile, mean total daily When PG reached 70 mg/dl, 100 µg glucagon was given sc. followed by 500 insulin dose 1.1 units/kg/day) were randomly assigned to Metformin (MET; µg after 2 hours. N=19) (up to 2000 mg/day) or placebo (PLB; N=18) and underwent a 2 hour 80 The PG time course after glucagon differed between HCD vs. LCD (Figure, mU/m2/min hyperinsulinemic euglycemic clamp and DEXA scan at baseline p=0.003). HCD had higher mean±SE peak rises after both first (48.6±23.4 vs. and 13 weeks. Treatment group comparisons were performed for the change 34.2±21.6 mg/dl, p=0.006) and second glucagon bolus (97.2±25.2 vs. 73.8±12.6 from baseline to 13 weeks in glucose infusion rate adjusted for blood glucose mg/dl, p=0.04). HCD had higher PG 2 hours after first (72.0±5.4 vs. 54.0±3.6 (BG) per kg of body weight (“GIR”; mg/kg/min) and GIR adjusted for BG per mg/dl, p=0.02) and second bolus (147.6±9.0 vs. 106.2±10.6 mg/dl, p=0.02). DEXA fat-free mass (“GIR lean”; mg/lean kg/min) in linear mixed models with We conclude that LCD may impair the treatment effect of glucagon on mild adjustment for gender and baseline value. The average steady-state BG from hypoglycemia. Thus, patient’s carbohydrate intake should be assessed when the baseline and 13- week euglycemic clamps was 99 and 95 mg/dl in MET low doses of glucagon are used in open loop and maybe also in closed loop and 96 and 97 mg/dl in PLB. Mean baseline GIR and GIR lean was 4.8±2.8 and settings. 8.2±4.0 in MET and 5.0±2.4 and 8.5±3.7 in PLB. At 13 weeks, a significant Figure. improvement was observed in the MET vs. PLB group for GIR (mean change +0.5 vs. -0.6; mean adjusted difference [95% confidence interval (CI)] 1.1 [0.0 to 2.2], P=0.04) and for GIR lean (mean change +0.7 vs. -1.1; mean adjusted difference [95% CI], 1.8 [0.0 to 3.6], P=0.04). Metformin resulted in improvement in IS in overweight adolescents with T1D. Further analysis of glucose and glycerol stable isotope data will determine tissue-specific changes in IS. Supported By: JDRF (17-2013-506)

135-LB Adverse Renal Outcomes among Sodium-Glucose Cotransporter 2 (SGLT2) Inhibitors: A Comprehensive Network Meta-analysis of Ran- domized Controlled Trials HUILIN TANG, DANDAN LI, JINGJING ZHANG, ZHENWEI FANG, TIANSHENG WANG, YIQING SONG, Indianapolis, IN, Beijing, China, Philadelphia, PA This network meta-analysis aimed to evaluate the comparative effect of sodium-glucose cotransporter 2 (SGLT2) inhibitors on adverse renal outcomes in patients with type 2 diabetes mellitus (T2DM) by synthesizing both direct and indirect evidence from randomized controlled trials (RCTs). Electronic data- bases (PubMed, EMBASE, and CENTRAL) were systematically searched up to January 27, 2016. Primary outcomes included a composite of renal impairment/failure events or events of acute renal impairment/failure as reported by the studies. A random-effects network meta-analysis was carried out to Supported By: Novo Nordisk Foundation calculate the odds ratio (OR) with 95% confidence interval (CI). The comparative effects of SGLT2 inhibitors were ranked with SUCRA probabilities. In total, 39 eligible RCTs (11 canagliflozin, 15 dapagliflozin, and 13 empagliflozin) involving 31,096 patients were included in the main analysis. Dapagliflozin was significantly associated with an increased risk of a composite of renal impairment/failure adverse events as compared with placebo (OR 1.77, 95% CI 1.34 to 2.34). Empagliflozin seemed to have a lower risk than dapagliflozin (OR 0.41, 95% CI 0.30 to 0.57) or canagliflozin (OR 0.51, 95% CI 0.29 to 0.89).

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LB37 Clinical Therapeutics/New TechLatenolo Breagy—Pkinghar Abstractsmacologic Treatment of Complications

137-LB including reduced compliance with 3 doses and reduced efficacy in type 2 dia- SGLT2 Inhibitors Ameliorate Hepatic Steatosis Independently of Vis- betics. HEPLISAV-B combines recombinant hepatitis B surface antigen (20μg) ceral Fat Reduction or Increase in Basal Metabolic Rate in Japanese with an oligonucleotide toll-like receptor 9 (TLR9) agonist as an adjuvant. A Patients with Type 2 Diabetes phase 3 study evaluated the safety and immunogenicity of HEPLISAV-B com- MASATAKA KUSUNOKI, DAISUKE SATO, YUKIE NATSUME, TAKAO NAKAMURA, pared with Engerix-B. In a randomized, multicenter, observer-blinded study, YOSHIHARU OSHIDA, Nagoya, Japan, Yamagata, Japan immunogenicity at week 28 was a co-primary endpoint in type 2 diabetics who In addition to the beneficial effects of SGLT2 inhibitors on glycemic con- received either 3 doses of Engerix-B (n=321) at Weeks 0, 4 and 24 or 2 doses trol in type 2 diabetic patients, it has been reported that these compounds of HEPLISAV-B (n=640) at weeks 0 and 4 (plus placebo at week 24). Among may contribute to amelioration of hepatic function in diabetic model rodents the 961 adult diabetics in the per-protocol population, age, sex and race were and diabetic patients. Regarding the mechanisms of improvement of hepatic generally similar across both treatment groups. In both groups 2/3 of sub- function, it is suggested that SGLT2 inhibitors may reduce lipogenesis and/or jects had diabetes for 5 or more years. The proportion of protected subjects enhance lipid oxidation in the liver. However, it has not been clear if SGLT2 (protected=anti-hepatitis B antibody titers ≥ 10mIU/mL) in the HEPLISAV-B inhibitors alter parameters of hepatic function in type 2 diabetic patients group at week 28 was 90.0% (95% CI: 87.4%, 92.2%) vs. 65.1% (95% CI: 59.6, complicated with hepatic steatosis and if the effects of these inhibitors are 70.3) in the Engerix-B group. The difference between the groups, 24.9% (95% related to body fat accumulation and oxidation. CI: 19.3%, 30.7%), was statistically significant. The safety profile including the In this study, we administered luseogliflozin (2.5 mg/day), a novel compound incidence of immune-mediated adverse events was similar in both treatment or dapagliflozin (5 mg/day) to 115 Japanese patients with type 2 diabetes groups. HEPLISAV-B protected a statistically significantly higher proportion complicated with hepatic steatosis for 6 months. Before the start of admin- of subjects with diabetes against hepatitis B when compared with Engerix-B. istration, hepatic steatosis was confirmed with hepato-renal echo contrast. HEPLISAV-B may be able to address a significant unmet medical need in dia- At the end of the administration period, body weight (BW), visceral fat area betics who should be routinely vaccinated against hepatitis B. (VFA), basal metabolic rate (BMR), serum lipids, parameters of hepatic function (serum AST, ALT and γ-GTP levels), and hepatic steatosis were compared 140-LB with them measured before the administration. Pioglitazone Associated Pedal Edema Resolved by Adding Sodium Six-month after the treatment, BW, VFA and hepatic steatosis were reduced Glucose Co Transporter 2 Inhibitor POSTERS Therapeutics (BW and VFA: P<0.01, respectively) while BMR was raised (P<0.05). Serum triglyc- ASHISH GAUTAM, PRABHAT KUMAR AGRAWAL, PRASHANT PRAKASH, DAYA

Clinical Diabetes/ eride was also reduced (P<0.05) whereas HDL cholesterol was slightly elevated KISHORE HAZRA, Agra, India (P<0.01). AST, ALT and γ-GTP were significantly lowered (AST: P<0.05; ALT and This study was initiated after observation from two cases. Use of Piogli- γ-GTP: P<0.01, respectively). However, the change of these serum parameters tazone (PGZ), a novel insulin sensitizer is often limited because of its com- indicating hepatic function did not correlate with the change of VFA or BMR. mon side effect, i.e., fluid retention and pedal edema. This study included 62 These results suggest that SGLT2 inhibitors improve hepatic function in subjects (30 study cases and 32 comparators). These patients were, who had type 2 diabetic patients complicated with hepatic steatosis and that the developed pedal edema after PZG (15/30 mg daily) based regimen started improvement may be taken place independently of the change in VFA or BMR. irrespective of other oral hypoglycemic agents (OHA’s) or insulin prescribed for sugar control. Patients were randomized one to one between study cases 138-LB and comparators. Study cases were given Sodium-glucose co-transporter 2 Liraglutide Protects against the Development of Atherosclerosis in (SGLT2) inhibitor (Canagliflozin) 100 mg once a day with individualized simul- Obese Pro-atherosclerotic LDLr-/- Mice taneous reduction of other OHA’s to avoid hypoglycemia. Monitoring of dia- GÜNAJ RAKIPOVSKI, BIDDA ROLIN, RIKKE KIRK, JANE LARSEN, ROBERT AUGUS- betic ketoacidosis was mandatory. Dose of PGZ not changed among cases. In TIN, LOTTE BJERRE KNUDSEN, Måløv, Denmark comparator group dose of PGZ was either reduced or completely withdrawn Recently, glucagon like peptide 1 therapy has been reported to have benefi- depending upon severity of edema. Both groups were followed for 4 weeks cial effects on cardiovascular outcomes beyond its well-known antidiabetic with subjective grade of edema and weight recorded before and after study and weight lowering effects in humans. In this study we evaluated the effect duration. 24 out of 30 study cases, whereas 12 out of 32 comparators showed of liraglutide in LDLr-/- mice on the development of atherosclerosis and inflam- complete remission of pedal edema. Fisher exact value calculated to be 0.0008 mation. Male LDLr-/- mice (6-8 wks, JAX, USA) on western diet (Research at P< 0.05. Average weight loss in 4 weeks of 30 cases was 3.8 Kg, whereas Diets, USA) were treated with vehicle (VEH) or liraglutide (LIRA) 1mg/kg, SC 1.6 Kg in control (Z-Score is -6.3668. The p-value is 0. The result is significant for 17 weeks (n=15-20/group). Plaque lesion area was quantified by the En at p≤ 0.05). Hypoglycemia experienced by 2 (6.66%) study subjects whereas Face method on a predefined section of thoracic aorta. Quantitative gene none from comparators. SMBG (self-monitoring of blood glucose) showed expression analysis was performed on aortic tissue applying the Nanostring elevated blood sugar levels in 5 (16.6%) study cases and 8 (25%) comparators. technology. Plasma cholesterol lipoproteins and triglycerides (TG) were deter- Besides this no other major side effects observed during study in both groups mined by HPLC. Body weight (BW) was measured daily. Data are presented as except one female who developed polyuria and urogenital infection in study mean±sem. The VEH group gained 65% in BW whereas the LIRA group gained group which resolved with oral antibiotics and antifungal. 17%, resulting in significant lower BW (VEH: 43.5±1.1g vs. LIRA: 30.9±0.9g; A judicious co-prescription of PGZ and SGLT2 inhibitor can avoid fluid over- p<0.0001). Treatment with LIRA resulted in a significant suppression of plaque load and pedal edema in diabetes mellitus. lesion development (VEH: 13±1.0% vs. LIRA: 2.8±0.9%; p<0.0001). LIRA also showed beneficial effects on plasma lipids resulting in significant reduction in 141-LB plasma TG (VEH: 11.5±0.7mmol/l vs. LIRA: 7.1±1.0mmol/l; p<0.0001), vLDL (VEH: Efficacy of Gastric Electrical Stimulation for Refractory Nausea in a 25.9±2.2mmol/l vs. LIRA: 9.6±2.4mmol/l; p<0.0001), LDL (VEH: 36.3±18.3mmol/l Large, Randomized Trial vs. LIRA: 18.3±2.1mmol/l; p<0.0001) and increase in HDL (VEH: 1.9±0.2mmol/l BRUNO GUERCI, BENOÎT COFFIN, NICOLAS MATHIEU, SÉBASTIEN FONTAINE, vs. LIRA: 3.5±0.2mmol/l; p<0.0001). The 10 most down regulated genes by LIRA STANISLAS BRULEY DES VARANNES, FRANK ZERBIB, ROBERT CALAZZO, JEAN- were, Interleukin-6, Matrix metalloproteinase 12 and 13, CD68, Cathepsin S, CHARLES GRIMAUD, FRANÇOIS MION, SAMY HADJADJ, CATHERINE PETIT, Neutrophil gelatinase-associated lipocalin, interleukin 1 Receptor Antagonist, LUCINE VUITTON, ALAIN ROPERT, ROMAIN ALTWEGG, PHILIPPE POUDEROUX, ETI- macrophage scavanger 1, serum amyloid A3 and secreted Phosphoprotein 1, ENNE DORVAL, MICHEL DAPOIGNY, BRUNO BONAZ, JEAN-MARC SABATE, PIERRE- predominantly genes related to inflammation. These data support the hypoth- YVES BENHAMOU, JEAN-LUC FAUCHERON, KA SLIM, GUILLAUME GOURCEROL, esis that treatment with liraglutide may beneficially affect atherosclerotic HÉLÈNE HANAIRE, ALFRED PENFORNIS, PHILIPPE DUCROTTÉ, Vandoeuvre lès changes in addition to potentially anti-inflammatory mechanisms. Nancy, France, Colombes, France, Grenoble, France, Toulouse, France, Nantes, France, Bordeaux, France, Lille, France, Marseille, France, Lyon, France, Poitiers, France, Cor- 139-LB beil-Essonnes, France, Besançon, France, Rennes, France, Montpellier, France, Nimes, Phase 3 Trial of Two Doses of Investigational Vaccine HEPLISAV- France, Chambray-lès-Tours, France, Clermont-Ferrand, France, Rouen, France B™ Compared with Three Doses of Licensed Hepatitis B Vaccine Gastric electrical stimulation (GES) is a surgically implanted treatment ENGERIX-B® in a Subpopulation of Adults Aged 18-70 with Type 2 option for refractory gastroparesis. This trial assessed the symptomatic effi- Diabetes cacy of GES (ENTERRA®) in a large-scale multicenter double-blind cross-over SAM JACKSON, BILL HEYWARD, LALITH AKELLA, ROBERT JANSSEN, Berkeley, CA trial (ClinicalTrials.gov Identifier: NCT00903799). Diabetics are at higher risk of infection with hepatitis B and the CDC rec- Eligible patients were aged from 18 to 70 years, with chronic nausea and/or ommends routine vaccination. Existing vaccines have important limitations vomiting (>12 months) refractory to prokinetics/antiemetics either idiopathic,

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LB38 HealthLate Care Brea Delkingiver Ay—Ebstractsconomics

postsurgical or due to diabetes mellitus (DM), and Leading to weight loss or and defined using appropriate ICD codes. We studied the difference in pri- significant reduction of food intake. mary outcome by gender, race (white, black, Hispanic, other), income quartile After a first period of 4 months for assessment of the symptoms, patients and primary payer (Medicare, Medicaid, private, other) using Chi-Square were implanted and followed for 2 periods of 4 months with the device on ON test. Multivariate analysis was done using mixed effects logistic regression or OFF. The primary outcomes were the score of vomiting (0=several weekly analysis adjusting for age and a modified Charlson/Deyo comorbidity (C/D) vomiting to 4=no vomiting) and quality of life by GIQLI score. The secondary index. A total of 57,477 hospitalizations for primary outcome (53,078 HY and end-points were metabolic control, nutritional status, and gastric emptying 4,399 HO) were identified out of a total of 1,546,983 all-cause hospitalizations (GE). among diabetic individuals. The mean age was 65.35 ±15.18 yrs, out of which The analyzes were performed in intent to treat for 172 patients (W/ 58% were whites, 17% were blacks whereas 52% were females. On bivari- M=66/34%; 72 DM, 100 non-DM patients): aged=45±12 yrs, BMI=22.7±5.3 kg/ ate analysis, hospitalization rates were higher in males vs. females (3.9% m2, symptoms lasting=5.1±5.9 yrs (vomiting score=0 [0-2], GIQLI=59.7±19), GE vs. 3.5%; p <0.01), blacks vs. whites (5.6% vs. 3.1%; p <0.01), lowest income delayed (80%), normal (20%). Diabetes duration=21±10 yrs, HbA1c=8.5±1.7%, quartile vs. highest quartile (4.2% vs. 2.9%; p <0.01) and having Medicaid/ rate of severe hypoglycemia=4.9±6.5 events/6M. Of the 172 implanted other vs. Medicare/private insurance (7.9%/11.7% vs. 1.8%/4.57%; p <0.01). patients, 149 were evaluated, no carry-over effect was observed. The These relationships were preserved after adjusting for age and C/D index in improved score vomiting was greater during ON vs. OFF (median score of multivariate analysis. Also, there was no multicollinearity in the regression vomiting: 2 [1 monthly vomiting]) vs. 1 [at least 1 weekly vomiting], p<0.001). model (Variance Inflation Factor < 2.5). We conclude that males, blacks, lower Clinical benefit was observed in both DM and non-DM populations, and the income quartiles and having non Medicare/non private insurance (i.e., Med- symptomatic effect of GES was greater in case of gastroparesis (p=0.009) icaid or other insurance) are independently associated with a higher rate in than in normal GE (p=0.056), while GE rate and GICLI score were not different hospitalizations for acute HY/HO complications among diabetic patients in between the 2 periods. No significant improvement in metabolic control was the U.S. reported. Number of drop-outs (23 patients), 1 pocket infection. In conclusion, the GES reduces the frequency of vomiting in patients with gastroparesis, 144-LB with or without DM, and refractory to all medications. Impact of a Patient Engagement Program on Patients with Type 2 Dia- betes from a Patient-Centered Medical Home Model POSTERS MAZI RASULNIA, BILLY S. BURTON, RAYMOND J. SAPUTELLI, SANDI SELZER, Therapeutics

Health Care Delivery—Economics DHIREN PATEL, Birmingham, AL, Trenton, NJ Clinical Diabetes/ Patient Centered Medical Home (PCMH) has had great impact on improving 142-LB quality of care through better care coordination and clinician alignment. An Diabetes Boot Camp Reduces A1c and Health-Care Services Utiliza- area that has had little attention is the integration and impact of external tion coaching and engagement services into the workflow of PCMH practices. MICHELLE F. MAGEE, CARINE M. NASSAR, STEPHEN J. FERNANDEZ, DEBRA W. In this study we compared two groups of patients who participated in a THAYER, MIHRIYE METE, GRETCHEN YOUSSEF, Washington, DC, Hyattsville, MD remote behavioral counseling intervention for management of type 2 diabe- A 12 week diabetes “Boot Camp” intervention offers learner-centered sur- tes. The first group of patients were enrolled in the intervention through the vival skills education (SSE) and algorithm-driven DM medication titration by New Jersey Academy of Family Physicians (NJAFP) PCMH (n=64), and the Endocrinologist-supervised Certified Diabetes Educators (CDE). The program non-PCMH group of patients either self-enrolled in the intervention or were is offered at 5 Primary Care Practices to adults with uncontrolled type 2 dia- enrolled by their clinician (n=102). The inclusion criterion for each group was betes (A1c≥9% and ≥ 1 additional risk factor for poor outcomes). Consented an HbA1c of 6.5% or higher at enrollment. patients attend two 1:1 visits followed by virtual visits via telephone/texting. There was no statistically significant difference in HbA1c at baseline SSE is tailored to baseline DM knowledge and medication adherence deficits. (p=0.531) or graduation (p=0.341) or weight at baseline (p=0.821) or gradua- An FDA cleared cellular-enabled blood glucose (BG) monitoring system (Tel- tion (p=0.777) between the PCMH group and non-PCMH group. However, both care BGM®) auto-transmits BGs to a provider dashboard in near-real-time. groups saw a statistically significant reduction of HbA1c (p<0.001) and weight The CDE reviews BGs and contacts patients at minimum weekly to discuss (p<0.001) through the intervention. Results suggest that, no matter the set- and make adjustments to DM medications and/or lifestyle, until glycemic tar- ting, a high-touch, patient centered engagement intervention is an effective gets are met. The patients then return to their PCP with a progress report. An solution for the management of type 2 diabetes. interim analysis of the first 81 patients (n=125) whom have completed the 6 Table 1. Results. month intervention has been conducted. Mean age is 57 + 9 yrs. All used the PCMH Group Non-PCMH Group p-value smart meter successfully and reported increased adherence with BG testing, n = 64 n = 102 knowing that a CDE was actively monitoring results. CDEs report that smart meter use facilitates timely BG management, including immediate inter- HbA1c Baseline 8.33% 8.49% 0.531 vention for significant hyper- and hypoglycemia, and saves time compared HbA1c Graduation 7.30% 7.14% 0.341 to traditional collating of BG. Mean A1c was 11.4% at baseline and 8.3% at Weight (lbs.) Baseline 219 220 0.821 3 months (p<0.001), representing a -3.1% absolute reduction. At 6 months, Weight (lbs.) Graduation 213 215 0.777 urgent PCP visits were reduced by 92% (p=0.005); missed days from work or usual activities by 77% (p=0.01); ED visits by 89% (p=0.002) when compared to the 6 months prior to baseline. The number of hospitalizations was low overall, with an 88% reduction at 3 months (p=0.03) and a 66% reduction at 6 145-LB months (p=0.13). This preliminary evidence demonstrates a significant impact Improving Glycemic Excursions in Nine Hospitals on glycemic control and healthcare utilization measures as the result of a GREG MAYNARD, JANET HOLDYCH, HEATHER KENDALL, TOM HOAG, KAREN concise, focused DM education and medication management intervention. HARRISON, Sacramento, CA, Pasadena, CA, Rancho Cordova, CA, Woodland, CA, Redwood City, CA Non-critical care adult inpatients from 9 Northern California hospitals 143-LB with ≥ 4 point-of-care (POC) blood glucose (BG) readings over ≥2 days were Sociodemographic Factors Predict Hospitalizations for Uncontrolled included in a Dignity Health effort to improve hyper- and hypoglycemia. Pro- Hyperglycemia and Hypoglycemic Complications among Diabetics in tocols for insulin management and hypoglycemia prevention were piloted at the U.S. one facility and rolled out to the cohort. Cohort hospitals benefitted from stan- KRISHMITA SIWAKOTI, SMITH GIRI, DIPEN KADARIA, SMRITI MANANDHAR, dardized order sets, education, mentoring from experts, feedback of metrics, Memphis, TN, Milwaukee, WI and measure-vention (coupling measurement of patients “off protocol” with Prominent socio-demographic disparities exist in the receipt of healthcare concurrent intervention to correct lapses in care). Balanced glucometric goals services in the United States. We aimed to examine the impact of socioeco- for each hospital were individualized to improve performance by 10-20% from nomic factors on hospitalizations for uncontrolled hyperglycemia (HY) and baseline or achieve top performance derived from Society of Hospital Medi- hypoglycemia (HO) among diabetics in the U.S. We utilized the Nationwide cine (SHM) benchmarking studies. (See Figure) The day-weighted mean (DWM) Inpatient Sample (NIS) from the years 2009-2011 to identify all adult hospi- blood glucose (BG) for the cohort improved by 11.4 mg/dL [CI 11.0 - 11.8]; all 9 talizations among patients with type 1/2 diabetes mellitus (DM) in the U.S. sites improved. Eight of 9 sites reduced severe hyperglycemic days, and the Hospitalization rate for HY and HO complications was the primary outcome

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LB39 HealthLate Care Brea Delkingiver Ay—Ebstractsconomics

percent of patient-days with any BG > 299 mg/dL for the total cohort improved questionnaire. Using NAFLD patients, we calculated impact scores and per- from 11.6% to 8.8% (RR 0.76 [95% CI 0.74 - 0.78]). The percent of patient-days formed factors analysis to reduce the number of items and place the items with any BG < 70 mg/dL remained unchanged at 3.6% for the cohort, and 8 into different domains. Each item was structured and scored on a Likert scale of 9 sites either reduced hypoglycemia by 20% or had rates under SHM best of 1-7. The resulting CLDQ-NAFLD was pre-tested to reduce redundancies. quartile rates. We demonstrated multi-hospital improvements in glycemic Psychometric testing is being carried out. control and severe hyperglycemia without significant increases in hypoglyce- Results: The initial questionnaire contained 75 items and was administered mia with the use of toolkits and metrics from SHM. to NAFLD patients (54.1±14.3 years old, 36% male, 72% obese, 32% with Figure. Glycemic Control Results at 9 Hospitals: 2011 vs. 2014. type 2 diabetes, 20% cirrhotic). After item reduction step, 38 items remained. Confirmatory factor analysis found that 98.7% of variance in these items would be explained by 6 factors with 25 items overlapping with the original CLDQ were found to be loading to these factors. After exclusion of duplicate items, a final CLDQ-NAFLD instrument with 36 items and 6 domains was developed: abdominal symptoms (rotated factor loadings 0.37-0.82, Cronbach alpha=0.88), activity (0.40-0.59, alpha=0.88), emotional (0.30-0.86, alpha=0.94), fatigue (0.24-0.82, alpha=0.93), systemic symptoms (0.29-0.81, alpha=0.80), and worry (0.68-0.92, alpha=0.97). CLDQ-NAFLD was subsequently pre-tested in 12 NAFLD patients (33% male, 25% cirrhotic, 25% with history of diabetes) to improve item clarity. CLDQ-NAFLD has excellent internal consistency (Cron-

bach alpha=0.80 to 0.94), content validity and face validity. Conclusion: CLDQ-NAFLD is a disease-specific HRQL instrument useful for clinical trials of patients with NAFLD and T2DM.

147-LB Telephone-delivered Behavioral Skills Intervention for African POSTERS Therapeutics Americans with Type 2 Diabetes

Clinical Diabetes/ LEONARD E. EGEDE, JONI S. WILLIAMS, DELIA C. VORONCA, JENNIFER A. CAMP- BELL, MULUGETA GEBREGZIABHER, CHERYL P. LYNCH, Charleston, SC Introduction: Diabetes disproportionately impacts African Americans (AA). We aimed to test the efficacy of a combined telephone-delivered education and behavioral skills intervention in AA with diabetes using a 2x2 factorial design. Methods: We randomized AA adults with baseline hemoglobin A1c (HbA1c) ≥9% to one of four groups: 1.) knowledge only (KN), 2.) skills training only (ST), 3.) combined knowledge and skills training (CI), or 4.) usual care (UC). Intervention groups received 30 minutes of education, skills training or both, while control group received general health education all via telephone. Par- ticipants were assessed at baseline, 3 months, 6 months, and 12 months. The primary outcome was HbA1c at 12 months post-randomization. Results: We screened 443 patients and randomized 255 participants to UC (64 [25%]), KN (63 [25%]), ST (65 [25%]), or CI (63 [25%]). There were 216 (85%) at 3 months, 194 (76%) at 6 month and 187 (73%) at 12 months with complete measurements. Based on intent-to-treat population after multiple imputation, the analysis of covariance with baseline HbA1c as the covariate showed that intervention groups did not differ significantly from the UC (KN: 0.49, p=0.123; ST: 0.23, p=0.456; CI: 0.48, p=0.105). Longitudinal mixed effects analysis showed that there was a significant decline in HbA1c over time for all treatment groups (-0.07, p<0.001). However, the rates of decline for the intervention groups were not significantly different from the usual care group (KN: 0.06, p=0.052; ST: 0.02, p=0.448; CI: 0.05, p=0.062). The satisfaction with the intervention and the perceived benefit of intervention were high for all treatment groups. Conclusions: For AA with T2DM, combined education and skills training did not achieve statistical significance compared to usual care, education alone, or skills training alone. These findings show that knowledge and skills training alone are not sufficient for achieving glycemic control at 12 months in AAs with poorly controlled diabetes. Supported By: National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases (R01 DK081121)

148-LB Field Study Comparing Siemens DCA 2000 A1c Test to ClearPath DS-120 Lens Fluorescence Biomicroscope in a Pharmacy Setting Supported By: Gordon and Betty Moore Foundation SHARDENDU MISHRA, KEITH IGNOTZ, PAUL WILLIAMS, RUDI SCHNEID, B. LAUT- ERBACH, San Diego, CA, Munich, Germany 146-LB To assess receptivity of ClearPath DS-120 Lens Fluorescence Biomicro- Development of a Validated Disease-specific Health-Related Quality scope (Freedom Meditech, San Diego, CA) as a screening test for uncontrolled (HRQL) Instrument for Patients with Nonalcoholic Fatty Liver Dis- glucose in comparison to the HbA1c, a field study was conducted in a phar- ease (NAFLD): CLDQ-NAFLD macy in Germany. Two devices were used, a point-of-care Siemens DCA 2000 ZOBAIR YOUNOSSI, MARIA STEPNAOVA, SHARON HUNT, Washington, DC HbA1c test and a ClearPath DS-120 which provides lens autofluorescence val- Patients with T2DM and NAFLD can have progressive course making ues using a non-invasive 6 second light-based scan of the eye. The all-comers them candidates for clinical trials. Integrating clinical with HRQL outcomes study included 29 subjects who opted-in to undergo both the ClearPath DS-120 is increasingly important. Our aim was to develop a disease-specific HRQL and the HbA1c tests. 5 subjects tested at or above ADA’s diabetes diagnosis instrument useful in efficacy trials of NAFLD. cutoff of 6.5% with HbA1c test. 4 out of 5 of these subjects showed elevated Methods: We used a variety of sources (available generic and liver-specific autofluorescence on the ClearPath test, which uses age matched cutoffs, instruments, interviews, expert input and focus groups) to develop initial an 80% sensitivity in reference to the A1c. HbA1c identified 24 subjects as

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LB40 HealthLate Care Brea Delkingiver Ay—Ebstractsconomics

nondiabetic, A1c < 6.5%, and 23 out of these 24 were below the autofluo- the RSA. By applying the RSA, 76.4% of the patients with STDR would have rescence cutoffs on ClearPath, a specificity of 96%. A1c and Fasting Plasma been identified before the program finished screening half of all patients. In Glucose tests have large uncertainties, as shown by NIH Guidance Publica- Cohort B, there were 105 patients with STDR (8.9% of 1,178). Of these, 88.6% tion, and low sensitivities (42.5%, 50% respectively), necessitating two tests (n=93) would have been similarly identified by the RSA. We conclude that a to improve screening accuracy. Using ClearPath DS-120 test for screening will simple risk-stratification algorithm can be successfully used to better identify improve receptivity due to its non-invasive nature, time efficiency, and imme- unscreened low-income, minority patients at high risk for STDR and blind- diate results. Lack of medical waste eliminates disposal needs, creating new ness, and may be used to prioritize early DR screening and lower their risk channels for opportunistic screening. Higher receptivity and new screening for blindness. opportunities will lead to earlier detection of diabetes and earlier interven- Supported By: California Community Foundation tion, in-turn reducing complications and saving healthcare costs. In conclusion, the autofluorescence values screen for the risk of diabetes concordant 151-LB with the results of the HbA1c test, thus the ClearPath DS-120 can be a useful Personalized Diabetes Management screening test for diabetes risk. DIMITRIS BERTSIMAS, ALEXANDER M. WEINSTEIN, DAISY ZHUO, NATHAN KAL- LUS, Cambridge, MA 149-LB Current clinical guidelines for management of type 2 diabetes mellitus HbA1c, Exercise, Depression, and Income Are Significant Determi- (T2DM) do not differentiate based on patient-specific factors. We present a nants of Health-related Quality of Life in Urban African American data-driven algorithm for personalized diabetes management that improves Men with Prediabetes and Vitamin D Insufficiency health outcomes relative to the standard of care. We model outcomes under HENRY J. ZELADA, ARFANA AKBAR, DEEPIKA KHANNA, LEONE STEFANO, 12 pharmacological therapies based on electronic medical records (EMR) for VIKRAM SINGH, BHARATHI REDDIVARI, SAMANTA LARIOSA, EN SEN TEN, RAJ 10,806 T2DM patients from Boston Medical Center. At each patient visit, we PATEL, BHARATHI REDDIVARI, ELENA BARENGOLTS, Chicago, IL analyze the range of outcomes under alternative care using k-nearest neigh- Adults at risk for type 2 diabetes (DM2) are likely to have comorbid conditions bor analysis. The nearest neighbors are chosen to maximize similarity on indi- affecting health-related quality of life (HRQoL). There are no studies dedicated vidual patient characteristics and medical history that are most predictive to HRQoL in AAM with prediabetes. The aim of this study was to examine the of health outcomes. The recommendation algorithm prescribes the regimen POSTERS independent effects of socioeconomic status (SES), psychological, and clinical with best predicted outcome provided the improvement of switching regi- Therapeutics determinants of health on HRQoL. Data for this cross-sectional study were mens exceeds a threshold. We evaluate the effect of recommendations on Clinical Diabetes/ obtained from a baseline visit for AAM (n=184) participating in DIntervention data not used for training the algorithm. Among the 48,140 patient-visits in at Veteran Administration trial (DIVA,NCT01375660). The subjects were urban the test set, the algorithm’s prescription mirrors the standard of care in 68.2% AAM, age 35-80 years, overweight or obese with prediabetes (A1c 5.7-6.4%) of visits. For patient-visits in which it differs from the standard of care, the and vitamin D insufficiency (25OHD<30 ng/mL). The individual global indicator mean ± SE reduction in HbA1c is 0.44% ± 0.03% (p<<0.001) from 8.37% under of QoL was assessed by the CDC HRQoL-14 questionnaire. The SES included the standard of care to 7.93% under our algorithm. Our prototyped dashboard marital status, number of people in the household, income, and education. visualizing how the recommendation algorithm works for a single sample Health evaluation involved smoking, exercising, depression, Charlson-index, patient could be used by providers to inform decisions regarding diabetes age, BMI, HbA1c, glucose at 2-hours OGTT, C-peptide, 25OHD, PTH, and tes- management (Figure 1). tosterone levels. The stepwise forward selection regression analysis was Figure 1. used for statistical assessment. The results showed that the average age, BMI, 25OHD, and HbA1c were 59 years, 32 kg/m2, 14 ng/ml, 6.1%, respectively. In final adjusted models, significant associations for HRQoL included (OR, 95% C): HbA1c (OR 3.66, CI 1.28-10.99, p=0.013), depression (OR 2.73, CI 1.42-5.40, p=0.003), exercising (OR 0.51, CI 0.27-0.96, p=0.039), and income (OR 0.29, CI 0.06-1.09, p=0.023). In conclusion, HbA1c level, depression, exercising, and income were equally important determinants of HRQoL. Both, the ADA and VA recommend HbA1c as a screening test for DM2. The VA also includes depression assessment among standard preventive measures and has several programs for promoting healthy lifestyle (e.g., “MOVE” program). Measuring HbA1c in people at risk for DM2 offers an opportunity for promoting healthy lifestyle and improving HRQoL. Supported By: U.S. Department of Veterans Affairs

150-LB An Effective Risk-Stratification Algorithm to Prioritize Diabetes Reti- Supported By: National Science Foundation nal Screening in Low Income, Minority Communities LILIAN SERPAS, YANG LU, JOHANA MACIAS, PAULINE GENTER, DAVID CAMPA, 152-LB ELI IPP, Torrance, CA, Los Angeles, CA The Frequency of Hypoglycemia in Hospitalized Patients Treated Routine screening for diabetic retinopathy (DR) is a cornerstone of second- with Insulin Increases Overall Costs Associated with Hospitaliza- ary prevention in people with diabetes because treatment of sight-threaten- tion and Length of Stay ing DR (STDR) - if recognized early enough - is effective in preventing visual JOSEPH ALOI, JAGDEESH ULLAL, RAYMIE MCFARLAND, AMY HENDERSON, Win- loss. Yet diabetes remains the single most common cause of blindness in the ston-Salem, NC, Norfolk, VA, Waltham, MA, Greenville, SC working-age population in the United States. Low DR screening (DRS) rates Hospital associated hypoglycemia is thought to drive inpatient associated account for this in part, and are especially prevalent in low-income minorities. complications and therefore cost, but little data exists on the actual financial To improve DRS in this population we developed a risk-stratification algorithm implications associated with inpatient hypoglycemia. (RSA) to identify patients at high risk for STDR and to prioritize DRS based on The aim for this study was to examine the association of incidence and risk. The algorithm was developed with patient registry data in Clinic 1, and severity of hypoglycemia for patients prescribed insulin during a hospitaliza- predicted STDR risk in Clinic 2, both clinics serving primarily minority patients tion with length of stay (LOS) and overall cost of the inpatient stay. in low-income areas of Los Angeles County. In Clinic 1, we used readily avail- This study evaluated approximately 44,400 patients admitted to an aca- able clinical data (age, sex, albumin-creatinine ratio, A1c, insulin use status) demic medical center during a 1-year period with a diagnosis of diabetes to develop an RSA to predict STDR in 752 patients with diabetes who had and who were prescribed insulin during hospitalization. Data analysis was routine DRS (% STDR = 13.9). The area under the Receiver Operating Charac- abstracted to compare LOS and overall cost of inpatient stay for patients who teristics curve was 79.8% with sensitivity being 69.2% and specificity 79.0%. were on insulin and experienced a significant hypoglycemic event (SHE: BG < We then applied the RSA to two retrospective validation cohorts in Clinic 2 50; n=387) to patients that did not experience significant hypoglycemia during to determine its effectiveness in identifying patients at high risk for STDR. the admission (n=44,000). Cohort A included 585 diabetic patients who underwent routine DRS. Fifty- As a group patients with SHE had increased LOS (12.3 vs. 4.3 days) and five of them (9.4%) had STDR, many of whom were ranked as high risk by higher overall costs ($83,000 vs. $29,700) compared to patients with diabetes

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LB41 PediatriLcsate—O Breabeskingity a nAbstractsd Type 2 Diabetes

treated with insulin without a SHE. Frequency of hypoglycemia was also asso- gave for not referring a patient for testing were lack of insurance coverage for ciated with increasing costs and LOS such that more than 3 SHE increased genetic testing (76%), uncertainty regarding which genes to test (32%), and LOS an additional 4 days (14.4 days) and increased associated costs for the uncertainty regarding the process for ordering genetic testing (28%). While admission an additional $27,000. the low response rate limits generalizability, our results suggest that physi- Patients with an admission diagnosis of diabetes treated with insulin dur- cians would benefit from increased knowledge of MODY. Lack of insurance ing hospitalization that experience at least one SHE have higher associated coverage for genetic testing is also a significant barrier, contributing to con- costs of hospitalization and LOS compared to similar patients without a SHE. tinued misdiagnosis of MODY 42 years after its initial description. Each incremental SHE increased cost by ~ $7,000 (2 SHE: $83,000, 3 SHE: $103,000, 4 SHE: $110,000, and > 4 :$117,000). These data support an association between inpatient hypoglycemia and Pediatrics—Obesity and Type 2 Diabetes increased costs of care mostly attributable to increasing LOS. Further prospective studies are needed to further clarify the association and identify 155-LB strategies to prevent hypoglycemia and possibly lower costs. Arterial Stiffness: Relationship to Diabetes Treatment and Glyce- mic Control in Adolescents with Type 2 Diabetes (T2D) in the TODAY 153-LB Clinical Trial Sepsis-related Dysglycemia: Can a Computerized IV Insulin Algo- AMY S. SHAH, LAURE EL GHORMLI, FIDA BACHA, SAM S. GIDDING, DAN HALE, rithm Improve Glycemic Control, Reduce Hypoglycemia, and Reduce NATASHA LEIBEL, LORRAINE E. KATZ, KRISTEN J. NADEAU, JEANIE B. TRYG- 30-Day Hospital Readmissions? GESTAD, ELAINE URBINA, Cincinnati, OH, Rockville, MD, Houston, TX, Wilmington,

JOSEPH ALOI, RAYMIE MCFARLAND, ROBBY BOOTH, AMY HENDERSON, Winston- DE, San Antonio, TX, New York, NY, Philadelphia, PA, Aurora, CO, Oklahoma City, OK Salem, NC, Waltham, MA Youth with T2D have increased arterial stiffness compared to their lean and Dysglycemia has been proven to have a negative impact on patient out- obese peers (1). Whether this increase in arterial stiffness is influenced by comes and hospital mortality. Many acute illnesses can result in stress hyper- prior diabetes treatment regimen or glycemic control is not known. glycemia, even for patients without diabetes. Sepsis is such an illness, and is We measured femoral, carotid, and foot pulse wave velocity (PWV) and one of the leading causes of in-hospital mortality. The aim of this retrospec- augmentation index (AIx) by Sphygmocor and brachial distensibility (BrachD) POSTERS Therapeutics tive study is to determine if patients experiencing sepsis-related dysglycemia by DynaPulse in 453 TODAY participants (age 20.8 ± 2.5 years, T2D duration Clinical Diabetes/ treated with Glucommander, a computerized insulin dosing algorithm, have 7.6 ± 1.5 years, 36.4% male, BMI 36.7 ± 8.2 kg/m2) 7 years post-randomization. different outcomes compared to patients treated with standard insulin pro- Arterial stiffness measurements in TODAY youth were compared to published tocols and order sets. data for nondiabetic obese and lean controls (1). We assessed whether dia- 340 patients with a diagnosis of sepsis were treated with Glucommander betes treatment (Metformin alone, Metformin + rosiglitazone or Metformin + (GM) IV or traditional IV insulin protocols (NonGM) for dysglycemia and were intensive lifestyle intervention) or glycemic control over time (A1c area under evaluated for differences in 1.) % of blood glucose (BG) in target glucose range the curve (AUC) adjusted for time in the study) were associated with arterial of 70-180 mg/dL 2.) % of Mild, Moderate and Severe Hypoglycemia (<40, <50, stiffness. <70 mg/dL, respectively) 3.) Patient Days with Mild, Moderate and Severe Youth with T2D had significantly increased arterial stiffness compared to Hypoglycemia (<40, <50, <70 mg/dL, respectively) and 5) 30-day hospital read- lean (all measures) and obese controls (AIx and PWV radial) (Table). Arterial missions. stiffness did not differ by diabetes treatment group. Lower A1c AUC was Patients on GM had a higher % in target range with 72% vs. 61%, a lower associated with lower PWV radial (r=0.13, p<0.0023) and PWV foot (r=0.19, % of BG less than 70 mg/dL at 0.51% vs. 1.88% and a lower severe hypogly- p=0.0080). cemia % of BG with GM at 0.0% vs. 0.3%. Days with hypoglycemia <70 mg/ These data suggest that improving glycemic control, a modifiable cardio- dL was lower with GM at 5.2% vs. 6.2% and days with severe hypoglycemia vascular risk factor, may be important to reduce vascular stiffness in youth <40 mg/dL was also lower with 0.0% for GM and 2.3% for NonGM. Readmis- with T2D. sions were very low in both groups with GM having 0 patients and NonGM Table. only having 5. Glucommander achieved a higher % of patients in target with less mild Arterial Stiffness Indicates Lean Obese TODAY p-value P value and severe hypoglycemia compared to traditional IV protocols. More prospec- Measurement worse Controls Controls T2DM compared compared tive studies are needed to analyze the impact on LOS and Readmissions for stiffness (n=241)* (n=241)* (n=453) to lean to obese patients with sepsis treated with IV insulin using standard insulin protocols PWV (m/s) femoral Higher 5.4 (0.7) 6.3 (1.1) 6.4 (1.5) P=0.0001 P=ns compared to computerized insulin algorithms. PWV (m/s) radial Higher 7.4 (1.1) 7.3 (1.0) 7.8 (1.3) P=0.0001 P=0.0001 PWV (m/s) foot Higher 8.0 (1.2) 8.1 (1.4) 8.4 (2.5) P=0.0228 P=ns 154-LB Augmentation index (%) Higher -0.5 (10.8) 2.7 (11.6) 8.3 (11.3) P=0.0001 P=0.0001 Maturity-Onset Diabetes of the Young (MODY) Remains an Elusive BrachD (mm/mmHg) Lower 6.97 (1.19) 5.51 (1.04) 6.06 (1.18) P=0.0001 P=0.0001 Diagnosis for Physicians ROCHELLE N. NAYLOR, JAZZMYNE MONTGOMERY, KATHERINE LINDAUER, SIRI Data are mean (SD). p-values from a 2-sample t-test comparing the mean ATMA W. GREELEY, LOUIS H. PHILIPSON, Chicago, IL of the lean and obese controls to the mean of the TODAY sample. *Lean Dominantly-inherited young-onset diabetes was described by Tattersall and obese controls from Reference (1) Urbina EM et al. J Hypertens. 2010 Aug;28(8):1692-8. in 1974, later termed MODY. The three commonly involved genes, HNF1A, HNF4A and GCK, were discovered between 1992 and 1996. Genetic testing for Supported By: National Institutes of Health MODY is available in multiple research and commercial laboratories. Correct diagnosis allows therapy based on the genetic cause and results in improved 156-LB glycemic control and appropriately decreased healthcare utilization. Despite Prevalence of Diabetes in U.S. Medicaid Pediatric Population, 2002- these described benefits, more than 80% of MODY goes unrecognized. We 2013 assessed MODY knowledge and experience with genetic testing for MODY YONG CHEN, TONGTONG WANG, R. RAVI SHANKAR, North Wales, PA, Rahway, NJ via a 42-item survey. This tool was distributed through a commercial e-mail Data on prevalence of type 1 (T1DM) and type 2 diabetes (T2DM) among listserv to physicians indicating practice in diabetes or endocrinology. The children covered by Medicaid are limited. This study estimated the preva- survey was distributed to 4,297 unique e-mails. However, e-mail open rate lence of T1DM and T2DM in the U.S. Medicaid pediatric population and com- was only 18%. 471 (11%) of openers accessed the survey link. In total, 125 pared to their counterparts covered by commercial insurance plans. Patients people completed the survey. 98% of responders had heard of MODY. Mean who were <18 years at first diagnosis of diabetes were identified from the score of MODY knowledge was 2.7 on a 1-4 Likert scale. 64% correctly identi- MarketScan Multi-State Medicaid Database from 2002 to 2013 (n=49637). fied sulfonylureas as first-line therapy for HNF1A-MODY. However, only 26% The overall and age-stratified prevalence of T1DM and T2DM are presented correctly responded that GCK-MODY does not need pharmacologic therapy below. Prevalence of T1DM in the Medicaid pediatric population is similar to outside of pregnancy, with 39% recommending various diabetes medications. that in the commercially insured population. However, prevalence of T2DM is Of the 78 physicians who had considered a diagnosis of MODY in any of their much higher in Medicaid and has increased significantly over time. This study patients, only 81% considered referral for genetic testing. Only 60% reported confirms that the higher rate of T2DM may relate to the socioeconomic status, successful referral for genetic testing. The most common reasons physicians race and other differences between these populations.

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LB42 PediatriLcsate—O Breabeskingity a nAbstractsd Type 2 Diabetes

Figure. Annual Prevalence of Pediatric Diabetes (Aged <18 Years), Mar- 158-LB ketScan Multi-state Medicaid Database and MarketScan Commercial Claims Use of TG/HDL Ratio and non-HDL Cholesterol to Identify Obese and Encounters Database (CCE), 2002-2013. White Youth with Nonalcoholic Fatty Liver ALEXIS NASR, SOJUNG LEE, SILVA A. ARSLANIAN, Pittsburgh, PA Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease in obese youth. We examined whether elevated fasting triglycerides to high- density lipoprotein cholesterol (TG/HDL) ratio and non-HDL-C are useful markers of NAFLD in youth. Participants included 52 obese white youth (BMI>95th percentile, 12-17 years) who had fasting plasma lipids and underwent proton magnetic resonance spectroscopy to quantify liver fat (LF). The abilities of TG/ HDL and non-HDL-C to predict NAFLD (LF ≥5%) were examined via logistic regression and receiver operating characteristic curve analyses. Despite similar age, BMI and total adiposity (%), youth with TG/HDL≥3 had a 2-fold higher LF (6.3 ± 1.4% versus 2.5 ± 0.5%, P<0.01) than youth with TG/HDL <3. Similarly, youth with non-HDL-C ≥120 mg/dL had a 3-fold higher LF (8.4 ± 1.9% versus 2.5 ± 0.4%, P<0.01) than youth with non-HDL-C <120 mg/dL. Both TG/HDL [odds ratio (OR): 1.97 (95% CI: 1.07-3.66)] and non-HDL-C [OR: 1.05 (95% CI: 1.01-1.09)] were Figure. Age-stratified Prevalence of Pediatric Type 2 Diabetes, MarketScan independent predictors of NAFLD after adjusting for gender, tanner stage and total adiposity. The area under ROC curve of TG/HDL and non-HDL-C for predict- Multi-state Medicaid Database, and MarketScan Commercial Claims and ing NAFLD was 0.73 (95% CI, 0.57-0.89, P=0.01) and 0.77 (95% CI, 0.60-0.94, Encounters Database (CCE), 2002-2013. P=0.004), respectively. TG/HDL and non-HDL-C are easily obtained markers in clinical settings and may help identify youth at high risk for developing NAFLD. Table. Characteristics of Participants Grouped by TG/HDL and Non-HDL Cholesterol (Mean ± SEM). POSTERS TG/HDL TG/HDL P Non-HDL-C Non-HDL-C P Therapeutics

<3 ≥3 <120 ≥ 120 Clinical Diabetes/ n 37 15 42 10 Age (years) 14.5 ± 0.2 14.8 ± 0.4 NS 14.5 ± 0.2 14.9 ± 0.5 NS BMI (kg/m2) 33.1 ± 0.7 34.4 ± 0.8 NS 33.1 ± 0.6 34.7 ± 0.7 NS Total adiposity (%) 43.1 ± 0.9 43.2 ± 1.3 NS 42.8 ± 0.8 44.7 ± 1.6 NS Liver fat (%) 2.5 ± 0.5 6.3 ± 1.4 0.003 2.5 ± 0.4 8.4 ± 1.9 0.001 ALT (IU/L) 19.3 ± 1.3 28.1 ± 4.1 0.005 19.5 ± 1.2 31.7 ± 5.7 0.002 AST (IU/L) 20.8 ± 0.7 24.3 ± 2.3 NS 20.7 ± 0.6 26.5 ± 3.2 0.02 Supported By: American Diabetes Association (7-08-JF-27 to S.L.); National Insti- 157-LB tutes of Health (5R01HL114857, 1R21DK083654-01A1, UL1RR024153, UL1TR000005); Menstrual Function in Girls with Youth-Onset Type 2 Diabetes (T2D) Children’s Hospital of Pittsburgh; Cochrane-Weber Foundation; Renziehausen Fund MEGAN M. KELSEY, BARBARA H. BRAFFETT, SONIA CAPRIO, MITCHELL GEFFNER, (to S.L.); U.S. Department of Defense (FA7014-02-2-001 to S.A.A.) LYNNE LEVITSKY, SIRIPOOM V. MCKAY, RACHANA SHAH, JENNIFER SPRAGUE, SILVA A. ARSLANIAN, Aurora, CO, Bethesda, MD, New Haven, CT, Los Angeles, CA, 159-LB Boston, MA, Houston, TX, Philadelphia, PA, St. Louis, MO, Pittsburgh, PA Surgical Therapy Is More Effective than Medical Therapy in the Little is known about the prevalence of menstrual dysfunction in girls with Treatment of Type 2 Diabetes (T2D) in Severely Obese Adolescents T2D. The prevalence of irregular menses in girls with T2D from the Treat- THOMAS H. INGE, LORI LAFFEL, TODD JENKINS, MARSHA MARCUS, NATASHA LEIBEL, ment Options for Diabetes in Adolescents and Youth (TODAY) study was MARY BRANDT, MORY HAYMOND, ELAINE URBINA, LARRY DOLAN, PHIL ZEITLER, determined at randomization. Demographics, metabolic characteristics, and Cincinnati, OH, Boston, MA, Pittsburgh, PA, New York, NY, Houston, TX, Aurora, CO sex steroid measures were compared between participants with regular (>5 Introduction: The relative risk and benefit of surgical treatment of T2D compared periods in the previous 6 mo.) and irregular menses (<3 periods in the previous to medical therapy has not been previously reported specifically for adolescents. 6 mo. AND menarche >1 yr prior to randomization). Menstrual history was by We compared change in T2D status and the frequency of hospital admission over self-report. All participants were taking Metformin. After excluding girls with 2 years among adolescents with T2D who were managed medically in the TODAY insufficient menstrual history data or using hormonal contraception, 278/452 study or with weight loss surgery in the Teen-LABS (TL) study. girls were included. Fasting glucose, lipids, and transaminases were mea- Methods: Analysis was performed using anthropometric and laboratory data sured at randomization. SHBG, estradiol, and testosterone (T) were measured from adolescents with T2D enrolled in the TL study (n=30), and a comparable group in a subset of the eligible girls (n=190). The prevalence of irregular menses of TODAY participants (N=63) with BMI >35 kg/m2. Frequency matching was used was high (n=54, 19%), with no differences in age (cohort mean ± SD=14.3 ± to ensure similarity of cohorts based on demographic factors and baseline HbA1c. 1.8 yrs), ethnicity (37% Hispanic, 35% black, 20% white), diabetes duration HbA1c was measured at the same reference laboratory for each cohort. (median [Q1, Q3] = 6 [4, 11] mo.), or HbA1c (mean ± SD=6.1 ± 0.8%) between Results: At baseline, TL subjects were older (16.9 vs. 15.3 years, p<0.01), had groups. Significant metabolic and hormonal differences emerged: those with more females (70% vs. 56%, p=0.03), and had higher BMI (54.4 vs. 40.5kg/m2, irregular menses had higher BMI (37.1 ± 7.3 vs. 34.3 ± 6.6 kg/m2, p=0.006); p<0.01) than TODAY subjects. By design, the groups were similar in race/ethnic- waist circumference (WC, 112.2 ± 14.6 vs. 106.9 ± 14.6 cm, p=0.02); ALT (34.4 ± ity and baseline HbA1c (6.8% [TL] vs. 6.2% [TODAY]). At 2 years, BMI change dif- 24.4 vs. 27.3 ± 20.3 U/L, p=0.009); insulinogenic index ([∆I30/∆G30], 2.1 ± 3.4 vs. fered significantly between groups, with 28% decrease in TL and 3.5% increase 1.2 ± 1.2 µU/mL per mg/dL, p=0.002); and T (44 ± 20 vs. 39 ± 38 ng/dL, p=0.01), in TODAY (p<0.01). Irrespective of medication use (including insulin use), HbA1c as well as lower insulin sensitivity ([1/IF], 0.04 ± 0.03 vs. 0.05 ± 0.04 mL/µU, declined in TL and increased in TODAY over time (group by time interaction, p=0.01), estradiol (50.5 ± 34.8 vs. 70.5 ± 56.4 pg/mL, p=0.01), and SHBG (13.6 p<0.01). At two years, HbA1c was 5.4% (95% CI: 4.8, 6.1) for TL subjects and ± 10.0 vs. 20.1 ± 23.1 nM, p=0.004). Menstrual dysfunction is common in girls 7.6% (95% CI: 7.2, 8.1) in TODAY subjects (p<0.01). At 2 years, 95% (95% CI: 70, with youth-onset T2D and is associated with metabolic and hormonal altera- 99) of TL subjects and 37% (95% CI: 24, 53) of TODAY had HbA1c values < 6.5% tions. These alterations remained significant after adjusting for % overweight (p<0.01). Thirty-three percent (10/30) of TL participants and 5% (3/63) of TODAY and WC. Future studies are needed to further characterize the associations participants and required any hospital admissions during the 2 year period. between metabolic and reproductive function in girls with T2D. Conclusions: Compared to medical management, surgical treatment of severely obese adolescents resulted in better glycemic control but was associated with a higher rate of subsequent hospitalization over the initial 2 year period. Supported By: National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases

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LB43 PedLateiatr Breaics—Tykingpe Abstracts 1 Diabetes

Pediatrics—Type 1 Diabetes from prior studies may be due to limitations with cortisol assays. We investigated hair cortisol as a novel biomarker of chronic stress in T1D. 160-LB The relationship of hair cortisol to diabetes-related factors (glycemic control and duration of diabetes) and to other factors (age, gender, and puberty) A Camp-based Intensive Education Intervention for Families of Young was examined in children with and without T1D, respectively. Age appropri- Children with Type 1 Diabetes Mellitus ate, validated assessments of stress by both child and parent were completed OLGA T. GUPTA, MARSHA MACKENZIE, ANGIE BURRIS, BONNIE JENKINS, NIKKI [short mood and feeling questionnaire (SMFQ), child and adolescent survey of COLLINS, JULIE SHERROD, JORDAN STREETMAN, ROCHELLE WILSON, EILEEN life experiences (CASE) and diabetes stress questionnaire (DSQ)]. SANTA-SOSA, SUNITA STEWART, PERRIN WHITE, Dallas, TX 114 children (72 children with T1D, 42 children without diabetes) had mean Type 1 diabetes (T1DM) in preschool age children presents unique challenges. age of 11.1 years (+/- 3.6) were recruited. Both groups were similar for gen- Parental stress around diabetes management tasks is high, and young children can have behavioral and emotional responses that interfere with diabetes care. der, ethnicity, pubertal stage, SES and parent education level. Hair cortisol in The objective of this project was to develop a structured, multidisciplinary, children with diabetes and without diabetes were not statistically different family-centered 3-day camp-based intervention to improve 1.) glycemic control [median (IQ range), 5.2 pg/mg (3, 9.6) vs. 6.1 pg/mg (3.9, 8.7), p = 0.43]. Chil- (HbA1c) and 2.) quality of life (QoL) in young children with T1DM and their parents. dren with controlled T1D (A1c <7.5%) had significantly lower hair cortisol than Eighteen children (ages 3-5 years) and their families were recruited to partici- children with uncontrolled T1D [3.4 pg/mg (2.6, 5.4) vs. 5.7 pg/mg (3.1, 11.2), pate in the 3-day camp-based intervention that included didactic and interac- p = 0.03]. No significant difference was found in hair cortisol when strati- tive parent education (glucose monitoring, insulin dosing, sick-day management, fied by age, gender, puberty, and diabetes duration. Child-rated self-stress on hypoglycemia, physical activity, nutrition, coping skills, diabetes pathogenesis, SMFQ (score >=12, signifying depression) and CASE showed positive correla- future therapeutic possibilities), child-centered education and family-based rection to A1c, with higher stress levels in subjects with higher A1c. reational activities. The difference pre-post camp in HbA1c was highly correlated In summary, children with diabetes and good glycemic control had sig- with the values at the pre-camp visit (R=0.626, p=0.005), so that subjects who nificantly lower hair cortisol compared to those with uncontrolled diabetes. had the highest HbA1c at baseline improved the most. From 1 month before to 1 Further investigation of factors affecting hair cortisol is needed. Perhaps month after the first camp session, there was statistically significant improve- interventions to reduce or reverse chronic stress may be beneficial to achiev- ment in parental hypoglycemia fear (HFS-P-YC [total] pre vs. post, 74.3 vs. 65.9, ing glycemic goals. POSTERS

Therapeutics p < 0.001). A similar increase was noted in the Behavioral Pediatric Feeding

Clinical Diabetes/ Assessment Scale (17.8 vs. 20.8, p<0.05), indicating an improvement in mealtime 163-LB functioning following the intervention. The parental portion of the Peds-Quality Improved CGM Performance Predicts CGM Use and Outcomes in of Life (QoL) Generic [total] improved significantly, (77 vs. 83, p<0.05). The change Pediatric Patients with T1D in Peds-QoL score was strongly correlated (R=0.650, p<0.005) with the score at LORI M. LAFFEL, LISA K. VOLKENING, WILLIAM J. MCMULLEN, DEBORAH A. BUT- the initial visit. These results indicate that a 3-day camp-based intensive educa- LER, MICHELLE L. KATZ, Boston, MA tion intervention can improve quality of life in parents of young children with Consistent use of continuous glucose monitoring (CGM) has been associ- T1DM and HbA1c in young children with suboptimal glycemic control. ated with improved glycemic control without severe hypoglycemia; however, Supported By: Children’s Clinical Research Advisory Committee consistent CGM use has been challenging in the pediatric population with T1D. In order to increase CGM use in pediatric patients, we designed a family- 161-LB focused behavioral teamwork intervention (TW) aimed at overcoming barriers Understanding the Impact of Diabetes Camp on Knowledge, Self- to CGM use. In a 12-month RCT, we implemented CGM with either the TW Care Behaviors, and Psychosocial Outcomes among Youth with intervention or standard care (SC) in 120 families of youth (51% male), 8-17 Type 1 Diabetes y/o, with T1D of ≥1 yr duration. CGM data were downloaded every 6 weeks MEGAN T. MARTIN, MONICA S. WIEDEMANN, SARAH WHOLEY, ANISHA S. and A1c was obtained every 3 months. Youth and parents completed surveys DHARSHI, TAMARA DARSOW, Alexandria, VA, Suitland, MD every 6 months. Mean youth age was 12.7±2.7 yrs, T1D duration was 6.1±3.6 American Diabetes Association Diabetes Camps are offered each summer to yrs, 84% were pump treated, BG monitoring frequency was 6.9±2.4 X/day, nearly 6,000 youth with diabetes across the United States. Camps are designed to A1c was 8.0±0.8%. Youth received the DexcomTM SEVEN PLUS CGM, the Dex- facilitate a traditional summer camp experience in a medically safe environment comTM G4 PLATINUM CGM, or began with the SEVEN PLUS and transitioned while fostering opportunities for children to develop basic diabetes self-care skills, to the G4 PLATINUM within 6 months. overcome feelings of isolation, and gain self-confidence. Between 2013 and 2015, After 12 months, 70% of participants were still using CGM but there was a study was conducted to better understand the impact of camp on 1.) knowledge no difference in CGM use between TW and SC groups. CGM use over the 12 of diabetes management, 2.) self-care behaviors, 3.) confidence to manage diabe- months was predicted solely by CGM device (Figure). CGM use predicted A1c. tes, and 4) emotional well-being of youth campers with type 1 diabetes. Over the 1-year study, there were modest improvements in both youth and A survey was conducted via online questionnaires administered to care- parent reported fear of hypoglycemia, quality of life, and diabetes-specific givers of camp participants at two times, 2 weeks prior to camp (N=1734) burden. The improved performance of CGM devices appears to predict CGM and 1 month post-camp (N=1075). Key demographics of represented youth use and outcomes in pediatric patients with T1D. were comparable across evaluation years (53% female, mean age 11.3, 53% Figure. CGM Device Predicts CGM Use, CGM Use Predicts A1c. diagnosed ≤ 3 years, 15% diagnosed ≤ 1 year). Paired-sample t-tests were performed to determine differences in means from pre- to post-camp. Data indicate improvements across all areas under investigation with particularly notable increases in overall knowledge of diabetes management, ability to manage problems independently, and confidence to manage diabetes independently. Newly diagnosed campers show the greatest improvement in ability to manage diabetes-related problems. Decreases in diabetes-related stress were also reported. Trends are consistent across evaluation years. Our results indicate that camp positively impacts a wide-range of camper outcomes, with newly diagnosed campers appearing to benefit the most from their experience. Future research will be conducted to better understand associations between outcomes and specific camp activities to facilitate pro- grammatic enhancements.

162-LB Supported By: National Institutes of Health (R01DK089349, P30DK036836) Hair Cortisol as a Novel Biomarker of HPA Axis in Children with Type 1 Diabetes 164-LB RATHNA MANDALAPU, SARAH MACLEISH, ROSE GUBITOSI-KLUG, REBECCA Change in Hemoglobin A1c following New ADA Targets for Children HAZEN, Cleveland, OH G. TODD ALONSO, BRIGITTE FROHNERT, LAURA PYLE, Aurora, CO Hypothalamic pituitary adrenal (HPA) axis dysregulation has been hypoth- In June 2014 the American Diabetes Association lowered recommended esized to affect glycemic control in type 1 diabetes (T1D). Inconsistent results hemoglobin A1c (HbA1c) targets to <7.5%, from <8.5% for children <6 years of

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LB44 Pregnancy—Basic Science/TranslatioLatenal B reaking AbstractsPregnancy—Clinical/Epidemiology

age and from <8.0% for children 6-12 years of age. Lower target HbA1c may exposure of high glucose can cause alterations in the cellular metabolism lead to better glycemic control in children but could increase the risk of severe of offsprings. Alterations in the mitochondrial metabolism may be a factor hypoglycemia. Patients with type 1 diabetes >12 months duration and age 0-25 responsible for the cardiac complications in offsprings of GDM mothers. years who were seen in Barbara Davis Center between January 1, 2014 and The aim of this study was to assess the cardiac mitochondrial respiration June 30, 2014 and between January 1, 2015 and June 30, 2015 were included. and mitophagy/autophagy in the offsprings of GDM mothers. Diabetes was There were 2518 unique patients with 6326 encounters. We analyzed the first induced by intraperitoneal injection of streptozotocin/nicotinamide (35mg/ HbA1c value per quarter (January through March, April through June) and self- kg; 230 mg/kg) in wistar rats. The offsprings were divided into two groups; reported severe hypoglycemic events (SH) during those dates. The number of one group was taken at the weaning stage (21 days) and the other at adult SH and the least-squares means of HbA1c by year and age group are shown. stage (120 days). Heart tissue samples were collected from each group at the A mixed-effects model combining all age groups did not show any significant appropriate age. Decreased expression of mitochondrial complex IV proteins differences between the years (p=0.75, LS means: for 2014, 8.98±0.04; for was observed in both the groups than in controls. Complex I protein expres- 2015, 8.97±0.04). Non-null values in the SH data fields increased from 33% in sion was lower in the weaning age group but showed a higher expression 2014 to 49% in 2015. Chi-square analysis of SH events for all ages showed no in the adult group even though the other complexes II, III and V did not vary difference between years (p=0.91). HbA1c values in affected groups did not much in both groups. So we analyzed the mitochondrial oxygen consumption show a significant change 1 year after the updated guidelines despite adop- rate in the adult group and found a decreased rate of complex I associated tion of new targets. Accurately assessing a change in SH may require larger, respiration. Respiratory control ratio (RCR) was found to be decreased with prospectively collected datasets or longer observation time. a concomitant increase in non oxphos respiration in the adult group. The LC3 Table. Least-squares Means from Mixed-effects Model of HbA1c and Number II expression was lower in the adult group indicating reduced autophagy, of SH by Year and Age Category. while there was no change in the weaning group. Even though there was an increase in the expression of mitochondrial complex I protein in the adult age, Year 2014 2015 complex I related oxygen consumption was lower indicating a dysfunctional Age Group N SH HbA1c LS Mean N SH HbA1c LS Mean P-value for HbA1c mitochondrial protein machinery, with impaired mitophagy. Our results sug- <6 years 103 0 8.48±0.15 92 3 8.33±0.17 0.38 gest impaired cardiac mitochondrial respiration and mitophagy/autophagy in 6-12 years 697 3 8.68±0.06 678 10 8.65±0.06 0.66 the adult offsprings of gestational diabetic mothers. POSTERS

Supported By: Department of Science and Technology, India; Council for Scien- Therapeutics 13-25 years 1171 12 9.22±0.05 1247 11 9.16±0.05 0.21

tific and Industrial Research, India; India Science and Engineering Research Board Clinical Diabetes/

165-LB Pregnancy—Clinical/Epidemiology High Prevalence of Sustained Kidney Injury in Pediatric Diabetic Ketoacidosis SARAH HATAB, NINA J. HAM, PAMELA WINTERBERG, ANDREW B. MUIR, Atlanta, 167-LB GA Impact of Gestational Diabetes Mellitus Glycaemic Control on Neo- Patients who develop acute kidney injury (AKI) are at a substantial risk for natal Weight Outcomes in Singleton and Twin Pregnancies future chronic kidney disease, even following apparent renal recovery. The pres- MARÍA A. GUILLÉN, BEATRIZ BARQUIEL, LUCRECIA HERRANZ, Madrid, Spain ence of diabetes further increases this risk. Impaired kidney function is typical A differential impact of gestational diabetes mellitus (GDM) on neonatal of diabetic ketoacidosis (DKA) and may result from a reversible physiological weight outcomes in singleton and twin pregnancies, has been proposed. We response to dehydration. Conversely oxidative stress and inflammation may aimed to evaluate the impact of glycemic control on neonatal weight out- cause kidney injury. In this study, we tested whether kidney damage occurs in comes. We assessed data from 360 women: 120 twin and 240 singleton preg- DKA and assessed for residual injury. Serum Creatinine (sCr) and novel urinary nancies. Type of treatment (diet ± insulin), third trimester HbA1c and maternal biomarkers of kidney damage (NGAL and KIM-1) were serially measured during weight gain were recorded. DKA treatment and 3-4 wk later in a cohort of 37 children with type 1 diabetes Rate of maternal weight gain (maternal weight gain - infant birth weight/ (T1D) and at baseline in 11 controls with well controlled T1D and 20 controls with total weeks gestation) was 0.16 ± 0.12 kg in singleton, and 0.26 ± 0.14kg poorly controlled T1D. Kidney damage was identified based on peak biomarker (p <0.001) in twin gestations. Insulinization rate was higher in singleton preg- levels exceeding the estimated bootstrap 95th%ile in controls. AKI was defined nancies (52.5% vs. 26.1%, p<0.001), however mean third trimester HbA1c as a 25% or greater increase in sCr. Biomarker levels were not significantly dif- was similar in both groups: 5.2 ± 0.4% (33± 4.4mmol/mol), in singleton vs. ferent between control groups. Median peak NGAL/Cr and KIM-1/Cr in DKA 5.1 ± 0.4% (32 ± 4.4mmol/mol) in twin pregnancies, (p=0.407). We observed patients were higher compared with median values in controls (NGAL/Cr: 842 a linear relationship between third trimester HbA1c and infant birth weight vs. 5ng/mg; KIM-1/Cr: 2.1 vs. 0.38ng/mg). AKI associated with renal damage ratio (birth weight/50th percentile weight for gestational age) in singleton was identified in 88% of DKA patients. 10% had damage without AKI (subclini- (r=0.199, p=0.003), but not in twin pregnancies (r=0.049, p=0.610). In conclu- cal AKI), 3% had neither AKI nor damage, and none had AKI without damage sion, neonatal weight outcomes in GDM twin pregnancies were not related (prerenal azotemia). AKI severity was not associated with any peak biomarker to glycaemic control. Probably, less stringent glycaemic goals in association level but was correlated with BUN concentrations at DKA presentation. Peak with fetal growth parameters monitoring could minimize the risk of over treat NGAL/Cr inversely correlated with DKA severity (p<0.001). NGAL/Cr and KIM-1/ GDM in multiple pregnancies, and therefore the increased risk for severe SGA Cr levels 3-4 wks after DKA resolution were elevated compared with those in neonates. controls (p=0.002 and 0.003). Thus, our study suggests that prerenal azotemia Table 1. Neonatal Weight Outcomes in Singleton and Twin Gestation and structural injury commonly coexist in DKA. Elevated injury biomarkers in Complicated with GDM. the convalescent phase of DKA support persistent immune response. Further Singleton Twin P OR 95% P studies will determine whether kidney damage is irreversible and contributes to Pregnancy Pregnancy value CI value the progression of diabetic kidney disease. (%) (%) LGA 12.6 12.5 0.989 0.97 0.40-2.38 0.962 Macrosomia 6.7 7.5 0.777 0.80 0.25-2.61 0.713 Pregnancy—Basic Science/Translational SGA 6.7 10.8 0.175 2.31 0.87-6.13 0.093 166-LB Severe SGA 2.5 8.3 0.012 4.59 1.30-16.23 0.018 Impairment of Cardiac Mitochondrial Respiration and Autophagy in Adjusted OR by pre-pregnancy maternal BMI, rate of maternal weight gain, the Offspring of Gestational Diabetic Rats hypertension or preeclampsia, smoking habit, chorionicity, severe fetal malformations, preterm delivery (<37 weeks) and parity. RAJI SASIKALADEVI RAJENDRAN, NANDINI RAVIKUMAR JAYAKUMARI, ANAND CHELLAPPAN REGHUVARAN, ASHOK SIVASAILAM, HARIKRISHNAN VIJAYAKU- MAR SREELATHA, VIVEK VELAYUDHAN PILLAI, JAYAKUMAR KARUNAKARAN, SRINIVAS GOPALA, Thiruvananthapuram, India The offsprings of gestational diabetic (GDM) mothers mostly have an increased propensity to macrosomia and childhood obesity. Intrauterine

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LB45 EpidemiLoloategy—C Breaardkingio Avbstractsascular Disease

168-LB Figure 1. Daily Living Activity and Regular Exercise Independently Reduce the Risk of Type 2 Diabetes in Women with a Previous History of Gesta- tional Diabetes Mellitus CHANG HO AHN, SOO HEON KWAK, TAE JUNG OH, KYOUNG MIN KIM, JAE HOON MOON, SUNG HEE CHOI, SOO LIM, KYONG SOO PARK, NAM H. CHO, HAK C. JANG, Seoul, Republic of Korea, Seongnam, Republic of Korea, Suwon, Republic of Korea Gestational diabetes mellitus (GDM), which is increasing worldwide, does not only affect the pregnancy outcome, but also affects the postpartum development of type 2 diabetes (T2DM). Physical activity is a cornerstone of lifestyle interventions to reduce the risk of T2DM and can be divided into two parts. One is daily living activity (DLA) consists of workplace and household activity, and the other is regular exercise (RE), a structured activity to improve physical fitness. We investigated differential impacts of DLA and RE on the postpartum development of T2DM in women with a previous history of GDM. Subjects were prospectively recruited at multiple centers in Korea. Follow-up evaluations including 75 g oral glucose tolerance test were done at 6 weeks postpartum and annually thereafter. The intensity of DLA and the type and frequency of RE were assessed. The subjects were divided into three groups according to the average amount of DLA and RE; least, low and high groups. The risk of T2DM was assessed using multivariate Cox proportional hazards 170-LB model. Total 418 women with previous history of GDM were recruited and Dietary Self-Care Behaviors During and After Pregnancy among had more than two follow-up evaluations with median duration of 4.0 years. Women with Gestational Diabetes Among them, 52 (12.4%) women developed T2DM. High DLA and RE inde- ROSETTE J. CHAKKALAKAL, TOM A. ELASY, Nashville, TN pendently reduced the risk of T2DM with HR of 0.39 (95% CI 0.18 - 0.83) and Women with gestational diabetes (GDM) often improve their diets dur- 0.37 (95% CI 0.17 - 0.84) compare to the least amount group, respectively in ing pregnancy as part of standard management. Maintenance of improved the multivariate analysis adjusted for age, body mass index, family history of dietary self-care behaviors after delivery could reduce their risk of type 2 dia- T2DM, breastfeeding, multiparity and fasting glucose level during pregnancy. betes (T2DM) later in life. The “Health of Mothers” (HOMe) study is a prospec-

Low DLA and RE did not significantly reduce the risk of T2DM, compare to the tive cohort study examining gestational weight gain and postpartum weight least group. In subgroup analysis, the impact of DLA and RE were higher in retention in women with GDM. We adapted the Personal Diabetes Question- groups of overweight and no family history of diabetes. Increased DLA and naire diet subscales to assess dietary self-care behaviors of HOMe partici- RE independently reduced the risk of T2DM in women with previous history of pants during and after pregnancy. Higher scores indicated more frequent use

G enetics GDM. The lifestyle management should focus on both DLA and RE. of diet information to guide eating behavior on the “Dietary Knowledge and POSTERS

Epidemiology/ Supported By: Korea Healthcare Technology R&D Project, Ministry of Health and Skills” subscale; more frequent use of specific decision-making strategies to Welfare, Republic of Korea (A111362); Seoul National University Bundang Hospital guide eating behavior on the “Diet Decision Making” subscale; more frequent (02-2015-043) interference of negative eating behaviors with dietary self-management on the “Eating Problems” subscale; and more frequent interference of environ- 169-LB mental, social, and emotional factors in attempts to adhere to healthy eating Improved Glucose Control in Pregnant Women with Type 1 Diabetes behaviors on the “Diet Barriers” subscale. We compared subscale scores dur- Using Continuous Glucose Monitoring (CGM) Share System ing and after pregnancy using paired t-tests. Participants’ (n=31) mean scores SARIT POLSKY, MARY K. VOELMLE, PRAKRITI JOSHEE, DOMINIQUE GIORDANO, were significantly higher for “Dietary Knowledge and Skills” during (22.27 +/- JANET K. SNELL-BERGEON, KATHERINE NAKAMURA, SATISH K. GARG, Aurora, 5.77) versus after (19.31 +/- 4.75) pregnancy (p=0.0008) and “Diet Decision CO, San Diego, CA Making” during (14.00 +/- 3.36) versus after (11.38 +/- SD 3.34) pregnancy The CGM Share (DexCom, San Diego, CA) uses remote monitoring such (p<0.0001). There were no significant differences in mean scores for “Eat- that family and friends (followers) can view glucose trends and receive sen- ing Problems” (5.11 +/- 1.31 versus 5.03 +/- 1.75, p=0.829) or “Diet Barriers” sor glucose alerts. The primary aim of this investigator-initiated pilot study (10.62 +/- 2.36 versus 10.59 +/- 2.94, p=0.867) during versus after pregnancy, was to evaluate change in glucose variability in pregnant women with T1D. respectively. GDM-affected women more frequently utilize diet information 17 subjects were non-randomly assigned to groups: 1.) CGM Share: women and specific decision-making strategies to guide eating behaviors during ver- with iPhone and followers with devices for data viewing, 2.) CGM Alone; sus after pregnancy. Promoting long-term maintenance of improved dietary women without Apple devices, and 3.) No CGM: women unwilling to use a self-care behaviors adopted during pregnancy could reduce rates of T2DM CGM. Subjects started CGM use no later than the first trimester. Each subject in this population. had a follower who filled out monthly surveys about the partner’s glucose Supported By: National Institute of Diabetes and Digestive and Kidney Diseases levels and his/her interventions for glucose alerts and values. Baseline char- (P30DK092986) acteristics were similar between groups (Figure 1A). In the interim analysis for women reaching ~20 weeks of gestation, CGM Share users (n=4) had a faster and larger reduction in A1c values compared with CGM Alone (n=5, Epidemiology—Cardiovascular Disease Figure 1B). Both groups significantly improved A1c at ~20 weeks. There was an increase in “time in range” (70-140mg/dL) and decrease in severe hypogly- 171-LB cemic range (<55 mg/dl) in CGM Share compared to CGM Alone (Figure 1B). Cardiovascular-Risk-Factors Control in a Diabetic Population Followers in CGM Share reported more frequent interventions for high and Attended in the Primary Care Setting—The IBERICAN Study low glucose events than followers in CGM Alone. We conclude use of CGM SERGIO CINZA-SANJURJO, ALFONSO BARQUILLA GARCÍA, JOSÉ LUIS LLIS- Share improves “time in range” and glucose control, and may improve long- TERRI CARO, JESÚS VERGARA MARTÍN, CRISTINA MURILLO JELSBAK, DANIEL term gestational outcomes. REY ALDANA, MA CRUZ DÍEZ PEREZ, MARÍA CLEMENCIA ZULUAGA ZULUAGA, ARMANDO SANTO GONZÁLEZ, FRANCISCO VALLS ROCA, Porto do Son, Spain, Cáceres, Spain, Valencia, Spain, Almería, Spain, Madrid, Spain, A Estrada, Spain, Murcia, Spain Objectives: The aim of the IBERICAN study was to determine the prevalence and incidence of cardiovascular risk factors as well as the development of cardiovascular outcomes in a population attended in Primary Care setting in Spain. In this study, cardiovascular risk factor control rates in diabetic patients were analyzed. Methods: IBERICAN is a longitudinal, observational, and multicenter study that is currently including patients aged 18 to 85 years old, attended in pri-

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LB46 EpidemiLoloategy—C Breaardkingio Avbstractsascular Disease

mary care setting in Spain. All patients will be followed-up at least during These results demonstrate that high IGF-1 levels are associated with 5 years. Adequate HbA1c, blood pressure and LDL-cholesterol control was favorable risk factor profiles at young age but upon approaching middle age; defined according to 2016 ADA, 2013 ESH-ESC and 2011 ESC-EAS guidelines, men with persistently high IGF-1 levels do not show a more favorable meta- respectively. bolic risk factor profile. The data is contrary to the observations that IGF-1 Results: A total of 572 patients (19.0%) had diabetes, of which 24.1% (n = is strongly correlated to risk factors associated with insulin resistance and 138) did not reach therapeutic goals. Mean HbA1c was 6.99±1.2%. Diabetic metabolic syndrome. patients were older (66.0±10.5 vs. 56.1±14.8 years; p <0.0001) and more com- Table. monly males (54.5% vs. 41.9%; p<0.0001). Hypertension (76.4% vs. 40.5%, p<0.0001), dyslipidemia (74.7% vs. 44.7%, p <0.0001), abdominal obesity (36.8% Gp Age IGF1 SBP Waist to Hip TG HDL HbA1c (ng/ml) (mmHg) (mg/dl) (mg/dl) (%) vs. 25.9%, p <0.0001) and physical inactivity (37.6% vs. 27.8%, p <0.0001) were more common in patients with diabetes. The degree of control of dyslipidemia 1 26.9*(2432) 322.3*(888) 120.7* (2316) 0.90*(2348) 127.1*(2293) 48.3**(2285) 5.2*(2326) was worse in diabetic patients (85.3% vs. 73.3%, p <0.0001). Left ventricular 2 57.6*(965) 237.0*(507) 135.6*(921) 1.00* (902) 188.5*(912) 45.9**(906) 5.9*(929) hypertrophy and microalbuminuria were more common in diabetics: 9.0% vs. 3 56.9 (68) 388.8*(68) 136.6 (68) 0.99 (66) 167.4 (68) 42.4 (68) 5.8 (66) 3.6%, p <0.0001 and 19.9% vs. 6.8%, p <0.0001, respectively. 4 57.4 (439) 213.6*(439) 134.8 (427) 0.99 (428) 162.3 (438) 45.9 (437) 5.8 (439) Conclusions: One out of 5 patients attended in Primary Care setting in Spain had diabetes. The clinical profile as well as cardiovascular risk factor control [*P <0.01, **P < 0.05 for comparable groups]. rates was worse in diabetics. 174-LB 172-LB The Impact of Chronic Hepatitis B Infection on Major Adverse Car- Methionine Sulfoxide Is Associated with Reduced Cardiovascular diovascular Events and All-Cause Mortality in Diabetic Patients—A Events in the VA Diabetes Trial Nationwide, Population-based, Nested Case-Control Study ARAMESH SAREMI, SCOTT K. HOWELL, PAUL J. BEISSWENGER, PETER D. CHIN SUNG KUO, YUNG TAI CHEN, PO HSUN HUANG, SHING JONG LIN, Taipei, REAVEN, Phoenix, AZ, Lebanon, NH Taiwan Post-translational protein modifications such as glycation and oxidation in The association between hepatitis B virus (HBV) infection and atheroscle- type 2 diabetes play an important role in the development of cardiovascular dis- rotic diseases remains uncertain, particularly in diabetic patients. We con- ease. To determine whether plasma levels of advanced glycemic end-products ducted a nationwide longitudinal cohort study to investigate the effects of and oxidation products (AGEs and OXs) predict the incidence of CVD events, chronic HBV infection on atherosclerotic diseases and all-cause mortality in we measured 5 specific AGEs: methlglyoxal hydroimidazolone, carboxymethyl diabetic patients. We used the Taiwan National Health Insurance Research lysine, carboxyethyl lysine, 3-deoxyglucosone hydroimidazolone (3DGH), and Database to identify diabetic patients with chronic HBV infection diagnosed glyoxal hydroimidazolone, in addition to, 2 oxidation products: 2-aminoadipic during 2000-2012. Chronic HBV infection was defined as having at least 3 acid (2-AAA), and methionine sulfoxide (MetSO), in 445 participants from the times in outpatient clinic or admitted with a diagnosis of HBV infection Veterans Affairs Diabetes Trial (VADT) at baseline. Only 3DGH (r=0.11, p=0.02), between January 1, 2000 and December 31, 2012. The association between

and 2-AAA (r=0.18, p<0.01), correlated with fasting glucose at baseline, none HBV infection and cardiovascular events including myocardial infarction, G enetics correlated with baseline HbA1c. Except for MetSO, all products correlated ischemic stroke, heart failure, and all-cause mortality was analyzed. The POSTERS Epidemiology/ negatively with GFR (r=-0.14 to -0.44, p<0.01). During an average follow-up time study cohort included 43,951 diabetic patients with HBV infection and 43,951 of 11±7 years, baseline MetSO, but not other modified amino acids, remained a matched diabetic control without HBV infection. During the median follow-up significant predictor of composite CVD events after adjusting for other relevant of 5.3±3.4 years, compared with matched cohort, HBV cohort had significant risk factors (Table). In conclusion, every unit increase in the Ln (MetSO) was low risk of myocardial infarction (HR 0.53 95% CI 0.46-0.60), ischemic stroke associated with a 52% lower risk of CVD events. The results of our study sug- (HR 0.58 95% CI 0.54-0.63), heart failure (HR 0.51 95% CI 0.44-0.59), and gest that higher levels of methionine sulfoxide, a product of the free radical all-cause mortality (HR 0.78 95% CI 0.76-0.81). Moreover, the impact of HBV scavenger methionine, is associated with decreased CVD events. on the sequential risk of cardiovascular diseases was lower in patients with Table. Cox Proprtional Hazard Analysis for Composite CVD Events*. severe diabetes. Chronic HBV infection is a protective factor of myocardial infarction, ischemic stroke, heart failure and all-cause mortality in diabetic Selected variables (by stepwise procedure) HR 95% CI p-value patients. These findings provide new insights into pathogenesis and future CVD history (yes vs. no) 3.19 2.15-4.75 <0.01 therapeutic strategies in diabetes. Duration of diabetes (years) 1.03 1.08-1.52 <0.01 Supported By: Taipei Veterans General Hospital (V105C-0207); Ministry of Science Mean HbA1c during the study (%) 1.28 1.00-1.18 <0.01 and Technology of Taiwan (MOST 104-2314-B-075-047) Ln (baseline methionine sulfoxide) 0.48 0.25-0.89 0.02 Other variables submitted to the stepwise selection procedure were: age, race/ 175-LB ethnicity, treatment assignment, history of hypertension, baseline AGEs, 2AAA, Effect of a Behavior-based Coaching Program on Risk Factor Reduc- and on-trial variables (BMI, triglyceride-to-HDL ratio, and GFR). *Composite tion in South Asians CVD events: MI, Stroke, CVD death, revascularization, inoperable coronary SNEHA BHAMRE, ASHISH MATHUR, ANITA SATHE, VIJAYA DEO, CESAR MOLINA, artery disease, CHF, and ischemic amputation. Mountain View, CA Supported By: American Diabetes Association (1-06-CR-32 to P.D.R.); National South Asians in a behavior based prevention program (exercise, diet, sleep Institutes of Health (R01-067690, 5R01-094775) and stress management) were examined for whether participation in, and frequency of coaching improved risk factors associated with cardiovascu- 173-LB lar disease (CVD) or diabetes (DM). Participants with baseline and at least 1 subsequent risk questionnaire, laboratory test, and physical exam from IGF-1 Values Do Not Correlate with Risk Factor Values Associated June 2008 to August 2015 were selected for this analysis. Lipid and meta- with Insulin Resistance bolic markers were compared between baseline and most recent follow-up. JAIMY PATEL, EVAN SIAU, LOUIS F. AMOROSA, New Brunswick, NJ, Bronx, NY Of 6,392 program participants, 714 were eligible for analysis. Of the 714, 162 Insulin Growth Factor 1 (IGF-1) is a growth hormone dependent polypeptide had no coaching touch points (CTPs) after initial results review. The remaining hormone with favorable anti-oxidant, anti-inflammatory and cytoprotective 552 were split into tertiles by coaching frequency: 1-3 CTPs (n=226), 4-5 CTPs properties. Yet IGF-1 levels decline with increasing age, weight and risk fac- (n=181), 6-10 CTPs (n=145). The change in BMI, fasting blood glucose (FBG), tors for metabolic syndrome. To clarify whether these associations are causal HbA1c, waist circumference (WC), waist/height ratio (WHtR), triglycerides or consequential; we analyzed the NHANES 1994 database and compared (TG), and TG/HDL statistically differed across the 4 coaching groups (p 0.03). IGF-1 values and metabolic syndrome risk factors between younger men [age ≤ Coaching was not associated with changes in blood pressure, cholesterol, 20-35, (Gp1)] and middle aged men [50-65,(Gp2)] as displayed in the Table. We LDL-C or HDL-C. Subjects with 4-5 CTPs had significantly greater decreases arbitrarily stratified men in Gp2 based on the mean IGF-1 value of 322ng/ml in WC, WHtR, and TG/HDL than those with 1-3 CTPs (p 0.03) or no coach- from Gp 1. Men in Gp 3 have IGF1>322 and Gp 4<322ng/ml. ≤ ing (p 0.03). Subjects with 6-10 CTPs had significantly greater decreases in Gp1 vs. Gp2 data [mean (n)] show an expected increase in metabolic risk ≤ BMI, WC, WHtR, TG, and TG/HDL than those with 1-3 CTPs (p 0.03) or no factors with age with a decline in IGF-1 levels. In contrast, aged matched ≤ coaching (p 0.01). Despite decreases in other metabolic risk factors, mean subjects who had high and low IGF1 levels [Gp3 vs. 4] did not differ in their ≤ FBG and HbA1c increased in all groups. The rise in FBG and HbA1c was sig- metabolic syndrome risk factor profiles.

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LB47 Epidemiology—CLatel Binireacalking—Di Aabstractsgnosis and Screening

nificantly less with 4-5 or 6-10 CTPs compared to 1-3 CTPs (p≤0.03) or no Figure. Baseline GDF-15 and 18-Month Outcomes. coaching (p≤0.009). There was no statistically significant change in risk factor modification between 6-10 and 4-5 CTPs, or between 1-3 CTPs and no coaching. In summary, South Asian participants with at least 4-5 CTPs focused on behavior change for 1 year, significantly improved lipid and metabolic risk factors for CVD and DM. In addition, increased coaching attenuated the drive to hyperglycemia perhaps caused by residual elevated BMI.

176-LB The Sequence of Formation of Endothelial Dysfunction in Men with Type 2 Diabetes IRINA A. KHRIPUN, ELENA V. BOVA, SERGEY V. VOROBYEV, Rostov-on-Don, Rus- sian Federation It is known that the ten-years experience of type 2 diabetes mellitus (T2DM) is accompanied by the presence of clinical manifestations of vascular complications in all patients. The sequence of the early signs of endothelial dysfunction (ED) has not been studied. The aim of the work was to determine the sequence of signs of ED with increasing duration of T2DM in men. The study was included 100 men (mean age 54,3 ± 5,3 years) with T2DM duration less than 10 years without an established diagnosis of cardiovascular disease. Supported By: Takeda Development Center Americas, Inc. Patients were divided into 2 groups: 1 - 60 patients with T2DM duration of less than 5 years, 2 - 40 men with T2DM experience of 5-10 years. ED was assessed biochemically - the level of nitric oxide (NO), the endothelial NO synthase type Epidemiology—Clinical—Diagnosis and 3 (eNOS3), ICAM-1, VCAM-1, E-selectin and instrumentally using ultrasound Screening parameter thickness of intima media (TIM) and arterial vasoreactivity brachial artery (BA) following by the procedure Celermajer. Statistical analysis was 178-LB performed using U-test Mann-Whitney. We found a reduction in the concen- One-Hour Postload Plasma Glucose Concentration and Future Risk of tration of eNOS3 and NO with increasing duration of T2DM for more than Diabetes: A 14-Year, Community-based Cohort Study 5 years. No significant differences in the levels of ICAM-1 and E-selecting TAE JUNG OH, SOO LIM, LEE KYUNG KIM, DONG HWA LEE, KYOUNG MIN KIM, were detected. With increasing duration of T2DM over 5 years was signifi- JAE HOON MOON, SUNG HEE CHOI, YOUNG MIN CHO, KYONG SOO PARK, HAK cantly (p = 0.04) rising in VCAM-1 concentration (1 group - 807[583;1093,5]; CHUL JANG, NAM H. CHO, Seongnam, Republic of Korea, Seoul, Republic of Korea, 2 group - 920,5[724;1255] ng/ml). No significant increase in TIM after 5 years Suwon, Republic of Korea G enetics of T2DM was found. There was a decrease in arterial vasoreactivity in the 2 In studies with Caucasians, plasma glucose level at 1 hour during oral glu- POSTERS

Epidemiology/ (10,2[6,4;16,4%) as compared to the 1 group (13,0[10;17]%), which remained in cose tolerance test (OGTT) was suggested as a powerful predictor for future the normal range. We found a new ultrasound index of ED - the timing until diabetes mellitus compared to fasting or postload 2 hour glucose levels. We the maximum vasodilation BA (TUMV). It was found an increase of TUMV in investigated the role of 1 hour glucose levels for predicting future diabetes the 2 (105[90;180] vs. 90[60;120] seconds) compared to 1 group. Biochemical mellitus in Koreans with normal glucose tolerance (NGT). A total of 3,929 and instrumental signs of ED appear in the first 5 years of current T2DM, long subjects with NGT at baseline were enrolled from the Korean Genome and before the clinical signs of vascular complications. The earliest of that is the Epidemiology Study. With indices of insulin sensitivity and β-cell function reduce in the level of eNOS3, NO, increase of VCAM-1, as well as an increase estimated from standard 75 g OGTTs performed every 2 years for 14 years, in new index - TUMV. the prediction power of 1 hour glucose for future diabetes was tested. The Supported By: Russian Science Foundation (14-25-00052) mean age and BMI of study population was 50.7 +- 8.2 years and 24.4 +- 3.0 kg/m2. During 14-year follow-up, 593 subjects (15%) developed diabetes mel- 177-LB litus. The area under the receiver operating characteristic curves for future Growth Differentiation Factor (GDF)-15 and Long-Term Outcomes in diabetes mellitus were higher for the 1 hour postload glucose levels than fast- Patients with Diabetes Mellitus in the EXAMINE Trial ing or postload 2 hour glucose levels (0.74 vs. 0.61 or 0.63). The cut-off value DAVID A. MORROW, CHRISTOPHER P. CANNON, PETR JAROLIM, GEORGE L. of ≥145 mg/dL identified future diabetes mellitus with 70% sensitivity and BAKRIS, WILLIAM C. CUSHMAN, STUART KUPFER, LANYU LEI, FAIEZ ZANNAD, 68% specificity. The subjects with≥ 145 mg/dL of 1 hour postload glucose had WILLIAM B. WHITE, Boston, MA, Chicago, IL, Memphis, TN, Deerfield, IL, Vandoeuvre lower β-cell function and a 2.35 fold increase risk of future diabetes mellitus lès Nancy, France, Farmington, CT compared to counterparts after adjusting for typical risk factors. The present Background: Interest has intensified for use of biomarkers to stratify car- study suggests that the 1 hour postload plasma glucose concentration is use- diovascular (CV) risk among patients (pts) with diabetes mellitus (DM). Growth ful for prediction of future diabetes mellitus. The 145 mg/dL of 1 hour postload differentiation factor (GDF)-15, an inflammatory cytokine that is a member of glucose, which represents deterioration of β-cell function, may be an optimal the transforming growth factor β family, is an attractive candidate for this cutoff for defining people at high risk. purpose. Methods: EXAMINE was a randomized, double-blind, placebo-controlled, 179-LB multinational CV safety trial of alogliptin in pts with type 2 DM enrolled 15-90 Viral Hepatitis A Infection Increases the Risk of Diabetes days after an acute coronary syndrome (ACS). We measured GDF-15 (R&D JAMES LIN, HORNG YIH OU, RUDRUIDEE KARNCHANASORN, WEI FENG, RAY- Systems) at baseline in all pts with available samples. GDF-15 was stratified NALD SAMOA, LEE MING CHUANG, KEN C. CHIU, Duarte, CA, Tainan, Taiwan, Kan- by established cutpoints at 1200 and 1800 pg/ml. The primary endpoint of sas City, KS, Taipei, Taiwan interest for this analysis was CV death and heart failure (HF). Diabetes is a multifactorial disorder with both genetic and non-genetic Results: 5193 pts with GDF-15 results were followed for 18 mo (median). components. Inflammation has been demonstrated to play a role in diabetes. The median GDF-15 value was 1247 pg/ml with 47% with values <1200 and Infection is well-known to cause inflammation which is an established risk 26% >1800. GDF-15 was strongly and independently related to CV outcomes factor for diabetes. Various infections have been implied a role in diabetes, adjusting for age, sex, type of index ACS, eGFR, and history of HF (Figure). such as Helicobacter pylori, hepatitis C, hepatitis B, and cytomegalovirus. In There was no excess of adverse CV events with alogliptin vs. placebo in high this study, the role of viral hepatitis A (HAV) infection in the development of risk patients identified with GDF-15 (>1800): CV death/HF 13.7% vs. 13.9% or diabetes was examined. CV death, MI, stroke 18.2% vs. 18.2%. Adult (≥20 years old) were included if their diabetes states could be defined Conclusions: Among pts with DM who were stable after a recent ACS, GDF- and history of HAV vaccination and its serology available from a national sur- 15 is a strong independent predictor of major CV events. Alogliptin was safe in vey that occurred between 2005 and 2012. Diabetes was defined by history, high risk patients identified with GDF-15. HbA1c, fasting or 2-hour plasma glucose. HAV vaccination was based on the self-reported history. HAV infection was defined by the absence of vaccination but presence of anti-HAV antibody. Logistic regression analysis was used

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LB48 Epidemiology—CLatel Binireacalking—Di Aabstractsgnosis and Screening

to calculate the odds ratio (OR) with 95% confidence intervals (95% CI) of ≥20 y enrolled in NHANES 2001-2002, 2011-2012 and 2013-2014 were retained diabetes with consideration of age, gender, BMI, race/ethnic group, current for analysis. T2D prevalence continues to increase in the U.S.; T1D prevalence smoking, alcohol consumption, family history of diabetes, education, and pov- remains stable. Prediabetes prevalence decreased from 2011-2012 to 2013- erty index. 2014; this could indicate more efficient prevention. 1: Menke A, et al. JAMA. This study included 19,942 subjects (51.42% female, aged 49±18 years, BMI 2015;314(10):1021-9. 2 28.94±6.75 kg/m , mean±STD). Among them, 17.37% were diabetes, 21.21% Table. Prevalence Estimate of Type 1 Diabetes, Type 2 Diabetes and Predia- had history of HAV vaccination, and 46.25% had anti-HAV antibody. Among betes from 2001-2002 to 2013-2014 (Point Estimates and 95% Confidence the subjects received HAV vaccination, only 53.89% had positive anti-HAV Intervals). antibody. When compared to the subjects without anti-HAV antibody, the subjects HAV infected subjects (defined by the absence of vaccination but presence of anti-HAV antibody) carried an increased risk of diabetes with an OR of 1.47 (95% CI: 1.53, P<0.000001). The increased risk of diabetes remained noted after adjustment of covariates with an OR of 1.17 (95% CI: 1.11-1.23, P<0.000001). Our results suggest that HAV infection is associated with increased risk of diabetes. As the liver plays a key role in glucose metabolism, HAV infection could play a role in the pathogenesis of diabetes. Supported By: Jie Chan Chen Foundation 182-LB Prediction of Clinical Diabetes by A1c and Glucose Levels 180-LB RAHSAAN R. OVERTON, MARY RHEE, SANDRA E. SAFO, MATTHEW J. MAGEE, Plasma Aldosterone Concentration Predicts the Incidence of Diabe- LISA R. STAIMEZ, EUN J. MIN, QI LONG, SANDRA JACKSON, LAWRENCE S. PHIL- tes Mellitus LIPS, Decatur, GA, Atlanta, GA TIEN JYUN CHANG, HUNG YUAN LI, TSE YA YU, JUNG NAN WEI, LEE MING Millions of Americans have unrecognized diabetes, but screening is gener- CHUANG, Taipei, Taiwan, Tainan, Taiwan ally nonsystematic, and we do not know how best to identify those at risk. The genetic variation of aldosterone synthase is associated with diabe- Since the best predictor of hyperglycemia is glycemia itself, we compared tes. Suppression of intestinal and urinary glucose absorption by aldosterone different measures of glycemia for prediction of clinically diagnosed diabetes through sodium-glucose cotransporters may be the key mechanism. How- within 3 years after nondiabetic studies at baseline. In a prospective obser- ever, it remains unclear whether plasma aldosterone predicts the incidence vational study at the Atlanta VA Medical Center 2009-2012, 1014 subjects of diabetes in human. In this study, we explored if plasma aldosterone con- had median age 57 years, BMI 30 kg/m2, were 96% male and 74% black, and centration is associated with the incident diabetes in a community-based had baseline assessment of A1c, an OGTT (after an overnight fast), and a 50-g prospective cohort without any anti-hypertensive medication. We recruited glucose challenge test (GCT) with glucose measured at 1 hour, as used in ges- 608 subjects without diabetes at baseline and followed them for an aver- tational diabetes screening (at any time of day, without requiring a prior fast). age of 4.01 years. Individuals who received anti-hypertensive medication G enetics

During yearly follow-up, diabetes was diagnosed according to use of ICD-9 POSTERS at baseline or during follow-up were excluded. Diabetes was diagnosed by codes and/or prescription of a diabetes drug. Predictive utility was assessed Epidemiology/ results from an oral glucose tolerance test and hemoglobin A1c, and if the by area under receiver operating characteristic (ROC) curves (c statistic). subject was taking hypoglycemic agents. Plasma aldosterone concentration Among single tests, A1c provided the highest ROC for prediction of diabetes at baseline was measured with an ELISA kit. During follow-up, 42 participants within 3 years, 0.724, slightly but not significantly higher than OGTT 1hr 0.714 (6.91%) developed type 2 diabetes. Plasma aldosterone concentration was and OGTT 2hr 0.703, and higher than all other tests (p<0.05). Combining A1c negatively associated with body mass index (r=-0.0978, p=0.0162), but was with one other glucose test provided a significant increase in ROC: 0.760 with not correlated with glycemic indices, HOMA2-%B, or HOMA2-IR (all p>0.05) OGTT 1hr, 0.751 with OGTT 2hr, 0.741 with GCTplasma and capillary, and 0.740 at baseline. Plasma aldosterone concentration significantly predicts the inci- with FPG – all p=ns vs. each other, and A1c + FPG and GCT were significantly dent type 2 diabetes, after adjusting for age, family history of diabetes, body higher than FPG or GCT alone (p <0.05). When baseline A1c was ≥6.0%, speci- mass index, HOMA2-%B, HOMA2-IR, and hemoglobin A1c (HR=0.83 for every ficity for prediction of clinically-diagnosed diabetes within 3 years was 90% 10 pg/ml increase in plasma aldosterone concentration, 95% CI 0.692-0.986, for added FPG >105 mg/dl, added OGTT 1hr >160 mg/dl, added OGTT 2hr >125 p=0.034; HR=0.31 for subjects with plasma aldosterone concentration in the mg/dl, and added GCTplasma >150 mg/dl. highest tertile, 95% CI 0.14-0.71, p<0.01). In conclusion, this is the first longi- Conclusions: A1c >6.0%, combined with a single additional glucose test– tudinal study to investigate the association of plasma aldosterone concentra- even 1 hour after a 50g oral glucose challenge, which can be performed tion and the incidence of type 2 diabetes. We found that the subjects with opportunistically – provides good predictive utility for identifying incident dia- higher plasma aldosterone concentration at baseline had a lower incidence betes within the subsequent 3 years, and could be used to identify individuals of type 2 diabetes. who would benefit from more frequent diabetes screening. Supported By: National Taiwan University Hospital (103-M2508); Ministry of Sci- ence and Technology of Taiwan (MOST 104-2314-B-002-124-MY3) 183-LB Abdominal Obesity and Diabetes by Sex: A Cross-Sectional Study in 181-LB Populations from North and South America Recent Trends in the Prevalence of Type 1 Diabetes (T1D), Type 2 Dia- ORISON O. WOOLCOTT, DEBORAH J. CLEGG, RICHARD N. BERGMAN, Los Angeles, betes (T2D), and Prediabetes in the U.S. CA HERVE CASPARD, JOHN J. SHEEHAN, PETER FENICI, NIKLAS HAMMAR, Gaithers- The potential sex-related differences in the link between abdominal obesity burg, MD, Fort Washington, PA, Cambridge, United Kingdom, Gothenburg, Sweden and diabetes remain controversial. We aimed to determine, in two nationally Previous studies have shown increasing prevalence of diabetes in the representative samples of adult populations, whether the prevalence of dia- U.S. between 1988-1994 and 2011-2012, diabetes prevalence increased in betes among individuals with abdominal obesity varies by sex. This is a cross- 1 the overall population and all subgroups evaluated. We aimed to evaluate sectional analysis of publicly available data from the National Household recent trends in the prevalence of T1D, T2D and prediabetes using data from Survey (ENAHO, Peru) for 2004-2005 and the National Health and Nutrition the U.S. National Health and Nutrition Examination Survey (NHANES) from Examination Survey (NHANES, United States) for 2005-2006 in individuals 2001-2002 to 2013-2014. Diagnosed diabetes was identified with the ques- aged ≥20 years. Abdominal obesity and diabetes were diagnosed based on tion: “Other than during pregnancy, have you ever been told by a doctor or on-site measured waist circumference and fasting glycemia, respectively. other health professional that you have diabetes or sugar diabetes?” T1D Diabetes prevalence ratio was determined using Poisson regression analysis was defined as age at diagnosis ≤30 y and requirement of insulin therapy. with robust standard errors. The final dataset consisted of 4,004 Peruvian Undiagnosed T2D was identified as A1c ≥6.5% in those without diagnosed individuals (2,006 women) and 2,084 individuals from the U.S. (1,075 women). diabetes. Prediabetes was identified as A1c of 5.7% to <6.5% in those without In Peru, the overall crude prevalence of diabetes did not differ by sex among diagnosed diabetes. Prevalence estimates from NHANES 2001-2002, 2011- individuals with abdominal obesity [women: 2.8% (95% confidence inter- 2012 and 2013-2014 were standardized by age group, gender and race/ethnic- val, CI: 2.0-3.7%); men: 4.0% (2.7-5.3%); P=0.145]. Likewise, in the U.S., the ity using population estimates for noninstitutionalized civilian U.S. residents prevalence of diabetes did not differ by sex among individuals with abdomi- from the Census Bureau on Jan 1 2014. 4492, 4966 and 5328 adults aged nal obesity [women: 13.8% (95% CI: 11.3-16.3%); men: 15.7% (12.3-19.1%);

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LB49 EpidemiLoloategy—Di Breakingabetes Abstracts Complications

P=0.392]. The prevalence ratio of diabetes in individuals with abdominal obe- T2D risk, respectively. Similarly, age at menopause was also associated with sity as compared with those without abdominal obesity was 3.07 (1.72-5.50) T2D risk in the same U-shaped as with RLS (P = 0.03). Further, years since in Peru and 2.90 (2.08-4.04) in the U.S., adjusting for age and sex. However, menopause (P = 0.003), but not history of cycle regularity and hormone use, we found no interaction of sex with body mass index (BMI) or waist circumfer- was associated with increased T2D risk. In conclusion, reproductive factors ence on the association with diabetes in Peruvian (BMI: P=0.938; waist cir- were associated with T2D risk among Chinese women indicating that either a cumference: P=0.217) or U.S. individuals (BMI: P=0.379; waist circumference: short or prolonged exposure to endogenous estrogen may be both important P=0.678). Our findings do not support gender differences in the prevalence in affecting T2D risk. The study support the notion that reproductive factors ratio of diabetes when adjusting for BMI or waist circumference. Whether the should be added in risk prediction algorithm to counsel women about their risk association between whole-body or abdominal fat mass with diabetes varies of developing T2D. by sex remains to be elucidated. Supported By: Jinchang Nonferrous Metals Corporation (JKB20120013); National Supported By: National Institutes of Health (DK29867, DK27619 to R.N.B.) Institutes of Health (D43TW 008323, D43TW 007864-01, DK66401); American Heart Association; China Scholarship Council

Epidemiology—Diabetes Complications 186-LB Creating Phenotypic Clusters for the Purpose of Identifying a Per- 184-LB sonalized HbA1c Target in Patients with Type 2 Diabetes Mellitus Early Glycemic Control after Type 2 Diabetes Diagnosis Is Most Criti- (T2DM) cal for Future Health and Survival MAYA LEVENTER-ROBERTS, BRADLEY H. CURTIS, TOMAS KARPATI, STEVEN NEDA LAITEERAPONG, ANDREW J. KARTER, JENNIFER COOPER, ELBERT S. M. BABINEAUX, ORNA REGES, XUANYAO HE, MOSHE HOSHEN, JIANMIN WU, HUANG, Chicago, IL, Bainbridge Island, WA AMICHAY AKRIV, GIL RUBIN, BECCA FELDMAN, ALENA STRIZEK, ITAMAR RAZ,

Type 2 diabetes trials have suggested that early hemoglobin A1c (HbA1c) con- RAN BALICER, Tel Aviv, Israel, Indianapolis, IN, Dublin, OH, Herzliya Pituach, Israel, trol leads to long-term reductions in complications and mortality. However, Jerusalem, Israel what “early” means relative to diabetes diagnosis is undefined. We studied Personalized HbA1c targets may serve to improve treatment guidelines and 8,043 newly diagnosed patients with type 2 diabetes and an initial A1c HbA1c outcomes. No previous study has created patient clusters for the purpose ≥8% from Kaiser Permanente Northern California (1997-2003) (mean follow- of predicting future risk of disease in correlation with underlying HbA1c. up 12 years). We categorized HbA1c values into early or late periods, defined by The purpose of this longitudinal study was to cluster patients with T2DM into different initial periods after diagnosis (1, 3, or 5 years) and remaining periods phenotypically similar risk groups using an electronic medical database from an integrated health care system, serving over 4.3 million members. We cre- (after 1, 3, or 5 years). We then categorized HbA1c values as good, moderate, or poor (<7%, 7 to <8%, ≥8%). Using Cox proportional hazard models, ated a cohort of 85,783 patients with a 3-7 year history of T2DM as of 1 Janu- we examined associations between early HbA1c control and future outcomes ary 2010 (index date). We trained two logistic regression models, adjusted for (microvascular and macrovascular events and mortality), adjusting for age, demographic, laboratory, and clinical profiles, to predict the relative preva- gender, race, cardiovascular risk factors, comorbidity, complications, and late lence of macrovascular complications or hypoglycemia as of index date. The

G enetics HbA . Compared to patients with early good control, patients with 1, 3 or 5 macrovascular complications model had an AUC of 0.81 (sensitivity 75.5%,

POSTERS 1c

Epidemiology/ years of early poor control all had increased risks of microvascular events specificity 71.8%). The hypoglycemia model had an AUC of 0.73 (sensitivity (e.g., 1 year, adjusted hazard ratio (HR) 1.54; 95% confidence interval (CI) 59.7%, specificity 75.1%). This process yielded four supervised clusters: low/ 1.01-2.36, p<.001). Only patients with 3 or 5 years of early poor control had low, high/low, low/high, and high/high risk of macrovascular complications increased risks of macrovascular events (e.g., 3-year, HR 1.68; CI 1.37-2.07, or hypoglycemia, respectively. The first cluster contained 49,182 patients p<.001); only patients with 5 years of early poor control had increased risks of with mean age 57.9 with low rates of pre-existing co-morbidities. The second mortality (HR 1.75; CI 1.18-2.59, p<.01). Patients with early moderate control cluster contained 21,970 patients with mean age 69.7, were predominantly did not have increased risks of outcomes compared to those with early good male with high Framingham score. The third cluster contained 6,054 patients control. Late HbA1c control was not related to outcomes. Our findings sug- with mean age 64.1, were predominantly female with high rates of diabetes- gest that a 1 year period of poor glycemic control immediately after diabetes specific complications and the highest rate of insulin use. The fourth cluster diagnosis increases the risk of microvascular complications; longer periods contained 8,577 patients with average age 71.6, high rates of anemia, and of early poor control are accompanied by additional risks of macrovascular high rates of both cardiac outcomes and insulin use. Supervised clustering can events and mortality. This study supports for efforts to diagnose diabetes and successfully create phenotypically distinct groups of patients who may ben- treat patients with poor control early in order to achieve long-term reductions efit from different guidelines, with adequate sample size and follow-up. Lon- in complication risk. gitudinal cohorts can serve to correlate observed risk of future outcomes with Supported By: National Institutes of Health underlying HbA1c in order to model an optimal personalized target HbA1c. Supported By: Eli Lilly and Company 185-LB Reproductive Factors and Risk of Type 2 Diabetes in an Occupational 187-LB Cohort of Chinese Women Trends in Nontraumatic Initial Lower Extremity Amputation Rates AIMIN YANG, SIMIN LIU, NING CHENG, HONGQUAN PU, MIN DAI, JIAO DING, among Veterans Health Administration (VHA) Users, 2000-2012 JUANSHENG LI, HAIYAN LI, XIAOBIN HU, XIAOWEI REN, JIE HE, TONGZHANG CHIN LIN TSENG, ORYSYA SOROKA, NISHA JANI, LEONARD POGACH, East ZHENG, YANA BAI, Lanzhou, China, Providence, RI, Jinchang, China, Beijing, China Orange, NJ Hormonal milieu has long been known to play an important role in the Reducing rates of total lower extremity amputations (LEAs) is a key Healthy development of type 2 diabetes (T2D), albeit uncertainties remain concerning People 2010 objective. This study aimed to assess trends in rates of non- what specific aspects of women’s reproductive history may affect T2D risk. traumatic initial LEAs (ILEAs) among VHA diabetes patients from 2000 to To understand the associations of reproductive factors with T2D risk among 2012. Using VHA and Medicare data for ICD-9-CM procedure codes (84.10- Chinese women and explore the role of endogenous estrogen in T2D develop- 84.19), we calculated annual age-and-sex standardized ILEA rates (per 1,000 ment, we conducted a cross-sectional analysis of baseline data from 16,114 patients) of major (84.15-84.19), minor (84.11-84.14), and total amputations women (11,051 premenopausal and 5,063 postmenopausal) aged 20 and among those free of LEAs in prior two years. above years who participated in an ongoing occupational cohort (Jinchang There were 547,382 and 1,320,758 diabetes patients in 2000 and 2012 with- Cohort Study) in China. Multivariable logistic regressions were modeled to out prior amputations, incurring 3,246 and 3,250 amputations, respectively. evaluate the associations of reproductive factors with T2D risk. After adjust- ILEA rates decreased by 59% (5.93 in 2000 to 2.44 in 2012); major and minor ing for potential confounders including occupation, early age at menarche ILEA rates decreased by 67% (2.10 to 0.69) and 54% (3.82 to 1.77), respectively. (under 12 versus 15-16 years) was associated with increased T2D risk (odds The relative rate change was lowest for toes (53%; 3.16 to 1.49). The ratio of ratio [OR]: 1.60, 95% confidence interval [CI]: 1.16, 2.22). Postmenopausal major-to-minor rates reduced from 0.55 in 2000 to 0.39 in 2012. Blacks were status was positively associated with T2D risk (OR: 1.54, 95% CI: 1.10, 2.14). more likely than whites and Hispanics to have ILEAs, but rates decreased in Reproductive life span (RLS) was significantly associated with T2D risk (P = all racial/ethnic groups. Relative changes were: blacks: 62% (7.64 to 2.93), 0.02), although displaying a U Shape relationship; compared to women with whites: 57% (5.61 to 2.39), and Hispanics: 68% (7.09 to 2.26). RLS in the middle (30-35 years), women with the shortest and longest RLS had We observed downward trends in age-and-sex adjusted rates across 13 23% (OR: 1.23, 95% CI: 0.98, 1.51) and 28% (OR: 1.28, 95% CI: 1.02, 1.61) higher years for all levels of ILEAs for the overall population and different races/

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LB50 ELpateide Bmireaolokinggy— ANbstractsutrition

ethnicity. We propose reporting of LEA rates by level and race to improve IR and OCs was examined by analysis of covariance. The prevalence of diabe- public health monitoring. tes was significantly higher in post-menopausal participants who had taken Figure. OCs for more than 6 months than in those who had never taken OCs. The association remained significant after adjusting for multiple confounding factors (odd ratio, 1.379; 95% CI, 1.115–1.707; P=0.003). The duration of OCs use was also positively associated with the prevalence of diabetes. Furthermore, taking OCs for more than 6 months led to a significant increase in fasting insulin levels and HOMA-IR in nondiabetic participants. Past use of OCs for more than 6 months led to a significant increase in the prevalence of diabetes in post-menopausal women, and increased IR in non-diabetes participants. These results suggested that prolonged use of OCs at a reproductive age is an important risk factor for developing diabetes in post-menopausal women.

Epidemiology—Nutrition

190-LB n-3 LCPUFA and Fish Intake in Pregnancy and Offspring Metabolic Parameters at Age 9 to 16—Does Gestational Diabetes Modify the Risk? EKATERINA MASLOVA, SUSANNE HANSEN, MARIN STRØM, THORHALLUR I. HALLDORSSON, LOUISE GROTH GRUNNET, ALLAN A. VAAG, SJURDUR F. OLSEN, Copenhagen, Denmark Marine n-3 long-chain polyunsaturated fatty acids (LCPUFA) are abundant in oily fish and have been associated with reduced risk of cardiometabolic Supported By: U.S. Department of Veterans Affairs (IIR 11-077 to C.L.T.) outcomes in adults. The evidence of an association between n-3 LCPUFA in early life and child metabolic health is less consistent, especially among high-

188-LB risk pregnancies affected by gestational diabetes mellitus (GDM). Our study Trends in Admissions and Mortality Rates from Diabetes Mellitus in included 1234 mother-offspring dyads (606 with a GDM index pregnancy and Central Belt of Ghana: A 31-Year Review 628 control dyads) nested within the Danish National Birth Cohort, a longitu- OSEI SARFO KANTANKA, EUNICE OPAREBEA ANSAH, Kumasi, Ghana dinal prebirth cohort. We assessed maternal n-3 LCPUFA (total, marine) and Longitudinal profiling of in-patient admissions and mortality trends from seafood (total, lean, oily) consumption using a food frequency questionnaire in gestational week 25 and interview data in weeks 12 and 30. The offspring G enetics diabetes provide useful insights into the magnitude of the burden of diabetes POSTERS in sub-Saharan Africa, and also serve as a sentinel on the state of out-patient were clinically examined at 9-16 years, including a DXA scan and a fasting Epidemiology/ diabetes care. This is a retrospective analysis of data on diabetes admissions blood sample. Anthropometry, body composition, plasma insulin, HOMA-IR, and deaths at a tertiary referral hospital in central Ghana between 1983 and cholesterol (total, LDL, HDL), and triglycerides were the primary outcomes. 2014. Rates of diabetes admissions or deaths were expressed as diabetes Effect estimates and 95% CI were calculated using multivariable regression admissions or deaths divided by total number of admissions or deaths respec- models adjusted for parental sociodemographic and lifestyle parameters. tively. Predictors of stroke mortality were determined using Cox proportional The median (IQR) intake of marine n-3 LCPUFA and total seafood were 0.33 hazards regression analysis. A total of 11,983 diabetes patients were admit- (0.35) g/day and 23 (24) g/day, respectively. We found no association for any ted over the period with a slight female predominance, female: male ratio of the exposures with offspring metabolic parameters. This was also true for of 1.1:1.0. Diabetes admission rates increased progressively from 2.36/1000 the GDM and control mother-offspring pairs. In secondary analyses, women admissions in 1983 to 14.94/1000 admissions in 2014 representing a 633% with GDM who reported eating no fish in week 12 and 30 (versus women rise over a 31-year period. In-patient case fatality rates increased from reporting fish intake >2 times/week at both time points) had offspring with 7.09/1000 deaths to 35.70/1000 deaths. The average 28-day mortality rate higher BMI (ratio of geometric means (RGM): 1.28, 95% CI: 1.06, 1.55), waist was 19.7%. Predictors of in-patient mortality were increasing age- aHR of circumference (RGM: 1.22, 95% CI: 1.05, 1.40), triglycerides (RGM: 1.77, 95% 1.23 (CI: 1.15-1.32) for age > 80 years compared with < 20 years, admissions in CI: 1.03, 3.03 ), and HOMA-IR (RGM: 2.16, 95% CI: 1.17, 3.97). In conclusion, 2000s compared to 1980s-aHR of 1.56 (1.21-2.01) and the presence of glyce- we observed no association of maternal n-3 LCPUFA and fish intake with mic complications such as ketoacidosis- aHR 2.67 (CI: 2.21-3.21), hyperosmolar offspring metabolic outcomes, although in a subsample of GDM pregnancies hyperglycemic states- aHR 1.52 (1.33-1.73) and symptomatic hypoglycaemia- consistent fish intake seemed beneficial. 1.64 (1.24-2.17) were associated with increased risk of death compared with Supported By: Novo Nordisk Inc; European Union (FP7/2007-2013, n°289346) normoglycemic diabetic admissions. Diabetes admission and mortality rates have increased significantly over the past three decades in central Ghana. 191-LB More intensive education on the risk factors for diabetes, acute diabetes care Prenatal Exposure to Famine and Trans-generational Risk of Type 2 as well as instituting hospital guidelines for diabetes control, reduction of Diabetes in Adulthood: A Population-based Study of Families in Con- modifiable risk factors for diabetes are urgently needed to reduce the poor secutive Generations in Suihua, China case fatality of diabetes in resource-limited settings. JIE LI, SIMIN LIU, TIANSHU HAN, YING LI, CHANGHAO SUN, Harbin, China, Provi- dence, RI 189-LB An increasing number of prospective studies have associated nutritional Long-Term Effects of Oral Contraceptives on the Prevalence of Dia- factors in early-life with risk of developing type 2 diabetes (T2D) in adulthood. betes However, there are very few studies available to examine whether the effects KWI HYUN BAE, SUNG WOO KIM, Daegu, Republic of Korea of early-life nutrition on adult T2D risk can be transmitted to the next genera- There is little information on whether past use of oral contraceptives tion. We investigated prenatal exposure to the Chinese famine of 1959-1961 (OCs) at child-bearing age influences the incidence of diabetes and insulin in relation to future risk of T2D in adulthood in two consecutive generations resistance (IR) after menopause. This study aimed to evaluate the asso- of families in Northern China. All of the 1,034 families (including 2,068 par- ciation of past use of OCs with the development of diabetes and IR in post- ents and 1,183 offspring) that met the selection criteria were recruited from menopausal women. This cross-sectional study was based on data from the the Suihua rural area that was affected by the Chinese Famine of 1959-1961. Korea National Health and Nutrition Examination Survey from 2007 to 2012. The parents born between October 1st 1959 and September 30th 1961 were Of the 50,405 participants, 6554 post-menopausal women were selected and defined as famine exposed, and those born between October st1 1962 and included in the analysis. The long-term effects of OCs use on the prevalence September 30th 1964 were classified as unexposed. Correspondingly, their of diabetes in post-menopausal women were examined using multivariate offspring were classified as having no parent, mother only, father only, or logistic analysis. In addition, fasting glucose and insulin levels were measured both parents exposed to famine. Prenatal exposure to famine was associated in 3338 nondiabetic post-menopausal women, and the association between with increased risks for hyperglycemia [multivariable-adjusted odds ratio (OR)

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LB51 LateEpi deBreamiolokinggy—O Abstractsther

and 95% confidential interval (CI): 2.13 (1.66-2.75)] and T2D [OR (95% CI): 2.56 diabetes that this algorithm identifies as having T2DM (94.0%) is in line with (1.64-4.14)] in adulthood in parental generation; furthermore, compared with what the literature states (90%-95%). Further, this algorithm allows adults the offspring of non-exposed parents, those of exposed parents, especially over age 30 to be typed with T1DM which is not possible using algorithm that both exposed parents, also had elevated risk for hyperglycemia [OR (95% CI): restrict typing with T1DM to those diagnosed under 30. It also acknowledges 2.00 (1.13-3.64)] in adulthood. Prenatal exposure to famine increased hyper- that not all people with T2DM are overweight nor are all those with T1DM at glycemia risk in at least two consecutive generations, supporting the impor- normal weight. tance of nutritional factors in determining T2D risk across generations. Supported By: National Natural Science Foundation of China (81130049, 194-LB 81302417) Risk of Metformin-associated Lactic Acidosis ABDELLATIF AHARAZ, ANTON POTTEGAARD, DANIEL P. HENRIKSEN, JESPER HALLAS, HENNING BECK-NIELSEN, ANNMARIE T. LASSEN, Odense, Denmark Epidemiology—Other Background: Metformin is a first line treatment for type 2 diabetes. Met- formin is suspected of causing lactic acidosis (LA) as a dangerous but rare side 192-LB effect, but the exact risk is uncertain. Trends in Diabetes Prevalence and Body Weight in a Large Popula- Methods: We performed a hospital based case control study among type 2 tion of Veterans, 2000-2014 diabetics living in the capture area of Odense University Hospital. Cases were MARGERY J. TAMAS, ANJALI KHAKHARIA, RICHARD B. ROTHENBERG, LAW- identified by any acute hospitalization with LA (ph<7.35, Lactate ≥2 mmol/l) RENCE S. PHILLIPS, Atlanta, GA in the period 1 June 2009 to 1 October 2013. Twenty-five age and sex matched Diabetes is a public health problem of epidemic proportions, but there is controls per case were sampled in a risk set manner. Current Metformin use limited understanding of age-related trends in body weight (wgt), a critical was defined as any prescription within the last 90 days. We used multivariate risk factor for diabetes and its complications. We used the VA Informatics and logistic regression to calculate odds ratios (OR), adjusting for kidney function, Computing Infrastructure (VINCI) to examine trends in diabetes and wgt in the HbA1c, and comorbidity (adj OR), and further for diabetes duration (adj OR2). largest integrated healthcare system in the U.S. There were 4,680,735 unique Results: The source cohort included 10.652 type 2 diabetics followed for patients with birth years from 1915-84, who had ≥ 4 outpatient visits within 41.650 person years. Median age 74 years and 51,5% were male. 163 indi- any consecutive 4-year interval during 2000-14; 35.6% had diabetes, defined viduals were hospitalized with lactic acidosis yielding an absolute risk of as ≥ 1 use of ICD-9 code 250.xx at an outpatient visit, any 2 uses of 250. 390/100.000 person years (95% CI 330-450/100.000 person years). Met- xx ICD-9 codes, or use of an antihyperglycemic medication. 92% of patients formin use had an OR of 0,69 (95% CI 0,44-1,10) for hospitalization with LA compared to non-use of Metformin. were male, 78% were white, and the mean age was 69 years. Birth cohorts were defined by 5-y intervals. Diabetes was more prevalent in men (37.5%) Conclusion: Among patients with type 2 diabetes, the absolute risk for than in women (23.6%), with the highest prevalence in the 1940-44 cohort acute hospitalization with LA is 390/100.000 person years (95%-CI 330- (43.6%), and the lowest prevalence in the 1980-84 cohort (6.0%). Median 450/100.000 person years). Metformin use is not associated with increased wgt at baseline was higher in men and women with diabetes (94 kg and 86 risk of lactic acidosis among type 2 diabetics.

G enetics kg, respectively) than in men and women without diabetes (84 kg and 73 kg, POSTERS Table. Metformin Associated Lactic Acidosis.

Epidemiology/ respectively). Median wgt increased linearly from 2000-14 (P < .001), with Lactate ≥2,0 Cases: Controls: OR Adjusted OR Adjusted OR2 greater increases in those without diabetes; the highest rate was in women Metformin/ Metformin/ without diabetes (0.39 kg/y). However, from 2000-14 wgt decreased in the no Metformin no Metformin oldest cohorts and increased in the youngest cohorts. Wgt changed faster at All 69 / 78 1,692 / 1,591 0.82 (0.59-1.16) 0.79 (0.54-1.17) 0.69 (0.44-1.10) younger ages, and was highest in those with diabetes and in women (women 0.04 vs. men 0.02 kg2/y, P < .001). eGFR > 90 21 / 17 522 / 620 1.49 (0.72-3.09) 1.47 (0.33-6.51) 7.51 (0.31-180.74) Conclusions: This is the first report of secular and longitudinal diabetes and eGFR 30-90 47 / 52 1,164 / 896 0.70 (0.46-1.05) 0.83 (0.53-1.29) 0.64 (0.37-1.09) wgt trends in a large, contemporary veteran population. Over 2000-2014, wgt eGFR < 30 – 6 / 75 – – – tended to increase in younger and decrease in older veterans. Those with diabetes were heavier than those without diabetes, but those with diabetes Charlson 0 24 / 16 1,098 / 918 1.44 (0.74-2.82) 1.21 (0.56-2.60) 1.27 (0.48-3.34) tended to have reduced further wgt gain than those without diabetes. Regard- Charlson 1 7 / 7 232 / 221 1.39 (0.29-6.78) 0.75 (0.11-5.01) err. less of diabetes status, the tendency to gain wgt over time, and to be heavier Charlson ≥2 38 / 55 362 / 452 0.84 (0.53-1.32) 0.83 (0.50-1.38) 0.59 (0.31-1.10) at a younger age, was higher in women than in men.

193-LB 195-LB Evaluation of Algorithms Used to Determine Diabetes Type Associated Risk Factors Rather than Intrinsic Disease Biology Lead SARAH LESSEM, Hyattsville, MD to Elevated Rates of Venous Thromboembolism among Patients with Most surveys that provide population-level estimates of diabetes either Hyperosmolar Hyperglycemic State (HHS) in the U.S. do not ask diabetes type or rely solely on self-reported diabetes type with KRISHMITA SIWAKOTI, SMITH GIRI, DIPEN KADARIA, SMRITI MANANDHAR, no ability to verify type. Instead, researchers using these survey data rely Memphis, TN, Milwaukee, WI on algorithms to categorize respondents as having type 1 diabetes (T1DM) Few prior studies have suggested that Hyperosmolar Hyperglycemic State or type 2 diabetes (T2DM) based on responses to survey questions. These (HHS) but not Diabetic Ketoacidosis (DKA) patients have an elevated risk of algorithms incorporate some combination of respondent’s age at diabetes venous thrombo-embolism (VTE) events. However, these studies are either lim- diagnosis, insulin use, time between diabetes diagnosis and insulin use, use ited by sample size or lack careful adjustment of important confounders. We of oral agents, body mass index (BMI), and self-reported diabetes type. This utilized the Nationwide Inpatient Sample (NIS) database to identify all adults study used 2005-2014 multi-year data from the National Health Interview >18 years diagnosed with DKA and HHS between 2009-2011 using appropriate Survey (NHIS), National Health and Nutrition Examination Survey (NHANES), ICD codes. Presence of VTE risk factors in the two groups was compared using and California Health Interview Survey (CHIS) to examine how the weighted bivariate methods. Multivariate logistic regression was used to identify the percent of respondents identified as having T2DM changes by algorithm and independent predictors of VTE in the overall cohort. Statistical analysis was calculated kappas to measure agreement between algorithms both overall done using STATA 13.0. A total of 251,872 unique hospitalizations were identi- and by race. Significant variation exists in the percent identified as having fied during the study period, out of which 86% had DKA (n=218,806) and 13% T2DM by algorithm (85.6%-96.2%) and in every combination of algorithms had HHS (n=33,066). As compared to DKA, HHS patients were older (mean in all three datasets showing much poorer agreement for minorities (.12-.33) age 56.9 vs. 40.7 yrs, p <0.001), males (54% vs. 45%, p <0.001), blacks (33% than for whites (.30-.62). vs. 21%, p <0.001), and have a higher prevalence of VTE risk factors including An algorithm in which respondents who report T1DM and using insulin are infection (27% vs. 23%, p <0.001), stroke (1.5% vs. 0.6%, p <0.001), history of typed as having T1DM whereas those who report T2DM or report T1DM and VTE (1.8% vs. 1.2%, p <0.001), malignancy (5% vs. 2.4%, p <0.001) and length no insulin are typed with T2DM appears to be most accurate. This algorithm of stay > 5 days (34% vs. 26%, p<0.001). There was a higher prevalence of VTE has higher kappas (.36-.52) with all other algorithms than any other combina- among patients with HHS (1.31% , n=434) as compared to DKA (1.01%, n=2215) tion of algorithms (.22-.29). Compared with other algorithms, agreement is (OR 1.30, 95% CI 1.17-1.44, p value <0.001). In a multivariate analysis, after higher both for minorities and whites and the weighted percent of people with adjusting for the above risk factors of VTE, there was no significant difference

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LB52 LateEpi deBreamiolokinggy—O Abstractsther

in the risk of VTE between the HHS vs. DKA patients (adjusted OR 1.01, 95% tion (Δ=1.1%) than controls, independent of age and ethnicity. Our findings show, CI 0.91-1.12, p=0.85). Our study is the largest known study till date comparing for the first time, that retinal microvascular structural and functional measures the prevalence and risk of VTE events among patients with DKA and HHS in remain different between women with and without a history of GDM 5 years the U.S. In this study, we found that HHS patients have a greater risk of VTE after delivery. A longer follow-up period in a larger sample may help to deter- events as compared to DKA, however this risk appears to be driven by a higher mine whether these microvascular persisting effects increase over time and prevalence of other risk factors of VTE in this population. even lead to future metabolic diseases. Supported By: National Medical Research Council of Singapore (CNIG/1108/2013) 196-LB Plasma Metabolomics Identified Novel Metabolites Associated 198-LB with Risk of Type 2 Diabetes in Two Prospective Cohorts of Chinese Life-Course Interaction between Fasting Blood Glucose and Body Adults Mass Index Affects Mid-adulthood Physical Performance GAOKUN QIU, AN PAN, ZHIBIN HU, HONGBING SHEN, FRANK B. HU, TANGCHUN BENJAMIN POLLOCK, PATRICK STUCHLIK, CAMILO FERNANDEZ ALONSO, RUPERT WU, Wuhan, China, Nanjing, China, Boston, MA BARSHOP, AZAD HUSSAIN, TIAN SHU, VIVIAN FONSECA, JACK GURALNIK, JEA- Metabolomics studies in Caucasians have identified a number of novel NETTE GUSTAT, LARRY WEBBER, WEI CHEN, EMILY HARVILLE, LYDIA BAZZANO, metabolites related to risk of type 2 diabetes (T2D), such as branched-chain New Orleans, LA, Baltimore, MD amino acids, aromatic amino acids, and certain lipids. In the present study, Sparse data exists documenting the effects of body mass index (BMI) and we sought to identify novel metabolites consistently associated with incident fasting blood glucose (FBG) from childhood through mid-life on physical per- T2D in two independent cohorts of Chinese adults. We performed targeted formance. In this study, we take advantage of repeated measurements across metabolomics (52 metabolites) of fasting plasma samples by liquid chroma- five decades of the Bogalusa Heart Study (BHS) to model poor physical per- tography-mass spectrometry in two nested case-control studies within the formance in middle-aged adults as a product of life-course BMI, FBG, and the prospective Dongfeng-Tongji (DFTJ) cohort and Jiangsu Non-communicable interaction between BMI and FBG. From our cohort of n=876 BHS participants, Disease (JSNCD) cohort. Controls were 1:1 matched with 1039 incident cases 173 (19.8%) exhibited poor physical performance as defined by short physical in the DFTJ cohort and 520 incident cases in the JSNCD cohort by age (±5 performance battery (SPPB) <10 at mid-life follow-up (mean±SD age=48.4±4.9 years) and sex. Mean age at baseline was 62.9 (SD 7.3) years in the DFTJ years). After adjustment for age, sex, race, education, and smoking, both life- cohort and 53.7 (SD 10.2) years in the JSNCD cohort, and mean follow-up was course BMI (p<.0001) and FBG (p<.0001) significantly predicted poor physical 4.6 (SD 0.2) and 7.6 (SD 1.1) years, respectively. We identified four metabo- performance, and their interaction was also highly significant (p=0.003) in gen- lites consistently associated with an increased risk of developing T2D in the eralized estimating equations models. Through childhood and young adulthood,

two cohorts by multivariate conditional logistic regression, including alanine, a lower BMI blunts the negative impact of high FBG on physical performance, phenylalanine, tyrosine and palmitoylcarnitine. In the meta-analysis of two whereas a higher BMI accelerates the negative impact of high FBG on physical cohorts, the odds ratios (95% confidence intervals, CIs) comparing extreme performance (Figure 1), even within a normal fasting glucose range. Our study quartiles were 1.77 (1.30-2.39) for alanine, 1.91 (1.41-2.59) for phenylalanine, highlights the importance of utilizing proven interventions to lower unhealthy 1.85 (1.38-2.48) for tyrosine, and 1.67 (1.24-2.25) for palmitoylcarnitine (all BMIs and FBG levels during young adulthood to lessen the chances of experi-

Ptrend lt 0.001). A metabolomic score of these four metabolites was calculated, encing limitations to physical performance as middle-aged adults. G enetics POSTERS and participants in the highest quartile of the metabolomic score had 2.28- Figure 1. Epidemiology/ fold odds of developing T2D (95% CI: 1.70-3.07; Ptrend = 6.67E-09) compared with those in the lowest quartile. In conclusion, we confirmed the association of alanine, phenylalanine and tyrosine with future T2D risk and further identified palmitoylcarnitine as a novel metabolic marker of incident T2D in two prospective cohorts of Chinese adults. Supported By: Natural National Science Foundation of China (81230069, 81390542, 81390543); National Key Basic Research and Development Program (2011CB503806); 111 Project; Program for Changjiang Scholars and Innovative Research Team in University; Priority Academic Program for the Development of Jiangsu Higher Education Institutions; Flagship Major Development of Jiangsu Higher Education Institutions

197-LB Five-Year Postpartum Retinal Vascular Structural and Functional Measures in Asian Women with a History of Gestational Diabetes Mellitus LING JUN LI, RYAN MAN, KENNETH KWEK, PETER GLUCKMAN, SEANG MEI SAW, YAP SENG CHONG, TIEN YIN WONG, ECOSSE LAMOUREUX, MICHAEL KRAMER, Singapore, Singapore, Montreal, QC, Canada Supported By: National Institute on Aging (R01AG041200) Gestational diabetes mellitus (GDM) is a known risk factor for postpartum metabolic diseases, which are underlied by vascular dysfunction. We previously 199-LB reported that GDM was associated with retinal microvasculature and sug- Lactation History, Serum Concentrations of Persistent Organic gested that transient hyperglycemia during pregnancy may cause small-vessel Pollutants, and Maternal Risk of Diabetes: Findings from NHANES dysfunction. Whether retinal microvascular abnormalities persist postpartum 1999-2006 may provide etiological evidence of the role of vascular dysfunction in disease GENG ZONG, PHILIPPE GRANDJEAN, XIAOBIN WANG, QI SUN, Boston, MA, Bal- progression i.e., from GDM to metabolic diseases. Thus, we investigated the timore, MD association between baseline GDM and 5-year postpartum retinal vascular Background: Lactation is an important route for eliminating POPs from structural and functional measures in Asian women. In this matched prospec- human body, and linked to increased diabetes risk. tive cohort study, 94 subjects (47 GDM cases and 47 age- and ethnicity-matched Objectives: To evaluate the association of lifetime breastfeeding with controls), were enrolled as part of the Growing Up in Singapore Towards healthy serum POPs and diabetes risk in women. Outcomes (GUSTO) study in 2009-2010 and re-assessed 5 years later in 2014- Methods: Among 4479 parous women, breastfeeding history was defined 2015. An oral glucose tolerance test (OGTT) was performed during 26-28 weeks as the number of children breastfed >1 month. Diabetes was identified by self- gestation at baseline and GDM was diagnosed according to WHO guidelines. reported diagnosis or hemoglobin A1c >6.5%. Twenty-four POPs were mea- Retinal examination was performed at the follow-up visit. Static retinal vascular sured in subsamples of 668 to 1073 participants, including 4 organochlorine structure (e.g., caliber) and dynamic function (e.g., arteriolar dilation %, arterio- pesticides, 4 polychlorinated dibenzo-p-dioxins and polychlorinated dibenzo- lar constriction %, venular dilation % according to flicker light) were assessed furans, 12 polychlorinated biphenyls (PCBs), and 4 perfluoroalkyl substances. using the dynamic vessel analyzer (FF450; Carl Zeiss GmbH, Jena Germany). Results: A total of 401 diabetes cases were diagnosed after the last deliv- Women with baseline GDM had narrower retinal arterioles (Δ=-6.2 µm) and ery. Compared to participants without lactation, odds ratios (95% confidence venular (Δ=-10.0 µm) caliber; and increased arteriolar (Δ=0.7%) and venular dila- interval) of having diabetes were 0.83 (0.61, 1.13) and 0.63 (0.44, 0.91) among

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LB53 EpideLatemi Boloreagy—Tyking Apebstracts 1 Diabetes

women with 1-2 and ≥3 lactation periods (P trend=0.03), respectively. The num- failure, and diabetes medications), PPDM was significantly associated with use ber of lactation periods was associated with lower serum oxychlordane, trans- of insulin (OR 11.1), alpha glucosidase inhibitors (OR 2.4), sulfonylureas (OR 2.0), nonachlor, PCB074, PCB138, PCB153, PCB169, PCB170, PCB180, and PCB194, and biguanides (OR 1.2) (all p<0.0001). Thiazolidinediones were not significantly perfluorooctanoic acid, and perfluorooctanesulfonic acid (P trend<0.05) which associated with PPDM (OR 1.01, p=0.74). GLP-1 receptor agonists and DPP-4 were 13% (PCB169, P=0.02) to 30% lower (oxychlordane, P=0.004) comparing inhibitors had statistically significant associations with PPDM, but utilization the ≥3 lactation periods to the no lactation group. The inverse association was very low (<2%) for each class. Based on this large cross-sectional analysis, between lactation and diabetes was only slightly attenuated after adjust- Veterans with PPDM maintain high HbA1c despite receiving more intensive ment for POPs. Stratified analyses showed stronger association between lac- therapy. This suggests that PPDM is not a result of undertreatment alone, and tation and diabetes among participants ≥60 years, and stronger association that other potential contributors (e.g., diet, non-adherence) must be better between lactation and POP among participants <60 years. accounted for in managing this population. Conclusions: Crudely classified lactation history was inversely associated Supported By: U.S. Department of Veterans Affairs (IIR 13-063 to G.L.J.) with concurrent POP burden and risk of prevalent diabetes. Prospective studies are needed to clarify whether and how lactation has a beneficial effect on incident diabetes through reducing POP burden. Epidemiology—Type 1 Diabetes Supported By: National Institute of Environmental Health Sciences (ES021372, ES022981); National Heart, Lung, and Blood Institute (R00-HL-098459 to Q.S.); 202-LB National Institute of Environmental Health Sciences (to X.W.) Ethnic Differences in Risk Factors, Complications, and Mortality in People with Type 1 Diabetes (T1D): A Systematic Review 200-LB KOMIL N. SARWAR, PHOEBE CLIFF, KAMLESH KHUNTI, KRISHNARAJAH NIRAN- Characterization of Veterans with Persistently Poor Diabetes Con- THARAKUMAR, PARTH NARENDRAN, Birmingham, United Kingdom, Leicester, trol: Data from a Nationwide Cohort United Kingdom MATTHEW J. CROWLEY, DAVID EDELMAN, THEODORE S. BERKOWITZ, VALERIE The epidemiology of T1D in South Asians (SA) is poorly understood. In con- A. SMITH, SANDRA L. WOOLSON, GEORGE L. JACKSON, Durham, NC trast, we know that type 2 diabetes (T2D) is 2-3 times more common in SAs Patients with persistent poorly-controlled diabetes mellitus (PPDM) – than in the white European (WE) population in the United Kingdom, and up defined as maintenance of HbA1c >8.5% for >1 year despite clinic-based to three times more common among people of African-Caribbean (AC) origin. care – are at high risk for complications and costs. In order to inform care Furthermore, SA with T2D develop the condition 5-10 years earlier than WE, innovation for this refractory population, we used a nationwide sample of have worse outcomes and die at a younger age. 300,784 Veterans with type 2 diabetes to examine patient factors associated We undertook a systematic review to explore the association of SA ethnic- with PPDM. Variables were constructed from Veterans Affairs FY2012 admin- ity in people with T1D by determining differences in risk factors, microvascu- istrative data; all patients had evidence for established clinic-based care as lar and macrovascular complications, and mortality compared to other ethnic indicated by >/=2 HbA1c measurements and >/=1 primary care visit in FY2012. groups. We conducted freetext and Mesh searches for T1D and SA ethnic Using multivariable logistic regression modeling with adjustment for clus- groups in both Medline and Embase. Full length papers and abstracts were

G enetics tering by site, we compared Veterans meeting criteria for PPDM (all FY2012 included in the search from 1946 to February 2016. A total of 11 studies were POSTERS

Epidemiology/ HbA1c >8.5%) to those with well-controlled diabetes (all HbA1c <8.0%) in included from the 4722 identified abstracts. terms of demographics and medical/mental health comorbidities. Our analytic Our review demonstrates SAs (and particularly female SAs) with T1D have population comprised 247,164 Veterans with well-controlled diabetes and higher mortality compared to WE, which is primarily due to cardiovascular 53,620 with PPDM. Following adjustment for age, sex, race, and other demo- disease. SAs also have significantly higher HbA1c than WE. Despite higher graphic/clinical factors, PPDM was significantly associated with: younger age HbA1c, rates of microvascular disease were the same as the WE population (OR 3.18 for age <40, 2.82 for 40-50, 1.86 for 50-60, 0.61 for 70-80, and 0.49 and some (neuropathy) even lower. SAs have lower levels of HDL cholesterol, for >80 (reference: age 60-70), all p<0.0001); male sex (OR 1.22, p<0.0001); and smoking rates were half that of WE. black/African-American race (OR 1.29 (reference: white), p<0.0001); Hispanic/ Compared to AC, SA had lower HbA1c, microalbuminuria, and systolic blood Latino ethnicity (OR 1.54 (reference: non-Hispanic/Latino), p<0.0001); marital pressure, and higher HDL. There were no statistically significant differences status (OR 1.22 for unmarried (reference: married), p<0.0001); and homeless- between these two ethnic groups in the remaining outcomes: cardiovascular ness (OR 1.25, p=0.0002). Depression (OR 1.07), hyperlipidemia (OR 1.14), and disease, retinopathy, neuropathy and BMI. higher weight (OR 1.02 for every 4.5 kg increase) had modest associations Our analysis highlights that ethnic disparities in macrovascular outcomes with PPDM (all p<0.01); post-traumatic stress disorder (OR 0.86) and alcohol evident in T2D may also be present may also be present for SA patients with abuse (OR 0.71) had negative associations with PPDM (all p<0.0001). This T1D. Secondly, we identify a need for a large, ideally prospective, cohort study characterization will inform the targeting and design of novel care delivery exploring the effect of ethnicity on the natural history of T1D. strategies for patients who remain poorly-controlled despite receiving clinic- based diabetes care. 203-LB Supported By: U.S. Department of Veterans Affairs (IIR 13-063 to G.L.J.) Impact of Neighbourhood Equity on Glycemic Control in Pediatric Type 1 Diabetes 201-LB ANTOINE B. CLARKE, DENIS DANEMAN, FARID H. MAHMUD, Toronto, ON, Canada Medication Use among Veterans with Persistently Poor Diabetes Background: The social determinants of health (SDH) have been heavily Control: Data from a Nationwide Cohort studied in the context of chronic diseases such as type 1 diabetes (T1D); how- MATTHEW J. CROWLEY, DAVID EDELMAN, THEODORE S. BERKOWITZ, VALERIE ever, many studies have tended to focus on income inequality despite the A. SMITH, SANDRA L. WOOLSON, GEORGE L. JACKSON, Durham, NC availability of more comprehensive measures of social equity. Patients with persistent poorly-controlled diabetes mellitus (PPDM)—defined Objectives: To evaluate the association between neighbourhood-level as maintenance of HbA1c >8.5% for >1 year despite clinic-based care—are at equity, as measured by the Neighbourhood Equity Index (NEI) - a measure high risk for complications and costs. To better understand treatment patterns encompassing 15 weighted indicators including economic, social, environ- in this refractory group, we used a nationwide sample of 300,784 Veterans with mental and community health-related factors - and glycemic control in our type 2 diabetes to examine associations between diabetes medication use pediatric T1D population. and PPDM. Variables were constructed from Veterans Affairs FY2012 admin- Methods: Hemoglobin-A1c (HbA1c) and other clinical data were obtained from istrative data; all patients had evidence for established clinic-based care as pediatric T1D patients (n=519) who attended the diabetes clinic at the Hospital indicated by >/=2 HbA1c measurements and >/=1 primary care visit in FY2012. for Sick Children (Toronto, Canada) between November 2013-2014. Postal codes Using multivariable logistic regression modeling with adjustment for clustering were used to identify the distribution of patients across city neighbourhoods by site, we compared Veterans with PPDM (all FY2012 HbA1c >8.5%) to those allowing HbA1c data to be linked to the NEI and its indicators. with well-controlled diabetes (all HbA1c <8.0%) in terms of medication use. Our Results: Mean HbA1c of patients was significantly correlated with NEI and analytic population comprised 247,164 Veterans with well-controlled diabetes 8 of its indicators. The strongest correlation with mean HbA1c was observed and 53,620 with PPDM. Overall, 71% of PPDM patients took >/=2 diabetes with the NEI score itself (R = -0.24, P<0.0001), followed by indicators related medication classes (vs. 42% of well-controlled patients) and 32% took >/=3 to education such a post-secondary completion (R = -0.175; P<0.0001) and (versus 9% of well-controlled patients). After adjustment for demographic/ municipal voting (R = -0.174; P<0.0001). Regression analysis demonstrated clinical factors (including chronic kidney disease, coronary heart disease, heart overall inequity, as measured by the NEI, was the most explanatory predictor

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LB54 GeLatenet Bireacs—Tykingpe A 1bstracts Diabetes of mean HbA1c (P<0.0001) in our pediatric T1D population compared to any 206-LB of its indicators, accounting for differences in HbA1c as large as 1.12% when A New, Specific Polymerase Chain Reaction Directed at Demethy- controlled for age, gender, T1D duration, insulin therapy, and number of annual lated and Demethylated CpG Sites at Position -182 of the Ins2 Gene clinic visits. Promoter Region from Whole Blood of Nonobese Diabetes (NOD) Conclusions: The NEI offers a more accurate representation of social ineq- Mice over 21 Months to Detect Shed, Dying Beta Cells, and Predict T uities by encompassing a wide range of weighted indicators. Our findings FRANK L. SCHWARTZ, LADONYA JACKSON, CINDY MARLING, RAZVON BUNESCU, showed NEI was a better predictor of HbA1c in youths with T1D than the indi- KELLY MCCALL, Athens, OH vidual indicators, providing evidence that measures of overall inequity may be We have developed a new PCR assay directed at the methylated CpG site better suited for the study of glycemic control in youths with T1D. of the Ins2 gene promoter region. This assay can detect dead and or/dying beta cells being shed into blood during the development of T1D in the NOD 204-LB mouse) model. Although the Ins2 gene is present in all mouse cells, only in Regulation of the Autoimmune Response in Slow Progression to the β-cell is the Ins2 gene activated through methylation and transcribed. Type 1 Diabetes Thus measuring methylated Ins2 gene fragments in whole blood samples it is ANNA E. LONG, DOROTHY J. BECKER, INGRID B. LIBMAN DE GORDON, F. SUSAN possible to detect dead or dying β-cells being shed by inflamed islet cells. We WONG, ANDREA STECK, MARIAN REWERS, PETER ACHENBACH, ALISTAIR J. first validated the assay using culturedβ TC6 and 3T3L1 cells to detect and dif- WILLIAMS, KATHLEEN M. GILLESPIE, Bristol, United Kingdom, Pittsburgh, PA, Car- ferentiate β-cells (βTC6) from non-β-cells (3T3L1) and demonstrated a lower diff, United Kingdom, Aurora, CO, Munich, Germany limit of detection range as low as 0.0001ng of DNA. We then spiked whole Multiple islet autoimmunity increases risk of diabetes but not all individu- blood samples with βTC6 cells and demonstrated a very high DI in β-cell als positive for two or more islet autoantibodies progress to disease within a “spiked” compared to “unspiked” whole blood samples. We obtained samples decade. The SNAIL Study seeks to harmonise data from longitudinal studies of whole blood from wild-type and severe combined immunodeficiency (SCID) to identify the characteristics of slow progression to type 1 diabetes. Samples NOD mice (do not develop T1D). Both NOD.WT and NOD.SCID mice spontane- from 125 individuals with multiple islet autoantibodies (IAA, GADA, IA-2A and ously shed β-cells into the blood beginning at 4 weeks of age as detected ZnT8A) for more than 10 years without progression were available from four by the assay. However, the DI is comparatively very low in NOD.SCID mice studies (Bart-Oxford (BOX) - UK; BABYDIAB - Germany; DAISY and Pittsburgh and none developed T1D. β-cell shedding (DI) was seen in all NOD.WT mice Diabetes - U.S.). Individuals enrolled in BOX provided “Rapid Progressor” which peaked at 8 weeks of age. However, the maximum peak and cumula- (diagnosed

a reciprocal reduction in high risk genotypes (24% vs. 48%; pCorr=0.005) but none carried protective HLA DQ6. Slow Progressors carried fewer HLA-Class and variability) between NOD.WT mice that developed T1D compared to those I B risk alleles (48%) than Rapid Progressors (86%; pCorr<0.001). Of 35 Slow that did not added significantly to our capacity to predict T1D risk in the NOD Progressors with longitudinal data available, only 13 (37%) retained multiple mouse model and demonstrate that PCR assessment of the demethylated Ins2 autoantibodies after 10 years (p<0.001). A reduction in positivity for IAA gene promoter region (DI) is a very accurate predictor of future diabetes risk and GADA was observed (p<0.001 and p=0.016 respectively) and in levels up to 7 weeks prior to onset. G enetics POSTERS of GADA, IA-2A and ZnT8A (p<0.05 for all). In addition, Slow Progressors had Supported By: Osteopathic Heritage Foundation Epidemiology/ lower levels of IA-2A IgG subclasses than individuals sampled close to diagnosis (p<0.05). Multiple autoantibody positivity is not maintained in some Slow 207-LB Progressors suggesting regulation of the autoimmune response. Continued Characteristics of Neonatal Diabetes in a Large Diabetes Center immuno-phenotyping of these individuals is required to elucidate the mecha- KATHERINE MANSEAU, HEIDI HARO, ALEXANDRA R. FOUTS, FRAN DONG, TAY- nisms underlying a decreased humoral response and delayed progression. LOR ARMSTRONG, LIPING YU, CHRISTINA M. CHAMBERS, GEORGEANNA J. Supported By: JDRF KLINGENSMITH, ANDREA STECK, Aurora, CO Neonatal Diabetes (NDM) is a rare monogenic form of diabetes defined classically as the occurrence of diabetes in the first 6 months of life. The aim Genetics—Type 1 Diabetes of this study was to analyze the characteristics and frequency of NDM at the Barbara Davis Center. A total of 51 unrelated subjects with diabetes onset 205-LB < 12 months of age were included in this study. All 8 subjects diagnosed < 6 months had neonatal genetic testing done and 21/43 subjects with onset > 6 months had testing for KCNJ11 and INS. Eight mutations were identified: one Withdrawn INS (onset at 11 months), two FOXP3 and five KCNJ11 gene mutations. Charac- teristics of these 9 NDM positive (including one subject diagnosed < 6 months with unknown mutation) compared to NDM negative subjects are shown in Table 1. NDM positive subjects had a higher frequency of the type 1 diabetes (T1D) protective allele HLA-DR2, DQB1*0602, while none had the T1D high risk HLA-DR3/DR4, DQB1*0302 genotype; they were more likely to have negative diabetes autoantibodies (78 vs. 38%, p=0.06). No differences in initial HbA1c, frequency of diabetic ketoacidosis, or other autoimmune diseases were found. NDM positive subjects were often treated successfully with sulfonylureas and had lower HbA1c at most recent visit (7.3 vs. 8.8%, p=0.02, adjusted for diabetes duration). Although rare, it is important for providers to correctly identify NDM patients through genetic testing as treatment and medical care is significantly different in these patients. Table 1. Characteristics NDM-positive NDM-negative P-value (N=9) (N=42) Female Gender 33% 48% 0.49 Ethnicity: Non-Hispanic white 89% 73% 0.42 Age at Diagnosis, months 3.3+3.2 10.2+1.5 0.0002 HbA1c at most recent visit, % 7.3 8.84 0.02 HLA-DR3 or HLA-DR4,DQB1*0302 38% 92% 0.017 HLA-DR2,DQB1*0602 50% 0% 0.0004 Sulfonylurea use at most recent visit 56% 0% <0.0001

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LB55 GeLatenet Bireacs—Tykingpe A 2bstracts Diabetes

Genetics—Type 2 Diabetes 210-LB A Case of MODY 5 with a Novel Mutation of HNF 1β Gene 208-LB YOU LV, ZHUO LI, KAN HE, YING GAO, XIANCHAO XIAO, YUJIA LIU, GUIXIA WANG, Modeling Diabetes Risk In Vitro: The PPARG2 Pro12Ala Polymor- Changchun, China phism’s Effect on Human Pluripotent Stem Cell-derived Adipocytes A Chinese 17 years old boy was admitted to our hospital because of CURTIS R. WARREN, CHAD A. COWAN, Cambridge, MA hyperglycemia, increased serum urea nitrogen and creatinine levels, with Genome-wide association studies have identified common variants at body weight loss (around 10kg) as well. He was treated with gliclazide (Dia- hundreds of loci that modulate the risk profile for development of type two micron), and no family history of diabetes or kidney diseases. On physical diabetes mellitus (T2DM). One variant commonly associated with T2DM is examination, his height was 150cm and body weight was 35kg (BMI 15.56kg/ 2 the Pro12Ala single-nucleotide polymorphism (SNP) of the PPARG2 gene. m ), with cephalus quadratus, rachitic rosary and a visible toe-out gait. The minor variant (Ala12) at this locus (present in ~15% of Caucasians and Laboratory examinations revealed that his fasting plasma glucose level was detected in worldwide populations) is protective against T2DM through an 12.32mmol/L (3.9-6.1mmol/L), HbA1c was 11.3%, fasting plasma C-peptide unspecified mechanism. level was 2.85nmol/L (0.37-1.47nmol/L), and not peak at 2 h of postpran- We hypothesized that the Ala12 variant protects from T2DM by changing dial, diabetic autoimmune antibodies were negative. Serum sodium, potas- the target gene profile of PPARG2 through altered interactions with transcrip- sium, calcium, phosphorus and magnesium were decreased, liver and kidney tional cofactors in white adipose tissue. To investigate this hypothesis we function increased, uric acid and parathormone increased, mild albuminuria, have employed clustered regularly interspaced palindromic repeats/CRISPR- low proportion of urine. He also presented with osteoporosis and cataracts. associated protein 9 (CRISPR/Cas) genome editing to generate a PPARG2 Abdominal CT scan showed bilateral atrophic kidney with multiple renal cysts, knockout human pluripotent stem cell line. We modeled the function of the mostly located at the junction of renal cortex and medulla, diameter was 0.3- PPARG2 Pro12Ala SNP in this genome-edited PPARG2-null background by dif- 0.7cm; and revealed hypogenesis of the body and tail of the pancreas. Kid- ferentiating knockout cells into white adipocytes via the inducible expression ney biopsy reported the mesangial cells and matrix were hyperplasia mildly; of either the major or minor PPARG2 variant. Transcriptional microarrays were immunoglobulin and addiment were negative by immunofluorescence. Elec- performed after 2 and 16 days of differentiation and revealed statistically tronic microscope presented the foot processes of glomerular epithelial cells significant variation in the gene expression profile between white adipocytes were merged segmentally. Genetic testing revealed an unreported amino acid differentiated using Pro12 or Ala12 PPARG2. mutation in exon 2 of hepatocyte nuclear factor (HNF) 1β (c.391C>T) which is a 30 genes were differentially expressed between the Pro12 and Ala12 white nonsense mutation of CAA by TAA at codon 131. This mutation was only iden- adipocytes. Gene ontology analysis indicates that extracellular matrix orga- tified on proband none of his family members. In a screening of oral glucose tolerance test, his mother and paternal uncle have been diagnosed diabetes;

nization is the single biological process significantly enriched in adipocytes expressing Ala12 PPARG2. Other adipocyte processes potentially affected by sibling sister, maternal uncle and paternal grandpa have impaired glucose tol- Pro12Ala genotype include insulin-stimulated glucose uptake, differentiation erance. The most common phenotype of HNF1β mutation is renal cysts and capacity and inflammatory cell recruitment. Mechanistic studies will define diabetes, base on the results we obtained, he was confirmed to have maturity functional capacities influenced by the Pro12Ala genotype in differentiated onset diabetes of the young (MODY) 5 with a novel mutation.

G enetics adipocytes, potentially identifying novel targets for the mitigation of the Supported By: Specialized Research Fund for the Doctoral Program of Higher POSTERS

Epidemiology/ onset of T2DM. Education Supported By: National Heart, Lung, and Blood Institute (U01HL100408, U01HL107440, R21HL120781); National Institute of Diabetes and Digestive and Kid- 211-LB ney Diseases (R01DK097768) Role of SREBP-1 as Regulator of S6K1 in the Liver VICTORIA N. JIDEONWO, MIWON AHN, SNEHA SURENDRAN, RAFAELA RUIZ, 209-LB YONYYONG HOU, NURIA MORRAL, Indianapolis, IN Identification and Functional Analysis of a Pima Indian-specific Approximately 75% of patients with type 2 diabetes are affected by non- G310D Substitution in Insulin-like Growth Factor 1 Receptor Gene alcoholic fatty liver disease (NAFLD). The liver plays a key role in maintain- that Associates with Type 2 Diabetes ing plasma glucose and lipid homeostasis. Lipid accumulation induces insulin GRAHAM S. SKELTON, YUNHUA MULLER, PENG CHEN, PAOLO PIAGGI, ANUP K. resistance by impairing the insulin signaling pathway. SREBP-1 is a transcrip- NAIR, SAYUKO KOBES, WILLIAM C. KNOWLER, CLIFTON BOGARDUS III, ROBERT tion factor of the basic helix-loop-helix leucine zipper family (bHLH-Zip) that L. HANSON, LESLIE J. BAIER, Phoenix, AZ plays a key function in de novo lipogenesis. SREBP-1 expression is induced The insulin-like growth factor 1 receptor (IGF1R) is involved in cell growth and by insulin, a process mediated by the mTORC1 complex. Emerging evidence glucose homeostasis. Studies in mice have indicated that metabolic changes indicates that SREBP-1 regulates several molecules of the insulin signaling that occur in insulin-resistant states may be a consequence of altered signals pathway, in a feedback regulatory mechanism. Thus, we questioned whether transmitted from a malfunctioning IGF1R. In the current study, 176 SNPs which SREBP-1 regulates molecules of the mTOR pathway by a similar feedback pro- 2 cess. Using adenoviral vectors, SREBP-1 was silenced in the liver of db/db tag (r ≥0.85) 1,977 non-coding variants (minor allele frequency [MAF] ≥5%) and 2 missense variants (MAF 1%) across the IGF1R locus (Chr15:99,091,768- mice. Remarkably, depletion of SREBP-1 resulted in a significant decrease in ≥ Ser473 99,607,759) were analyzed for association with type 2 diabetes (T2D) in 7,738 S6K1 and a concomitant increase in Akt . S6K1 is a downstream effector Pima Indians. Several SNPs had a nominal association with T2D (39 SNPs had of mTORC1, and it has been shown to negatively regulate the insulin signaling a P<0.05 adjusted for age, birth year, sex, European/Indian admixture, fraction pathway by phosphorylating and inhibiting Rictor, a subunit of the mTORC2 Pima and genomic control). Conditional analyses demonstrated that 2 of these complex. mTORC2 phosphorylates Akt at Ser473, and this site is needed for SNPs, an upstream rs8035741 and a novel missense G310D (risk allele fre- full activation of Akt. Our data shows that silencing SREBP-1 resulted in lower Thr1135 quencies of 0.78 and 0.03, respectively, D’=0.95, r2=0) represent independent levels of Rictor . These data suggest that the lower levels of S6K1 led to Ser473 signals in their association with T2D (adjusted P=5.5x10-5, OR=1.29[1.16-1.44] decreased mTORC2 inhibition, thereby increasing Akt . Overall, our data and adjusted P=0.005, OR=1.53[1.19-1.97], respectively). The T2D risk alleles illustrates that SREBP-1 has additional functions besides its well-established for these SNPs also associated with an earlier age of T2D onset (P=0.002, role at regulating lipogenesis, and may control S6K1 and the mTOR pathway HRR=1.16[1.06-1.28] at rs8035741; P=0.02, HRR=1.29[1.05-1.59] at G310D). in a feedback mechanism. The G310D had a stronger association with T2D in 4,177 women (P= 3 x 10-5, OR=2.12[1.50-3.02]) as compared to 3561 men (P= 0.88, OR=1.03[0.71-1.49], Psex interaction = 0.005). The G310D variant was not found in 2,687 additional American Indians from other tribes. IGF1R was further studied in vitro to determine whether the amino acid change affected receptor function. Data from a luciferase assay showed that IGF1R with the T2D risk allele D at position 310 had an 18% decrease (p=0.01) in activation of the downstream PI3K/ AKT pathway. Therefore, we propose that 6% of Pima Indians have a unique G310D which may impair IGF1 signaling pathways, thereby inducing metabolic changes that lead to the development of T2D.

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LB56 Late BreaImmunkingolo Abstractsgy

212-LB Immunology Imputation-based Reanalysis of 70,000 Individuals from Publicly Available GWAS Data Reveals Novel Additive and Recessive Sus- 214-LB ceptibility Loci for Type 2 Diabetes Sitagliptin Modulates the Immune Response of Mononuclear Cells of SÍLVIA BONÀS-GUARCH, MARTA GUINDO-MARTÍNEZ, PAULA CORTÉS-SÁN- Human Peripheral Blood (PBMC) CHEZ, IRENE MIGUEL-ESCALADA, ELIAS RODRÍGUEZ-FOS, FRIMAN SÁNCHEZ, MARCELO M. PINHEIRO, SUSANA N. DINIZ, CLAUDETE J. VALDUGA, CAROLINE L. MERCÈ PLANAS-FÈLIX, SANTI GONZÁLEZ, PASCAL TIMSHEL, TUNE PERS, CLAIRE STOPPA, RENATA GORJÃO, São Paulo, Brazil C. MORGAN, CARLOS DÍAZ, ROSA M. BADIA, JOSE C. FLOREZ, JORGE FERRER, Dipeptidyl peptidase IV (DPP-IV) is a multifunctional glycoprotein trans- JOSEP M. MERCADER, DAVID TORRENTS, Barcelona, Spain, Copenhagen, Denmark, membrane type 2 with an ample tissue distribution. DPP-IV is also known London, United Kingdom, Boston, MA as CD26, an antigen of cellular surface, expressed in T lymphocytes. The Despite the identification of thousands of T2D association loci through expression of CD26 is low on resting lymphocytes, occurring an increase of genome-wide association studies (GWAS), only a small fraction of the esti- its expression on the surface of this cells following its activation by several mated heritability has been explained for the vast majority of complex dis- mitogens, including phytohaemagglutinin (PHA). DPP-IV inhibitors have shown eases, such as type 2 diabetes (T2D). One potential cause is the poor coverage immune modulator results. Sitagliptin is a potent DPP-IV inhibitor, used to treat of low and rare allele frequency variants in early GWAS arrays. In addition, type 2 diabetes mellitus. In this study, we showed that the treatment of PBMC the role of recessive variants in T2D has not been previously assessed in a with 50 µg/ml of sitagliptin, after being stimulated with PHA, inhibited the large-scale meta-analysis. We used 1000G and UK10K reference panels to proliferation in 100% of this cells, modulated the production of cytokines in perform genotype imputation and association testing in ~70K individuals addition to decreasing the expression of CD26. (12,931 cases and 57,196 controls) from six publicly available T2D GWAS data- We showed that the effect of the sitagliptin on the proliferation was con- sets. We performed the association study testing for both the additive and centration dependent. Sitagliptin treatment can not only inhibit IL-10 and IFN-γ the recessive risk model. We identified seven novel loci, including a missense cytokines, as also completely abolish IL-6 expression by PBMCs. On the other -10 low-frequency variant (MAF=0.02, OR=1.19, p=2.72×10 ) in the EHMT2 gene. hand, high levels of IL-4 were detected in culture supernatants from sitaglip- When testing the recessive risk model, we identified a novel locus driven by tin treated cells. Our data demonstrated, in vitro, that sitagliptin increased a low-frequency variant near PELO gene. Individuals homozygous for this vari- the secretion of Th2 cytokine, decreased Th1 cytokine and may prevent Th17 ant showed more than four-fold increased risk for T2D (MAF=0.02, OR=4.5, cytokine production on peripheral human lymphocytes. p=1x10-10). The leading variant was located in an active transcription regulatory region according to ENCODE data. Carriers of this variant showed reduced Figure 1. Level of Cytokines in PBMC after being Stimulated with PHA, With- expression of PELO gene in several T2D relevant tissues, such as adipose tis- out (PHA) e With Sitagliptin Treatment (SITAGL). (Paired T Test). sue and pancreas according to GTEx data (1x10-16

213-LB Known and Novel Mutation in GCK Are the Most Common Cause of POSTERS I mmunology/

MODY in the U.S. Monogenic Diabetes Registry Transplantation MAY SANYOURA, LISA LETOURNEAU, SIRI ATMA W. GREELEY, ROCHELLE N. NAYLOR, LOUIS H. PHILIPSON, Chicago, IL Maturity-onset diabetes of the young (MODY) is a monogenic form of diabetes characterized by an early onset, autosomal dominant inheritance, and a primary defect in β-cell function. MODY represents approximately 2% of all diabetes cases and is frequently misdiagnosed as type 1 or type 2 diabetes. Accurate diagnosis of MODY through genetic testing changes treatment, with benefits to glycemic control or costs of diabetes care. Worldwide, mutations in HNF1A are the most common cause of MODY. However, in the first 215-LB and largest national monogenic diabetes registry in the United States, GCK Exendin-4 Treatment Alters the Subpopulations of CD4+ T Helper mutations are the most common cause of MODY. The University of Chicago Cells and CD4+CD25+Foxp3+ Regulatory T Cells, and the Masses of Kovler Monogenic Diabetes Registry is dedicated to correctly diagnosing Spleen and Thymus in Biobreeding Rats families with uncommon genetic forms of diabetes. To date, more than 1250 ALBERTO CEBADA-ALEU, LAURA QUINTANA-LOPEZ, CARMEN SEGUNDO, MAN- families have enrolled in our research studies. We utilized a custom designed UEL AGUILAR-DIOSDADO, Cádiz, Spain next-generation sequencing panel for the detection of variants in more than The restoration of immune tolerance is a key strategy in type 1 diabetes. 140 genes associated with monogenic diabetes. A total of 203 families (321 Recently, several studies have reported a reduction of insulitis after a gluca- patients) were found to have pathogenic mutations causative of MODY. 67% gon-like peptide-1 or its analog Exendin-4 (Ex4) treatment, in animal models of probands had MODY due to GCK mutations whereas only 26% had MODY of spontaneous autoimmune diabetes. In our study, evidence has provided due to HNF1A mutations. We identified 17 novel variants that were consid- that Ex4 induces modifications in the subpopulations of CD4+ T Helper and ered likely pathogenic, 9 of which segregated with multiple diabetic family CD4+CD25+Foxp3+ Regulatory T (Treg) cells, and the masses of spleen and members. Functional assessments are ongoing. Probands met the classic thymus in Biobreeding rats (BB). Animals were intraperitoneally treated with diagnostic criteria with a mean age at diagnosis of 26 years , mean BMI of a dose of 40 microgram Ex4/kg/day or vehicle for 5 weeks before onset of 22.86kg/m2, and mean HbA1c of 6.63%. Overall the clinical characteristics diabetes. In addition, Wistar rats were used as healthy control subjects. Our were similar for those with previously described GCK mutations. Within the group has observed that Ex4 reduces the relative masses of spleen (Wistar: U.S. Monogenic Diabetes Registry, GCK-MODY is the most common mono- 2.113 ± 0.04768, Vehicle: 2.715 ± 0.06433, Ex4: 1.994 ± 0.1304) and thymus genic diabetes type. Treatment for GCK-MODY is not recommended outside (Wistar: 1.955 ± 0.07422, Vehicle: 2.650 ± 0.1980, Ex4: 1.567 ± 0.1536) signifi- of pregnancy due to ineffectiveness of glucose-lowering therapy and lack of cantly until reaching Wistar rat level. The total population of CD3+ T cells was long-term complications. Therefore, correct genetic diagnosis is essential not affected by Ex4 in the main lymphoid organs. However, population of CD4+ to avoid unnecessary medication exposure and healthcare utilization in this T Helper cells were lower in thymus in contrast to vehicle group (Wistar: 90.44 important diabetes subtype. ± 0.9501%, Vehicle: 93.42 ± 2.154%, Ex4: 85.43 ± 2.269%). CD4+CD25+Foxp3+

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LB57 Late BreaImmunkingolo Abstractsgy

Treg subpopulation was also altered in thymus of Ex4 treated BB rats, show- 218-LB ing an increase of cell number (Wistar: 0.2400 ± 0.02846%, Vehicle: 0.3880 ± An IL-7 Receptor Blocking Antibody Increases the Ratio of Tregs to 0.05267%, Ex4: 0.8060 ± 0.1436%). Insulitis was decreased in pancreas due Effector Memory T Cells (TEM) and Increases PD-1 Expression on T to a higher amount of islets without any infiltration (Vehicle: 29.66 ± 3.318%, Cell Subsets in the Peripheral Blood of Patients with Type 1 Diabe- Ex4: 59.60 ± 3.936%), and the presence of CD4+CD25+Foxp3+ Treg cells was tes—Immune Biomarkers of a Phase 1 Study in Adults Diagno significantly improved (Vehicle: 6.536 ± 0.9593%, Ex4: 9.795 ± 0.9717%). BISHU J. GANGULY, SAMANTHA L. BUCKTROUT, JOHN B. CHENG, CHAN- Based on these findings, we conclude that Ex4 treatment modifies not only DRASEKHAR UDATA, TENSHANG JOH, MEGAN SHANNON, HONG WAN, MAT- the morphology of spleen and thymus, but also the subpopulations of CD4+ TEO LEVISETTI, JANET B. MCGILL, BRUCE W. BODE, KEVAN C. HEROLD, PAMELA T Helper and CD4+CD25+Foxp3+ Treg cells in thymus and pancreas, which D. GARZONE, RN-168 CLINICAL STUDY TEAM, South San Francisco, CA, Groton, CT, demonstrates that they may be related to the reduction of insulitis. La Jolla, CA, San Diego, CA, St. Louis, MO, Atlanta, GA, New Haven, CT Supported By: Amylin Pharmaceuticals, Inc. IL-7 receptor-α (IL-7R) signaling is crucial for T cell development and survival, particularly after encounter with antigen. RN168 (PF-06342674) is a human IgG1 216-LB antibody that blocks IL-7 binding to IL-7R. In the ongoing B4351003 clinical study, thirty-seven (30 active + 7 placebo) adult subjects diagnosed with type 1 diabe- iPLA2β-derived Lipids Contribute to Macrophage Polarization Favor- ing an Inflammatory Phenotype tes (T1D) within 2 years of study entry received multiple subcutaneous doses of JASON W. ASHLEY, ALEXANDER NELSON, WILLIAM D. HANCOCK, ROBERT N. either placebo or RN168 (1, 3, 8 mg/kg q2w or 6 mg/kg q1w) for 12 weeks with BONE, HUBERT M. TSE, SASANKA M. RAMANADHAM, Philadelphia, PA, Birming- follow-up for an additional 6 weeks. A dose-dependent inhibition of ex vivo IL-7- ham, AL, Indianapolis, IN induced STAT5 was observed in peripheral blood T cells. CD4+ and CD8+ CCR7-/ Type 1 diabetes (T1D) is an autoimmune disorder characterized by the CD45RA-effector memory T cells were reduced as much as ~65% from baseline destruction of pancreatic β-cells by autoreactive T-cells. Macrophages (Mφs) (at the 1 and 3 mg/kg dose), resulting in an increase in the relative ratio of CD4+ play a vital role in presenting autoantigens to T-cells to initiate the autoim- Foxp3+ Tregs to effector memory cell populations. RN168 treatment appeared mune events during the onset of T1D. Mφ activation towards tissue repair is to have a smaller effect on naïve T cells (maximum of ~35% decrease at 3 mg/ directed by a variety of extracellular signals and mediated by multiple intrac- kg dose). A trend towards increased PD-1 expression in CD4+ and CD8+ T cells provided evidence of a polarization to an exhausted or tolerized phenotype. ellular pathways. Activation of group VIA phospholipase A2 (iPLA2β) leads to accumulations in arachidonic acid, lysophospholipids, and eicosanoids, which The marked similarity of T cell modulation by RN168 to that observed in the can promote inflammatory responses and contribute to several pathologies alefacept trial (TiDal) suggests these pharmacodynamic effects may result in (i.e., cancer, autoimmunity, neurodegeneration). We investigated the impact clinically relevant immunomodulatory activity in recent-onset T1D. of iPLA2β on Mφ polarization between pro-inflammatory M1 and anti-inflam- -/- matory M2 phenotypes by comparing peritoneal Mφs from WT and iPLA2β 219-LB mice. When compared to WT, induction (qRT) of M1 markers (Arg2 and iNOS) Evaluation of Novel “Diabetic” Antibodies in Wild-Type and Tlr3 -/- via classical activation was significantly reduced in Mφs from iPLA2β mice, Knockout NOD Mice while M2 markers (MRC1, ARG1, CCL2, and STAT6) were significantly elevated SARAH METRO, MARIA CECILIA COURREGES, FRANK SCHWARTZ, KELLY D. under naïve conditions and significantly further induced during alternative MCCALL, Athens, OH -/- activation in iPLA2β Mφ. Moreover, iPLA2β-deficiency reduced classical acti- Nonobese diabetic (NOD) mice spontaneously develop type 1 diabetes (T1D) vation-mediated induction of eicosanoid (12-LO and COX2) and ROS (NOX4) when raised in a sterile environment and enteroviruses such as Coxsackievirus generating enzymes. Consistently, inhibition of 12-LO (CDC) and COX2 (Indo- B4 (CVB4) trigger an acceleration of T1D when administered to mice after a methacin) promoted M2 and reduced M1 phenotype. Based on these findings, “threshold of insulitis” at 8 weeks (wks) of age. Previously, we demonstrated

it is speculated that reducing iPLA2β activity would promote a protective envi- in cultured beta (β) cells and in NOD mice that β-cell death is mediated in part ronment by altering Mφ polarization towards the M2 phenotype. by activation and downstream signaling of toll-like receptor 3 (TLR3). Recently, Supported By: National Institutes of Health, National Institute of Diabetes and 3 anti-CBV4 antibodies (abs) (anti-T1DM, anti-COXSA, and anti-CA) have been Digestive and Kidney Diseases isolated from the sera of recent-onset T1D patients and were shown to induce β-cell apoptosis. To determine the role of TLR3 in virus-induced β-cell apop- POSTERS I mmunology/

Transplantation 217-LB tosis leading to T1D, we quantified these abs in the serum of both WT and Immunoassay of Pathogenic CD8+ T Cells Against Five Epitopes from TLR3 knockout (KO) NOD mice using custom ELISAs. Serum abs were obtained Islet Antigens Improve Immune Diagnosis of Type 1 Diabetes between 4-8 wks of age and every 3 days (d) for 2 wks following CVB4 infection. YUN SHI, YANG CHEN, YONG GU, XINYU XU, LINGLING BIAN, FAN YANG, SHUANG Insulitis in the pancreas of infected and uninfected WT and KO NOD mice at the CHEN, LI JI, JIN LIU, JING ZHU, ZHENG ZHANG, QI FU, YUN CAI, HENG CHEN, same time periods were also assessed. Interestingly, prior to CVB4 infection, KUANFENG XU, XIANGTING XU, MIN SUN, XUQIN ZHENG, JIE SHEN, HONGWEN WT mice exhibited a spontaneous spike in all 3 abs at 5 wks of age. Following ZHOU, MEI ZHANG, TAO YANG, Nanjing, China CBV4 infection, KO mice exhibited significantly higher levels of diabetes abs Although autoantibodies against islet antigens have been shown as effec- beginning at d-3 compared to infected WT mice, yet these mice do not develop tive markers for the prediction and diagnosis of type 1 diabetes, a signifi- T1D. Insulitis increased at 7-8 wks before CBV4 infection with most insulitis cant fraction of newly diagnosed patients is seronegative. More importantly, seen in WT mice at 8 wks. All 3 abs and insulitis scores increased dramatically autoantibodies are not required for β-cell destruction. Since pathogenic CD8+ in both cohorts following CBV4 infection. The levels of the 3 abs were slightly T cells play a central role in the destruction of pancreatic β-cells in type 1 dia- higher in the KO mice at each time point but insulitis was not significantly dif- betes, T-cell assays could contribute to both preclinical diagnosis and immune ferent from WT mice. These results demonstrate that these specific abs are surrogate end points for clinical trials. This study was to explore a satisfactory actually present in both cohorts of NOD mice prior to viral infection and follow- pathogenic CD8+ T- cell assay to more accurately diagnose type 1 diabetes. ing CBV4 infection, antibody titers were greatest in the KO on ds 3, 5, and 7 yet Pathogenic CD8+ T-cell IFN-γ enzyme-linked immunospot (ELISpot) against they do not develop T1D. These observations link the obligatory requirement 28 epitopes derived from 7 β-cell auto-antigens and radio-binding assay or of TLR3 in the pathogenesis of CBV4 induced T1D in the NOD mouse while the ELISA for islet-autoantibodies were performed in 109 HLA-A2+ subjects. higher antibodies following infection in the KO mice do not. New-onset autoantibody-positive type 1 diabetic patients responded to 16 epitopes among 28 epitopes by ELISpot in comparison with healthy controls. 220-LB We, furthermore, determined ELISpot response against two epitopes was an Immunomodulatory Microparticle Vaccine Induces Tolerogenic Den- optimal positive cutoff (75.0% sensitivity, 94.4% specificity), and it was more dritic Cells and Prevents Human T-Cell Proliferation sensitive in children (93.3% sensitivity, 94.4% specificity). Pathogenic CD8+ MAIGAN A. HULME, JAMAL LEWIS, JOSHUA STEWART, TODD M. BRUSKO, T cell response kept high accuracy (71.4% sensitivity, 94.4% specificity) to MARK A. ATKINSON, BENJAMIN KESELOWSKY, Gainesville, FL, Davis, CA reflect type 1 diabetes, even with 5 islet-specific epitopes. Notably, 77.8% Type 1 diabetes (T1D) results from the loss of immune tolerance to insulin- new-onset and 25.0% long-standing seronegative type 1 diabetic patients producing pancreatic beta cells. A major therapeutic goal in T1D is the induction were positive by ELISpot assay. Moreover, sensitivity to detect type 1 diabe- of persistent immune tolerance to beta cell antigens without global immunosup- tes could reach 91.1% while ELISpot assay was complemented with autoan- pression. We have developed a formulation consisting of large poly-lactic-co- tibody determinations. glycolic acid (PLGA) microparticles (MPs) providing local controlled release of Pathogenic CD8+ T- cell measurement could be a satisfactory application in TGF-β1 and GM-CSF, and small phagocytosable MPs encapsulating Vitamin D3 clinical diagnosis and etiologic classification in type 1 diabetes. and denatured insulin. In previous work, this tolerogenic vaccine formulation pre-

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LB58 LateT Brareansplakingn Atatbstractsion

vented T1D in nonobese diabetic (NOD) mice. In order to translate this therapeu- TNF-α and Hexokinase2 gene expression was observed in peritoneal cells tic approach, we sought to assess the impact of this formulation on human APC from imatinib- treated obese and diabetic mice (all p<0.05). activation state and subsequent T cell activity. We generated monocyte-derived In summary, attenuation of macrophage activation by imatinib could serve DCs (moDC) and incubated them for 48 hr in media alone, with TGF-β1 and Vita- as a screening tool to assess the impact of differential macrophage activation min D3 MPs, or with unloaded MPs at equivalent ratios. moDCs were assessed on metabolic disease parameters. This could help to decipher pathways and for activation state following LPS exposure or co-cultured with allogeneic T cells mechanisms involved in metabolic diseases and potentially be exploited in to assess T cell proliferation. moDCs treated with factor-loaded MPs failed to future translational applications. upregulate HLA-DR and the costimulatory molecules CD40, CD80, and CD86 in Supported By: Swiss National Science Foundation response to LPS, indicative of maturation resistance. Additionally, MP loaded moDCs increased expression of the checkpoint receptors PD-L1 and Galectin 223-LB 9. MP-treated moDCs also suppressed alloantigen-induced T cell proliferation, Nivolumab-induced Autoimmune Diabetes May Be Primarily Medi- with an increased expression of FOXP3 in T cells and enhanced expression of the ated by Cell-Mediated Immunity negative regulator PD-1. These results support the induction of tolerogenic APC EDWARD H. YANG, JING H. CHAO, Seattle, WA and a regulatory T cell phenotype in both murine models and in in vitro human Nivolumab, an anti-programmed cell death-1 monoclonal antibody (anti- studies, further supporting the clinical translation of this vaccine formulation. PD-1 mAb), is increasingly used to treat cancers and has been reported to Supported By: National Institutes of Health precipitate autoimmune diabetes, with few reported cases in humans. All patients have at least 1 positive autoantibody. We report a case of antibody- 221-LB negative overt diabetes following the use of nivolumab, presumed to be Dynamic Shifts in Adipose Tissue Inflammation with Acute High-Fat entirely driven by cell-mediated immunity. Diet in Mice A 65-year-old man with metastatic rhabdomyosarcoma with no personal or BYRON HETRICK, ADRIAN HUFFARD, CARRIE MCCURDY, Eugene, OR family history of diabetes received 2 doses of nivolumab. His BMI is 27kg/m2 Chronic, low grade inflammation associated with obesity is recognized as and weight 92kg. After 30 days, he presented with polyuria and polydipsia and a critical link between obesity and insulin resistance. Enrichment or deple- was found to have a VBG of 535mg/dl, an arterial pH of 7.11, an anion gap of tion of leukocyte subtypes in obese adipose tissue relative to lean promotes 18, and a beta-hydroxybutyric acid of 2.11mmol/L—a presentation consistent a pro-inflammatory state. Specifically, obese adipose tissue is enriched in pro- with DKA. He was treated with IV insulin per hospital protocol. Four days later, inflammatory leukocytes including B cells, neutrophils, CD8+ T-cells, NKT cells, he was discharged on a total daily dose of 120 units of insulin, with an insulin: and M1 macrophages and decreased in anti-inflammatory leukocytes such as weight ratio of 1.3 unit/kg and blood glucose of 88-143mg/dl. Two weeks later, eosinophils, M2 macrophage and regulatory T-cells. Since leukocyte subtypes his insulin dose was reduced by 40% to maintain euglycemia. Initial C-peptide stimulating adipose tissue inflammation have generally been studied in isolation, was <0.1 ng/mL with a concurrent VBG of 320mg/dl. Two weeks later, we held little is known about their temporal changes and relative importance in the initia- his insulin to permit a rise in VBG to 246mg/dl, and his C-peptide remained <0.1 tion of the inflammatory cascade. We hypothesize that the immunophenotype of ng/ml. His anti-GAD antibody, insulin autoantibody, and islet autoantibody 2 col- adipose tissue is dynamic and will respond to acute changes in adipocyte expan- lected within 36 hours of initiating insulin, and zinc transporter 8 autoantibody sion. We measured the effect of 3 days of high fat diet (HFD; 45% fat calories) on 12 days later, were 0 mmol/L, 0 nmol/L, <0.8 U/mL, and <10.0 U/mL, respec- the leukocyte composition expressed as a percent of CD45+ cells in epididymal tively. (EPI) and subcutaneous (SQ) fat pads in C57BL/6J mice by flow cytometry. After Animal studies have demonstrated anti-PD-1 mAb-induced insulitis and 3 days of HFD, B, NKT, and invariant NKT cells were significantly increased in diabetes mediated by T cells, as well as a lack of correlation between insu- the EPI, while eosinophils and overall T-cells were reduced. The reduced T-cell lin autoantibodies and the development of diabetes. Our patient’s onset of number was primarily due to reduced numbers of regulatory T-cells. Macrophage insulinopenia in his 7th decade following the use of nivolumab and his lack of numbers were not changed, but there was an increased number of TNF-α+ mac- autoantibodies highly suggest that nivolumab-induced diabetes may be primar- rophages. These results indicate that in EPI, the initiation of a pro-inflammatory ily mediated by cell-mediated immunity rather than humoral immunity. More state is preceded by a down-regulation in anti-inflammatory cells, allowing pro- studies are needed to further elucidate the underlying mechanisms in humans. inflammatory activation, potentially via B cells. The SQ fat pad is more resistant POSTERS to the pro-inflammatory state. Accordingly, pro-inflammatory leukocytes did I mmunology/ Transplantation not increase after 3 day HFD exposure. Surprisingly, we observed an increase Transplantation in eosinophils and an increase in IL-10 expressing M2 macrophages, suggesting that components of this fat depot work actively to prevent inflammation. 224-LB Supported By: 5R01DK095926 Continuous Glucose Monitoring Following Pancreatectomy and Islet Autotransplantation 222-LB JOSE JIMENEZ-VEGA, RANJIT CHIMA, MAISAM ABU-EL-HAIJA, TOM LIN, JOSEPH Potential Role of Tyrosine Kinase Inhibitors on Macrophage Polar- PALERMO, LINDSEY HORNUNG, JAIMIE NATHAN, DEBORAH A. ELDER, Cincinnati, OH ization in Metabolic Disease Background: Total or partial pancreatectomy and islet auto transplantation SHEFAA AL ASFOOR, THERESA ROHM, CLAUDIA CAVELTI-WEDER, Basel, Switzerland (IAT) is offered to patients with chronic pancreatitis with incapacitating pain It has previously been shown that tyrosine kinase inhibitor (TKI) treatment not amenable to medical or endoscopic therapies. IAT is performed with the of patients with chronic myeloid leukemia leads to improvement of glycemic goal to prevent the development of brittle diabetes. In the early post-surgical control. Reduced beta-cell apoptosis and insulin resistance have been postu- period, hyperglycemic is detrimental to the transplanted islet. lated as underlying mechanisms. As TKIs have been described to influence the Objective: To determine if a Continuous Glucose Monitoring (CGM) device activation status of tumor-associated macrophages and leukemia cells, we can monitor blood glucose (BG) trends in an accurate way during the post- hypothesized that in metabolic disease TKIs induce a shift from pro- to anti- surgical period of pancreatectomy and IAT. inflammatory macrophages, potentially mediating improved glycemic control. Methods: A total of 5 patients underwent IAT at our institution (4 with total Peritoneal cells of male C57 mice were polarized for 6 hrs in vitro to a pro- and 1 with partial pancreatectomy). Post operatively, patients used a CGM (M1) or anti-inflammatory (M2) phenotype with or without concurrent TKI- device (Dexcom G4 Platinum) to monitor BG trends. After IRB approval, a ret- treatment (1uM imatinib). For in vivo analysis, male C57 mice at 4 weeks were rospective chart review of BG data (serum glucose, Point of care (POC), and put on a 3-months high fat diet with (diabetic group) or without (obese group) CGM data) from the duration of their ICU stay. a single-dose of the beta-cell toxin streptozocin (130mg/kg). Animals were Results: 45 time-matched measures on all 3 monitoring methods were treated with oral imatinib (100mg/kg) or saline during the 2 weeks before sac- found. 69% of the CGM readings were within 15mg/dL and 62% were within rifice. Macrophage polarization was assessed by gene and protein expression 10mg/dL when compared to serum glucose (8.9% false positive readings). of pro- and anti-inflammatory markers. The mean absolute difference (MAD) was 15.2mg/dL, and the mean absolute In vitro, gene expression of the pro-inflammatory cytokines TNF-α relative difference (MARD) was 13.1%. 89% of the POC readings were within (p<0.001), IL-6 (p<0.01), IL-1β (p<0.05) and iNOS (p<0.001) was reduced in 15mg/dL and 84% were within 10mg/dL of serum values (0% false positive M1-macrophages upon imatinib treatment compared to untreated M1-con- readings). The mean absolute difference (MAD) was 6.9mg/dL and the mean trols (n=6-15), while these changes were not found in unpolarized or M2- absolute relative difference (MARD) was 5.8%. macrophages. TNF-α protein in the supernatant of M1-macrophages was The CGM device did not significantly differ from serum glucose (p=0.19). also diminished (M1 2512±541, M1+imatinib 1177±48pg/ml). In vivo, reduced The POC did not significantly differ from the serum glucose (p=0.39).

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LB59 InsulLinate Act Breaion—Akingd iApocbstractsyte Biology

Conclusion: The CGM device was found to be a reliable tool in monitoring 227-LB glucose values in the post-surgical IAT patients in an ICU setting. Future stud- Evidence for Beta Cell Dedifferentiation as a Cause for Sustained ies are needed to validate these results. Graft Dysfunction Following Peri Engraftment Hypoxia in Clinical Islet Transplantation 225-LB SCOTT J. ANDERSON, SARAH L. ARMOUR, MICHAEL G. WHITE, EKATERINE Findings in Mixed Meal-Tolerance Test Before and After Total Pan- BERISHVILI, HELEN MARSHALL, THIERRY BERNEY, JAMES A. SHAW, Newcastle, createctomy and Islet Autotransplantation United Kingdom, Geneva, Switzerland YU KUEI LIN, R. MATTHEW WALSH, TYLER STEVENS, RITA BOTTINO, BETUL A. Islet transplantation has become an established therapy to prevent recur- HATIPOGLU, Cleveland, OH, Pittsburgh, PA rent life threatening hypoglycaemia in type 1 diabetes. Restoration of normal Total pancreatectomy (TP) is increasingly performed to relieve the pain of β-cell function has remained elusive in comparison to nondiabetic controls chronic pancreatitis (CP), and islet autotransplantation (IAT) aims to prevent and whole pancreas transplant recipients. We hypothesised that β-cell dedif- postsurgical diabetes. There is currently no presurgical assessment that can reli- ferentiation may play a role in sustained impaired graft function post-trans- ably predict metabolic outcomes after TPIAT. This historical cohort study aims plant into the hypoxic intra-portal vein niche. to determine whether presurgical mixed meal-tolerance test (MMTT) predicts Islet dedifferentiation phenotypes were assessed in sections from a human insulin independence (II), and to assess its association with postsurgical MMTT explanted liver transplant. The recipient had received a combined islet/liver profiles in patients receiving TPIAT for painful CP. MMTT was performed before transplant for cystic fibrosis associated disease. Islets were fully functional at surgery in 37 patients, and again after surgery in 25 of those patients. Plasma the time of explant. To model peri-transplant hypoxic stress, isolated human blood glucose, insulin, proinsulin and C-peptide were measured at 0, 15, 30, 60, islets were exposed to 1% oxygen or normoxia for 24 hours. (De) differen- 120, 180, 240 and 300 minutes after study mixed meal. At postsurgical visits, II tiated β-cell phenotype was quantified by rtPCR and immunofluorescence was defined as good glycemic control (HbA1c<7%) without any insulin use, and staining. Functional changes were assessed by glucose stimulated insulin insulin dependence (ID) was defined as the need of conventional insulin program secretion (GSIS). for glycemic control. Partial insulin independence (PII) was defined by the need β-cells within transplanted islets demonstrated co-expression of mesen- of some insulin supplement, mostly once-a-day long-acting insulin, to maintain chymal (vimentin) and α cell (glucagon) phenotypic markers. Dedifferentia- controlled glycemia. The relationship between metabolic outcomes and peak tion was further evidenced by loss of mature endocrine marker urocortin-3 time/value of glucose, insulin, proinsulin and C-peptide, and proinsulin/insulin in insulin-positive cells. All dedifferentiation phenotypes were absent in area-under-curve (AUC) ratio during MMTT were assessed. Presurgical MMTT control pancreas. Human islets subjected to hypoxic challenge demonstrated laboratory evaluation did not predict metabolic outcomes. In postsurgical MMTT, decreased expression of mature β-cell genes: insulin (0.8 fold), Pdx1 (0.4 fold), an association between II or PII and peak glucose time (30, 30 and 120 minutes, Nkx6.1 (0.6 fold) and urocortin 3 (0.6 fold). Immunofluorescence demonstrated p=0.002), peak insulin value (403.8, 228.3 and 111.0 mcU/mL, p=0.014), and peak insulin/vimentin co-expressing cells and β-cell specific loss of urocortin-3. proinsulin time (60, 180, 210 minutes, p=0.007), peak C-peptide value (4.3, 3.0, Dysfunction was evidenced by impaired GSIS: 4.1±0.6 fold (control) vs. 2.2±0.1 0.8 ng/mL, p=0.001) (II, PII, ID, respectively) were observed. An increase in the fold (hypoxia). insulin/proinsulin AUC ratio by 138.7 predicts II, with an OR of 5.04 (95% CI 1.00- β-cell dedifferentiation and plasticity towards insulin/glucagon co-express- 25.46, p=0.004). In our study, presurgical MMTT glucose, insulin, proinsulin, ing cells has been demonstrated following clinical islet transplantation, with C-peptide and insulin/proinsulin ratio did not correlate with II. ex vivo evidence that this dysfunctional phenotype can be induced by short term hypoxic stress. 226-LB Aerobic Exercise Still Poses a Challenge for Glucoregulation in Insu- 228-LB lin-Independent Islet Transplant Recipients IGF-II Restores Rapamycin-induced Suppression of Beta-Cell Differ- JANE E. YARDLEY, NORMAND G. BOULÉ, DEANNA R. FUNK, JORDAN REES, entiation and Expansion of Adult Pancreas Stem Cells SAEED R. ESHGHI, KITTY K. CHEUNG, TOLULOPE O. OLATEJU, PETER SENIOR, CHENG LIN SUN, GUI XIA WANG, KUN HO YOON, Changchun, China, Seoul, Repub- Camrose, AB, Canada, Edmonton, AB, Canada lic of Korea Islet transplantation (ITx) is effective to prevent severe hypoglycemia in We underwent this study to find a way to protect against the harmful effects type 1 diabetes, but may not fully normalize glucose regulation. In animal stud- of rapamycin on differentiation and expansion of porcine neonatal pancreas ies, moderate-intensity aerobic exercise can induce hypoglycemia despite ITx. cell clusters (NPCCs) comprised primarily of pancreatic precursor cells. We hypothesized that changes in plasma glucose during and after aerobic exer- Rapamycin treatment resulted in a marked reduction in the number of β-cells,

cise in ITx patients would be greater than during a comparable resting control insulin contents, and cell viability in monolayer-cultured porcine NPCCs, but day. On 2 separate days, 7 insulin independent ITx individuals (3:4 male: female; IGF-II treatment possible to preserved the damages caused by rapamycin treatment. IGF-II treatment recovered decreased expression of pancreas- age=48.7±6.6 years, HbA1c=6.5±0.6%) performed either moderate-intensity specific genes include insulin, PDX-1 and NeuroD/Beta2 and simultaneously cycling (60% of VO2 max) or seated rest for 45 minutes at the same time of day (i.e., before supper) in random order, and at least 48 hours apart. Participants reversed the rapamycin induced Foxo1 cytosolic nuclear translocation along with the decreased gene expression and increased phosphorylation of Foxo1.

POSTERS replicated the timing and composition of food intake as closely as possible.

I nsulin Action/ Plasma glucose was sampled before the exercise/rest condition, as well as Furthermore, IGF-II treatment was sufficient to offset the adverse effects of immediately after and every 15 minutes for the next hour. A significant (p<0.01) rapamycin on differentiation and expansion of porcine NPCCs 8 weeks after M olecular etabolism time by condition interaction was found, with plasma glucose being lower after transplantation in diabetic nude mice. Taken together, IGF-II treatment might the end of exercise compared to control. Postprandial increases in interstitial prove an effective method for minimizing the deleterious effects of rapamycin glucose after the evening meal (measured by continuous glucose monitoring) on differentiation and expansion of porcine NPCCs. were greater on exercise days compared to control days (p<0.05). These data suggest that aerobic exercise still poses a challenge for glucoregulation despite restoration of insulin independence after ITx. Insulin Action—Adipocyte Biology Figure. 229-LB Adipose Insulin Receptor Activity Controls Whole-Body Glucose Homeostasis: Revisiting the Adipose-specific Insulin Receptor Knockout Mouse MAX FRIESEN, CAROLYN HUDAK, FANG XIA, CHAD COWAN, Cambridge, MA Type 2 diabetes has a well-defined progressive pathogenesis of disease, beginning with insulin resistance in metabolic tissues such as adipose. The insulin receptor regulates critical metabolic functions like glucose and lipid metabolism via downstream intracellular signaling. Insulin signaling in adipose tissue increases glucose uptake and lipogenesis, halts lipolysis and affects the secretion of various adipokines. Previous studies have used the adipose-specific aP2 promoter to drive Cre recombinase expression. Insr Supported By: Alberta Diabetes Institute knockout mice created using this aP2-Cre strategy (FIRKO mice) were pro-

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LB60 Insulin Action—CLateell Breaularking an dA bstractsMolecular Metabolism

tected from obesity and glucose intolerance. Later studies demonstrated the reversible model for investigating the roles of IR and IGF-1R signaling in patho- promiscuity of the aP2 promoter, casting doubts upon the tissue specificity of genesis of lipodystrophy including adipose-liver and -β-cells cross talk. aP2-Cre models. It is our goal to use the increased precision of the Adipoq promoter to investigate tissue-specific Insr function. Towards this end we gener- 232-LB ated an adipose-specific Insr knockout (AIRKO) mouse using an Adipoq-driven Loss of UCP1 Disrupts Glucose Metabolism in Female Mice Cre recombinase. AIRKO mice are less insulin sensitive throughout life, and VICTORIA J. VIEIRA-POTTER, NATHAN C. WINN, MICHELLE L. GASTECKI, REBECCA less glucose tolerant than wild-type (WT) littermates at the age of 16 weeks. J. WELLY, TERESE M. ZIDON, T’KEAYA L. GAINS, MAKENZIE L. WOODFORD, NATA- AIRKO mice in contrast to WT littermates are unaffected by age or dietary LIA KARASSEVA, HAROLD SCOTT SACKS, JAUME PADILLA, Columbia, MO, Los regimen in their insulin sensitivity, and are comparably insulin resistant to Angeles, CA old or obese WT mice. The AIRKO mouse is protected from high-fat diet- Uncoupling protein 1 (UCP1), the characteristic protein of brown (B) adipose induced weight gain. This correlates with a 90% reduction in tissue weight tissue (AT) is also present in white (W) AT during “browning.” BAT activity and of major adipose depots compared to WT littermates, but is accompanied by WAT browning inversely associate with insulin resistance (IR) in rodents and hepatomegaly and increased fatty liver. These data indicate that adipose Insr humans. While WAT inflammation predicts IR, WAT browning may ⇓ inflam- function is crucial to whole-body metabolism and has profound effects on mation. We hypothesize that UCP1 improves IR due to ⇓ inflammation via ⇓AT adiposity and hepatic homeostasis. We believe the inconsistency between oxidative stress. We reasoned that female mice null for UCP1 would have ⇑ our data and the FIRKO mouse study is driven by aP2-Cre ablation of Insr in susceptibility to Western diet (WD)-induced AT inflammation and IR. UCP1-/- a non-adipose cell type. Further research with tissue-specific promoters will (KO) and wild-type (WT) mice (age, 6 wks) fed WD or control diet (CD) for 28 provide insight into beneficial effects of attenuating insulin signaling. wks (at 25°C) were compared for food intake, weight gain, adiposity, energy Supported By: National Institute of Diabetes and Digestive and Kidney Dis- expenditure (EE) and fuel oxidation (indirect calorimetry), physical activity eases (R01DK097768); National Heart, Lung, and Blood Institute (U01HL100408, (beam breaks), IR (estimated via glucose tolerance test AUC (GTT) and fasting U01HL107440, R21HL120781) insulin), WAT and BAT inflammation (gene expression), and indicators of WAT and BAT mitochondrial function and oxidative stress (gene and protein expres- 230-LB sion, TBARS). Despite no differences in food intake, EE, activity, or weight gain, SORLA Facilitates Insulin Receptor Signaling in Adipocytes and KO developed IR, exacerbated by WD (GTT: diet, genotype, both P<0.01; fasting Exacerbates Obesity insulin: genotype x diet (int), P=0.04). Despite no WAT mass differences, KO VANESSA SCHMIDT, Berlin, Germany WAT had greater inflammatory gene expression (~385%⇑ IL6, P=0.014; ~200% SORL1, encoding the intracellular sorting receptor SORLA, is a major genetic ⇑ MCP1, P=0.027; ~100% ⇑ TNFα, P=0.05) and ⇑ susceptibility to WD-induced risk factor for familial and sporadic forms of Alzheimer’s Disease. Now, GWAS oxidative stress via TBARS (int, P=0.05). In BAT, a striking 500% ⇑ in mass have also associated SORL1 with obesity in humans and mouse models, sug- was observed only in KO/WD (int, P<0.01) along with increased leptin mRNA gesting a novel function for this receptor in control of metabolism. Studying (int, P<0.02), both suggestive of WD-induced BAT “whitening.” Paralleling this, mouse models with loss or tissue-specific overexpression of SORLA as well remarkable gene expression differences were observed such that KO BAT had ⇑ as obese human subjects, we identified the underlying molecular mechanism MCP-1 (int, P=0.01), macrophage (CD68, P<0.01; ITGAM, P<0.01; CD11c, P=0.04), whereby SORLA promotes insulin-induced suppression of lipolysis in adi- and ER/oxidative stress (p22phox, P<0.01; p47phox, P<0.01; HSPA5, P<0.01; pocytes. Specifically, SORLA acts as sorting factor for the insulin receptor DDIT3, P<0.01) mRNA and ⇓ BAT mitochondrial subunit protein expression (COX (IR) that re-directs internalized receptor molecules from endosomes to the I, II, IV; all P<0.05). Our findings uncover a previously unrecognized role for UCP1 plasma membrane to enhance IR surface exposure, and to strengthen insulin in protecting against IR via a mechanism independent of total adiposity. signal reception in target cells. Overactivity of SORLA in adipose tissue blocks Supported By: Cardiometabolic Disease Research Foundation (to J.P.); Sears Trust hydrolysis of triacylglycerides and causes excessive deposition of body fat. In Research Foundation (to J.P.); National Institutes of Health (K01 HL-125503 to J.P.); contrast, Sorl1 gene inactivation accelerates breakdown of triacylglycerides University of Missouri (to V.J.V-P.) in adipocytes and protects from diet-induced obesity. Our findings provide a molecular explanation for the association of SORL1 with human obesity and confirm a genetic link between neurodegeneration and metabolism to con- Insulin Action—Cellular and Molecular verge on this receptor. Metabolism

231-LB 233-LB

A Mouse of Model of Acute Reversible Lipodystrophy with Dual Inhi- bition of Insulin and IGF-1 Receptors KAZUKI TAJIMA, JUN SHIRAKAWA, YU TOGASHI, YASUO TERAUCHI, Yokohama, Withdrawn Japan Lipodystrophy is characterized by a selective loss of adipose tissue which is

accompanied by severe insulin resistance, hyperinsulinemia, hyperglycemia, POSTERS and fatty liver. Insulin receptor (IR) and IGF-1 receptor (IGF-1R)-mediated sig- I nsulin Action/ naling mediates metabolic and mitogenic activities in various tissues. Here we administered OSI-906 (45 mg/kg), an orally dual inhibitor of IR and IGF-1R, to M olecular etabolism mice once daily for 7 days and conducted histological and gene expression analysis of metabolic tissues on the day of the last injection or after 7 or 21 days of drug withdrawal (Day 14 or Day 28). The OSI-906-treated mice had shown acute, systemic insulin resistance with continuous hyperglycemia and hyperinsulinemia until day 7, but not day 14. At day 7, weight and adipocyte size of epididymal fat were significantly reduced in mice with OSI-906 (n=8, P<0.01). This was associated with a decreased levels of leptin mRNA, and an increased expression of lipolysis-related genes Lpl and Atgl. Strikingly, the lipodystrophy in OSI-906-treated mice were fully recovered to normal conditions at day 14. The changes in the above gene expressions were also reverted to normal levels. Weight and triglyceride (TG) content of the liver, and liver G6Pase, PGC1α and CD36 mRNA levels were significantly upregulated in OSI-906-treated mice at day 7, but not at day 14. OSI-906 also significantly increased pancreatic β-cell mass and proliferation. Interestingly, β-cell mass did not regress after drug withdrawal, although the increased β-cell proliferation had been restored to normal levels at day 14. Next, we injected OSI-906-treated mice with leptin (1 mg/kg/day) for 7 days. Leptin slightly improved blood glucose levels and reduced hypertrophy and TG content in the liver, but not affected adipose tissue in OSI-906-treated mice. Taken together, we established a novel rapid,

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LB61 Insulin Action—CLateell Breaularking an dA bstractsMolecular Metabolism

234-LB 236-LB Hepatic Insulin Degrading Enzyme Knockdown Does Not Improve Activation of Cd11b in Neutrophils and Monocytes: A Useful Acute Glucose Metabolism in DIO-Rodents Target Engagement Biomarker to Address Low-Grade Chronic Inflam- JENSON QI, TONYA MARTIN, MEGAN TOWERS, MATTHEW M. RANKIN, JIANY- mation in Diabetes ING LIU, KEITH DEMAREST, LISA NORQUAY, SEUNGHUN P. LEE, ALESSANDRO FRANKLIN LIU, Kenilworth, NJ POCAI, Spring House, PA Increased tissue inflammation has been implicated in the progression and Insulin-degrading enzyme (IDE) is a protease that cleaves insulin and other severity of diabetes and cardio-metabolic diseases. Inhibition of the Leu- bioactive peptides. Insulin catabolism has been postulated to be mediated kotriene B4-Receptor 1 (BLT1) has been reported to decrease adipose tissue primarily by IDE without definitive in vivo confirmation. IDE knockout mice inflammation and to protect against systemic insulin resistance and hepatic have elevated insulin levels, but exhibit impaired glucose tolerance. Recent steatosis in DIO mice (Nat Med. 2015, 21:239). To understand the effects of data generated with small molecule inhibitors challenge IDE’s role as primary BLT1 antagonists (BLT1i) in type 2 diabetic preclinical and clinical models, we mediator of insulin clearance in vivo. Several IDE inhibitors were recently proposed inhibition of LTB4-driven CD11b activation in neutrophils and mono- reported to inhibit insulin degradation in vitro and pharmacological inhibition cytes in whole blood measured by flow cytometry, as a suitable target engage- of IDE in vivo has been reported in rodent models with inconclusive results. To ment biomarker (TE BMx). To validate the TE BMx assay, Rhesus whole blood better understand potential implications of IDE inhibition on insulin and glu- was treated ex vivo or alternatively rhesus and mice were treated in vivo with cose regulation, we used Ambion® in vivo siRNAs against mouse IDE to knock- either BLT1 specific antagonist (BLT1i) or BLT1/BLT2 antagonists (BLT1/BLT2i) down the IDE expression in the livers of diet-induced obese (DIO) mice. Two with higher affinity for BLT1. A dose dependent inhibitory effect of BLT1i and IDE directed siRNAs resulted in a significant reduction of hepatic IDE mRNA BLT1/BLT2i on CD11b activation in neutrophils was observed in Rhesus blood levels as compared to the control siRNA group by 65% or 72%, respectively, treated ex vivo. In addition, 90% inhibition of CD11b activation was observed three days after a single injection of siRNA-invivofectamine® 3.0 complexes in the whole blood of lean Rhesus treated with 30 mg/kg of BLT1i for 2 h and in the tail veins of DIO mice. However, no significant reduction of glucose AUC in dysmetabolic rhesus treated with ascending doses of BLT1i for one week. (area under the curve; mg/dl*120 min) was observed after an oral glucose tol- To back-translate to rodent models, more suitable to address the correlation erance test (OGTT, N=8/group; p=NS siRNA vs. control siRNA). There was no of acute TE BMx with chronic efficacy, a time course treatment of lean and ob/ significant difference in plasma insulin levels 15 min or 120 min after the glu- ob mice with various doses of BLT1i significantly decreased LTB4-driven CD11b cose challenge. We performed a second study with two sequential injections activation in neutrophils in a dose dependent manner. In ob/ob mice, 14-day of an IDE siRNA in DIO mice at Day 0 and Day 3. At Day 6, hepatic IDE mRNA treatment with BLT1i significantly reduced adipose tissue inflammation. In expression was decreased by ~70% and a reduction of hepatic IDE protein summary, a CD11b activation assay from whole blood was established as a TE levels was also observed (N=10). No significant difference in the glucose AUC BMx assay that empowers translation from rodents to rhesus and humans. values (mg/dl*120 min) or in plasma insulin levels at 15 min or 120 min during the OGTT between the two groups was observed (N=10/group; p=NS siRNA 237-LB vs. control siRNA). Our results show that inhibition of IDE does not improve Tissue-specific Diurnal Patterns of TRIB3 Expression Coordinate glucose tolerance in a mouse model of obesity and insulin resistance and do Whole Body Metabolic Homeostasis: Role of the Cardiac Circadian not support inhibition of IDE for the treatment of diabetes. Clock XIAOBING LIU, WEI ZHANG, MINSUNG KANG, MARTIN E. YOUNG, W. TIMOTHY 235-LB GARVEY, Birmingham, AL Chronic GPR40/120 Dual Agonist Treatment Significantly Improves Background: We have previously shown that TRIB3 is a glucose-respon- Hyperglycemia and Insulin Sensitivity Compared to GPR40 Agonism sive protein that can impair insulin-responsive glucose transport, and act as Alone in ob/ob Mice a nutrient sensor to oppositely regulate fuel metabolism between fat and SANTHOSH SATAPATI, ALEKSANDR PETROV, XIAOLAN SHEN, RAFAEL MAYORAL, muscle during periods of fasting or nutrient excess. However, whether TRIB3 OKSANA PALYHA, YING CHEN, STEPHEN PREVIS, JUNMING YIE, LIANGSU WANG, coordinates nutrient homeostasis over the course of a day is unknown. JIN SHANG, Kenilworth, NJ Hypothesis: TRIB3 expression fluctuates diurnally in response to prandial G-protein-coupled receptors, GPR40 and GPR120 play an important role in and post-prandial conditions, exhibiting a circadian rhythm in metabolically insulin secretion and insulin sensitization and each has been evaluated as active tissues. a potential target to treat diabetes and metabolic disorders. GPR40 is pref- Results: We measured TRIB3 expression in heart, muscle and liver isolated erentially expressed in β-cells and potentiates insulin secretion in response from wildtype (WT) mice at 3-hour and 6-hour intervals. Interestingly, cardiac

to medium and long chain fatty acids. GPR120 is a physiological receptor for TRIB3 levels oscillated regularly with peaks occurring every 6-hours in the ω3 fatty acids in macrophages, adipocytes and enteroendocrine cells mediat- 3-hour-interval group. In muscle, TRIB3 expression also oscillated in a Biphasic ing anti-inflammatory and insulin sensitizing effects. Previously, independent pattern, with peaks occurring every 12 hours. In contrast to cardiac and skeletal studies have documented beneficial effects of GPR40 and GPR120 agonism muscle, TRIB3 levels in the liver displayed a cosine wave, peaking in the light in rodent models of insulin resistance and diabetes. In the current study we cycle. To determine whether such time-of-day-dependent oscillations were con- hypothesized that GPR40/120 dual agonism results in improved glucose lower- trolled by intrinsic circadian clocks, two mouse models were utilized: 1.) cardio- POSTERS

I nsulin Action/ ing, and insulin sensitizing effects compared to GPR40 agonism alone. To test myocyte-specific CLOCK mutant (CCM); and 2.) cardiomyocyte-specific BMAL1 this, 5-week old male ob/ob mice were treated with either a GPR40 specific knockout (CBK) mice. In both models, oscillations in cardiac TRIB3 expression M olecular etabolism agonist (cmpd A, 100mpk) or a GPR40/120 dual agonist (cmpd B, 30 mpk) for 4 were disrupted and levels were significantly increased (p<0.05). Surprisingly, weeks. Hyperinsulinemic-euglycemic clamp was performed to measure insu- TRIB3 rhythms in skeletal muscle and liver were also altered in CBK mice. lin sensitivity. Both GPR40 agonist and GPR40/120 dual agonist significantly Conclusion: (i) TRIB3 oscillates in a time-of-day-dependent manner with improved ambient hyperglycemia (252 vs. 387 mg/dl, p ≤ 0.0001 and 171 vs. tissue-specific patterns; and (ii) the cardiac circadian clock regulates TRIB3 387 mg/dl, p ≤ 0.0001 respectively) and hyperinsulinemia compared to vehicle oscillations in the heart and has a critical effect on TRIB3 expression in mus- treated animals. However, dual agonist significantly improved ambient glyce- cle and liver. Further, in light of previous data, these diurnal patterns of TRIB3 mia (171 vs. 252 mg/dl, p ≤ 0.05) compared to GPR40 agonist treatment alone. expression represent a novel mechanism coordinating whole body metabolic Furthermore, dual agonist significantly increased glucose infusion rate (GIR) homeostasis via tissue-specific regulation of fuel utilization. measured by hyperinsulinemic-euglycemic clamp compared to both vehicle Supported By: National Institutes of Health (DK038746, DK083562); U.S. Depart- (19.4 ± 1.4 vs. 3.4 ± 1.4 mg/kg/min, p ≤ 0.001) and GPR40 agonist (19.4 ± 1.4 ment of Veterans Affairs; University of Alabama at Birmingham Diabetes Research vs. 6.4 ± 2.4 mg/kg/min, p ≤ 0.01) treatment; a marked difference indicating Center (P60 DK079626) improved insulin sensitivity. In conclusion, these data demonstrate GPR120 confers synergistic efficacy when used in combination with GPR40 agonism, 238-LB resulting in superior glucose lowering and improved insulin sensitivity. The Role of Glucose Transporter 12 in Muscle Glucose Metabolism VY HOANG, SUZANNE ROGERS, SANDRA GALIC, Fitzroy, Australia, Bundoora, Australia Glucose transport into skeletal muscle via facilitative glucose transporter (GLUT) proteins is a rate limiting step in post-prandial glucose clearance. Thus, the activity of GLUT proteins is critical for whole body glucose homeostasis. Defects in the function of insulin sensitive transporter GLUT4 are known to contribute to skeletal muscle insulin resistance that occurs in obe-

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LB62 insulin Action—Glucose Transport Late Breaking AbstractsInsulin Action—Signal Transduction, And Insulin Resistance In Vitro Insulin, and Other Hormones sity and type 2 diabetes. The glucose transporter GLUT12 is also expressed of ligand for the receptor. In HUH-7 cells, IRAB-A acts as a sensitizer and but in skeletal muscle but its role in glucose homeostasis is unclear. To assess can induce IR signaling alone. Acutely, the antibody significantly decreased the contribution of GLUT12 to muscle metabolism and glucose disposal, we fed blood glucose 2 h after SC injection in C57Bl/6 mice, and persisted for generated muscle-specific GLUT12 knockout (GLUT12 mKO) mice. Metabolic up to 2 weeks (n=8). A concomitant reduction in insulinemia was observed (7 characterization of GLUT12 mKO mice unexpectedly revealed enhanced insu- day AUC: 3mpk, -31.0±21.7%; 10mpk, -45.2±15.5%), consistent with a reduced lin sensitivity compared to wild type littermates. In intraperitoneal insulin and demand for endogenous insulin secretion. To test the effect of IRAB-A on glu- glucose tolerance tests, GLUT12 mKO mice exhibited increased insulin sensi- cose tolerance, a 2g/kg OGTT was performed 24 h post-injection in fasted tivity and no difference in glucose tolerance. Serum levels of non-esterified mice. Fasted blood glucose was 46.8±3.2mg/dL in IRAB-A treated mice ver- fatty acids and insulin were also lower in GLUT12 mKO mice compared to sus 116.5±8.8mg/dL in control mAb injected mice (n=8; p<0.0001). Although wild type. However, insulin-induced Akt activation was unchanged in GLUT12 IRAB-A improved glucose tolerance (28.8% lower AUC/120min; p<0.0001) mKO muscle. Thus, the enhanced insulin sensitivity of GLUT12 mKO muscle and reduced glucose-stimulated insulin-secretion (64.2% lower AUC/120min; may involve processes downstream of Akt that regulate GLUT4 translocation. p<0.001), IRAB-A was observed to alter the kinetics of the post-glucose chal- Further measurements of the respiratory exchange ratio in metabolic cages lenge glycemic excursion. Analysis of insulin and C-peptide showed no inap- show that GLUT12 mKO mice have a preference for lipid versus carbohydrate propriate insulin clearance; fasting glucagon levels were elevated in IRAB-A oxidation, indicating a reduced ability for glycogen synthesis. Overall our find- mice, but suppressed by the glucose challenge. Phosphoprotein analysis of ings identify glucose transport via GLUT12 is important in regulation of both liver and gastrocnemius tissue demonstrated significantly elevated levels muscle and whole body glucose metabolism. This regulation may occur by of (P)Y1150/1151-Insulin Receptor 24 h following IRAB-A injection; however, altering muscle substrate utilization. phospho-Akt levels were only elevated in skeletal muscle, not liver, at this time point. Further studies in DIO mice demonstrated effects of IRAB-A on fed blood glucose and insulinemia, and alteration in glycemic excursion dur- Insulin Action—Glucose Transport and ing glucose challenge following single dose or 4-wk treatment. IRAB-A rep- Insulin Resistance In Vitro resents a unique long acting modulator of glucose homeostasis in vivo with insulin-sensitizing and agonist activity. 239-LB Maternal Obesity Reduces Skeletal Muscle Insulin Sensitivity in 241-LB Fetal and Juvenile Japanese Macaques The Hippo Pathway Effector Taz Is a Critical Regulator of PPARγ WILLIAM CAMPODONICO-BURNETT, BYRON HETRICK, DIANA TAKAHASHI, Activity and Insulin Sensitivity SIMON SCHENK, CARRIE MCCURDY, Eugene, OR, Beaverton, OR, La Jolla, CA DALILA EL OUARRAT, MATTHEW RIOPEL, DENISE LACKEY, GAUTAM BANDYO- Obesity during pregnancy confers a greater risk of offspring developing PADHYAY, JERROLD M. OLEFSKY, La Jolla, CA metabolic disease; however the mechanism is unknown. We hypothesized Obesity-driven type 2 diabetes has reached global epidemic proportions, that maternal obesity combined with a western-style diet (WSD) during preg- and causes insulin resistance and adipose tissue dysfunction in ~382 mil- nancy would result in reduced insulin sensitivity in fetal muscle that persists lion people in the western world. The nuclear receptor PPARγ, is as a master in juveniles independent of offspring obesity. To test this hypothesis, adult regulator of adipogenesis, and its function can be regulated by multiprotein female macaques were chronically fed a WSD to induce obesity (Ob; defined complexes. Among these are transcriptional corepressors, which have vari- as >30% body fat) compared to lean females maintained on a control diet ous effects on metabolic dysfunction and insulin resistance. However, the (Ln; <25% body fat). We measured insulin-stimulated 2-deoxyglucose uptake physiological role and underlying mechanism of PPARγ corepressor function (IS-2DGU) and signaling in fetal rectus femoris (RF) collected mid-3rd trimester in metabolic tissue is not fully understood. and in gastrocnemius collected at 14 months of age from offspring of Ln and Here, we identified the Hippo pathway effector TAZ (Transcriptional co- Ob dams that were weaned to CTR diet at 7 months (Ln/CTR, Ob/CTR). In fetal Activator with PDZ-binding motif) as a transcriptional corepressor of PPARγ RF from Ob dams, IS-2DGU was decreased 78% compared to Ln, demonstrat- and show that TAZ is important for adipocyte biology and glucose homeo- ing dramatic insulin resistance. In parallel, insulin-stimulated phosphorylation stasis. of Akt at residues T308 and S473 was reduced 46% and 39%, respectively, Adipocyte specific TAZ knockout mice (AKO) showed significantly improved and AS160 phosphorylation at T642 was reduced 75%. Both insulin receptor glucose tolerance and insulin sensitivity compared to WT littermate controls and IRS-1 abundance was decreased in Ob compared to Ln, while GLUT1, PI3 when fed high fat diet (HFD). Furthermore, PPARγ response genes were upreg- kinase, and Akt abundance did not change. In lean juvenile offspring exposed ulated in adipose tissue from AKO mice and PPARγ ser-273 phosphorylation

to maternal obesity and WSD during early development (Ob/CTR), IS-2DGU in was reduced. Adipose tissue macrophage infiltration and inflammation were gastroc was 62% lower than Ln/CTR. The decrease in 2DGU corresponded to also decreased in obese HFD AKO mice compared to their WT littermates. a similar decrease in insulin-stimulated Akt phosphorylation at T308 (55%) CO-IP studies revealed that Extracellular signal-Regulated Kinase (ERK) and S473 (58%) in Ob/CTR compared to Ln/CTR. Reduced insulin sensitivity dependent ser-273 phosphorylation of PPARγ enhances TAZ-PPARγ associa- may arise from dysfunction in both positive and negative regulators of insulin tion. Furthermore, with the use of PPARg phosphorylation mutants and MEK signaling. In fetal RF from Ob dams, Rictor abundance, an upstream activa- inhibitors we demonstrate that TAZ no longer interacts with PPARg. These POSTERS tor of Akt, was decreased. Overall, exposure to maternal obesity resulted results indicate that under HFD conditions, repression of PPARg activity by I nsulin Action/ in a persistent decrease in offspring muscle insulin sensitivity that was not TAZ is regulated by ser-273 phosphorylation, and could explain how TAZ dele- reversed by a transition to a healthy diet and may explain the increased risk of tion leads to improved glucose and insulin homeostasis. These results raise M olecular etabolism metabolic diseases in offspring born to an obese mother. the possibility that TAZ may be a useful target for future therapeutics in the Supported By: National Institutes of Health (K12 HD057022, R24 DK090964) treatment of type 2 diabetes and other insulin resistant diseases. Supported By: National Institutes of Health

Insulin Action—Signal Transduction, 242-LB Insulin, and Other Hormones Novel Insulin Receptor mAb Induces In Vitro and In Vivo Insulin Resistance 240-LB ANNE M. CIENIEWICZ, SIMON A. HINKE, THOMAS KIRCHNER, RUPESH K. NAN- A Novel Insulin Receptor mAb Modulates Insulin Signaling and Alters JUNDA, KATHARINE E. D’AQUINO, MARK L. CHIU, NATHANIEL H. WALLACE, Glucose Homeostasis In Vivo FUYONG DU, JOHN R. MABUS, ROBERT A. PERKINSON, DANA L. JOHNSON, KEITH T. DEMAREST, EILYN R. LACY, JEAN M. WHALEY, YIN LIANG, RUSSELL B. SIMON A. HINKE, ANNE CIENIEWICZ, THOMAS KIRCHNER, NATHANIEL WAL- LINGHAM, ANTHONY J. KIHM, Spring House, PA LACE, FUYONG DU, JOHN MABUS, ROB PERKINSON, ANTHONY KIHM, RUSSELL Improved understanding of diabetes pathogenesis and the development of LINGHAM, DANA JOHNSON, KEITH DEMAREST, JEAN WHALEY, YIN LIANG, therapeutics is dependent on reliable experimental models of insulin resis- Spring House, PA Positive allosteric modulation of the insulin receptor using novel insulin sen- tance. We report a novel monoclonal antibody, IRAB-B, a potent antagonist sitizing monoclonal antibodies may provide alternative therapies to restore that binds specifically to the insulin receptor (IR) with nanomolar affinity (2.5 glycemic control in type 2 diabetes. We have identified a mAb, IRAB-A, that nM). IRAB-B binds the IR simultaneously with ligand. In vitro, IRAB-B prevents insulin induced IR phosphorylation (IC = 6.5 nM). Dose titration showed binds specifically to the insulin receptor (K : 3.2nM) and increases the affinity 50 d clear shifts of the insulin response with 30 nM IRAB-B resulting in a 10-fold

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LB63 Insulin Action—SignalLate Tra Bnreasdkinguctio An,bstracts Insulin, and Other Hormones

EC50 shift. Time course experiments demonstrated that IRAB-B blocks the nomenon was even more pronounced during palmitic acid treatment, which IR for at least 72 hrs. IRAB-B also decreased downstream signaling result- revealed an ever greater increase in S473 Akt phosphorylation and IRS-2 ing in reduced insulin induced phosphorylation of IRS-1 and Akt in HuH7 expression in hepatocytes treated with PHDi compared to controls. To deter- cells and glucose uptake in 3T3 cells. In vivo, IRAB-B rapidly induced robust mine whether or not this effect was dependent upon Hif2α, primary hepato- hyperglycemia (>400 mg/dL) in normal mice within 6 hours of injection. The cytes were transfected with Hif2α siRNA, then subjected to PHDi treatment. effect of a single dose was sustained for at least 2 weeks with peak levels Upon insulin stimulation, Hif2α siRNA knockdown blocked the increase in Akt of at least 600 mg/dL. Notably, IRAB-B hyperglycemia was normalized by the phosphorylation compared to scrambled siRNA cells. This suggests that the GLP-1 receptor agonist, Exendin-4. Finally we compared IRAB-B activity to metabolic improvements associated with PHDi treatment require stabiliza- the mixed IR antagonist, S961, that binds at the IR orthosteric site. In vitro, tion/induction of Hif2α protein expression. If the PHD/hypoxia program can IRAB-B and S961 demonstrate different kinetics and potencies of IR and Akt be modified in a way that leads to improved insulin sensitivity, it would be an phosphorylation. In vivo, dose titration experiments with normal mice dem- attractive pathway to intervene as a treatment of insulin resistance. onstrated 1.0 mg/kg S961 or 10 mg/kg of IRAB-B induced hyperglycemia of Supported By: National Institute of Diabetes and Digestive and Kidney Diseases ~450 mg/dL. However, these cohorts showed significantly different insulin levels with IRAB-B treated animals showing >50 ng/mL and S961 ~30 ng/mL 245-LB (n=8; p<0.01). Thus IRAB-B presents several advantages over S961 as a tool An Akt1-Atg13 Interaction Mediates Starvation-induced Autophagy to block the insulin receptor as IRAB-B is a pure antagonist and exhibits a in Cardiomyocytes sustained effect in vitro and in vivo. We conclude IRAB-B is a valuable tool in QUAN JIANG ZHANG, E. DALE ABEL, BHARAT JAISHY, KENSUKE TSUSHIMA, Iowa generating multiple mammalian models of hyperglycemia and hyperinsuline- City, IA mia and may help characterize these altered conditions. IRAB-B may provide Autophagy is an evolutionarily conserved and cell autonomous lysosomal- insight into the pathophysiology of diabetes and be used to evaluate candi- dependent process, which is critical for cell survival under conditions of date therapeutics. nutrient deprivation. This study sought to confirm that Akt1 may regulate autophagy by interacting with Atg13 in cardiomyocytes. H9C2 cells were 243-LB starved in nutrient deplete medium (ND, glucose-free HBSS+0.5 mM pyru- Soluble Amyloid Precursor Protein Beta Links Type 2 Diabetes and vate) for 2 h, and mice were fasted for 24 h (6:00 PM to 6:00 PM). Nutrient Alzheimer’s Disease through Partial Agonism of Insulin Receptor withdrawal in H9C2 cells or food deprivation in mice increased autophagic HONGLI CHEN, CHRISTIAN PEHMOLLER, YUJI SHI, TONI WHITTARD, ASHLEY flux as shown by increased LC3-II content and LC3-II/I ratio, and decreased ROBSHAW, LIYA KANG, CHARLES E. NOLAN, CRAIG L. HYDE, OLIVIER BEZY, Cam- accumulation of p62 and NBR1 (P<0.05, n≥10), which was significantly attenu- bridge, MA ated when insulin at 100 nM was added to ND medium for 1 h (P<0.05, n≥10) Recent studies have shown common disease symptoms and risk factors or 20 min after 0.25U/kg was injected via tail (P<0.05, n≥4). When Akt1 was between both type 2 diabetes mellitus (T2D) and Alzheimer’s Disease (AD). If silenced using siRNA or knocked out using a Cre-lox strategy, autophagic flux insulin resistance (IR) is intrinsically related to T2D development, it is now well induced by ND was markedly attenuated (P<0.05, n≥6). In contrast, silencing established that central IR is a hallmark of AD. Conversely, individuals with Akt2 in H9C2 cells or knocking out Akt2 in mouse hearts increased autophagic AD are more likely to exhibit impaired fasting glucose levels. We hypothesized flux as shown by increased LC3-II content and less accumulation of p62 that products of amyloid precursor protein (APP) proteolysis, i.e., amyloid pep- (P<0.05, n≥6). Under nutrient replete/fed conditions, Atg13 is sequestered in tides Aβ and soluble APPβ (sAPPβ), could play a role in the onset of IR in a protein complex with FIP200 and ULK1/2. Nutrient deficiency leads to dis- peripheral tissues. In patients, we observed that plasma Aβ 1-40 was signifi- sociation of this complex and dephosphorylation of Akt1, and promotes an cantly (p < 1.0e-05) higher in Pre-T2D and T2D subjects compared to healthy interaction between dephosphorylated Akt1 and Atg13, which is required for subjects. Aβ 1-40 was significantly associated with Triglycerides (positively, initiating autophagy. Phosphorylation of Akt1 disrupts the Akt1-Atg13 protein p < 0.001) and HDL (negatively, p < 0.01), even after adjusting for obesity and complex and inhibits autophagic flux. These data reveal a previously unknown T2D status. We then explored susceptibility to diet induced IR of a mice model role for Akt1 and identify a novel signal mechanism that induces autophagy in of AD (Tg2576 mice overexpressing swAPP in brain). When placed on a high- response to nutrient deficiency or fasting. fat diet, Tg2576 had increased levels of plasma Aβ species and sAPPβ compared to WT. High-fat fed Tg2576 mice became more obese as well as more 246-LB glucose and insulin intolerant. Compared to WT animals, Tg2576 animals dis- A New Gene Therapy for Type 1 Diabetes Based on In Vivo AAV-medi- played worsen insulin resistance in adipose tissue, muscle and liver. In vitro, ated IGF1 Expression to the Pancreas

acute treatment of human and murine primary hepatocytes or murine 3T3- CRISTINA MALLOL, ESTEFANIA CASANA, VERONICA JIMENEZ, ALBA CASELLAS, L1 adipocytes with recombinant sAPPβ, but not with Aβ species, activated CLAUDIA JAMBRINA, VICTOR SACRISTAN, MERITXELL MORRÓ, LAIA VILÀ, InsR and downstream canonical insulin signaling cascade. Direct interaction XAVIER LEON, FATIMA BOSCH, Barcelona, Spain between sAPPβ and InsR was confirmed by co-immunoprecipitation. Chroni- Type 1 diabetes is characterized by progressive autoimmune destruction of cally, and similar to insulin, sAPPβ induced InsR desensitization. Comparison insulin-producing beta-cells that leads to severe insulin deficiency. To prevent of human insulin and sAPP Copper Binding Domain (CuBD) structures revealed

POSTERS or counteract overt hyperglycemia therapeutic approaches aim at preserving

I nsulin Action/ striking similarities supporting that sAPPβ could act as partial agonist of InsR. the loss of pancreatic beta-cell mass, expanding the number of beta-cells, or These observations provide a new insight in pathological similarities between interrupting the autoimmune process that destroys islets. Insulin-like growth M olecular etabolism T2DM and AD patients. factor 1 (IGF1) is a potent mitogenic and pro-survival factor for beta-cells, as well as having immunomodulatory properties. Here we report the first dem- 244-LB onstration that overexpression of IGF1 specifically in the pancreas prevents Pan-Prolyl Hydroxylase Inhibition in Hepatocytes Improves Insulin and counteracts spontaneous autoimmune diabetes in NOD mice. Pancreas- Sensitivity specific gene transfer was achieved through the use of AAV vectors combined MATTHEW RIOPEL, YUN SOK LEE, JERROLD M. OLEFSKY, La Jolla, CA with microRNA target sequences. This approach enabled robust, long-term Prolyl hydroxylase enzymes (PHD1, 2 and 3) are responsible for target- IGF1 expression in the pancreas and prevented IGF1 production in off-target ing the hypoxia inducible factors (Hif1α and Hif2α) for degradation in times tissues. Treatment of pre-symptomatic NOD mice with AAV-IGF1 showed to normoxia. During hypoxia, PHDs do not hydroxylate Hifs and Hif protein decreased lymphocytic infiltration of the islets and lower levels of expression expression is sustained, which leads to activation of Hif target genes. of antigen-presenting molecules, inflammatory cytokines and chemokines Recently, Hif2α was shown to influence insulin sensitivity and insulin signal- important for tissue-specific homing of effector T cells, all of which prevented ing in hepatocytes. We further explored these results through the use of a beta-cell loss. Furthermore, AAV-mediated IGF1 delivery to older mice with small molecule pan-PHD inhibitor (PHDi) in high-fat diet-fed (HFD) mice and established pathology stopped autoimmune progression and reduced diabe- primary murine hepatocytes. Treatment of HFD mice with PHDi led to a signifi- tes incidence to 20%, with sustained normoglycemia and normoinsulinemia in cant improvement in glucose tolerance, which was associated with increased rescued animals. Collectively, these data suggest that AAV-based IGF1 gene Hif2α and Irs-2 protein expression in the liver. When primary murine hepa- delivery to the pancreas may represent a promising therapeutic approach for tocytes were treated with PHDi, there was sustained protein expression of prevention and treatment of autoimmune diabetes. Hif2α, along with induction of Hif target genes such as Pdk1, Vegf-A, and Irs- Supported By: Ministerio de Economía y Competitividad, Plan Nacional I+D+I 2. During insulin stimulation, PHDi-treated hepatocytes showed significantly (SAF2011-24698, SAF 2014-54866-R) increased Akt Serine 473 phosphorylation compared to controls. This phe-

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LB64 Integrated PLhateysi oloBreagy—kingIn Asbstractsulin Secretion In Vivo

247-LB injury caused insulin resistance (p=0.022). To investigate the role of IL6, we Super-resolution Single Molecule Localization Microscopy of the conducted thermal injury upon IL6-/- mice. Four day after thermal injury, serum Exocytotic Machinery Underlying Insulin Secretion insulin levels and the IITT were in the normal range. Moreover, the IGTT was DEIRDRE M. KAVANAGH, ALISON DUN, RORY R. DUNCAN, COLIN RICKMAN, Edin- indistinguishable from the controls suggesting that insulin sensitivity of ther- burgh, United Kingdom mally injured mice was improved significantly in the absence of IL6. Next Insulin secretion requires the fusion of insulin-containing vesicles with the we investigated the phosphorylation of the insulin signaling cascade in liver plasma membrane through the process of exocytosis. Membrane fusion is and skeletal muscle of thermally injured WT and IL6-/- mice. In liver, insulin driven by the action of SNARE proteins. In β-cells, various SNARE isoforms stimulated phosphorylation of Akt (S473), Gsk3β (S9), Tsc2 (S939) and mTOR exist; these include: syntaxin1a, 3 and 4 and SNAP-23 and SNAP-25 (t-SNAREs) (S2448) was not changed after thermal injury of WT or IL6KO mice; however, at the plasma membrane, together with VAMP2 on the vesicular membrane. compared against WT muscle, insulin stimulated phosphorylation of these Type 2 diabetes (T2DM) occurs when β-cells can no longer compensate for the proteins increased significantly in IL6-/- muscle 4 days after thermal injury. prolonged high elevations of glucose, leading to insufficient insulin secretion. Moreover, thermal injury IL6-/- muscle displayed reduced phosphorylation of Single molecule localization microscopy (SMLM) utilizes photoswitchable several stress activated kinases—Jnk (T183), NFκB (S536) and p38 (T180)— fluorescent probes to control the density of fluorescent emitters. By imaging compared against thermally injured WT muscle. We conclude provisionally photoswitching events repeatedly over thousands of frames we can build up that thermal injury dysregulates insulin signaling and metabolism in skeletal a precise map of fluorophore positions. Combining SMLM with diffraction-lim- muscle of mice, which is associated with the induction of serum IL6 levels. ited microscopy we have examined the co-location of t-SNARE proteins and Supported By: National Institutes of Health insulin vesicles in HIT-T15 cells. Using GFP tagged insulin, or immunostaining for insulin, we were able to observe the relative spatial distribution of vesicles to individual t-SNARE molecules. Applying a Bayesian approach of quantita- Integrated Physiology—Insulin Secretion tive cluster analysis, we systematically compared t-SNARE membrane clus- In Vivo tering following normal and elevated glucose exposure. We observed that t-SNARE proteins form clusters of low and high molecular density with a non- 250-LB random spatial distribution on the plasma membrane. Furthermore, we do not GPR142 Controls Glucose-dependent Insulin Secretion and Incretin observe t-SNAREs clustered directly underneath insulin vesicles, noting only Hormone Release to Improve Glucose Metabolism partial overlap between the two. Overall, these results provide new insight HUA V. LIN, ALEXANDER M. EFANOV, JINGRU WANG, JUAN J. CARRILLO, XIANK- into the molecular organization of t-SNARE proteins at the plasma membrane ANG FANG, LISA S. BEAVERS, XUESONG WANG, Indianapolis, IN, Shanghai, China of β-cells. GPR142, a putative Tryptophan receptor, is expressed in pancreatic islets Supported By: Medical Research Council and the gastrointestinal tract and has been investigated as a novel therapeutic target for the treatment of type 2 diabetes (T2D) by virtue of its insulin 248-LB secretagogue activity. However, the ligand affinity and signaling pathways A Novel Method Enabling the Use of Small Muscle Samples to Iden- downstream of this receptor remain obscure. Furthermore, whether stimula- tify Insulin Effects on Akt2 and AS160 Subcellular Localization tion of insulin release by GPR142 is glucose-dependent is not known, nor is XIAOHUA ZHENG, GREGORY CARTEE, Ann Arbor, MI any potential role of this receptor in gastrointestinal hormone regulation. In Akt protein kinases play overlapping and distinct roles in many physiologi- this study, we show that in addition to Tryptophan, Phenylalanine can also cal processes. Akt1 and Akt2 are the highly expressed in skeletal muscle, and activate GPR142 signaling, while none of the other naturally-occurring amino Akt2 is more important for insulin-stimulated glucose transport. In adipocytes acids has significant activity. Both native and synthetic GPR142 agonists can Akt-isoform diversity in insulin-mediated subcellular localization is crucial activate Gq as well as Gi signaling in a cell system with recombinant receptor for isoform-specific function, but little is known about Akt isoform-specific expression. However, in primary pancreatic islets, a native cellular system, the localization in muscle tissue. Subcellular localization by fractionation is chal- insulin secretagogue activity of GPR142 agonists only requires Gq activation. lenging, in part because existing methods typically require grams of tissue. Importantly, stimulation of insulin secretion by GPR142 agonists in pancre- Therefore, the purpose of this study was to develop a method to evaluate atic islets is strictly glucose-dependent. Tryptophan and a synthetic GPR142 subcellular protein localization requiring only 50 mg muscle and assess insu- agonist increase insulin and the incretin hormones glucagon-like peptide-1 lin effects on Akt localization. Rat soleus strips were isolated and incubated and glucose-dependent insulinotropic polypeptide (GIP) and improve glucose with or without insulin. Muscle lysates subsequently underwent ultra-speed disposal in mice in a GPR142-dependent manner. In contrast, Phenylalanine centrifugation. Membrane (Na+, K+ ATPase and insulin receptor) and cytoso- improves in vivo glucose disposal in mice independently of GPR142. Notewor- lic (LDH) fraction markers were used to validate the purity of fractions. With thy, refeeding-induced elevations in insulin and GIP are blunted in GPR142 null insulin-stimulation, Akt2, but not Akt1, had significantly (P<0.05) increased mice. In conclusion, GPR142 agonists represent a novel class of potential T2D abundance in the membrane, but not cytosol. Similar Akt isoform specific- therapies that leverage amino acid sensing pathways to enhance glucose- ity has been previously demonstrated for insulin-stimulated adipocytes, but dependent insulin secretion and incretin hormone release. this is a novel result for muscle tissue. In addition, Akt substrate of 160 kDa (AS160; also called TBC1D4), an Akt2 substrate and key regulator of insulin- 251-LB stimulated glucose transport, was significantly (P<0.05) increased in mem- A Rapid and Precise Method for Simultaneous Measurement of brane, but not cytosol, with insulin-stimulation. In conclusion, we developed Endogenous and Synthetic Insulins, Proinsulin, and C-peptide Levels a novel method for assessing subcellular localization of insulin signaling pro- Using High-Resolution MS teins in small muscle samples. This method will enable experiments aimed GREGORY BYRAM, MARIE SOLEIL GAUTHIER, DENIS FAUBERT, OMID HEKMAT, at advancing understanding of the roles of Akt localization for altered insulin BENOIT COULOMBE, REMI RABASA-LHORET, PIERRE GARNEAU, KATHERINE sensitivity with physiological conditions, e.g., obesity or exercise. CHABOT, BRYAN KRASTINS, MARYANN VOGELSANG, GOURI VADALI, MARY F. LOPEZ, Cambridge, MA, Montreal, QC, Canada I ntegrated 249-LB Accurate measurement of insulin, C-peptide and proinsulin and their rela- POSTERS Serum Il6 Mediates Acute Inflammation and Skeletal Muscle Insulin tive abundance ratios is useful for the identification of insulin resistance, Resistance during Thermal Injury hypoglycemia, beta cell function, insulinoma, risk of cardiovascular disease Physiology/Obesity SAURABH TRIKHA, MORRIS F. WHITE, Boston, MA and other pathologies associated with the metabolic syndrome and diabetes. Insulin resistance and glucose intolerance are associated with systemic An accurate test is also needed for monitoring the levels of synthetic insulins inflammation, but the mechanisms linking these processes are complex and in patients undergoing insulin therapy. Unfortunately, commercially available unresolved. To investigate the relation between acute inflammation and insu- insulin tests suffer from a significant degree of cross-reactivity and interfer- lin action, we exposed mice to thermal injury under anesthesia. Serum IL6 ence making their clinical usefulness limited (1-3). Based on our previous work (interleukin 6) was elevated about 6 fold compared against sham treatment (4), we developed and validated a multiplexed test that combines immunoen- until the experiment was terminated after 4 days; however, other cytokines richment with MS detection to quantify insulin, proinsulin, C-peptide and any including TNFα were not changed significantly. We conducted intraperitoneal synthetic insulin analogs present in serum or plasma samples. Our assay is glucose (IGTT) and insulin tolerance tests (IITT) four days after thermal injury. sensitive enough to detect and robustly quantify targeted analytes at sub ng/ Compared against sham treatment, glucose tolerance was indistinguishable ml levels while maintaining a wide dynamic range (3 orders of magnitude). (p=0.267) after thermal injury. By contrast, IITT suggested that the thermal The high selectivity of the assay allows confident differentiation of target

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LB65 Integrated PLhateysi oloBreagy—kingIn Asbstractsulin Secretion In Vivo

analyte mass spec signal from the background matrix. The resulting method 254-LB is universally applicable for precise (% CV<10) quantification of proinsulin, Chronic Oral Treatment with Palmitic Acid Esters of Hydroxy Stearic endogenous insulin, C-peptide and synthetic insulin variants individually or Acids (PAHSAs) Improves Ambient Glycemia, Insulin Sensitivity and simultaneously without the need to drastically change the components of Adipose Inflammation in High-Fat Diet (HFD)-fed Mice the assay. We utilized the developed assay to measure insulin and C-peptide JENNIFER LEE, PEDRO M. VIEIRA, ISMAIL SYED, KERRY WELLENSTEIN, ANDREW levels in a small cohort of clinical samples from insulin sensitive obese (n=9) N. NELSON, ODILE PERONI, DIONICIO R. SIEGEL, ALAN SAGHATELIAN, BARBARA and T2D obese (n=8) patients. The results demonstrated significantly lower B. KAHN, Boston, MA, La Jolla, CA levels of both analytes (p=0.02 insulin, p=0.07 C-peptide) in the insulin sensi- We recently discovered a novel class of endogenous antidiabetic and anti- tive obese patients. 1. Dayaldasani A et al. Ann Clin Biochem 2015 2:312 2. inflammatory lipids called PAHSAs. PAHSAs are reduced 40-55% in serum Couchman L et al. Ann Clin Biochem 2015 Online First August 3 3. Parfitt C et and 70% in adipose tissue (AT) of insulin-resistant vs. insulin-sensitive people al. Clin Biochem 2015 pii: S0009-9120(15)00278 4. Peterman S et al. Proteom- and correlate highly with insulin sensitivity measured by euglycemic clamp. A ics 2014 14:1445. single PAHSA dose improves glucose tolerance and insulin secretion but not insulin sensitivity. Here we aimed to determine whether chronic oral PAHSA 252-LB treatment improves metabolic status in HFD-fed mice. In HFD-fed mice, daily Characterization of GPR40 Deficiency in Goto-Kakizaki Rats oral administration of 5- and 9-PAHSAs (30mg/kg of each X30 days) lowered JIN SHANG, SHENG PING WANG, ALEKSANDR PETROV, OKSANA PALYHA, glycemia (163±4 vs. 176±4 mg/dL, p<0.05) and improved insulin sensitivity MYUNG SHIN, JOHN MUDGETT, LIANGSU WANG, ANDREW HOWARD, Kenil- determined by insulinemia (0.8±0.1 vs. 1.1±0.1 ng/mL, p<0.05) and glucose X worth, NJ insulin product (132±11 vs. 200±18 mg/dL X ng/mL, p<0.05) 5 hours after food GPR40, a fatty acid sensing G protein coupled receptor, has emerged as a removal compared to vehicle-HFD mice, without a change in body weight or promising target for type 2 diabetes. Using the zinc finger nuclease technol- adiposity. Oral PAHSA administration increased plasma GLP-1 (64±4 vs. 44±2 ogy, we previously reported the generation and characterization of a GPR40 pM, p<0.05) and insulin (2.7±0.4 vs. 1.7±0.1 ng/mL, p<0.05) levels in 30 min- knockout (KO) rat line in the Wistar-Hans background in which the KO rats utes, resulting in reduced glycemic excursion (243±5 vs. 288±9 mg/dL, p<0.05) carry a small deletion and insertion with a stop codon, resulting in the pre- 5 minutes following glucose gavage compared to vehicle-HFD mice. PAHSA mature truncation of the GPR40 protein at the region of TM2. In the current treatment reduced the number of pro-inflammatory CD11c+ macrophages by study, we present the generation and phenotypic characterization of a GPR40 50% and increased the number of anti-inflammatory CD206+ macrophages null allele in the Goto-Kakizaki (GK) rats, a non-overweight type 2 diabetic 2-fold in AT. Also, PAHSA treatment reduced numbers of TNF+ and IL-12+ AT model. The entire coding region of GPR40 was completely deleted in the GK macrophages by ~60% in HFD mice. In summary, chronic oral PAHSA treat- KO rats. We did not observe major differences in basal plasma glucose, insu- ment improves insulin sensitivity and glycemia and reduces AT inflammation lin or FFA levels between GPR40 KO GK rats and their littermate controls. in insulin-resistant HFD mice. Thus, because PAHSA levels are reduced in Glucose and intralipid challenge tests were conducted to further compare the insulin-resistant people before type 2 diabetes (T2D) occurs, restoring PAHSA two lines. IPGTT with a GPR40 selective agonist confirmed the loss of GPR40 levels may reduce T2D risk. Also, PAHSA treatment may improve insulin sensi- activity in the GPR40 KO GK rats as significant reduction in glucose excur- tivity, adipose inflammation, and glycemic control in T2D patients. sion was observed in littermate rats but not in the homozygous GPR40 KO GK Supported By: National Institutes of Health/National Institute of Diabetes and rats. We further examined pancreatic islet function by pancreatic perfusions. Digestive and Kidney Disease (R01 DK098002, P30DK57521); JPB Foundation The arginine-stimulated insulin secretion was impaired in the GPR40 KO GK (5T32DK007516-30) rats compared to the littermate GK rats. The effect on enhancing glucose- dependent insulin secretion by a GPR40 agonist was blunted in the GPR40 255-LB knockout rats. Surprisingly, the effect of a GLP-1R agonist on insulin secretion A Brain Mechanism for Coupling of Insulin Secretion to Insulin Sen- was also partially dampened in the GPR40 KO GK rats. Taken together, our sitivity Revealed by Cold Exposure results demonstrate that the GPR40 null GK rats are a valuable tool for inves- KENJIRO MUTA, MILES E. MATSEN, JARRELL T. NELSON, NIKHIL K. ACHARYA, tigating GPR40 biology and for determining whether beneficial effects as well DARKO STEFANOVSKI, RICHARD N. BERGMAN, GREGORY J. MORTON, MICHAEL as safety liability of GPR40 agonists are mechanism-based. W. SCHWARTZ, Seattle, WA, Kennett Square, PA, Los Angeles, CA Although the capacity of pancreatic β-cells to adjust insulin secretion in 253-LB response to prevailing insulin sensitivity is crucial for normal glucose homeo- Insulin Secretion and Glucose Homeostasis in Cholecystokinin-defi- stasis, the underlying mechanism remains unknown. Since glucose intolerance cient Mice and type 2 diabetes result if insulin secretion is not appropriately increased in JONATHAN WENG, SILVANA OBICI, MICHAEL HASS, SYDNEY PENCE, PATRICK states of insulin resistance, a compelling rationale exists for investigation into TSO, CHUNMIN LO, Athens, OH, Cincinnati, OH underlying mechanisms. Based on growing evidence of a key role for the brain Cholecystokinin (CCK) is secreted by the enteroendocrine cells in the small in glucose homeostasis, we developed a cold exposure paradigm with which intestine in response to lipid intake and stimulates insulin secretion via a CCK test the hypothesis that changes in autonomic outflow link insulin secretion to 1 receptor-dependent pathway. CCK-gene knockout (CCK-KO) mice fed a low- insulin sensitivity. Consistent with earlier reports, we found that in rats, cold fat diet (LFD) or high-fat diet (HFD) for 10 weeks have impaired insulin secre- exposure (5°C for 24h) potently inhibits insulin secretion, and since glucose tion in response to glucose challenge despite increased insulin sensitivity. We tolerance was minimally impacted, we hypothesized that a compensatory hypothesized that CCK regulates insulin secretion and glucose homeostasis. increase of insulin sensitivity must have occurred. To test this hypothesis, we Research Design and Methods: After 10 weeks of LFD or HFD, insulin used a frequently sampled intravenous glucose tolerance test with minimal secretion and glucose homeostasis in CCK-KO mice and their wild-type (WT) model analysis, and our data confirm that the effect of cold to suppress insulin controls were determined in response to a hyperglycemic clamp and an intra- secretion (by >50%, as assessed by the acute insulin response to glucose peritoneal administration of CCK. (AIRg): 667±41 vs. 372±33 (μU/ml)/min; P<.05) was offset by a proportionate Results: After 10 weeks of LFD or HFD, CCK-KO mice had a basal glucose increase of insulin sensitivity (measured as the insulin sensitivity index (SI):

I ntegrated 2.83±0.38 vs. 6.64±0.93 (ml/μU)/(1/min); P<.05). To investigate the role of the

POSTERS and insulin level comparable to that of WT mice. Animals maintained on LFD had similar plasma glucose and insulin levels for both groups during the hyper- sympathetic nervous system (SNS) in this adaptation to the cold, we repeated

Physiology/Obesity glycemic clamp. In addition, exogenously administered CCK reduced plasma the study using a continuous iv infusion of either the alpha-adrenergic receptor glucose and increased plasma insulin in WT mice. After 10 weeks of HFD, (α-AR) blocker phentolamine or its vehicle. We found that the potent effects CCK-KO mice had lower overall insulin secretion at steady state than the WT of cold-exposure both to reduce AIRg and to increase SI were rapidly and fully mice. CCK significantly reduced plasma glucose in CCK-KO mice with signifi- reversed by acute α-AR blockade, with glucose tolerance once again being cantly increased insulin secretion relative to their control animals maintained minimally affected. We conclude that cold exposure elicits highly coordinated, on HFD. potent and reciprocal adjustments of insulin sensitivity and insulin secretion, Conclusion: CCK is involved in regulating insulin secretory capacity and glu- and that these metabolic adaptations are mediated by the SNS. cose homeostasis in mice following chronic consumption of HFD. Supported By: National Institute of Diabetes and Digestive and Kidney Diseases Supported By: National Institutes of Health (DK83550, DK97436) (DK083042, DK090320, DK101997 (to M.W.S.); DK089056 (to G.J.M.)

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LB66 Integrated PLhateysi oloBreagy—kingIn Asbstractsulin Secretion In Vivo

256-LB 257-LB Novel Chemiluminescent ELISA for Highly Specific and Sensitive The Incretin Effect in Sulfonylurea-treated KATP-related Monogenic Measurement of GLP-1 Accurately Detects Postprandial Changes Diabetes Compared to Matched Healthy Controls: Insulin Response CORINTH AULD, HANNA BLOMSTER, HAMPUS ELOFSSON, LISA GRUFMAN, to Oral and Intravenous Glucose Is Near-Normal but Blunted and ANDERS LUNDEQUIST, SOFIA MOGENSEN, HANNA RITZÉN, MARIA SCHWAN- Prolonged BECK, Winston-Salem, NC, Uppsala, Sweden DAVID CARMODY, KRISTEN E. WROBLEWSKI, LISA R. LETOURNEAU, NANCY The incretin Glucagon-like peptide 1 (GLP-1) has garnered a lot of interest DEVINE, ROCHELLE N. NAYLOR, LOUIS H. PHILIPSON, SIRI ATMA W. GREELEY, because it both stimulates the release of insulin and suppresses glucagon Chicago, IL secretion. The dual influence that GLP-1 exerts on pancreatic function has Activating mutations in KCNJ11 (encoding the Kir6.2 subunit of the ATP- made it an attractive target for pharmacological interventions, giving rise to sensitive potassium channel) are the most common monogenic cause of the development of peptide mimetics and inhibitors of DPP-4. In the absence neonatal diabetes, but mechanisms by which sulfonylurea-treated individu- of DPP-4-inhibitors, GLP-1 is rapidly converted from the active 7-36NH2 to the als exhibit excellent glycemic control remain poorly understood. Five adult inactive 9-36NH2. Thus, an assay able to recognize both active and inactive sulfonylurea-treated subjects with KCNJ11-diabetes and 5 healthy controls forms is very useful for monitoring the total GLP-1 level in biological fluids. matched for gender, age and BMI, underwent oral glucose tolerance tests A study led by Jens J. Holst, who discovered GLP-1, revealed that perfor- (OGTT) and isoglycemic glucose infusions (IGI). IGI allows for quantification mance of currently available commercial assays for total GLP-1 is lacking. To of the incretin effect using variable rate dextrose infusion to match an indi- address the need for a reliable assay for determining total levels of GLP-1, vidual’s OGTT glucose curve (Figure A-B). We found that KCNJ11 subjects had Mercodia has developed an ELISA with excellent specificity, sensitivity and higher glucose levels overall, including fasting hyperglycemia, higher peaks, dynamic range. The Mercodia Total GLP-1 ELISA employs a chemiluminescent and delayed normalization following OGTT and during IGI (p<0.05 by paired substrate giving the user the ability to measure samples with GLP-1 levels t-tests). Overall insulin and C-peptide responses as area under the curve (AUC) from 0.75 to 300 pmol/L in just over 2 hours using only 25 μL of plasma or were not different during OGTT or IGI, but change from baseline to peak lev- serum (see Table). Importantly, the performance of the GLP-1 (X-36NH2)- els was greater in controls (p<0.05). Insulin and C-peptide levels returned to specific assay is not affected by complex sample matrices and shows no baseline in controls but remained elevated in subjects after 4 hours (Figure cross-reactivity to the 11 proteins tested, enabling accurate measurement of C-F). Further study will clarify the effect of incretins and other treatments, postprandial changes in total GLP-1 levels. and determine whether prolonged insulin response may contribute to spo- Table. Performance Summary for Mercodia Total GLP-1 ELISA. radic hypoglycemia. Figure.

Supported By: American Diabetes Association (1-11-CT-41 to L.H.P.); National Institutes of Health (K23DK094866, P30DK020595, UL1TR000430, R03DK103096) I ntegrated POSTERS 258-LB Intestinal Epithelial O-GlcNAc Signaling Modulates Microbiota– Physiology/Obesity Host Interactions in Inflammation and Glucose Metabolism MING ZHAO, HAI BIN RUAN, Minneapolis, MN The gut microbiota plays a fundamental role for host metabolism and immune response. Alterations in microbial composition and function have been associated with many diseases, including obesity, diabetes, inflammatory bowel disease, and liver diseases. Microbial metabolism yields a number of bioactive molecules such as short-chain fatty acids (SCFAs) that may modulate host physiology; however, the molecular mechanisms by which host cells sense and Precision based on 12 runs. Cross-reactivity as compared to GLP-1(9-36NH2), respond to microbiota-derived molecules are largely unknown. O-linked β-N- where N.D. means a signal below Calibrator 1 for the concentrations used. acetylglucosamine (O-GlcNAc) signaling has been proposed as a nutrient sensor in diverse metabolic processes. Herein, we investigated the role of O-GlcNAc

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LB67 InteLategrated Brea Pkinghys iAolobstractsgy—Liver

in microbiota-host interactions in intestinal inflammation and glucose metabo- sistent with our in vitro work, there were corresponding effects on downstream lism. We found that intestinal epithelial levels of O-GlcNAc reduce in response Sirt1 targets, as well as on PPARα and PPARδ (~70% stimulation, p<0.01). These to microbial depletion and can be rescued by SCFAs in mice. Intestinal epithe- data support the clinical potential of a combination of L-leucine with low doses lial cell (IEC)-specific knockout of O-GlcNAc transferase (OGT) in mice causes of Metformin (calculated as 0.5-1 g/d human equivalent) and sildenafil (1-2 mg/d epithelial barrier dysfunction, microbial dysbiosis, and intestinal inflammation. calculated human equivalent) in treatment of NASH. Meanwhile, IEC-Ogt KO mice show increased numbers of intestinal L cells, elevated serum GLP-1 levels, improved glucose metabolism, and decreased body 261-LB weight when compared with control mice. Fecal transplantation into antibiotic- Demethylation of Hepatic DPP-4 in Young C57BL/6J Mice Modulates treated mice demonstrated that microbial dysbiosis in IEC-Ogt KO mice is not Transcriptional Activation by Glucose, and Associates with Obesity important for the progression of intestinal inflammation, but is sufficient to drive SOPHIE SAUSSENTHALER, CHRISTIAN BAUMEIER, ANNE KAMMEL, THOMAS the improvement of glucose homeostasis and the loss of body weight. On the LAEGER, ANNETTE SCHÜRMANN, ROBERT SCHWENK, Nuthetal, Germany, Pots- other hand, IEC-specific overexpression of OGT downregulates intestinal gluca- dam, Germany gon gene expression and levels of serum GLP-1 and insulin. These results dem- Hepatic DPP-4 expression is elevated in patients suffering from nonalco- onstrate that, in response to microbiota-derived SCFAs, epithelial O-GlcNAc holic fatty liver disease and insulin resistance. However, it is not known if signaling maintains intestinal homeostasis by restraining the inflammation and this is a cause or consequence of the disease. Here, we investigated the role the incretin effect. of DPP-4 in hepatic glucose homeostasis and tested if inter-individual differ- Supported By: American Heart Association (14SDG20120052) ences in DPP-4 expression are mediated by epigenetic changes. Expression and DNA methylation of the DPP-4 gene were investigated in livers of 6 weeks old C57BL/6J mice which were either prone or resistant to Integrated Physiology—Liver diet-induced obesity. In addition, primary hepatocytes were transduced with an adenovirus coding for murine DPP-4 and effects on hepatic insulin sensitiv- 259-LB ity and glucose release were assessed. Regulation of Hepatic Gluconeogenesis by Human Long, Noncoding Already at 6 weeks of age, DPP-4 expression was significantly elevated RNAs in livers of obesity-prone mice when compared to obesity-resistant animals. XIANGBO RUAN, Bethesda, MD DNA methylation of four intronic CpG sites were reduced, of which posi- We have recently demonstrated that long non-coding RNAs (lncRNAs) are tions 877, 1253 and 1255 correlated with elevated DPP-4 expression. In vitro important regulators of glucose and lipid metabolism in mice. However, since methylation of this region resulted in substantially reduced reporter activity, lncRNAs are much less conversed between human and mouse than protein whereas high glucose treatment led to an elevated reporter activity which coding genes do, the function of lncRNAs in human metabolism and physi- was accompanied by a reduced CpG methylation at position 1255. Overex- ology is largely unknown. Hepatic gluconeogenesis is a major pathway that pression of DPP-4 in primary mouse hepatocytes resulted in a remarkable maintains plasma glucose levels during fasting and is also a key contribu- elevation of hepatic glucose output, which was associated with increased tor to hyperglycemia in diabetes. To identify human lncRNAs that regulate glycogen content and reduced insulin stimulated AKT-phosphorylation. hepatic gluconeogenesis, we systemically screened lncRNAs that are induced In summary, our results indicate that individual differences in hepatic by fasting signals in both hepG2 cells and primary human hepatocytes. Among DPP-4 expression are associated with changes in gene methylation early in the most induced lncRNAs, knocking down an lncRNA we termed lncGIRG life. Moreover, we showed that elevated DPP-4 expression directly affects (glucagon-induced repressor of gluconeogeneis) results in increased glucose hepatic glucose release and therefore might participate in the progress of production in primary human hepatocytes. We further demonstrated that obesity and insulin resistance. induction of lncGIRG by glucagon is dependent on Fox01, a key transcriptional Supported By: German Ministry of Education and Research (01GI0922); German regulators of hepatic gluconeogenesis in both mouse and human. Genom- Research Foundation (GK1208) ewide gene expression analyses revealed that loss-of-function of lncGIRG leads to increased expression of a number of genes in gluconeogenic path- 262-LB way including G6pc and Pck1. Our results suggest that lncGIRG might serve as Biliary Uridine Regulates Energy Homeostasis a negative regulatory mechanism of hepatic gluconeogenesis in human, and YINGFENG DENG, ZHAO WANG, RUTH GORDILLO, PHILIPP E. SCHERER, Dallas, TX lncRNAs such as lncGIRG could potentially constitute important therapeutic A steady supply of plasma uridine is critical for cell function and survival. targets for diabetes. Understanding the regulation of its uptake, biosynthesis and clearance is fun- Supported By: National Institutes of Health damentally important for systemic homeostasis. Previous studies suggested a rapid turnover of plasma uridine (~3 min), primarily regulated by the liver. 260-LB Our observations demonstrate that the rapid turnover of plasma uridine is A Leucine, Metformin, and Sildenafil Combination Regresses Nonal- mediated through the bile. We found uridine is enriched in bile at a concen- coholic Steatohepatitis (NASH) in Mice tration that is 10- fold of plasma concentrations. Similar to bile salts, uridine MICHAEL B. ZEMEL, ANTJE BRUCKBAUER, OMAR FLORES, Knoxville, TN, Nashville, enters the enterohepatic circulation. Moreover, we established a role of this TN enterohepatic uridine circulation for thermoregulation. High plasma uridine Nonalcoholic fatty liver disease (NAFLD) and NASH occur predominantly in concentrations prompt hypothermia associated with fasting. The bile-medi- diabetes and obesity and are characterized by suppression of the Sirt1/AMPK ated release of uridine reverses systemic hypothermia, and in the process axis, while Sirt1 stimulation or overexpression relieves both the steatosis and also improves insulin sensitivity in a leptin-dependent manner. Since feed- inflammation of NASH. We have shown leucine to allosterically activate Sirt1 ing is a natural trigger for bile release, our observations indicate that feed- and synergize with other Sirt/AMPK pathway activators, and that leucine-Met- ing and plasma uridine homeostasis mutually influence each other, and both formin reverses NAFLD in mice. PDE5 inhibition also activates Sirt1 secondary processes are coupled to thermoregulation and energy homeostasis. Uridine to eNOS activation, and leucine-PDE5 inhibitor combinations similarly reverse synthesis and biliary clearance highlight a new role of bile in systemic regu- I ntegrated

POSTERS NAFLD in mice; however, we have found the triple combination of leucine, Met- lation of growth and metabolism, and mechanistically link insulin and leptin formin and sildenafil to generate greater synergy and reverse NASH in mice. resistance. Physiology/Obesity To optimize doses of Metformin and sildenafil in the combination, we induced Supported By: American Diabetes Association (7-08-MN-53 to P.E.S.); Ameri- NASH in mice via high fat (60%) supplemented with cholesterol (1.25%) and can Heart Association (14SDG18440002 to Z.W.); National Institutes of Health cholate (0.5%) (HF/ATH) diet and then randomized to combinations of leucine (R01-DK55758, R01-DK099110 to P.E.S.) (24 g/kg diet), Metformin (0.5 – 1 g/kg diet) and sildenafil (6.25-100 mg/kg diet). The HF/ATH diet caused significant steatosis, inflammation, Kupfer cell activa- 263-LB tion and fibrosis. The leucine-Metformin-sildenafil combinations significantly Sex-specific Association between Serum Uric Acid and Nonalco- reduced steatosis (43%), inflammation (55%), Kupfer cell activation (40%) and holic Fatty Liver Disease in Type 2 Diabetic Patients fibrosis (50%). Since our previous work demonstrated dose-response up to 0.5 NENGGUANG FAN, YONGDE PENG, Shanghai, China Metformin/kg diet (~40% of therapeutic dose), this was utilized as the lowest Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease dose here, and no further benefit accrued from a higher dose in the combination. worldwide. Clinical studies have suggested a pathogenic role of serum uric Sildenafil in the combination exhibited dose-response improvements in each acid (SUA) in the development of NAFLD in several populations. The present variable up to a maximum effect at 25 mg/kg diet (<10% therapeutic dose). Con- study was designed to determine the relationship between SUA and NAFLD in

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LB68 InteLategrated Brea Pkinghys iAolobstractsgy—Liver

type 2 diabetic patients, who have a high incidence rate of NAFLD. A total of reduce transaminase levels (SFRP5 vs. control, 202.1±9.36 vs. 315.40± 225.80, 541 type 2 diabetic subjects underwent a healthy checkup program and were P < 0.05). The mRNA expression of liver inflammatory cytokines IL-1β, IL-6, classified depending on the presence of ultrasonographically detected NAFLD TNFα and MCP-1 expression level was decreased significantly after the inter- or the tertiles of SUA. It was found that SUA was significantly higher in type vention of SFRP5 protein.High purity of the recombinant SFRP5 protein was 2 diabetic subjects with NAFLD than those without NAFLD in men, but not in made. Both in vitro and animal experiments proved its activity. Recombinant women. Furthermore, the prevalence rate of NAFLD increased progressively SFRP5 protein can be used for the treatment of NASH. across the SUA tertiles only in men. After adjusting for age, duration of diabe- Supported By: Sheng Kang Hospital Development Center (SHDC12012220); tes, BMI, blood pressure, eGFR and HOMA-IR, the odd ratio for NAFLD was 1 Shanghai Committee of Science and Technology (12431900205); Shanghai Bureau (reference), 2.93 (95% CI 1.25-6.88) and 3.93 (95% CI 1.55-9.98), respectively, of Human Resources and Social Security in the tertiles of SUA in men. Contrastly, SUA levels in women were not independently associated with the risk of NAFLD. Our data suggests that SUA is 266-LB specifically associated with NAFLD in male type 2 diabetic subjects, indepen- Evidence of Altered Glucose Metabolism in Liver-specific Adropin dent of insulin resistance and other metabolic disorders. Knockouts JOSEPH R. STEVENS, CLEMENCE GIRARDET, RYAN MCMILLAN, RANDALL L. 264-LB MYNATT, MATTHEW W. HULVER, ANDREW A. BUTLER, St. Louis, MO, Blacksburg, Characterization of PNPLA3, A Multifunctional Enzyme Associated VA, Baton Rouge, LA with Fatty Liver Disease The peptide hormone adropin regulates fuel selection in skeletal muscle CRAIG HAMMOND, NENGYU YANG, CHRISTOPHER CORKINS, MAJA DEUTER- to favor glucose over fat oxidation [Diabetes 63(10):3242-52; Mol Metab. 4(4): REINHARD, THOMAS SENG, LUCILLE LAVALLETTE, JAMES MCGEE, HAI BUI, PAUL 310-24]. Hepatic expression of the Energy Homeostasis Associated (Enho) MILLIGAN, GABOR VARGA, ANTHONY BUTTERFIELD, JOHN LOCKWOOD, MING gene encoding adropin is very high relative to other peripheral tissues, and is SHANG KUO, YUEWEI QIAN, JUAN JOSE CARILLO, JAMES PERFIELD, Indianapolis, sensitive to metabolic condition and dietary macronutrients. Whether adropin IN expressed in liver acts systemically to regulate glucose and fat metabolism Nonalcoholic steatohepatitis (NASH) is a prevalent liver disease character- is not known. We flanked the adropin open reading frame in exon 2 of the ized by steatosis, inflammation and fibrosis which occurs with 2-fold greater Enho gene of C57BL/6J mice with LoxP sites, using 6.Cg-Tg (Alb-cre)21Mgn/J frequency in T2DM. A polymorphic variant (I148M) in the lipid droplet pro- mice to suppress liver adropin synthesis. Enho expression in LAdrKO was tein Patatin-Like Phospholipase Domain-Containing 3 (PNPLA3) is strongly reduced 80% compared to controls, but was normal in other tissues (brain, associated with liver fat content and NASH in humans and may also affect cardiac and skeletal muscle). While body weight is normal, female LAdrKO glucose homeostasis. PNPLA3 is reported to have both triglyceride hydrolase exhibit a modest but highly significant increase in fat mass (6.97±0.18 vs. and lysophosphatidic acid acyltransferase activities, but which activity con- 6.19±0.19g; P=0.006) and fluid content (3.56±0.05 vs. 3.36±0.05g; P=0.005) tributes to liver disease is controversial and whether they reside in separate relative to controls, with no significant difference in fat free mass (FFM) catalytic sites is unknown. We analyzed public gene expression data sets (15.33±0.12 vs. 15.54±0.12g). This phenotype was not observed in males (data from human liver biopsies and found increased expression of PNPLA3 in obese not shown). Expression profiling of male and female LAdrKO and controls indi- nondiabetics and obese patients with poorly controlled diabetes, consistent cates altered glucose production/utilization in LAdrKO with increased liver with previous reports which showed hepatic steatosis in rodents and humans Pck1 mRNA (expression relative to 36B4 in arbitrary units for sex: 1.56±0.12 is associated with increased PNPLA3 expression and suggesting the protein vs. 1.06±0.11,P<0.01) and skeletal muscle expression of Pdk4 mRNA (kinase may act primarily as a triglyceride biosynthetic enzyme. Given the potential inhibitor of the pyruvate dehydrogenase complex) (1.94±0.26 vs. 1.04±0.25, of PNPLA3 as a therapeutic target for NASH, we characterized PNPLA3 in P<0.05) in both sexes. LAdrKO also exhibited enhanced conversion of pyruvate vitro. Tagged PNPLA3 has lipase activity capable of hydrolyzing radiolabeled injected ip. into glucose (“pyruvate tolerance test”), fasting hyperglycemia triolein. Using mass spectrometry, we showed that both the wild-type and and a lower respiratory exchange ratio, suggesting reduced glucose oxida- I148M enzymes catalyze the formation of phosphatidic acid, a lipid species tion. implicated in insulin resistance. siRNA knockdown of PNPLA3 in human hepa- In summary, these results suggest suppression liver adropin expression toma cells decreased the content of newly-synthesized 14C-acetate-labeled results in systemic changes in glucose metabolism mimicking a prediabetic triglyceride, while lipidomics analysis revealed changes in the cellular levels condition (impaired fasting glucose/enhanced glucose production/reduced of multiple triglyceride species. The lipase inhibitor orlistat blocked in vitro glucose utilization). PNPLA3 lipase activity without affecting acyltransferase activity, while targeted mutation of the catalytic serine in the conserved lipase domain had no 267-LB effect on acyltransferase activity. Together, these data suggest the existence Anaplerotic Regulation of Hepatic Gluconeogenesis of independent catalytic sites on PNPLA3 that could be targeted to design DAVID A. CAPPEL, STANISLAW DEJA, XIAORONG FU, JOAO DUARTE, SHAWN C. PNPLA3 modulators. BURGESS, Dallas, TX Hepatic gluconeogenesis (GNG) is essential to maintaining blood glucose 265-LB during fasting or exercise. Dysregulation of this process contributes to dia- The Effect of Recombinant SFRP5 Protein on Nonalcoholic Steato- betic hyperglycemia. The generation of phosphoenylpyruvate from oxaloac- hepatitis etate by PEPCK is considered the rate controlling step of hepatic GNG. Studies XIAOLONG ZHAO, JIURU SUN, PEILI CHEN, YIMING LI, Shanghai, China from our lab have shown that a 90% knockdown of hepatic PEPCK resulted in Nonalcoholic steatohepatitis (NASH) has become the major cause of only a 40% reduction in GNG. To further explore control of hepatic GNG, we chronic liver disease and liver carcinoma that threatens people’s life In the targeted pyruvate carboxylase (PC), which catalyzes anaplerotic flux of pyru- context of obesity epidemic. SFRP5 (secreted frizzled-related protein 5) is an vate into the TCA cycle as oxaloacetate. To test PC’s role in hepatic GNG, we anti-inflammatory adipokine modulating metabolism dysfunction. This study created a liver-specific PC knockout (LPCKO) mouse. LPCKO’s are viable, fer- aims to observe the effect of recombinant SFRP5 protein on NASH. We set up tile, and show normal growth and development. No difference was observed I ntegrated

the process of prokaryotic expression and purification of recombinant SFRP5 in fasting or fed blood glucose between LPCKO and wild-type mice. Fasted POSTERS protein. Mice NASH model was induced by methionine choline deficient diet serum ketones are elevated in LPCKO mice, suggesting reliance on ketogen- for two weeks. SFRP5 protein treatment group were received intraperitoneal esis during fasting. We performed liver perfusion studies with stable isotope Physiology/Obesity injection with a dosage of 10ug/kg SFRP5 protein twice a day for two weeks. tracers in the LPCKO mice to measure metabolic flux though GNG and the Saline was used as control. Inflammation and fatty lesion score of liver tissue TCA cycle. LPCKO mice display an approximately 80% reduction in both GNG pathology and serum transaminase level were compared. Purity of recombi- and TCA cycling. Hepatic GNG was not rescued in LPCKO mice by provision nant SFRP5 protein is 95% identified by high performance liquid chromatog- of alternative anaplerotic substrates propionate and glutamine in a second raphy. Its molecule size is 36096.08 tested by mass spectrography. In vitro liver perfusion study. Our findings show that PC is essential for normal hepatic experiments this protein can specifically binded with Wnt5a which suggest energetics and glucose production but is not the sole rate-limiting step in its activity in vitro. Endotoxin levels of this recombinant protein is 0.1EU/ug- hepatic gluconeogenesis. 0.01EU/ug (tested by tachypleus amebocyte lysate (TAL)-LAL method) that is Supported By: National Institutes of Health (FDK105741A); The Welch Foundation suitable for animal experiment. SFRP5 protein can significantly improve liver (1-804-03) inflammation score (SFRP5 vs. control, 1.40±0.97 vs. 2.20±0.63, P < 0.05) and fatty lesion score (SFRP5 vs. control, 1.40±0.70 vs. 2.20±0.0.47, P < 0.05),

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LB69 Integrated Physiology—LateMacro Breanukingtr iAebstractsnt Metabolism and Food Intake

Integrated Physiology—Macronutrient 270-LB Metabolism and Food Intake Regulatory Role of AMPK in CRH Neurons in the PVH in Social Stress- induced Alteration of Food Selection Behavior 268-LB YASUHIKO MINOKOSHI, TATSUYA SATO, SHIKI OKAMOTO, Okazaki, Japan Corticotropin releasing hormone (CRH) secreting neurons in the paraven- Higher Intestinal Dietary Fat Storage and Slower TG Absorption Ben- tricular hypothalamus (PVH) have important roles for the stress responses. efit Nocturnal and Fasting Plasma Lipids in Insulin Resistance We recently revealed that activation of AMPK in the CRH neurons in the MIRIAM JACOME-SOSA, QIONG HU, NHAN LE, CAMILA M. MANRIQUE, ELIZA- PVH (PVH-CRH neurons) increased carbohydrate selection. In the present BETH J. PARKS, Columbia, MO Data demonstrate that fat stored in the intestine from one meal appears in study, we examined whether AMPK in PVH-CRH neurons regulates stress- plasma TG-rich lipoproteins (TRL) after consumption of the next meal. How- induced alteration of food selection behavior. We found that social defeat ever, such a “second meal effect” varies substantially among individuals. We stress activated AMPK in a subset of PVH-CRH neurons and increased car- hypothesize that this effect is a beneficial physiological characteristic influ- bohydrate selection over fat selection in C57BL/6J mice. The change in food enced by the cephalic phase (CP) of food intake. Here, we investigated CP lipid selection was blunted by inhibition of CRH expression in the PVH by lentivirus flux using a sequential meal paradigm followed by subsequent sham feed- expressing shRNA or inhibition of neuronal activity of PVH-CRH neurons by ing to elicit the CP response. Men and women (n=14, age 32±8 y) underwent DREADD technology. We further examined the effect of preferential expres- IVGTTs to asses insulin sensitivity and 24h-metabolic tests including isotope- sion of shRNA for AMPK in PVH-CRH neurons using CRH-Cre knock-in mice labeled meals. Meal fat absorption rates were determined by isolation of TRL and lentivirus vector. Inhibition of AMPK expression in PVH-CRH neurons and GC-MS analysis. Compared to insulin-sensitive subjects, insulin-resistant completely suppressed alteration of food selection after social defeat stress. subjects had higher BMI (24±0.9 vs. 34±3.2; P=0.01), trunk fat% (15.3±0.6 Furthermore, preferential expression of constitutively active form of AMPK in vs. 22.4±2.2; P=0.005) and insulin AUC after dinner (84.9±7.6 vs. 149.1±16.8; PVH-CRH neurons mimicked the stress-induced carbohydrate selection. We P=0.005). For the whole group, faster dinner absorption rates were associated also found that social defeat stress increased neuropeptide Y (NPY) expres- with higher extended contributions of both lunch and dinner fat to TRL-TG sion in the dorsomedial hypothalamus (DMH), and administration of NPY Y1 through the night (r=0.85, r=0.92, respectively; P=0.0001). Furthermore, faster receptor (Y1R) antagonist into the PVH inhibited stress-induced alteration of dinner absorption rates resulted in higher fasting plasma TG the next morn- food selection. These results suggest that AMPK in PVH-CRH neurons plays a ing (r=0.75; P=0.001). Interestingly, after dinner, individuals with the highest crucial role in stress-induced carbohydrate selection. NPY signal in the PVH is CP lunch peak also exhibited greater nighttime intestinal dinner-fat storage, likely involved in the carbohydrate selection after social defeat stress. which was secreted during sham feeding the next morning. Furthermore, in Supported By: Grants-in-Aid for Scientific Research from the Ministry of Educa- insulin-resistant subjects, a lower intestinal lunch-fat storage was corre- tion, Culture, Sports, Science and Technology of Japan; Japan Science and Technol- lated with a detrimentally faster dinner absorption rate (r=-0.91; P=0.004). In ogy Agency summary, investigation of individual variability in the diurnal control of meal fat storage/transport, supports a phenotype of intestinal physiology that is 271-LB reproducible within a given subject and constant across meals. Treatment Metabolic Effects by H. pylori Infection and Eradication: Case-Con- strategies that slow fat absorption may be promising therapeutic approaches trol Study to lower hyperlipidemia in insulin resistance. ISABEL M. CORNEJO-PAREJA, M. MAR ROCA-RODRÍGUEZ, LETICIA COÍN- Supported By: American Diabetes Association (1-13-TS-12 to E.J.P.) ARAGÜEZ, CRISTINA DÍAZ-PERDIGONES, MARÍA MOLINA-VEGA, CARMEN HERNÁNDEZ-GARCÍA, ARACELI MUÑOZ-GARACH, JUAN ALCAIDE-TORRES, CAR- 269-LB LOS CLU-FERNÁNDEZ, LAURA VIÑUELA-GONZÁLEZ, LAURA MORA-NAVAS, ISA- GCN2 Recapitulates FGF-21-dependent Metabolic Effects Following BEL MANCHA-DOBLAS, FRANCISCO J. TINAHONES, Málaga, Spain, Cádiz, Spain To evaluate changes in carbohydrates metabolism, lipid profile and intake Short but Not Long-Term Protein Restriction regulating hormones induced by 75 g oral glucose tolerance test (OGTT), THOMAS LAEGER, DIANA C. ALBARADO, LEXIE TROSCLAIR, JOHN HEDGEPETH, before and after antibiotic treatment in patients colonized by H. pylori, com- CHRISTOPHER D. MORRISON, Nuthetal, Germany, Baton Rouge, LA FGF-21 plays a physiological role in the response to protein restriction pared to healthy controls. (PR), and prior data implicate the General Control Nonderepressible 2 (GCN2) Clinical data, carbohydrate and lipid metabolism, ghrelin and GLP-1 levels kinase as the amino acid sensor linking PR to FGF-21 induction. Therefore, before and after eradication treatment were analyzed in a prospective study. we hypothesized that GCN2-deficient mice would fail to respond to reduced We studied 40 cases and 21 controls (60% and 57.1% women, respectively). dietary protein intake and thereby recapitulate the phenotype of FGF-21-KO Average age was 46.9 ± 2 vs. 44.5 ± 2.7. 70% vs. 57% had family history of mice. digestive disorders and 58% vs. 43% clinical history of gastrointestinal disease. C57BL/6J mice (WT), FGF-21- and GCN2-KO mice on the B6 background After antibiotic therapy, we found significant decrease in HbA1c (p=0.014), 60’ were used. Control and low protein (LP) diets were made isocaloric by equally (p=0.018) and 120’ (p=0.019) glucose post OGTT, and significant increase in varying protein [18% (control) and 4% (LP) of energy] and carbohydrate con- HDL cholesterol (p=0.021). There are significant changes in basal ghrelin lev- tent while keeping fat content constant. Diets were offered for 6 months, with els (p=0.05). Comparing infected population by H. pylori and healthy people, we found lower insulin levels at 30’ (p=0.042) and 60’ (p=0.03) post OGTT in behavioral, metabolic and tissue endpoints measured. FGF-21-KO mice failed to respond to the LP diet with changes in energy infected patients. We observed higher LDL cholesterol levels (p=0.043) and expenditure, food intake, body weight or metabolic gene expression. LP diet lower HDL cholesterol levels (p=0.539) in cases. These differences disappear increased circulating FGF-21 above 4 ng/ml in WT-mice at 2 weeks, whereas after treating the infection. Negative correlations between ghrelin, lipids

the induction of FGF-21 by LP diet was markedly blunted in GCN2-KO mice metabolism and pancreatic reserve were observed in controls. 90% of patients (1.5 ng/ml). GCN2-KO mice also replicate the phenotype of FGF-21-KO mice completed correctly the treatment and 32% used Ranitidine although 97.5% of by showing no metabolic or behavior response to PR after 2 weeks. However, them erradicated H. pylori after conventional antibiotic treatment. after 6 months on a LP diet circulating FGF-21 concentration was increased Conclusions: H. pylori eradication includes improvements in carbohydrate

I ntegrated and lipid metabolism. POSTERS in WT-mice (8.4 ng/ml) and rose in GCN2-KO mice to 5.3 ng/ml. This increase in FGF-21 in GCN2-KO coincided with the appearance of metabolic responses Cases and controls showed significant positive correlations between Physiology/Obesity to PR. anthropometric measurements, carbohydrates and lipids metabolism. In conclusion, the delayed response to PR in GCN2-deficient mice is Ghrelin correlated negatively with lipids metabolism and pancreatic reserve explained by the delayed increase in circulating FGF-21. Thus, these data in controls. demonstrate that FGF-21 is persistently elevated by dietary PR and required Carbohydrates and lipid metabolism differences between healthy and H. for LP-induced changes in metabolism, with GCN2 serving as a unique part of pylori infected people disappeared after antibiotic treatment. this mechanism. More than 95% of patients achieved H. pylori eradication with conventional antibiotic treatment. Supported By: National Institutes of Health (R01DK081563); German Research Supported By: Instituto de Salud Carlos III (CIBER CB06/03/0018, PI12/02355); Foundation (LA 3042/2-1) Consejería de Economía, Innovación, Ciencia y Empleo (PI11-CTS-08181); Fondo Europeo de Desarrollo Regional (FEBER)

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LB70 InteLgaterated Brea Phkingysiolo Abstractsgy—Muscle

272-LB dose endotoxin treatments would augment insulin-signaling and glycogen syn- Nicotinic Acid Timed to Feeding, but Not Fasting, Reverses Ectopic thesis acutely and prove harmful with chronic exposure and additionally, that Lipid Accumulation and Improves Glucose Control in Obese Zucker acute low-dose treatments in mice would result in improved glucose homeo- Rats stasis. Interestingly, short-term endotoxin treatments had no effect on insulin TOBIAS KROON, TANIA BACCEGA, JOHAN GABRIELSSON, NICHOLAS D. OAKES, signaling or glycogen synthesis in human primary muscle cells, while long-term Uppsala, Sweden, Gothenburg, Sweden treatments decreased glycogen synthesis (9.728 ± .408 vs. 8.427 ± .459 nmol/ Our goal was to find a nicotinic acid (NiAc) dosing regimen that achieves mg prot/h P=.02). In the mouse model, short-term endotoxin treatments resulted durable plasma free fatty acid (FFA) lowering, sufficient to reverse ectopic in significant improvements in glucose homeostasis (362.1 ± 12.22 vs. 268.0 ± lipid accumulation and thereby improve metabolic control in obese Zucker 18.20 AUC P=.0003) that were independent of changes in insulin secretion. This rats. The aim of this study was to compare effects of feeding-period vs. fast- effect may be partly attributed to an inhibitory action of LPS on liver glucose ing-period NiAc dosing on metabolic control. NiAc was dosed as a 12 hr sub- production. Additional studies are necessary to understand the mechanisms cutaneous infusion (8.5 hr constant infusion plus 3.5 hr gradual step-down) responsible for these effects on glucose metabolism. using programmable, implantable mini-pumps. Food was available during the Supported By: R01DK078765 12 hr dark period only. Following 5 days of treatment an oral glucose tolerance test (OGTT) was performed. It was found that NiAc administration timed 275-LB to feeding decreased ectopic lipid accumulation in liver (47%, P<0.01) and Effects of Different Types of Dietary Fats on the Cardiometabolic Phe- heart (↓38%, P<0.05) and reduced plasma fructosamine compared to vehicle notype of Rats Consuming an Obesogenic, High-Fat, High-Sucrose controls. In response to OGTT, plasma FFA levels were reduced (AUC ↓46%, Diet P<0.01) with amelioration of hyperglycemia (AUC ↓22%, P<0.01) and hyper- HEIDI KOCALIS, KEVIN NISWENDER, Los Angeles, CA, Nashville, TN triglyceridemia (AUC ↓55%, P<0.05). By contrast, NiAc administration timed Adoption of a high-calorie, saturated fat enriched Western-style diet to fasting did not reverse ectopic lipid accumulation or ameliorate glucose is associated with the increased prevalence of obesity and cardiovascular intolerance or dyslipidemia. In conclusion, NiAc dosing regimen has a major diseases. Substitution of saturated fat with monounsaturated fat in the diet impact on correcting metabolic disturbances in obese Zucker rats. Specifi- may be beneficial in improving manifestations of these diseases in humans. cally, dosing in conjunction with feeding (but not fasting) robustly lowers FFA, Here, we sought to determine if the type of fat consumed in a high-fat, obe- reverses ectopic lipid accumulation and profoundly improves glucose control. sogenic diet can influence the development of cardiometabolic disease in an animal model of diet-induced obesity. Male rats were fed one of 2 specially 273-LB formulated, micronutrient and calorie matched, high-fat, high-sucrose diets Carrageenan-induced Decline in Sulfatase Activity Contributes to (Kcal%=45% fat, 20% protein, 35% carbohydrate) enriched in either satu- Metabolic Impairment in Diabetes rated fat (SF) (Kcal%=36% SFA, 45% MUFA) or monounsaturated fat (MU) JOANNE K. TOBACMAN, LEO FEFERMAN, SUMIT BHATTACHARYYA, Chicago, IL (Kcal%=8% SFA, 71% MUFA. After 10 weeks of ad libitum feeding, we mea- Exposure to the common food additive carrageenan leads to glucose intol- sured body weight and body composition (NMR), plasma hormone and lipid erance and insulin resistance and exacerbates the impact of the high-fat diet levels and cardiac mRNA expression of gene markers of fibrosis and inflam- in the C57BL/6J mouse. These effects are due predominantly to inhibition mation. After 10 weeks, rats that consumed SF and MU diets gained similar of insulin signaling by effects on inflammation. Inflammatory effects of car- amounts of total weight and fat mass. There were no differences in plasma rageenan are mediated through TLR4 and through reactive oxygen species. In levels of insulin or leptin but plasma triglyceride levels were increased 2-fold addition, exposure to carrageenan leads to increased expression of GRB10, in rats fed MU compared to SF high-fat diet. Total levels of free fatty acids a negative regulator of insulin signaling. Carrageenan exposure also leads (FFA) did not differ between the two high-fat diets, however, the composition to decline in activity of the chondroitin sulfatases, arylsulfatase B (ARSB; of FFAs were altered to reflect the dietary fat composition. In plasma of rats N-acetylgalactosamine 4-sulfatase) and N-acetylgalactosamine 6-sulfatase the consumed MU diet, SFA levels were 30% lower, and PUFA levels were (GALNS). ARSB removes the 4-sulfate group from the non-reducing end of 40% lower, while MUFA content was elevated by 1.8-fold above SF diet lev- chondroitin 4-sulfate; GALNS removes the 6-sulfate group from the non- els. Relative to MU diet, consuming SF diet was associated with higher mRNA reducing end of chondroitin 6-sulfate. In hepatic, pancreatic, colonic, muscle, expression levels of the cardiac fibrosis markers alpha smooth muscle actin and adipose tissue of C57BL/6J mice exposed to carrageenan (10 µg/ml) (2.7-fold) and ST2 (2.3-fold), as well as the inflammatory cytokine gene TNF in their water supply, activity levels of these sulfatases were significantly alpha (2.2-fold). These finding suggest that dietary fat composition influences reduced. Decline in ARSB, either in HepG2 cells that are silenced by siRNA or cardiometabolic health, independent of caloric intake or body adiposity. in hepatic tissue of ARSB-deficient mice, leads to decline in the oxygen consumption rate and increase in extracellular acidification rate. These changes are associated with decline in expression of the mitochondrial carrier pro- Integrated Physiology—Muscle tein (MCP)-1 and in mitochondrial pyruvate. Mitochondria appear abnormal following carrageenan, consistent with marked changes in cellular metabo- 276-LB lism. Sustained effects of carrageenan in the hepatic cells and tissue may be Role of trans-Golgi–associated GTPase ARFRP1 in High-Intensity attributable to some extent to the effects of Interleukin-8, which binds more Performance to chondroitin 4-sulfate when ARSB is reduced. Further assessment of the DEIKE HESSE, THOMAS LAEGER, MICHAELA RATH, JOSEFINE WÜRFEL, ANNETTE carrageenan-induced inhibition of sulfatase activity may yield new insights SCHÜRMANN, Nuthetal, Germany into mechanisms by which chondroitin sulfates contribute to the development The monomeric GTPase ARFRP1 controls a trans-Golgi associated proof the metabolic effects of diabetes. tein cascade that influences protein trafficking required for the regulation Supported By: American Diabetes Association (1-12-BS-216 to J.K.T.) of the intracellular lipid storage and lipoprotein secretion. Enduring exercise increases fat oxidation in the muscle. Therefore, we hypothesize that ARFRP1 274-LB might contribute to differences in exercise performance by modulation of I ntegrated

Acute Low-Dose Endotoxin Treatment Results in Improved Whole- nutrient partitioning in muscle. POSTERS Body Glucose Homeostasis in Mice Arfrp1flox/flox mice were intercrossed with mice expressing the Cre JOSEPH R. STEVENS, RYAN MCMILLAN, STEFAN HARGETT, SUSANNA KELLER, recombinase under the Mck promoter. Arfrp1flox/flox and Arfrp1mus-/- were Physiology/Obesity MATTHEW HULVER, St. Louis, MO, Blacksburg, VA, Charlottesville, VA subjected to a running protocol on a metabolic treadmill with metabolic and Obese individuals present with an increased inflammatory tone as com- tissue endpoints measured. pared to healthy, normal-weight individuals, and this associates with insulin Arfrp1mus-/- mice did not show impaired voluntary activity but were resistance. A factor thought to contribute to increased inflammation in obese exhausted under conditions of high intensity performance (HIP). They stopped and diabetic states is elevated blood endotoxin levels. In nonobese and insulin running earlier (mean ± sem; 20.9 ± 0.5 min) than control mice (31.1 ± 1.1 min). sensitive individuals, endotoxin concentrations follow with diurnal feeding pat- Basal respiratory quotient (RQ) of Arfrp1mus-/- mice (0.68 ± 0.01) was lower terns with elevations in the post-prandial state that return to baseline levels compared to control mice (0.76 ± 0.03) and increased faster towards earlier in the post-absorptive state; a pattern that is disrupted in the context of high exhaustion due to reduced whole body O2 consumption during HIP. As plasma fat feeding. The goals of these studies were to assess the effects of very-low lactate concentrations were unaltered between genotypes for the whole dose endotoxin on insulin signaling and glucose flux in a human primary skeletal period we conclude that the mice did not stop running because of an over- muscle cell line as well as in a C57/Bl6 mouse model. We hypothesized that low- acidification. Expression analysis of quadriceps muscle and heart indicate that

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LB71 InteLgaterated Brea Phkingysiolo Abstractsgy—Muscle

Arfrp1mus-/- mice show a shift towards oxidative muscle fibers as well as a whereby skeletal muscle energy expenditure is modulated to alter susceptibil- significant reduction in Vegf-b expression. ity for obesity. In conclusion, ARFRP1 in muscle is essential for acute exercise bouts in Supported By: National Institutes of Health (DK095774) mice. Metabolic alterations in blood and the RQ point towards a higher basal fatty acid oxidation with an earlier switch to carbohydrate metabolism in mus-/- 279-LB Arfrp1 mice. Gene expression data indicate a diminished muscle vascu- Local Phosphatidylethanolamine Synthesis Mediates Exercise- mus-/- larization which might lead to an O2 dept in Arfrp1 mice. induced Remodeling of Skeletal Muscle Mitochondria Supported By: German Federal Ministry of Education for Research (01GI0922); JORDAN M. JOHNSON, TIMOTHY D. HEDEN, EDWARD J. WENTZLER, TARA M. German Research Foundation (SFB958) NAROWSKI, KATSUHIKO FUNAI, Greenville, NC Mitochondria are highly dynamic and capable of tremendous expansion to 277-LB meet cellular energetic demands. Exercise training promotes skeletal muscle Hsp20-mediated Activation of Exosome Biogenesis in Cardiomyo- mitochondrial proliferation to increase aerobic capacity, a large determinant cytes Improves Cardiac Function and Angiogenesis in Diabetic Mice of metabolic health. Mitochondrial phospholipids provide an essential struc- XIAOHONG WANG, HAITAO GU, YUTIAN LI, GUO CHANG FAN, Cincinnati, OH tural and biophysical environment for the enzymes of the electron transport Background: Decreased heat shock protein (Hsp) expression in type 1 system (ETS), but there is limited information on how mitochondrial mem- and type 2 diabetes has been implicated as a primary factor contributing to brane lipids are generated and/or modified in response to exercise. Following diabetes-induced organ damage. We recently showed that diabetic cardio- five weeks of treadmill exercise training, mitochondrial phosphatidyletha- myocytes could release detrimental exosomes, which contain lower levels of nolamine (PE) content was increased in skeletal muscle from C57BL/6J mice, Hsp20 than normal ones. concomitant with an increase in expression of phosphatidylserine decar- Methods and Results: To test whether such detrimental exosomes could be boxylase (PSD), the PE-synthetic enzyme resident in the inner mitochondrial modified in cardiomyocytes by raising Hsp20 levels to become protective, we membrane. We hypothesized that elevated PSD mediates exercise-induced utilized a transgenic (TG) mouse model with cardiac specific-overexpression increases in respiratory function. In C2C12 myotubes, PSD overexpression of Hsp20. TG and wild-type (WT) mice underwent daily peritoneal injection was sufficient to increase oxidative capacity and induce expression of genes of streptozotocin (STZ, 50µg/g) for 5 days to induce diabetes. We observed involved in mitochondrial biogenesis. In contrast, myotubes lacking PSD have that overexpression of Hsp20 significantly attenuated STZ-caused cardiac decreased maximal respiration and reduced fatty acid oxidation. To study the dysfunction, hypertrophy, apoptosis, fibrosis and microvascular rarefaction. effects of PSD overexpression in vivo, mice with skeletal muscle-specific Moreover, Hsp20-TG cardiomyocytes exhibited an increased exosome gen- tamoxifen-inducible knock-in of PSD (PSD-MKI) were generated. High-resolu- eration by direct interaction of Hsp20 with Tsg101. Of importance, exosomes tion respirometry studies in permeabilized muscle fibers revealed greater non- derived from TG-cardiomyocytes encased higher levels of Hsp20, p-Akt, Sur- ADP stimulated complex I activity and a trend for increased complex II and III vivin and SOD1 than WT-exosomes, and protected against in vitro hypergly- maximal activity in PSD-MKI compared to control, without increasing overall cemia-triggered cardiomyocyte death, as well as promoted endothelial cell mitochondrial content. These findings suggest that skeletal muscle PSD pro- proliferation under hyperglycemia conditions. In addition, Hsp20-enriched motes improvement in mitochondrial quality, a mechanism that may partly exosomes collected from TG cardiomyocytes were administered into diabetic mediate the exercise-induced increase in aerobic capacity. Our future experi- mice via the tail vein injection (1µg/g body weight, 5 times every other day), ments include investigation of how PSD-MKI mice may respond to metabolic and elicited protection against STZ-induced cardiac adverse remodeling, com- insults that lead to diabetes. pared to WT-exosome-treated controls. Lastly, blockade of exosome genera- Supported By: National Institutes of Health (DK095774) tion by GW4869 remarkably offset cardioprotection presented in Hsp20-TG mice under diabetic conditions. 280-LB Conclusions: Our results indicate that elevation of Hsp20 in cardiomyocytes Treatment with Selective GPR120 Agonists Decreases Plasma Glu- can offer protection in diabetic hearts through the release of instrumental cose and Increases Glucose Uptake in Skeletal Muscle and Brown exosomes. Thus, Hsp20-enriched exosomes might be a novel therapeutic Adipose Tissue in a Novel fZDF Rat Model agent for diabetic cardiomyopathy. DAN ZHOU, DANIEL METZGER, OKSANA PALYHA, YING CHEN, VINIT SHAH, Supported By: National Institutes of Health (R01-087861) STEPHEN PREVIS, GEORGE EIERMANN, MELISSA KIRKLAND, JIYAN XUE, OLGA PRICE, DAPHNE SZETO, SCOTT EDMONSON, GREGORY ADAMS, CHARLES JAYNE, 278-LB SHOUWU MIAO, SKRIKANTH VENKATRAMAN, JASON COX, WU YIN, Kenilworth, Phospholipid Methylation Deficiency Increases Skeletal Muscle NJ Energy Expenditure and Prevents Obesity GPR120, a G-protein coupled receptor of unsaturated long-chain fatty acids, ANTHONY R. VERKERKE, JORDAN M. JOHNSON, PATRICK J. FERRARA, CHIEN TE has been demonstrated as a potential target for treating diabetes and related LIN, TERENCE E. RYAN, TIMOTHY D. HEDEN, EDWARD J. WENTZLER, TARA M. metabolic diseases. Treatment with GPR120 agonist decreases body weight NAROWSKI, P. DARRELL NEUFER, KATSUHIKO FUNAI, Greenville, NC and reduces blood glucose in various animal models. In this study, we tested Membrane phosphatidylethanolamine (PE) can be tri-methylated to form potent and selective GPR120 agonists using fZDF rats to explore its role on phosphatidylcholine (PC) by the enzyme PE methyltransferase (PEMT). Mice regulation of glucose homeostasis. A single oral dose of compound A did not with a whole-body deletion of PEMT (PEMTKO) exhibit elevated resting decrease fasting glucose or improve glucose excursion in rats following an oral metabolic rate and are protected from diet induced obesity. However, the glucose challenge. Subchronic treatment of GPR120 agonists, but not acute mechanism behind increased respiration in PEMTKO is unknown. We tested treatment is required to demonstrate glucose lowering efficacy in fZDF rats. our hypothesis that PE methylation deficiency promotes an increase in skel- A potent compound B ranging from 10 mg/kg to 100 mg/kg dose dependently etal muscle energy expenditure. Cellular respiration in isolated intact muscle lowered both fed and fasting plasma glucose independent of body weight fibers measured in vitro revealed an increased resting O2 consumption in after 5 days of treatment in fZDF rats. The high dose of compound B corrected PEMTKO muscles compared to wild-type (WT). Consistent with these findings, the blood glucose level to that of lean controls. Plasma TG, glycerol and liver I ntegrated

POSTERS data from intact skeletal muscle studied ex vivo also suggested that rest- TG were also significantly reduced. A 28-day chronic treatment of compound ing and contraction-stimulated respiration were greater in PEMTKO vs. WT. B demonstrated durable glucose lowering effect along with dose dependent

Physiology/Obesity Increased muscle energy expenditure was not due to mitochondrial proton reduction of plasma TG and insulin. Glucose uptake measured by 2-deoxy glu- uncoupling (ATP production per O2 reduction), as confirmed in permeabilized cose (2DG) challenge revealed that compound B significantly increased glu- fibers and isolated mitochondria. Instead, muscle PE methylation deficiency cose uptake in skeletal muscles (soleus, EDL and gastrocnemius) and brown promoted an apparent decrease in transport stoichiometry of sarco/endoplas- adipose tissue but not in white adipose tissue. All together, we demonstrated mic reticulum (SR/ER) Ca2+-ATPase (SERCA) (Ca2+ uptake/ATP hydrolysis), sug- that potent and selective GPR120 agonist (compound B) reduced blood glu- gesting that futile energy expenditure of SERCA ATPase might be responsible cose by increasing skeletal muscle and brown adipose tissue glucose uptake for increased metabolic rate in these muscles. Phospholipidomic analysis in fZDF rats. These beneficial effects of GPR120 agonist might be due to sec- revealed that PEMT knockout results in a deceased PC/PE ratio in muscle SR ondary effects of improved overall metabolic tissue health. but not mitochondria. Our preliminary studies show that mice with muscle- specific knockout of PEMT (PEMT-MKO) are protected from diet-induced obesity, exhibit increased energy expenditure, and show improved glucose tolerance. These data suggest a novel phospholipid-dependent mechanism

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LB72 IntegratedLate P hByreasiolokinggy—O Abstractsther Hormones

281-LB 283-LB Integrin-linked Kinase Accelerates Skeletal Muscle Fat Oxidation Antidiabetic Effects of Novel, Long-Acting Amylin Analogue ZP4982 and Accumulation during Obesity in ZDF Rats DANIEL LARK, ELIJAH TREFTS, MERRYGAY JAMES, ROY ZENT, AMBRA POZZI, JOLANTA SKARBALIENE, RASMUS JUST, Glostrup, Denmark DAVID H. WASSERMAN, Nashville, TN Amylin improves glycemic control by inhibition of food intake and gastric Recent reports demonstrate that integrins, at least in part through integrin- emptying, and suppression of glucagon secretion. Here we investigated the linked kinase (ILK), contribute to the etiology of skeletal muscle (SkM) insu- antidiabetic effects of long-acting amylin analogue ZP4982 in Zucker Diabetic lin resistance (IR). However, the mechanisms connecting ILK to IR are poorly Fatty (ZDF) rats. understood. The objectives of this project were to determine the impact ZDF rats aged 9-10 weeks were dosed s.c., for 4 weeks with vehicle, ZP4982 of SkM ILK deletion in high fat (HF)-fed mice on: 1.) fat utilization, 2.) gene (30 nmol/kg, dosed every 5th day), or liraglutide (40 nmol/kg, bid). The antidi- transcription and 3.) fat storage. Indirect calorimetry and mitochondrial func- abetic effects of ZP4982 were investigated by measurements of non-fasting tion studies demonstrate that HF-fed mice with SkM-specific deletion of ILK and fasting blood glucose (BG), HbA1c, and glucose tolerance during an intra- have decreased whole body and SkM fat oxidation independent of changes peritoneal glucose tolerance test (IPGTT). in energy expenditure, food intake or body composition. These decreases in ZP4982-treated rats had significantly lower non-fasting BG after 2 weeks of whole body and SkM fat oxidation are accompanied by a ~80% decrease treatment, as well as at the end of the study (p < 0.001 vs. vehicle). Also, fast- in AMPK activation. Transcriptome-wide RNA sequencing of gastrocnemius ing BG was significantly lower in ZP4982-treated rats at the end of the study muscle from five-hour fasted wild type C57BL/6J mice identified 280 genes (p < 0.001 vs. vehicle). The beneficial effects on BG were also reflected in that are differentially expressed following chronic HF feeding; expression HbA1c levels (Figure 1). ZP4982 clearly improved glycemic control vs. vehicle- of 75% of these genes are increased. Gene Ontology (GO) analysis revealed treated rats, and caused a greater reduction in HbA1c levels than liraglutide. that of the 211 up-regulated genes, 101 (48%) encode membrane-associated Moreover, ZP4982 significantly increased insulin levels and lowered BG proteins and 30 (14%) encode extracellular space proteins. Kyoto Encyclope- during IPGTT, confirming improved glucose tolerance (P < 0.001 vs. vehicle). dia of Genes and Genomes (KEGG) analysis indicated increased peroxisome In conclusion, treatment with long-acting amylin analogue ZP4982 markedly proliferator activated receptor (PPAR) pathway activation (pAdj = 2.89e-06) in improved glycemic control and glucose tolerance in diabetic rats, suggesting HF-fed mice. Ingenuity Pathway Analysis (IPA) revealed that SkM ILK deletion the antidiabetic potential of long-acting amylin based therapies. attenuated gene expression changes related to insulin resistance and lipid Figure 1. HbA1c Changes after 4 Weeks of Treatment. synthesis. Chromatographic assessment of lipid from gastrocnemius of HF- fed mILK-KO mice demonstrates a ~33% decrease in free fatty acid, a ~50% decrease in stored triglyceride in SkM but a 15% increase in phospholipids. Our findings demonstrate a critical role for SkM ILK in the regulation of fat oxidation and storage that appears to be mediated by PPAR and AMPK signaling and support a paradigm in which oxidative metabolism can be targeted through the extracellular matrix. Supported By: National Institutes of Health (R01 DK054902, U24 DK059637, P30 DK020593, T32 DK007061)

Integrated Physiology—Other Hormones

282-LB Beta-Cell GLP-1R Contributes to Improved Glucose Tolerance after Vertical Sleeve Gastrectomy in Mice DARLINE GARIBAY, ANNE K. MCGAVIGAN, SEON LEE, AARON D. SHOWALTER, Data were analyzed using one-way ANOVA followed by Dunnett’s multiple MERVYN D. MICHAEL, KYLE W. SLOOP, BETHANY P. CUMMINGS, Ithaca, NY, India- comparison test, ***p<0.001 vs. vehicle; student’s two-tailed, unpaired t-test #p<0.05 vs. liraglutide. n=12. Data are mean ±SEM. napolis, IN Vertical sleeve gastrectomy (VSG) produces high rates of type 2 diabetes remission; however, the mechanisms responsible for this remain undefined. 284-LB Post-operative increases in postprandial glucagon-like peptide-1 (GLP-1) Fibroblast Growth Factor-21 Decreases Hyperglycaemia in Insulin- secretion may contribute; however, previous work has been equivocal. In order Deficient Mice Housed both in Standard and Thermoneutral Tem- to test the contributions of β-cell GLP-1 receptor (GLP-1R) signaling we used perature a β-cell specific tamoxifen-inducible GLP-1R knockout mouse model. At 8 wks PETR ZOUHAR, BIRGITTE ANDERSEN, KIRSTEN RAUN, BARBARA CANNON, JAN of age, β-cell specific GLP-1R+/+ (WT) and GLP-1R-/- (KO) male mice were placed NEDERGAARD, Stockholm, Sweden, Måløv, Denmark on a high fat diet (HFD) for 6 wks and then switched to HFD supplemented Fibroblast growth factor-21 (FGF-21) is a cytokine that ameliorates both with 400 mg tamoxifen/kg diet for the rest of the study, a dosing strategy pre- obesity-associated and insulin-deficiency dependent hyperglycaemia. viously validated in this model. Mice underwent sham (Sham WT and Sham Importantly, room temperature, which is used in most animal experiments, KO) or VSG (VSG WT and VSG KO) surgery at 16 wks of age and were fed is below the thermoneutral zone of mice, i.e., the metabolic rate of these mice ad libitum post-operatively (n=5-8 per group). Mice underwent oral glucose is elevated due to the additional cost of thermogenesis. In contrast, humans tolerance testing (OGTT) at 3 wks and were euthanized at 6 wks after surgery. are thermoneutral at room temperature. To assess the relevance of the thera- Body weight and food intake were reduced in VSG WT and VSG KO compared peutic effect of FGF-21 for humans, animal experiments should be performed with their respective sham-operated controls (p<0.05). However, body weight in thermoneutral temperature. FGF-21 effects in various housing tempera-

and food intake did not differ between genotype for either treatment. OGTT tures have been already tested in murine models of diet-induced obesity but I ntegrated POSTERS data revealed an improvement in glucose tolerance in VSG WT, but not in VSG not yet in insulin-deficient mice.

KO. Furthermore, the glucose AUC during the OGTT was significantly elevated To compare the antidiabetic effects of FGF-21 in thermoneutral and stan- Physiology/Obesity in VSG KO compared with VSG WT (Glucose AUC0-120: Sham WT = 26788 ± dard temperatures, mice (C57Bl/6 males) were acclimated either to 20 or 30 1296, Sham KO = 30273 ± 4521, VSG WT = 22312 ± 2439, VSG KO = 30766 °C. They were made diabetic by 5 times 50 mg/kg streptozotocin injections, ± 2799 mg·min/dl; p<0.05). Interestingly, the augmentation in glucose-stimu- which resulted in development of hyperglycaemia (blood glucose > 16 mM). lated insulin secretion during the OGTT was blunted in VSG KO compared with Subsequently, mice were treated for 3 weeks with vehicle, or 3 mg/kg FGF-21 VSG WT (OGTT percent increase in insulin from baseline to peak values: Sham once daily. Body weight, food intake, blood glucose and glycated haemoglobin WT = 148 ± 48, Sham KO =96 ± 43, VSG WT =294 ± 79, VSG KO =138 ± 31%; were monitored during the experiment. p<0.05). Overall, our data suggests that β-cell GLP-1R signaling contributes to Regardless of housing temperature, FGF-21 treatment lowered blood glu- improved glucose regulation and insulin secretion after VSG. cose. Importantly, the positive effect on glycated haemoglobin levels was observed to the same extent at both temperatures. Plasma leptin levels tended to increase and IGF-1 levels to decrease, but the changes were only significant at standard temperature.

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LB73 IntegratedLate P hByreasiolokinggy—O Abstractsther Hormones

In conclusion, the insulin-independent glucose-lowering effects of FGF-21 287-LB are present in both standard and thermoneutral temperatures. Also other Enteroendocrine Cell-derived Activin-beta (Actβ) Enhances AKH/ parameters (such as leptin and IGF1) are regulated in a similar way at both glucagon Action and Contributes to Hyperglycemia temperatures, while the extent of effects can differ. This implies that the ben- WEI SONG, Boston, MA eficial effects of FGF-21 on blood glucose should be relevant in humans. Insulin and glucagon play fundamental and counteractive roles in carbohy drate homeostasis. In addition to insulin resistance, enhanced glucagon action 285-LB also contributes to hyperglycemia in the context of high caloric diet. In contrast ApoA-IV Regulates Glucose Homeostasis through Glucose Uptake in to the wealth of knowledge regarding insulin action regulation, little is known Mouse Adipose and Muscle Tissues about the physiological regulation of glucagon signaling. To identify new regu- XIAOMING LI, FEI WANG, MIN XU, PHILIP HOWLES, PATRICK TSO, Xi’an, China, lators of glucagon signaling, we established a conserved glucagon-induced Cincinnati, OH hyperglycemia model in Drosophila overexpressing fly glucagon encoded by Insulin resistance is a risk factor for type 2 diabetes mellitus. The loss of Akh (Adipokinetic hormone). We combined in vivo RNAi screen and genetic insulin sensitivity inhibits both the downregulation of hepatic gluconeogen- validation and identified the activin type I receptor, Baboon (Babo), and one of esis and the stimulation of glucose uptake by myocytes and adipocytes in its ligand, Activin-β (Actβ), as important regulators of glucagon/AKH signal- response to the serum level of glucose. ApoA-IV produced by enterocytes is a ing. Deficiency of Babo or Actβ significantly impaired AKH action in the fat major component of high-density lipoprotein, and plays roles in the transport body which is equivalent to the liver, and abolished hyperglycemia associated of serum lipids and the satiation signal. In our previous studies, we firstly with high-sugar diet in Drosophila. Importantly, Actβ production in enteroen- showed that ApoA-IV improved glucose homeostasis by suppressing hepatic docrine cells was significantly increased and promoted fat body AKH action gluconeogenesis in the absence of insulin and enhancing insulin secretion. and elevated glycemic level in response to high-sugar diet. Finally, we found However, it is unclear whether ApoA-IV enhances glucose uptake in insulin that in mouse primary hepatocytes Activin A treatment potently enhances targeting tissues. We investigated the effect of ApoA-IV on glucose uptake in glucagon signaling as well as glucagon-induced glucose production. In sum- adipocytes and muscle cells and its mechanism. mary, we have identified an evolutionarily conserved mechanism whereby We found that treatment of ApoA-IV before insulin administration lowered activin signaling enhances glucagon action to impact hyperglycemia and/or fasting blood glucose in diabetic KKAy mice, suggesting that r-m-ApoA-IV diabetes pathogenesis. increased insulin sensitivity. ApoA-IV increased glucose uptake in cardiac Supported By: American Diabetes Association (1-16-PDF-108) muscle and adipose tissues in vivo through mechanism that was insulin independent. Furthermore, the glucose uptake rates for skeletal muscle in the 288-LB ApoA-IV-KO mice were significantly lower than those of the wide type mice, Electrical Neuromodulation of the Carotid Sinus Nerve as a Novel suggesting that efficient glucose uptake in skeletal muscle requires ApoA-IV Therapeutic Approach for the Treatment of Type 2 Diabetes as well. Moreover, cell culture experiments showed that ApoA-IV improved SILVIA V. CONDE, JOANA F. SACRAMENTO, BERNARDETE F. MELO, SONAL PATEL, glucose uptake in adipocytes and myocytes in the absence of insulin, and DANIEL CHEW, WESLEY DOPSON, VICTOR PICKOV, ALI ROBINSON, BRAD HOLIN- ApoA-IV upregulated Akt expression and GLUT4 translocation in adipocytes. SKI, NISHAN RAMNARAIN, MARIA P. GUARINO, Lisboa, Portugal, Stevenage, These results suggests that ApoA-IV acts directly upon adipose and muscle United Kingdom tissues to improve glucose uptake indirectly via insulin signaling. Our findings Our previous results have shown that carotid chemoreceptors respond to that ApoA-IV regulates glucose uptake in adipocytes and myocytes could be insulin and pre-emptive surgical transection of the carotid sinus nerve (CSN) potential therapeutic targets for treating insulin resistance. prevents the development of insulin resistance in animal models of predia- Supported By: National Institutes of Health (DK92138, DK103557 to P.T.), DK59630 betes (Ribeiro et al. Diabetes 2013). We hypothesized that, bilateral functional CSN denervation performed after 14 weeks of a high-fat/high sucrose 286-LB diet would be a viable therapeutic strategy. Our results demonstrated that Recombinant Leptin Administration Lowers Plasma Angiopoietin- surgical CSN transection improved insulin action and glucose homeostasis like Protein 8 (ANGPTL8) Levels in Patients with Lipodystrophy and that this was maintained for the duration of the 11 week study (data not RANGANATH MUNIYAPPA, REBECCA J. BROWN, BRENT S. ABEL, MARY F. WAL- shown). In our search for reversible, non-ablative approaches, bilateral high TER, ELAINE COCHRAN, PHILLIP GORDEN, MONICA C. SKARULIS, Bethesda, MD frequency alternating current (50 KHz) conduction block of the CSN over 9 Lipodystrophy (LD) syndromes are rare, leptin-deficient disorders character- weeks restored insulin resistance and glucose tolerance to normal physiologi- ized by hyperinsulinemia, severe insulin resistance, and hypertriglyceridemia. cal values. The block was non-destructive to the nerve, as seen with return of Reduced triglyceride clearance due to impaired lipoprotein lipase (LPL)- insulin resistance and glucose tolerance upon cessation of block. In conclu- mediated lipolysis contributes to severe hypertriglyceridemia. Angiopoietin- sion, we present the first evidence of non-destructive, reversible electrical like proteins (ANGPTL), in particular ANGPTL8 (also known as betatrophin), blocking as a potential therapeutic approach in type 2 diabetes. reduce the clearance of triglycerides by inhibiting LPL. Hyperinsulinemia is a Figure. strong inducer of ANGPTL8 expression. Whether circulating ANGPTL8 levels are altered in LD and the effects of leptin therapy are unknown. In this study we compared plasma ANGPTL8 in lean (n=21), obese (n=42), and LD (n=24) individuals. In a subgroup of LD patients (n=12) who were on stable doses of oral hypoglycemic and lipid lowering agents, we examined if leptin therapy lowers plasma ANGPTL8. ANGPTL8 levels (pg/mL) were significantly higher in patients with LD (mean [95% CI]) (3863 [1740, 5987]) compared with obese (956 [832, 1080], p<0.05) and lean individuals (570 [459, 680], p<0.05). In the combined cohort of lean and obese individuals plasma ANGPTL8 directly correlated with total body fat, fasting insulin levels, total and LDL cholesterol, I ntegrated

POSTERS and indirectly correlated with insulin sensitivity index. Stepwise regression analyses revealed that insulin sensitivity index and total cholesterol were

Physiology/Obesity independent predictors of circulating ANGPTL8 levels. In patients with LD, there was a significant decrease in total cholesterol, triglyceride, and A1c levels following leptin therapy. Post-leptin, ANGPTL8 concentrations decreased significantly (5505 pg/mL [1756, 9255] vs. 1427 [976, 1879], p=0.002). These Supported By: GlaxoSmithKline novel findings suggest that elevated plasma levels of ANGPTL8 may play a role in hypertriglyceridemia observed in leptin-deficient states. Furthermore, lower ANGPTL8 levels may contribute to the triglyceride lowering effect of 289-LB The Development of Inducible Mfgf-21 Transgenic Mouse for Study- leptin therapy in patients with lipodystrophy. ing the Mechanism Underlying Metabolic Actions of FGF-21 Supported By: National Institute of Diabetes and Digestive and Kidney Diseases KOOK HWAN KIM, SEONG HUN KIM, MYUNG SHIK LEE, Seoul, Republic of Korea Fibroblast growth factor-21 (FGF-21) is an endocrine hormone that is primarily expressed in the liver by a variety of environmental or metabolic stimuli.

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LB74 LateO Bbesreaitkingy—Anim Abstractsal

FGF-21 acts a key regulator in the adaptive response to diverse physiological identified the heart as the main organ of glucose disposal (3-5 fold increase conditions such as nutrient deprivation or overload, cold exposure and exer- in TAC). Cardiac GLUT4 expression was decreased, but GLUT1 expression was cise. In addition, FGF-21 has shown beneficial effects on various metabolic increased with TAC. Also, lower fasting glucose and increased glucose clear- diseases such as nonalcoholic fatty liver disease (NAFLD), nonalcoholic ste- ance correlated with echocardiographic left ventricular dilation, consistent atohepatitis (NASH), insulin resistance, diabetes and obesity. FGF-21 is able with a causative relationship. to exert therapeutic effects via its pleiotropic actions in multiple target organs As fasting glucose is highly regulated and primarily maintained from gly- such as adipose tissue, liver, pancreas, and brain. Despite numerous studies cogen stores, these were assessed. Liver and skeletal muscle glycogen were on metabolic effects of FGF-21, little is known about the molecular mecha- depleted after TAC (7.2 vs. 2mg/g and 0.3 vs. 0.17mg/g, respectively), but myo- nism underlying its actions. Here, we generated inducible FGF-21 transgenic cardial glycogen content did not differ. Oral glucose substitution after TAC (iFGF-21 Tg) mice overexpressing the mouse FGF-21 gene using a tetracycline- partially prevented hypoglycemia and weight loss, restored liver and muscle inducible system. We showed that iFGF-21 Tg mice exhibit decreased body glycogen and reduced cardiac dilation and mortality (6-month-survival: 37% weight without reduced food intake compared to control mice after feeding a TAC vs. 67% TAC+Sucrose). In HF-patients, negative correlation of serum-nt- high-fat diet supplemented with doxycycline. In addition, these mice showed pro-BNP with HOMA-index disappeared over 6 months of HF-therapy. enhanced glucose clearance and reduced fasting glucose, insulin or choles- In summary, low fasting glucose and increased glucose turnover are key terol levels under obese condition. We performed microarray analysis in the metabolic abnormalities in mice with TAC-induced HF. Increased cardiac glu- liver of iFGF-21 Tg mice to identify novel mechanisms underlying the action of cose consumption appears to deplete glycogen stores. Glucose substitution FGF-21 in metabolic improvement. We observed the change of expression of partially prevented cardiac cachexia, preserved glycogen stores and reduced known and novel genes that may involve in the metabolic beneficial effects of left ventricular dilation and HF mortality. In conclusion, strategies restoring FGF-21. Thus, these results suggest that iFGF-21 Tg mouse model provides a glucose availability may be beneficial in HF. novel tool to investigate molecular mechanisms underlying the action of FGF- Supported By: Federal Ministry for Education and Research (01E01004) 21 in improvement of metabolic diseases. Supported By: Korean Ministry of Education, Science and Technology 292-LB (2013R1A6A3A04065825) Functional Analysis of SNAT5 in Amino Acid Stimulated Glucagon Secretion 290-LB YAN XU, SHIUHWEI CHEN, ZHIJIANG HUANG, QING LIU, WEN HONG LI, Dallas, Glucagon Response in C-Peptide Positive vs. C-Peptide Negative TX Patients with Type 1 Diabetes under Hypoglycemic Clamp vs. Real- Amino acids are potent secretagogues of glucagon secretion, yet mecha- Life Setting nisms underlying amino acid stimulated glucagon release remain poorly under- SABINE ZENZ, PETRA BAUMANN, MARTINA BRUNNER, ADELHEID PUFFING, stood. To identify key molecular players regulating glucagon secretion, we MICHAEL WOLF, MARKUS RUMPLER, MARTIN HAJNSEK, HARALD SOURIJ, sorted islet alpha cells from glucagon receptor knockout mouse (Gcgr(-/-)) and THOMAS R. PIEBER, JULIA K. MADER, Graz, Austria analyzed their gene expression by RNA-Seq. Gcgr(-/-) mice displayed glucagon It has been suggested that in long-standing type 1 diabetes (T1D) coun- hypersecretion and we hypothesized that genes upregulated in alpha cells of ter-regulatory response to hypoglycemia is blunted. Glucagon response to Gcgr(-/-) mouse may play important roles in regulating glucagon release. hypoglycemia was tested in a hypoglycemic clamp setting (clamp) vs. hypo- Differential gene expression analysis revealed that Slc38a5 gene (encod- glycemia under real-life conditions using a meal/insulin challenge (real-life) ing a sodium-coupled neutral amino acid transporter, SNAT5) was the highest in C-peptide positive (C-pep+) vs. C-peptide negative (C-pep-) subjects with up-regulated gene in Gcgr(-/-) islet cells. We then generated SNAT5 knockout T1D. In the clamp study subjects underwent a hyperinsulinemic, hypoglyce- mouse (SNAT5-KO). Compared to wild type controls (C57/Bl6), SNAT5-KO mic clamp. In the real-life study subjects were investigated over 12 h at the mouse maintained the same metabolic parameters including blood glucose, research center and received a standardized meal with 180% of their short- insulin, islet cell mass, and IPGTT. In perfused mouse pancreas, both alanine acting insulin dose. Glucagon response during hypoglycemia was defined as and arginine reliably caused biphasic glucagon secretion in SNAT5-KO and area under the glucagon curve during the first hypoglycemic episode. Glucose control animals. However, the second phase of alanine stimulated, but not was measured every 5min (Super GL). Glucagon samples were taken using for arginine stimulated, glucagon secretion was reduced in SNAT5-KO islets, sug- glucagon measurement validated BD P800 blood collection tubes and analysis gesting a specific role of SNAT5 in mediating neutral amino acid stimulated was performed using a glucagon-specific sandwich ELISA (Mercodia). C-pep+ glucagon release. was defined as C-peptide level≥ 0.05nmol/l. Baseline characteristics were the To test if SNAT5 upregulation is sufficient to enhance alanine stimulated following for the clamp group: 11 C-pep- (age 37±13 y, 6 female, BMI 25±2kg/ glucagon secretion, we overexpressed SNAT5 in mouse islets. Glucagon m2, HbA1c 7.5±0.8%, diabetes duration 24±10 y) and 10 C-pep+ (age 40±13 y, perifusion assay of infected islets showed the same glucagon release as the 5 female, BMI 24±2kg/m2, HbA1c 7.3±0.9%, diabetes duration 3±2 y). Subjects islets infected with a control virus, arguing that upregulation of SNAT5 per se in the real-life study were as follows: 11 C-pep- (age 32±8 years, 4 female, was not enough to increase glucagon secretion. We are currently assaying BMI 24±3kg/m2, HbA1c 7.3±1.2%, diabetes duration 19±8 y) and 5 C-pep+ (age the amino acid importing activity of SNAT5 in alpha cells. Further, we are 38±17 y, 2 female, BMI 23±1kg/m2, HbA1c 7.7±0.9%, diabetes duration 10 ±15 y). generating SNAT5/Gcgr double knockout mice to study the role of SNAT5 in In the clamp study, C-pep+ had a significantly higher glucagon response during alpha cell hyperplasia and glucagon hypersecretion in vivo when glucagon hypoglycemia than C-pep- (Mann-Whitney-U: 4.7±3.2 vs. 1.5±1.7, p=0.0083). signaling is disrupted. During the real-life experiment no statistically significant difference was seen Supported By: National Institutes of Health; JDRF (C-pep+ 0.1±0.08 vs. C-pep- 0.1±0.04, p=0.56). C-pep+ showed a higher glucagon response compared to C-pep- during hypoglycemic clamp conditions, but in contrast to previous studies not during real-life conditions. Obesity—Animal Supported By: European Commission FP7 (305343-SPIDIMAN) 293-LB I ntegrated

291-LB MetAP2 Inhibition Reduces Plasma Methionine and Branched-Chain POSTERS The Selfish Heart—Failing Myocardium Causes Hypoglycemia and Amino Acids in DIO Mice Mortality in Heart Failure JIANHUA ZHANG, JIANFENG XU, YANG LI, NANNAN ZHANG, QIAN LIU, MARC Physiology/Obesity ILONKA PECIK, MARIA KNOCKE, RUDOLF WERNER, TAKAHIRO HIGUCHI, BETTINA CAO, XILIN LIU, MINGJIAN LU, ZHENG HUANG, Shanghai, China J. KRAUS, Wuerzburg, Germany Methionine aminopeptidase 2 (MetAP2) catalyzes the hydrolytic removal Heart failure (HF) and diabetes are comorbidities with high prevalence and of the initiator methionine from nascent proteins. It was recently shown that poor prognosis. We investigated if changes in cardiac glucose utilization in HF pharmacological inhibition of MetAP2 enzyme activity by Beloranib resulted affect systemic glucose metabolism. in significant fat loss in severely obese humans and PWS patients, with HF was induced by transverse aortic constriction (TAC) in mice. Cardiac concomitant reduction of plasma LDLc, triglyceride and C-reactive protein. function and glucose- and insulin-tolerance were followed for six months. However, the underlying mechanism for weight loss efficacy remains largely Fasting glucose was lower in TAC-mice compared to sham-operated animals unknown. Here we report that chronic treatment with a peripherally-distrib- (95±4 vs. 108±4 mg/dl and 98±6 vs. 124±7 mg/dl after 1 and 6 months), and uted MetAP2 inhibitor A-800141 in high-fat diet-induced obese mice resulted glucose clearance was increased. Serum insulin levels and insulin sensitivity in robust weight loss, reduced plasma cholesterol, triglyceride, AST and ALT were not enhanced. PET-imaging (F18-FD-glucose) 1 and 6 months after TAC levels, and improved liver steatosis. Plasma metabolite analysis revealed that

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LB75 LateO Bbesreaitkingy—Anim Abstractsal

A-800141 treatment significantly reduced plasma levels of methionine and 296-LB branched-chain amino acid (BCAA) independent of reduced food intake. Given A Non-cell-autonomous Mechanism of Beige Adipocyte Mainte- that dietary restrictions of methionine and BCAA cause fat loss in obese nance and Its Role on Energy Homeostasis rodent models, we supplemented methionine, BCAA, folate and B12 in the BIAO WANG, San Francisco, CA high-fat diet before and during a 2-week treatment with A-800141. The sup- There are two types of uncoupling protein 1/UCP1+ adipocytes: classical plementation reversed plasma methionine and BCAA deficit, but was unable brown adipocytes in brown adipose tissue (BAT) and beige adipocytes scattered to block the reduced body weight and food intake elicited by the inhibitor. within white adipose tissue (WAT). Beige adipocyte abundance in rodents and These results suggested that the decreased plasma levels of methionine and humans is dynamically regulated by ambient temperature. Importantly, obese BCAA did not play a causal role for reduced body weight and food intake by individuals have reduced UCP1+ thermogenic adipocytes, suggesting that MetAP2 inhibitor treatment. However, the change in plasma methionine and beige adipocyte dynamics may have regulatory roles on energy homeostasis. BCAA levels may potentially serve as biomarkers for MetAP2 inhibition in However, the precise mechanisms of beige adipocyte homeostasis, especially vivo. its maintenance, are unknown. Here we show that a genetic program in white adipocytes governs “beigeing” properties of preexisting beige adipocytes in a 294-LB non-cell-autonomous fashion. We found that loss of cAMP production specifi- Beneficial Cardiometabolic Effects of Vertical Sleeve Gastrectomy cally in white adipocytes, not in beige adipocytes, abolished beige adipocyte Are Mediated by Glucagon-like Peptide (GLP-1) expansion in inguinal WAT (iWAT) induced by chronic beta-adrenergic stimu- RAYMOND G. LAU, SUNIL KUMAR, CHRISTOPHER HALL, THOMAS PALAIA, COL- lation. On the other hand, augmentation of cAMP-dependent transcription by LIN E. BRATHWAITE, KENETH HALL, DREW RIDEOUT, LOUIS RAGOLIA, Mineola, removing Salt-inducible kinases/SIKs or deleting their upstream kinase, Liver NY kinase b 1/Lkb1, in white adipocytes led to a sustained beige adipocyte popu- Vertical sleeve gastrectomy (VSG) has shown beneficial metabolic effects lation in iWAT. Lineage tracing experiments showed that the beige adipo- through the modulation of glucagon-like peptide-1 (GLP-1). However, its impact cytes in adult adipocyte Lkb1 knockout mice (Lkb1AKO) were indeed the same on cardiovascular disease has not been fully explored. We investigated the population of beige adipocytes formed during postnatal development, while effects of VSG using a diabetic and obese rodent model, Zucker diabetic fatty they lost their beige markers in adult wild-type mice. The class IIa HDAC4 (ZDF) rodents. Animals were divided into four groups (i) sham (n=4), (ii) sham was hypophosphorylated and activated in adipocytes from Lkb1AKO mice. Loss with GLP-1 agonist (n=4), (iii) VSG (n=4) (iv) VSG with GLP-1 antagonist (n=4). of adipocyte HDAC4 in Lkb1AKO mice reversed their beige adipocyte expan- The study was carried out for 12 weeks and all parameters were measured sion phenotype, and transgenic mice expressing constitutively active HDAC4 before surgery, 6 weeks, and 12 weeks following surgery. At the end of the (H4-TG) in adipocytes exhibited marked beige adipocyte expansion. Notably, study, a myograph was performed using aortic tissue and it was found the the appearance of beige adipocytes in both Lkb1AKO and H4-TG mice occurred GLP-1 agonist and VSG group showed enhanced vasorelaxation and vasocon- prior to the improvements of metabolic performances under high-fat diet . striction. Similarly, triglyceride levels in GLP-1 agonist and VSG group (346 Our results reveal an unexpected role of white adipocytes in beige adipocyte +/- 25.5, 143 +/- 3 mg/dL) significantly decreased compared with sham (478 maintenance and metabolic homeostasis. +/- 21 mg/dL). However, blood pressure remains unchanged as compared to Supported By: National Institute of Diabetes and Digestive and Kidney Diseases; sham controls. Weights of GLP-1 and VSG agonist group (399.5 +/- 5.6 g, 439.8 Larry L. Hillblom Foundation +/-7 g) were decreased as compared to sham (511.3 +/- 19.4 g). Blood glucose also was decreased in GLP-1 agonist and VSG groups (154 +/- 44 mg/dL, 252 297-LB +/- 41.5 mg/dL) compared with sham (367 +/- 8.5 mg/dL). Our results suggest, Novel Genes on Rat Chromosome 10 Are Linked to Body Fat Mass, the beneficial cardiometabolic effects of VSG are mediated through GLP-1. Preadipocyte Number, and Adipocyte Size in Rats and Humans NORA KLÖTING, ANIKA WEINGARTEN, LUCIA TURCHETTI, KNUT KROHN, PETER 295-LB KOVACS, MICHAEL STUMVOLL, MATTHIAS BLÜHER, Leipzig, Germany Irx3 Modulates Adipocyte Browning by Directly Regulating Mito- The genetic architecture of obesity is multifactorial. We have previously chondrial Complex I Genes identified a quantitative trait locus (QTL) on rat chromosome 10 in a F2 cross of SAMANTHA LABER, THOMAS P. AGNEW, ROGER D. COX, Oxford, United Kingdom Wistar Ottawa Karlsburg (WOKW) and Dark Agouti (DA) rats responsible for SNPs in the first intron of Fto have repeatedly been shown to have the obesity. The QTL was confirmed in congenic DA.WOKW10 rats. To pinpoint the strongest association with human BMI in genome wide association studies. region carrying causal genes, we established two new sub-congenic lines, L1 A recent report by Claussnitzer et al. (NEJM, 2015) revealed that intronic Fto and L2, with refined segments of chromosome 10. All lines were extensively SNPs are within an enhancer specific to the adipocyte lineage and that risk characterized under different diet conditions. We employed transcriptome allele carriers have altered Irx3 and Irx5 expression early in adipocyte dif- analysis in visceral adipose tissue (AT) by RNA-Seq technology to identify ferentiation.Our results show that silencing of Irx3 in mouse pre-adipocytes potential underlying genes in the segregating regions. Three candidate genes causes them to develop into brown-like adipocytes as measured by increased were measured in human paired samples of visceral and subcutaneous (SC) mRNA expression of mitochondrial transport chain and biogenesis genes (e.g., AT (N=304) individuals with a wide range of body weight and glucose homeo- Pgc1a, Cox7a, Cox8b, Elovl, Dio2) at day 8 of adipogenic stimulation. Bioener- stasis. getics analysis using the Seahorse Bioflux analyzer at day 8 of differentiation Under chow diet, body weight as well as fat mass measurements showed show increased basal respiration, proton leak, ATP production and maximal that male sub-congenic strains remained obese compared to parental strain respiration in pre-adipocytes that have been silenced for Irx3 compared to whereas under high fat diet (HFD) conditions L1 rats were protected from diet control, a profile that is consistent with increased mitochondrial respiration induced obesity. Interestingly, adipocyte size distribution in subcutaneous in brown-like adipocytes. Using ChIP-Seq for the transcription factor IRX3, we and epigonadal (EPI) AT of L1 sub-congenic rats did not undergo typically bal- identified the targets of IRX3 in early differentiating mouse primary pre-adi- looning under HFD and the number of preadipocytes in AT was significantly pocytes. We identified > 2000 peaks in proximal promoter regions ≤( 1kb) and elevated in L2 compared to L1 and parental rats. Transcriptome analysis gene ontology of the respective genes revealed that mitochondrial genes are identified 3 candidate genes in visceral AT on rat chromosome 10. In humans,

I ntegrated those candidate genes were differentially expressed between SC and visceral

POSTERS significantly overrepresented (P=2.2E-11; PANTHER Overrepresentation Test). STRING analysis of identified mitochondrial genes showed that these genes AT and one gene, head involution defective (HID1) mRNA was strongly cor-

Physiology/Obesity can be clustered into 3 main processes: i) Mitochondrial ribosomal structure, related with parameters of obesity and glucose metabolism. ii) mitochondrial complex I assembly/units and iii) Mitochondrial membrane Our data provide novel candidate genes for obesity which map on rat chro- transporters. This suggests a cell-autonomous role for Irx3 in pre-adipocytes mosome 10 in an interval 102.2-104.7Mb strongly associated with body fat where Irx3 mediates mitochondrial structure/function which has implications mass regulation, preadipocyte number and adipocyte size in rats. Our human for adipocyte browning and thermoregulation. Our findings provide novel mRNA results suggest that changes in AT HID1 expression are related to fat mechanistic insight into how alteration of Irx3 leads to changes in adipose distribution and glucose homeostasis. tissue development, a cellular mechanism that may explain the genomic asso- Supported By: DFG SFB1052, DZD 82DZD00601 ciation with BMI in humans. Supported By: Medical Research Council

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LB76 LateO Bbesreaitkingy—Anim Abstractsal

298-LB tion of TLR4 signaling may be important in the establishment of steatosis and Aging- and Metabolism-related Changes Shift the Fate of Bi-potent that phenylmethimazole (C10), a novel TLR3/4 inhibitor developed in our labo- Bone-resident Progenitor Cells Leading to Increased Bone Marrow ratory, may prevent steatosis in a C57BL/6J mouse model of NAFLD. Male Adiposity C57BL/6J mice were placed on either a low fat diet (LFD, 10% fat) or HFD THOMAS H. AMBROSI, LUIS R. SARAIVA, TIM J. SCHULZ, Nuthetal, Germany, (60% fat) and randomly divided them into 6 groups (n=8 for each group) as Doha, Qatar follows: LFD, HFD sham injection (stress control), DMSO (vehicle control), Aging, increased caloric intake, and metabolic diseases are accompanied HFD 0.1 mg/kg C10, HFD 1.0 mg/kg C10, HFD 10 mg/kg C10. Treatments were by the accumulation of bone marrow adipocytes. The pathophysiological administered once daily via intraperitoneal injection for 18 weeks. Histologi- effects of ectopic adipocytes in the bone compartment are presently a matter cal examination illustrated that HFD-fed C10-treated mice have less hepatic of discussion and changes on the progenitor cell level are mostly unknown. lipid content than HFD-fed sham and DMSO-treated mice, a finding that was We confirm that long bones of aged mice show a decrease of osteogenic and confirmed by hepatic triglyceride quantification. Down-regulation of hepatic an elevation of adipogenic marker expression. Bi-potent adipo-osteogenic pro-inflammatory cytokine expression (TNF-α) was observed in HFD-fed C10- progenitors residing within the bone maintain their adipogenic, but not their treated mice compared to HFD-fed sham and DMSO mice as were key media- osteogenic potential when isolated from aged animals. Moreover, short-term tors of triglyceride (TG) synthesis. These data indicate that C10 effectively high fat diet feeding for three days results in higher adipocyte numbers in prevents steatosis as well as hepatic inflammation and TG synthesis, lending the bone marrow cavity compared to animals maintained on standard diet support to the hypothesis that TLR4-mediated inflammation may play a key (SD). This effect is more pronounced in aged animals. Consistently with these role in the establishment of steatosis by modulating TG synthesis. Thus, we observations, proliferation of adipo-osteogenic progenitor cell populations is provide evidence that TLR4-mediated inflammation is linked to alterations in rapidly and significantly induced in aged animals in response to short-term hepatic lipid metabolism leading to the development of steatosis and that C10 dietary cues when compared to young animals. Purely osteo-chondrogenic may be a therapeutic for the treatment of NAFLD. populations are not affected. Microarray analysis further suggests that changes in extra-cellular matrix production support this pro-adipogenic 301-LB switch. In summary, our findings imply that age-related changes on the pro- Dietary Curcumin Intervention Attenuates Body Weight Gain in High genitor cell level favor adipogenesis over an osteogenic regeneration pheno- Fat Diet Fed Mice via Inhibiting Fat Tissue Inflammation andI ncreas- type, an effect that is mirrored under HFD conditions or states of metabolic ing Brown Adipocyte UCP1 Expression impairment such as diabetes. This might have detrimental effects on bone ZHUOLUN SONG, XAVIER REVELO, WEIJUAN SHAO, KEJING ZENG, LILI TIAN, HEL- homeostasis which in turn could affect systemic health. ENA LEI, MINNA WOO, DANIEL WINER, TIANRU JIN, Toronto, ON, Canada Adipose tissue inflammation and excessive energy intake are two major 299-LB causative factors of obesity. Therapeutic agents that can simultaneously tar- Correction and Prevention of Hyperglycemia, Hyperinsulinemia, and get these two pathological events are desired for obesity treatment. A few Obesity, in Diet-induced Obese Mice, by a Glucagon Receptor Anti- previous studies have demonstrated the appreciable body weight lowering body effect of the dietary polyphenol curcumin in high fat diet (HFD) fed mouse ZHIQING SHI, JINGQI HUANG, FENG LIANG, HAI YAN, Camarillo, CA, Beijing, China models, and this function was attributed to its anti-inflammatory and anti-oxi- A human glucagon receptor antagonizing antibody, REMD-477, is in clini- dative properties in adipose tissues and elsewhere. We show here for the first cal development for T1DM and T2DM treatment. Its therapeutic potential for time that curcumin intervention in HFD fed mice not only reduced fat tissue obesity indication was tested using R477a, an REMD-477 analog (7.5 mg/kg, macrophage infiltration, but also reduced the ratio of M1 to M2 macrophages. SC, weekly), in both Treatment and Preventive settings in the high fat diet In vitro curcumin treatment was shown to reduce M1 but increase M2 mac- (HFD)-induced obesity (DIO) in male mice, with Vehicle (VC), Pair-Feeding (PF) rophage marker expression in Raw264.7 cells. In rat primary mature adipo- and Normal Diet (ND) as controls (N=10/Group). cytes, curcumin treatment reduced the expression of inflammatory cytokines. HFD for 20 wk in VC mice resulted in DIO (38% greater gain in body weight, Furthermore, curcumin intervention in HFD fed mice increased energy expen- BW, vs. ND), hyperglycemia (12.7±1.5 mM), hyperinsulinemia (1,737±837 pM) diture, associated with increased UCP1 and its upstream regulators (PGC-1, and impaired oral glucose tolerance test (OGTT). In a DIO Treatment setting, PPARα and PPARγ) in brown adipose tissue. We have also verified that UCP1 R477a given from week 8 HFD for 12 wk, reduced daily caloric intake (10.9%) promoter activity can be stimulated by curcumin treatment in two naive cell and BW (9.2%), restored euglycemia (7.2±0.5 mM), and normalized OGTT (all systems. We hence conclude that curcumin intervention plays a dual modula- P<0.01). Hyperinsulinemia was corrected (508±238; 260±172 pM), by 8 or 12 tory role in preventing obesity by targeting adipose tissues: attenuating white wk Treatment, respectively. R477a induced an 11x rise in serum GLP-1, contrib- adipocyte inflammation and increasing brown adipocyte activity. uting to reduced food intake. PF marginally improved hyperglycemia (11.0±1.1 Supported By: Canadian Institutes of Health Research mM), but had no effect on BW, insulin, or OGTT. In a Preventive setting, R477a, started and given concurrently with HFD for 20 weeks, prevented DIO (34% 302-LB lower BW), lowered glucose (6.1±0.5 mM) and insulin (61±37 pM) levels (All An Acceleration of NAMPT-mediated NAD Synthesis Is Necessary P<0.01, or P<0.05, vs. VC). Liver triglyceride content was reduced (21.4±14.5 vs. for the Differentiation of 3T3-L1 Preadipocytes 131.6±46.5 mg/g, P<0.01, vs. VC) in the Preventive setting. In both Treatment KEISUKE OKABE, ISAO USUI, AKIKO TAKIKAWA, SHIHO FUJISAKA, KAZUYUKI and Preventive settings, R477a did not affect AST, ALT, Alkaline Phosphatase TOBE, TAKASHI NAKAGAWA, Toyama, Japan and γ-GT enzyme activities, indicating no liver toxicity. Nicotinamide adenine dinucleotide (NAD) is a key co-enzyme implicated in In conclusion, R477a, as a Treatment, corrected hyperglycemia, hyperin- many cellular redox reactions. It also acts as a substrate for poly (ADP-ribose) sulinemia, normalized OGTT, and reduced weight gain in the established DIO polymerases (PARPs) and sirtuins and plays key roles in diverse biological pro- mice. R477a, as a Preventive measure, prevented DIO, and maintained nor- cesses. In mammalian cells, NAD is predominantly synthesized through the mal insulin, glucose and OGTT, in the HFD-fed mice. Our study highlights the salvage pathway in which nicotinamide (NAM) is converted to nicotinamide clinical potential of a glucagon receptor antibody in correcting and preventing mononucleotide (NMN) catalyzed by Nampt and then NMN is converted to

hyperinsulinemia, a key contributing factor for obesity. I ntegrated

NAD catalyzed by Nmnat. Although a number of omics-based studies have POSTERS been performed to determine the metabolic changes during the differentiation 300-LB of 3T3-L1 cells, few have focused on the role of NAD metabolism. Therefore Physiology/Obesity Phenylmethimazole Alleviates Nonalcoholic Fatty Liver Disease in the role of Nampt-mediated NAD synthesis in adipocyte differentiation still C57BL6/J Mice Fed a High-Fat Diet remains to be elucidated. In this study, we employed liquid chromatography- ASHLEY PATTON, TYLER CHURCH, STEPHEN BERGMEIER, DOUG GOETZ, RAMIRO mass spectrometry (LC/MS) and gas chromatography-mass spectrometry (GC/ MALGOR, JEAN THUMA, KELLY D. MCCALL, FRANK SCHWARTZ, Athens, OH MS)-based targeted metabolomics to elucidate the role of Nampt-mediated Nonalcoholic fatty liver disease (NAFLD) is the hepatic manifestation of NAD synthesis in the differentiation of 3T3-L1 cells. NMN and NAD started both metabolic and inflammatory-mediated diseases. Activation of toll-like to increase around day 4 after the induction of the differentiation, which was receptor 4 (TLR4) signaling by free fatty acids (FFAs) up-regulates expression compatible with the increase of Nampt and Nmnat1. In addition, other meta- of pro-inflammatory cytokines that are known to stimulate de novo lipogene- bolic changes also occurred. For example, most metabolites in glycolysis, TCA sis in hepatocytes, suggesting that inflammation resulting from TLR4 signaling cycle, and pentose phosphate pathway were increased. To examine whether may be critical for the development of high fat diet (HFD)-induced steatosis. the increased NAD level was necessary for the adipocyte differentiation, we Thus, we hypothesized that hepatic inflammation resulting from FFA activa- treated 3T3-L1 cells with FK866, a specific chemical inhibitor ofN ampt, after

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LB77 LateO Bbesreaitkingy—Anim Abstractsal

the induction. FK866 reduced NMN and NAD synthesis and significantly pre- 305-LB vented the lipid accumulation of 3T3-L1 cells. Moreover, the gene expression The Central Nucleus of Amygdala Regulates Energy Status via AMPK of C/EBPα and PPARγ, the master regulator of adipogenesis, was remarkably in Response to Nutrients and Hormones suppressed. These results indicate that the increased NAD level is necessary GISELE CASTRO, LAÍS WEISSMANN, NATÁLIA FERREIRA MENDES, MÁRIO JOSÉ for the differentiation of 3T3-L1 cells. We suppose epigenetic modification by ABDALA SAAD, PATRICIA O. PRADA, Campinas, Brazil sirtuins or poly ADP-ribosylation may be involved and further investigation AMP-activated protein kinase (AMPK) has a crucial role in the regula- is required. tion of energy balance, particularly through effects on the hypothalamus, in response to nutrients and hormones. The central nucleus of amygdala (CeA) is 303-LB part of reward system and contributes to control food intake (FI) in response GABA Protects against Obesity by Activating Thermogenesis in to hormones and neural inputs. Herein, we aimed to determine whether 1.) Brown Adipose Tissues AMPK is an energy sensor in CeA responding to nutrients and hormones; 2.) YUN WAN, DONGDONG JIANG, QIAOLI CUI, WENJUAN LIU, ZHIHONG WANG, RUI AMPK in CeA contributes for normal counter regulatory hormone response LIU, QINGHUA WANG, Shanghai, China, Toronto, ON, Canada during hypoglycemia. Prolonged fasting (24h) increased and refeeding (2h) The objective of this study is to examine whether γ-aminobutyric acid reduced AMPKThr172 phosphorylation in CeA of control rats. CeA glucose infu- (GABA), an endogenous transmitter producing in the endocrine system exerts sion increased AMPKThr172 after 1 h accompanied by reduced FI. This effect regulatory effects in brown adipose tissue (BAT). We used diet-induced obese was blunted by Compound C injection prior to glucose in CeA. Fed control (DIO) mouse model (C57BL/6, male, 5 week of age) to address this important rats increased FI in response to ghrelin infusion in CeA and this effect was question. We found high fat diet (HFD) feeding induced remarkable obesity accompanied by enhanced AMPKThr172 and NPY mRNA in this region. In addi- in these mice, which was significantly attenuated (10%, p<0.001) by GABA tion, fed control rats received AICAR in CeA, which increased AMPKThr172 and treatment (6 mg/ml, through drinking water). Our results showed, after 12 FI up to 2h, declining after 4 hours. Chronic melanocortin agonist (MTII) infu- weeks intervention, GABA significantly improved glucose tolerance deter- sion in CeA decreased AMPKThr172, FI and body weight. In contrast, chronic mined by intraperitoneal glucose tolerance test (IPGTT, AUC: control vs. melanocortin antagonist (SHU9119) infusion in CeA increased AMPKThr172, FI GABA=3141.5±159.5 vs. 2435.8±322.0,p<0.01), and increased insulin sensitiv- and body weight (BW). In 12 h fasted animals, 2-deoxy-glucose (2DG) infusion ity determined by insulin tolerance test (ITT, AUC: control vs. GABA=947.5±55.9 in CeA increased AMPKThr172, accompanied by increased FI and glycemia up to vs. 518.9±85.9,p<0.001). Although GABA treatment did not change food intake 3h. Further, by using a minipump to infuse alpha 1/2 AMPK siRNA for 7 days in or water consumption, studies using Comprehensive Lab Animal Monitoring CeA of control rats, we observed a decrease in BW, FI and a lack of response System (CLAMS) showed that GABA increased the O2 consumption (control to 2DG in terms of FI. In summary, our results indicated that AMPK is regu- vs. GABA=2633.45±106.3 vs. 2890.5±77.6, p<0.001), CO2 production (control lated by nutrients as glucose, hormones as ghrelin and by melanocortin sys- vs. GABA=2082.2±112.1 vs. 2250.48725±134.2,p<0.05) and energy expen- tem in CeA contributing to FI control. In addition, preliminary results suggest diture normalized by body weight (control vs. GABA=13.3±0.6 vs. 14.4±0.6, that AMPK may be important for glucose sensing in CeA. In conclusion, our p<0.05). Remarkably, while GABA did not significantly change the physical results suggested that AMPK acts as an energy sensor in extra-hypothalamic activity in these DIO mice, GABA-treated mice kept higher core temperature regions such as CeA and plays a role in the complexity of the control of energy during 6 hours’ cold exposure studies (0h: 35.8±0.5 vs. 36.3±0.6, p<0.05; 1h: balance. 35.5±0.3 vs. 35.3±0.5, p>0.05; 2h: 35.0±0.6 vs. 35.5±0.7, p<0.05; 4h: 35.3±0.5 Supported By: Fundação de Amparo à Pesquisa do Estado de São Paulo, Brazil vs. 35.9±0.4, p<0.05; 6h: 35.2±1.1 vs. 36.1±0.4, p<0.05). BAT activity studies evaluated by uptake of 18F-fluorodeoxyglucose showed higher BAT activity 306-LB in GABA-treated DIO mice compared to those non-treated (p<0.01). Our find- Kinomic Analysis of Adipose Inflammation from Antiretroviral Ther- ings suggest that GABA stimulates thermogenesis in BAT, enhancing energy apy-Treated Diabetic Mice expenditure and improving the metabolic homeostasis in DIO mice, providing KIRK M. HABEGGER, ADAM R. WENDE, HUBERT M. TSE, Birmingham, AL a potential target against obesity and metabolic disorders. Antiretroviral therapy (ART) has markedly improved HIV-1 patient survival. However, with the extension of the patients’ lifespan, new clinical problems 304-LB associated with ART and metabolic dysregulation have arisen. Prolonged A Screening of White to Brown-Like Adipocyte Reprograming Mol- ART does not restore complete immune function and health is compromised ecules with a Knock-in Cell Model at many levels by persistent immune hyperactivation, chronic inflammation, HAN WANG, XIE LUO, FENG LIU, MATTHEW HART, PEI WANG, San Antonio, TX cardiovascular diseases, obesity, and diabetes. We hypothesized that pro- Obesity is a worldwide health problem; the search for novel weight loss inflammatory adipose infiltrating macrophages contribute to ART-associated therapies is an ever growing need for patient care. There are different types metabolic disorders in patients with HIV-1. To test this, we treated age- and of adipocytes: the white adipocytes (WAT) function as energy storage; brown weight-matched C57Bl/6J mice for 80 d with the most common ART, Atripla, and beige adipocytes (BAT) are for the expenditure of energy through uncou- while on chow or high fat diet (HFD, 58%). Within each treatment/diet group, pled protein 1 (UCP1) to generate heat. We propose to directly reprogram half of the mice were depleted of CD4+ T cells to model patients with HIV. white adipocyte to brown or beige adipocytes, so that the amount of WAT will Mice on a HFD displayed diet-induced obesity and increased caloric intake as be reduced; and brown/beige to white adipocyte ratio will be increased. This compared to chow-fed controls. While ART treatment mildly suppressed body will have positive effects on obesity and aging related metabolic diseases. mass accumulation in chow-fed mice, the combined insults of HFD and ART To achieve this, we generated a reporter cell line where Ucp1 expression significantly increased weight gain and fat mass by 6.8% and 8.6%, respec- can be easily monitored. Using homologous recombination method and the tively. ART treatment also impaired glucose tolerance (8 wk) and exacerbated Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) genome insulin resistance (12 wk) in HFD mice, but was reversed in the chow-fed, ART- editing technique, we inserted a firefly luciferase reporter into the Ucp1 treated mice. To define the mechanisms of metabolic alterations due to Atripla gene locus of mouse white preadipocyte 3T3-L1 cells. After validation of the treatment, we performed kinomic arrays on purified adipose tissue-infiltrating reporter line, cells were used in small molecule screenings. A total of 2,480 macrophages. Our results supported a marked decrease in PKCdelta activ-

I ntegrated ity by CD4 depletion, increased epidermal growth factor receptor 3 (ERBB3)

POSTERS compounds have been tested from a library of pharmacologically active compounds and a library of known bioactive and human-safe small molecules. A activity in HFD, and decreased anaplastic lymphoma kinase (ALK) signaling

Physiology/Obesity total of 31 compounds have been identified to stimulate an over 2-fold increase in ART plus HFD groups depending on CD4 status. Our data suggest that of luciferase activity. Among these hit compounds, two kinase inhibitors ken- ART exacerbates the insults of a diabetogenic HFD, partly due to modulating paullone and BIO were picked for further validation. These two molecules can kinase signaling in adipose tissue infiltrating macrophages. Anti-obesity and induce a dose dependent luciferase response in knockin cells and upregulate -diabetes therapies targeting inflammation and kinases may be advantageous Ucp1 expression in the parental 3T3-L1 cells; and also induce a higher oxygen in the treatment of HIV-1 associated metabolic disorders. consumption rate compared with DMSO-treated adipocytes. Supported By: University of Alabama at Birmingham Center for AIDS Research; In our study, small molecule screening with this knockin reporter system University of Alabama Comprehensive Diabetes Center showed promising results. Further validation of our hit compounds will not only provide biological mechanisms for the adipocyte reprogramming study, it will also provide potential therapies for obesity and age-related metabolic diseases. Supported By: Barshop Institute for Longevity and Aging Studies; University of Texas Health Science Center at San Antonio

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LB78 LateO Bbesreaikingty—Hum Abstractsan

307-LB metabolic aspects of the adipose tissue. Weaning LDLr-KO male mice were Neuron-specific Lipoprotein Lipase Deficiency Leads to Improved randomly distributed into five groups fed with a high fat diet (40% of energy Glucose Tolerance Despite Obesity as fat) containing polyunsaturated (PUFA), palmitic (PALM), palmitic interest- HONG WANG, KIMBERLEY D. BRUCE, TIAN YU, HONG GAO, ANDREW LIBBY, erified (PALM INTER), stearic (STEAR) or stearic interesterified (STEAR INTER) ANDREA ZSOMBOK, ROBERT H. ECKEL, Aurora, CO, New Orleans, LA fats during 16 weeks. Dietary intake, body weight, adipose tissue histology, Endogenous glucose production (EGP) plays a key role in the pathogenesis lipid feaces content, inflammatory and lipolitic gene and protein expres- of type 2 diabetes. It is well established that liver metabolism can be altered sion were determined. Dietary intake were not different among the groups. by neuronal inputs, however, mechanisms related to the autonomic control of The interesterification process did not alter fat absorption PALM vs. PALM hepatic metabolism remain unclear. Lipoprotein lipase (LPL), the rate-limiting INTER (7.97±0.73 vs. 9.29± 0.23), STEAR vs. STEAR INTER (32.51±14.24 vs. enzyme for the hydrolysis of circulating triglyceride (TG)-rich lipoproteins, is 15.67±4.53). However, as expected both diets rich in stearic acid presented widely expressed throughout the nervous system and neuronal LPL can modu- higher lipid content in the faeces as compared to the others. Although PALM late systemic metabolism. We have previously shown that mice with a neu- INTER (18.1±4.2) presented higher weight gain than STEAR (14.10±2.65) and ron-specific LPL deficiency (NEXLPL-/-) develop obesity on standard chow by STEAR INTER (14.32±3.0), the former presented higher visceral (4.04±0.45) 6 mo; a phenotype that was also observed, albeit delayed, in 12 mo heterozy- and subcutaneous (2.17±0.39) adipose tissue and epididymal adipocyte diam- gous (NEXLPL+/-) mice. Here, we show that despite obesity, inactivity, hyper- eter (4356±1190) when compared to others. There were no difference among leptinemia and hyperinsulinemia, 12 mo NEXLPL-/- mice display normal fasting the inflammatory cytokines gene expression. Although PALM INTER induced plasma glucose levels, and improved glucose tolerance. This phenotype was less ATGL expression as compared to PALM, it was observed a higher TNFα also observed in NEXLPL+/- mice by 18 mo. Interestingly, using hyperinsulin- synthesis and IKKα/β phosphorylation than PALM and PUFA in this group. mic euglycemic clamps, we found that whole body glucose infusion rate was This effect can be attributed to the activation of the upstream NFkB signaling 2.2 fold higher in 21 mo NEXLPL+/- mice compared to WT, and EGP was more inflammatory pathway. In conclusion, interesterification process did not influ- suppressible at low (2.5 and 5.0 mU/Kg/min) insulin concentrations compared ence fat absorption, meanwhile interesterified fat enriched with palmitic acid to WT mice (P<0.05). Furthermore, we used the Pseudorabies Virus 152 (PRV- (PALM INTER) induced higher adipose tissue content, adipocytes hypertro- 152) to identify novel liver-related neurons in the paraventricular nucleus of phy and local inflammatory response in LDLr-KO mice. FAPESP 2011/24083-7; the hypothalamus. Patch clamp recording revealed reduced inhibitory post- 2012/50249-2. synaptic currents (6 mo) in slices from NEXLPL-/- mice compared to WT (P<0.05), implying enhanced parasympathetic tone, consistent with reduced hepatic glucose production. Our findings suggest that LPL may be a novel fea- Obesity—Human ture of liver-related neurons, and highlights neuronal LPL as a potential target for the development of strategies to improve glucose homeostasis, even in 310-LB the presence of obesity. Comparable Efficacy and Safety of Liraglutide 3.0 mg across Base- Supported By: National Institutes of Health line BMI Subgroups STEN MADSBAD, GABRIELLA LIEBERMAN, TRINE V. SKJØTH, SØREN K. LILLEØRE, 308-LB RALPH A. DEFRONZO, Hvidovre, Denmark, Ramat Gan, Israel, Søborg, Denmark, San Characterization of FATZO Mice for Diabetes and Obesity Research Antonio, TX RICHARD G. PETERSON, CHARLES VAN JACKSON, BRIA SNEED, BRIAN A. DROZ, This 3-year trial examined effects of liraglutide 3.0 mg, as adjunct to diet MERVYN D. MICHAEL, PAUL J. EMMERSON, TAMER COSKUN, Indianapolis, IN, and exercise, in delaying the onset of T2DM (primary endpoint) in adults with Muncie, IN prediabetes and BMI ≥30 kg/m2, or ≥27 kg/m2 with comorbidities. Here we Obesity is a growing health threat. Developing drug treatments to fight the evaluate glycemic control endpoints and safety in BMI subgroups post hoc. sequelae require an understanding of disease progression and pathophysiol- Individuals randomized 2:1 to once-daily s.c. liraglutide 3.0 mg or placebo, ogy. Current preclinical animal models used in obesity and diabetes research with a 500 kcal/day deficit diet and 150 min/week exercise, were divided into have monogenic defects. Monogenic obesity is uncommon in humans. Having baseline BMI subgroups: 27-29.9 (n=62), 30-34.9 (n=624), 35-39.9 (n=737) and an animal model with a polygenic background, showing many signs of meta- ≥40 kg/m2 (n=831). Efficacy data are from an ANCOVA, with LOCF imputation. bolic disease, is essential for development of treatments targeting different Clinicaltrials.gov ID: NCT01272219. Baseline characteristics of 2254 random- stages of metabolic disease progression. In this study, we aimed to characterized individuals were (mean±SD): age 47.5±11.7 years, 76.0% female, weight ize a new mouse model with and without diet containing high fat. 107.6±21.6 kg, BMI 38.8±6.4 kg/m2, A1c 5.7±0.3%. While on treatment, 26 FATZO mice were developed by crossing AKR/J and C57BL/6J mice with individuals in the liraglutide group and 46 in the placebo group (3% vs. 11%) selective breeding for obesity, insulin resistance and hyperglycemia at Pre- developed T2DM over 3 years. No significant interactions between treatment ClinOmics. Eight to 10 week old male FATZO mice with body weights rang- and baseline BMI subgroup were seen for weight or glycemic control end- ing from 24 to 43 g were placed in low (29.4±0.7 g), middle (35.7 ±0.7 g) and points (Table), indicating consistent treatment effects across subgroups. Total high (38.9 ±0.7 g) weight groups. Mice selected for these groups (n=8) were and serious adverse events, gastrointestinal and hypoglycemic events had either fed Purina 5008 or D12492 (60% fat diet). Body weight, food intake and similar incidences across BMI subgroups. Liraglutide 3.0 mg, as adjunct to diet blood glucose were measured weekly while insulin was measured every two and exercise, consistently improved glycemic control endpoints and beta-cell weeks. An oral glucose tolerance test (OGTT) was performed after 8-weeks function, and enhanced insulin sensitivity across BMI subgroups. to assess glucose disposal. Pancreas was collected for the determination of Table. Changes in Body Weight and Glycemic Control Parameters. insulin. Data are represented as mean ± standard error (SEM) and statistical difference was determined (one-way ANOVA, p<0.05). Our results indicated that even with a low fat diet, FATZO mice showed progressive signs of insulin resistance that was highly correlated with body weight. Consumption of a diet containing high fat was shown to enhance dis-

ease progression and also cause loss of pancreatic insulin. I ntegrated In conclusion, the FATZO mouse model is a good animal model to study POSTERS obesity-induced diabetes accompanied with insulin resistance leading to Physiology/Obesity hyperglycemia and progressive loss of islet β-cell function.

309-LB Interesterified Fat Enriched with Palmitic AcidI nduces Inflammation in Adipose Tissue By IKK Phosphorylation Pathway in LDLr-KO Mice Supported By: Novo Nordisk A/S MARIA SILVIA LAVRADOR, MILESSA SILVA AFONSO, DENNYS E. CINTRA, MAR- CIA KOIKE, VALÉRIA SUTTI NUNES, SERGIO CATANOZI, EDNA NAKANDAKARE, ANA MARIA LOTTENBERG, São Paulo, Brazil The interesterified fats, rich in saturated fatty acids in sn-2 position, have currently been used in the industrialized foods and may contribute to the obesity development. Therefore the aim of this investigation is to elucidate

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LB79 LateO Bbesreaikingty—Hum Abstractsan

311-LB 313-LB Chenodeoxycholic Acid as a Potential Prognostic Marker for Roux- The Effect of Intentional Weight Loss on Fracture Risk in Diabetics: en-Y Gastric Bypass Surgery in Chinese Obese Patients with Type 2 Results from the Look AHEAD Clinical Trial Diabetes KAREN C. JOHNSON, CORA E. LEWIS, CATHERINE WOMACK, KATELYN R. GAR- HAOYONG YU, Shanghai, China CIA, LYNNE E. WAGENKNECHT, HENRY J. POWNALL, EDWARD S. HORTON, Objective: Roux-en-Y gastric bypass (RYGB) has been increasingly used as XAVIER PI-SUNYER, EDWARD GREGG, ANN V. SCHWARTZ, Memphis, TN, Birming- an effective treatment for obesity-related type 2 diabetes (T2DM) patients. ham, AL, Winston-Salem, NC, Houston, TX, Boston, MA, New York, NY, Atlanta, GA, Bile acids (BAs) act as endocrine-signaling molecules and are involved in San Francisco, CA regulating metabolic homeostasis in response to RYGB. We aimed to test the Although intentional weight loss is an important treatment option for over- hypothesis that BAs may have potential value to predict the therapeutic out- weight diabetics, the effects on long term fracture risk are not known. In the come after RYGB. Look AHEAD Trial we examined whether long term intentional weight loss Methods: We applied a targeted metabolomics approach to quantitatively would increase fracture risk in persons with type 2 diabetes. Participants measure 26 serum BAs in a total of 361 subjects from two independent stud- were randomized to an intensive lifestyle intervention (ILI) with diet and ies, using ultra-performance liquid chromatography triple quadruple mass increased physical activity designed to achieve and maintain > 7% weight spectrometry. The relative proportion of each BA in total BAs (TBA) was calcu- loss or to diabetes support and education (DSE). Fractures were ascertained lated to minimize the large variations in BA pool size among individuals. First, every 6 months by self-report and confirmed with central adjudication. The we evaluated the changes of BA levels within 12 months for 38 obese patients baseline mean age of participants was 59 years, 59% were women, 63% were who were diagnosed with T2DM and received RYGB, and examined their role white, and the mean BMI was 36 kg/m2. Weight loss over the intervention in predicting the diabetes remission 2 years after the surgery. Second, the BA period (median 9.6 years) was 6.0% in ILI and 3.5% in DSE. After a median profiles were compared among different metabolic phenotypes of individuals follow-up of 11.3 years, 730 participants had a confirmed incident fracture from a cross-sectional study (n=327), including 126 lean subjects with normal (358 in DSE vs. 372 in ILI). There were no statistically significant differences glucose tolerance (NGT), 76 overweight NGT, 48 obese NGT, 44 overweight in total or hip fracture rates. However, compared to DSE, the ILI group had a subjects diagnosed with T2DM, and 33 obese subjects with T2DM subjects. statistically significant 39% increased risk of a frailty fracture (composite of Results: In the metabolic surgery study, patients in the remission group hip, pelvis, upper arm, shoulder, or clavicle) Intentional long term weight loss had shorter duration of diabetes, lower glycated haemoglobin (HbA1c), higher in diabetics was not associated with an overall increased risk of fracture but C-peptide and chenodeoxycholic acid (CDCA) proportion at baseline. Multiple may be associated with an increased risk of frailty fracture. logistic regression analysis indicated that a higher level of CDCA relative to TBA Table. (CDCA%) and shorter duration of diabetes at baseline were associated with a greater chance of diabetes remission. In the cross-sectional study, CDCA% was Fracture Type DSE Number ILI Number Unadjusted P-value Fully Adjusted * P-value significantly higher in obese individuals with T2DM than the NGT group. of Events of Events HR (95% CI) HR (95% CI) Conclusion: CDCA% might act as a potential prognostic marker of RYGB. All Fractures 358 372 1.025 (0.887, 1.185) 0.74 1.032 (0.893, 1.193) 0.67 Those diabetic patients with higher CDCA% may benefit more from the Hip 17 26 1.511 (0.82, 2.785) 0.19 1.554 (0.843, 2.865) 0.16 RYGB. Frailty 70 98 1.392 (1.025, 1.892) 0.03 1.43 (1.052, 1.944) 0.02 312-LB *Model adjusted for age, gender, race, baseline BMI, and bone active agents. Weight Loss and Improvement in Glycemic Control: Results from a Supported By: National Institute of Diabetes and Digestive and Kidney Diseases/ 26-Week, Phase 2, Randomized, Placebo-Controlled, Clinical Trial of National Institutes of Health Beloranib in Patients with Obesity and Type 2 Diabetes JOSEPH PROIETTO, MARK ARYA, NEALE COHEN, FERDINANDUS J. DE LOOZE, 314-LB CHRISTOPHER GILFILLAN, PAUL M. GRIFFIN, STEPHEN HALL, THOMAS NATHOW, Weight Loss and Improvement in Body Composition: Results from a GEOFFREY S. OLDFIELD, DAVID N. O’NEAL, ADAM ROBERTS, BRONWYN G. 26-Week, Phase 2, Randomized, Placebo-Controlled, Clinical Trial of STUCKEY, DENNIS YUE, JARET MALLOY, DONGLIANG ZHUANG, KRISTIN TAYLOR, Beloranib in Patients with Obesity and Type 2 Diabetes THOMAS HUGHES, DENNIS KIM, Heidelberg, Australia, Maroubra, Australia, Mel- TERRI KIM, JARET MALLOY, DONGLIANG ZHUANG, KRISTIN TAYLOR, JOSEPH bourne, Australia, Sherwood, Australia, Box Hill, Australia, Herston, Australia, Malvern PROIETTO, Boston, MA East, Australia, Ipswich, Australia, Cardiff, Australia, Fitzroy, Australia, Geelong, Aus- Beloranib inhibits MetAP2, an enzyme that influences fat metabolism, syn- tralia, Nedlands, Australia, Camperdown, Australia, Boston, MA thesis, and storage, and was recently shown to reduce weight in patients Beloranib inhibits MetAP2, an enzyme that influences fat metabolism, with obesity+T2DM. Body composition was measured using bioimpedance for synthesis, and storage. This clinical trial investigated the effect of beloranib the per-protocol (PP) population. The randomized portion of the trial was con- on body weight (BW) in patients with obesity+T2DM, a population particu- cluded early due to the number of venous thromboembolic events observed larly refractory to meaningful BW loss. The primary efficacy endpoint was in clinical trials of beloranib. Baseline characteristics (N=66): 50% male, 91% BW change from baseline after 26 weeks for the per-protocol (PP) popula- white, (mean±SD) age 55±6 years, weight 111.4±20.8 kg, BMI 39.0±6.3 kg/ tion. The randomized part of the trial was concluded early due to the num- m2, A1c 8.3±1.0%, fat mass 36-42%; stable noninsulin diabetes therapy was ber of venous thromboembolic events observed in clinical trials of beloranib. permitted. Most common reasons for exclusion from the PP population were Baseline characteristics (N=66): 50% male, 91% white, (mean±SD) age 55±6 early study closure (N=65) and withdrawal due to adverse events (AEs; N=11). years, BW 111.4±20.8 kg, BMI 39.0±6.3 kg/m2, A1c 8.3±1.0%, FPG 194.2±47.6 The LS mean±SE change from baseline in weight for placebo was -3.1±1.2% mg/dL; stable noninsulin diabetes therapy was permitted. The most common (N=22) vs. -13.5±1.1% with 1.2 mg beloranib (N=25), and -12.7±1.3% with 1.8 reasons for exclusion from the PP population were early study closure (N=65) mg beloranib (N=19, both p<0.0001). The change in fat mass was -7.4±2.7% and withdrawal due to adverse events (AEs; N=11). The LS mean±SE change (N=22) vs. -24.1±2.5% and -21.7±2.9% (both p<0.001) for placebo vs. 1.2 and in BW for placebo was -3.1±1.2% (N=22) vs. -13.5±1.1% with 1.2 mg beloranib 1.8 mg beloranib. The change in lean mass was 0.6±1.8% vs. -5.0±1.7% and

I ntegrated (N=25, LS mean±SE difference -10.4±1.6, p<0.0001) and -12.7±1.3% with 1.8 -5.7±2.0% (both p<0.05). Beloranib-treated patients had improvements in POSTERS mg beloranib (N=19, -9.6±1.6, p<0.0001). More beloranib- vs. placebo-treated waist and hip circumference, liver fat, leptin, and adiponectin vs. placebo

Physiology/Obesity patients had BW loss ≥5% (92-95% vs. 27%) and ≥10% (64-74% vs. 5%; all (p<0.05). In the Safety population (N=152), most common AEs more frequent p<0.0001). Change in A1c was -0.6±0.2% with placebo vs. -2.0±0.2% and with beloranib vs. placebo were sleep related (eg, abnormal dreams, insom- -2.0±0.3% with 1.2 and 1.8 mg beloranib (both p<0.0001). Week 26 mean A1c nia). There were no severe hypoglycemia AEs. The incidence of serious AEs in beloranib-treated patients was 6.3%. In the Safety population (N=152), was low and similar across treatment groups, with 1 event of pulmonary the most common AEs more frequent with beloranib vs. placebo were sleep embolism on beloranib. In patients with obesity+T2DM, beloranib significantly related (eg, abnormal dreams, insomnia). There were no severe hypoglyce- improved body composition, with results indicative of reduced central/vis- mia AEs. The incidence of serious AEs was low and similar across treatment ceral adiposity, and had favorable changes in adipocyte biomarkers. Safety groups, with 1 event of pulmonary embolism on beloranib. Beloranib produced and tolerability were consistent with prior beloranib clinical trials in patients statistically significant and clinically meaningful BW loss and improvement in with obesity. A1c in patients with obesity+T2DM. Safety and tolerability were consistent Supported By: Zafgen, Inc. with prior beloranib clinical trials in patients with obesity. Supported By: Zafgen, Inc.

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LB80 LateO Bbesreaikingty—Hum Abstractsan

315-LB 317-LB Improvement in Glycemic Parameters: Results from a 26-Week, Durable Diabetes Remission after Bariatric Surgery Is Associated Phase 2, Randomized, Placebo-Controlled, Clinical Trial of Beloranib with Reduced Incidence of Microvascular Events in Patients with Obesity and Type 2 Diabetes KAJSA SJÖHOLM, BJÖRN CARLSSON, MARKKU PELTONEN, LENA M. CARLS- JARET MALLOY, DONGLIANG ZHUANG, THOMAS HUGHES, DENNIS KIM, JOSEPH SON, Gothenburg, Sweden, Mölndal, Sweden, Helsinki, Finland PROIETTO, Boston, MA, Heidelberg, Australia Bariatric surgery leads to diabetes remission and reduces the incidence of Beloranib inhibits MetAP2, an enzyme that influences fat metabolism, syn- diabetes complications in many obese patients with type 2 diabetes (T2D). thesis, and storage, and was recently shown to reduce weight in patients We have here examined the importance of durable diabetes remission for the with obesity+T2DM. In this analysis, predefined glycemic parameters were prevention of microvascular complications in 343 patients with baseline T2D assessed for the per-protocol (PP) population. The randomized portion of treated by bariatric surgery (banding, n=61; vertical banded gastroplasty, n = the trial was concluded early due to the number of venous thromboembolic 227; gastric bypass, n = 55) in the prospective Swedish Obese Subjects study. events observed in clinical trials of beloranib. Baseline characteristics (N=66): Age was 48.7±5.9 years, BMI was 42.1±4.7, and median follow-up time was 50% male, 91% white, (mean±SD) age 55±6 years, weight 111.4±20.8 kg, BMI 19 years. Microvascular events (retinopathy, nephropathy and neuropathy, 39.0±6.3 kg/m2, A1c 8.3±1.0%, FPG 194.2±47.6 mg/dL; stable noninsulin dia- whichever came first) were traced in nationwide registers. We considered betes therapy was permitted. The most common reasons for exclusion from a patient to have T2D if he or she reported the use of diabetes medication the PP population were early study closure (N=65) and withdrawal due to or if fasting blood glucose concentration was 110 mg per deciliter (6.1 mmol adverse events (AEs; N=11). After 26 weeks, the LS mean±SE change from per liter) or higher. Remission was defined as blood glucose levels lower than baseline in A1c for placebo was -0.6±0.2% (N=22) vs. -2.0±0.2% with 1.2 mg 110 mg per deciliter and no diabetes medication. At the follow-up examina- beloranib (N=25) and -2.0±0.3% with 1.8 mg beloranib (N=19, both p<0.0001). tion 15 years after bariatric surgery, 30% of the patients were in diabetes At week 26, mean A1c in beloranib-treated patients was 6.3%. More belo- remission. Patients who were in remission after 15-years had significantly ranib-treated patients achieved A1c<7% (72% and 74%) vs. placebo (23%, lower incidence of microvascular events compared those who were not in p<0.01) and A1c≤6.5% (68% and 63%) vs. placebo (18%, p<0.01). There were diabetes remission (incidence rates of 8.0 and 26.0 per 1000 person-years, also improvements in FPG (p<0.001), insulin sensitivity (p<0.05), beta-cell adjusted HR 0.19 [95% CI; 0.07-0.50], p=0.001. We conclude that in patients function (measured by HOMA; p<0.01), and a trend for improved postprandial treated by bariatric surgery who experienced long-lasting remission the risk glucose with beloranib vs. placebo. In the Safety population (N=152), the most of microvascular diabetes complications was reduced by over 80% compared common AEs more frequent with beloranib vs. placebo were sleep related (eg, to those that were not in remission at the 15-year follow-up. abnormal dreams, insomnia). There were no severe hypoglycemia AEs. The Supported By: National Institute of Diabetes and Digestive and Kidney Diseases; incidence of serious AEs was low and similar across treatment groups, with Swedish Research Council, Swedish Federal Government; Swedish Diabetes Foun- 1 event of pulmonary embolism on beloranib. In patients with obesity+T2DM, dation beloranib treatment over 26 weeks significantly improved glycemic control, including insulin resistance and beta-cell function. Safety and tolerability 318-LB were consistent with prior beloranib clinical trials in patients with obesity. Adipocyte, Visceral Fat, and Family History of Type 2 Diabetes Supported By: Zafgen, Inc. PIMJAI ANTHANONT, MICHAEL D. JENSEN, KAZANNA C. HAMES, Rochester, MN 316-LB Background: A major risk factor of type 2 diabetes (T2DM) is a positive fam- Long-Term Incidence of Microvascular Events in Relation to Incident ily history of diabetes. First degree relatives of T2DM patients are often insu- Type 2 Diabetes in Obese Patients with Prediabetes Treated by Bar- lin resistant and have been reported to have larger adipocytes than matched iatric Surgery or Usual Care controls without a family history. LENA CARLSSON, KAJSA SJÖHOLM, BJÖRN CARLSSON, MARKKU PELTONEN, Objective: Assess whether a family history of T2DM is a predictor of Gothenburg, Sweden, Mölndal, Sweden, Helsinki, Finland abdominal adipocyte size independent of age, sex, and abdominal subcutane- We have previously shown that the risk of diabetes in obese patients with ous (SC) fat area by CT imaging. Furthermore, we assess whether a family prediabetes is markedly reduced by bariatric surgery. We have now examined history of T2DM is related to femoral adipocyte size, visceral fat area by CT if bariatric surgery prevents long-term (up to 26 years) microvascular compli- imaging, or triglycerides (TG). cations in patients with prediabetes in the Swedish Obese Subjects (SOS) Methods: We extracted adipocyte, body composition, and demographic study, and if prevention is greater in patients who do not develop diabetes. data of nondiabetic volunteers who participated in research studies between Microvascular events (retinopathy, nephropathy and neuropathy) in SOS study 1995 and 2015 at Mayo Clinic and ascertained the family history of T2DM from participants with baseline prediabetes (impaired fasting glucose), treated by the electronic medical record. Multivariate regression analysis was used to bariatric surgery (n=301) or usual care (n=290) were traced in nationwide reg- whether a family history of T2DM predicts abdominal adipocyte size after isters. Median follow-up was 19 years. Bariatric surgery was associated with adjusting for known variables. reduced incidence of microvascular events [IR 3.9 and 18.7 per 1000 person Results: Although abdominal and femoral adipocyte size in individuals with years in the surgery and control groups, respectively; HR=0.19 (0.12-0.31), family history of T2DM were larger than those without family history (0.743 p<0.001]. At or before the 15-year examination, the fraction of patients who ± 0.331 vs. 0.627 ± 0.333 µg of lipid/cell, P<0.001; 0.809 ± 0.293 vs. 0.723 developed diabetes was 15.6% in the surgery group and 54.5% in the control ± 0.326 µg of lipid/cell, P=0.014, respectively), this was confounded by the group. Those with incident diabetes had higher incidence of microvascular positive family history group being older and having a greater BMI and per- events compared to those who had not developed diabetes (9.3 vs. 2.9 per cent body fat. In multiple linear regression analysis with abdominal adipocyte 1000 person years, respectively; p=0.009 in the surgery group and 22.6 vs. size as the dependent variable, age, family history of T2DM, and abdominal 14.0 per 1000 person years, respectively; p=0.028 in the control group). Bar- SC fat area were significant predictors of adipocyte size for a one-tailed test iatric surgery was associated with reduced incidence of microvascular events whereas sex (P=0.47) was not. In contrast, family history of T2DM was not a both in prediabetics that developed diabetes (HR=0.36; p=0.007) and in those predictor for femoral adipocyte, visceral fat area or TG. In subgroup analysis,

who did not (HR=0.20; p<0.001). We conclude that bariatric surgery reduces we also found a family history of T2DM could predict abdominal adipocyte I ntegrated the long-term incidence of microvascular disease in obese patients with pre- size in the subjects with normal fasting glucose (P=0.048). POSTERS diabetes. Conclusions: In adults with normal fasting glucose, but not with mild fast- Physiology/Obesity Supported By: National Institute of Diabetes and Digestive and Kidney Diseases ing hyperglycemia, abdominal fat cell size is greater in those with a positive (R01DK105948); Swedish Research Council; Swedish Federal Government; Swedish family history of T2DM. Diabetes Foundation

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LB81 LateO Bbesreaikingty—Hum Abstractsan

319-LB achieve similar prevalence of T2D remission despite significantly greater Coadministration of Canagliflozin (CANA) and Phentermine (PHEN) weight loss at 1 year after LRYGB. Longer term follow-up will determine for Weight Management in Overweight and Obese Adults durability of these results. PRISCILLA A. HOLLANDER, HAROLD E. BAYS, JULIO ROSENSTOCK, MARY ELLEN FRUSTACI, ALBERT FUNG, NGOZI ERONDU, Dallas, TX, Louisville, KY, Raritan, NJ 321-LB CANA is an SGLT2 inhibitor approved for type 2 diabetes mellitus (T2DM) Chronic Hyperinsulinemia Causes Epigenetic Alteration and treatment that increases urinary glucose excretion and provides a calorie Increased Expression of the Fibrosis and Cancer Biomarker PDGFA deficit, leading to weight loss that has plateaued over 26 weeks in T2DM in Liver of Obese People with Diabetes studies. As CANA may cause increased calorie intake, adding PHEN, an appe- AMAR ABDERRAHMANI, LOIC YENGO, MICKAEL CANOUIL, STEPHANE CAUCHI, tite suppressant, may facilitate further weight loss. This 4-arm, 26-week, ROBERT CAIAZZO, FRANÇOIS PATTOU, PHILIPPE FROGUEL, Lille, France Phase 2 study evaluated the efficacy/safety of CANA 300 mg + PHEN 15 mg Insulin resistance is a key feature of obesity and of T2D, but its contribution (CANA/PHEN), PHEN 15 mg, CANA 300 mg, and placebo (PBO) in 334 adults to nonalcoholic fatty liver diseases (NAFLD) and its complications including, without T2DM who had BMI 30 to <50 kg/m2 or, if with hypertension and/or fibrosis and cancer is unknown. We investigated the liver methylome and tran- dyslipidemia, BMI 27 to <50 kg/m2 (mean weight, 102.9 kg; BMI, 37.3 kg/m2). scriptome in European women undergoing bariatric surgery (96 T2D cases and At week 26, weight loss was statistically superior with CANA/PHEN vs. PBO 96 normoglycemic controls matched for age and BMI), using Infinium Human- (P <0.001; Figure). CANA/PHEN, PHEN 15 mg, CANA 300 mg, and PBO pro- Methylation450 BeadChip arrays and Illumina HumanHT Whole-Genome HT duced weight changes of -7.5%, -4.1%, -1.9%, and -0.6%. Significantly more Assays. We only identified one genome-wide significant differentially methy- patients achieved ≥5% weight loss with CANA/PHEN vs. PBO (66.7% vs. lated CpG site in the fibrosis and cancer marker “Platelet Derived Growth Fac- 17.5%; P <0.001). CANA/PHEN also resulted in a significant PBO-subtracted tor alpha (PDGFA)” locus. The average DNA methylation at this site was 41.3% reduction in systolic BP (-4.2 mmHg; P = 0.015). CANA/PHEN was generally in T2D cases and 60.3% in normoglycemic controls (p=2.5×10-8). Hypomethy- well tolerated, with no new or unexpected safety signals. CANA/PHEN, PHEN lation at this site was associated with elevated PDGFA gene expression, 15 mg, CANA 300 mg, and PBO were associated with changes in heart rate hyperinsulinemia, systemic insulin resistance and nonalcoholic steatohepa- of +3.5, +4.1, +0.7, and -0.7 bpm. In conclusion, CANA/PHEN provided signifi- titis (NASH). Moreover, increased PDGFA expression and decreased methyla- cantly greater weight loss vs. PBO in overweight/obese adults, suggesting its tion in T2D cases were associated with liver fibrosis. This association was potential use in chronic weight management. replicated in other European liver samples. Mendelian randomization con- Figure. Percent Change in Body Weight over 26 Weeks. firmed a direct effect of insulin levels GWAS associated SNPs on the PDGFA hypomethylation. In Immortalized Human Hepatocytes (IHH), chronic hyperinsulinemia hampered insulin signaling, resulting in a reduction of methylation at this PDGFA site and higher PDGFA mRNA and protein levels. Exposure of IHH cells to chronic hyperinsulinemia further increased PDGFA secretion. IHH culture with blocking PDGFA antibodies improved insulin signaling induced by hyperinsulinemia, suggesting an autocrine and negative role of PDGFA in hepatocyte insulin signaling. These findings provide novel biological mechanism linking chronic hyperinsulinemia to hepatic insulin resistance and liver complications of obesity and T2D. The data may open avenues to treat NAFLD associated complications in T2D. Supported By: European Genomic Institute for Diabetes (ANR-10-LABX-46); European Commission; Regional Council Nord Pas de Calais; European Regional Development Fund

322-LB Supported By: Janssen Research & Development, LLC The Levels of Zinc-a2-Glycoprotein in Polycystic Ovarian Syndrome Women Before and After Therapeutic Intervention with Exenatide or 320-LB Metformin Laparoscopic Sleeve Gastrectomy vs. Roux-en-Y Gastric Bypass for SIYUAN ZHENG, YING ZHANG, EN LIU, TAO LONG, JIAHUI LU, XIN LIU, JIAHE YAN, the Treatment of Type 2 Diabetes—12-Month Results of a Double- LIN CHEN, YOUTAO ZHANG, YI GONG, TINGTING MAI, FANG WANG, Guangzhou, Blind, Randomised Trial China RINKI MURPHY, NICHOLAS EVENNETT, MICHAEL CLARKE, STEVEN ROBINSON, To determine circulating Zinc-a2-Glycoprotein (ZAG) levels in PCOS BRONWEN JONES, DAVID KIM, RICHARD CUTFIELD, LINDSAY PLANK, HISHAM women and control subjects, and to investigate the ZAG changes in women HAMMODAT, MICHAEL BOOTH, Auckland, New Zealand with polycystic ovary syndrome (PCOS) and its alteration after exenatide It is unclear which of the two most commonly performed types of bariat- or Metformin treatment. This study was comprised of a series of cross- ric surgery, laparoscopic sleeve gastrectomy (LSG) or laparoscopic Roux-en- sectional and interventional studies of 142 PCOS and 30 healthy women Y gastric bypass (LRYGB), is most effective for obese patients with type 2 from the general population and outpatients of the Internal Medicine diabetes (T2D). We examined the comparative ad interim effectiveness of Department at the Third Affiliated Hospital, Guangzhou Medical Univer- LSG or LRYGB at 1 year in achieving T2D remission using different HbA1c sity, China. 62 overweight/obese of PCOS women were randomly assigned thresholds. Single-centre, double-blind, randomized, clinical trial conducted to 3 months of exenatide injection (10μg bid) or oral Metformin (1000mg in New Zealand. Eligibility criteria included age 20-55 years, T2D of at least bid). OGTT were performed to assess glucose tolerance and insulin sen- 6 months duration and BMI 35-65kg/m2 for at least 5 years. Recruitment of sitivity. Outcome measures were ZAG levels, anthropometric, glucolipid 114 patients completed in October 2014. Randomization 1:1 to LSG (n=58) metabolism makers, sex hormone level and inflammatory state. Circulating I ntegrated

POSTERS or LRYGB (n=56) used random number codes disclosed to the surgeon after ZAG was significantly lower in PCOS women than healthy women (P<0.01). induction of anesthesia. A standard medication adjustment schedule was Circulating ZAG was significantly lower in overweight/obese (BMI≥24kg/ Physiology/Obesity used during post-operative metabolic assessments scheduled for 5 years m2) women than normal-weight (BMI<24kg/m2) PCOS women (P<0.01). Cir- when primary outcome of T2D remission defined by HbA1c <42mmol/mol culating ZAG level correlated negatively with BMI, AG, WHR, TG, LDL-c, without diabetes medications, is planned. Ad interim analysis at 1 year FBG, Fins, 2hIns, HOMA-IR, hs-CRP and positively with HDL-c, HOMA-IS, showed 109/114 completed 12 month follow-up. Participants were 55% SHBG. After 3 months of exenatide or Metformin treatment, there were sig- women, 17% Maori, 8% Pacific. Mean (±standard deviation) HbA1c pre- nificant increase in circulating ZAG in both treatment groups (ZAG baseline operatively was 63mmol/mol ±16 (29% on insulin therapy, 65% on oral glu- 46.54±13.25 ng/ml vs. after treatment 56.41±11.25ng/ml, P<0.01; Metformin cose lowering therapy alone). Proportions achieving HbA1c <39mmol/mol, baseline 47.81±15.16 ng/ml vs. after treatment 55.67±11.36 ng/ml, P<0.01) <42mmol/mol, <48mmol/mol, or <53mmol/mol without the use of diabetes following improved anthropometric, metabolic makers (P<0.01), but no sta- medication in LSG vs. LRYGB were 43% vs. 38% (p=0.56), 49% vs. 52% tistically significance in the mean changes of serum ZAG level between the (p=0.85), 72% vs. 75% (p=0.83), and 77% vs. 80% (p=0.82) respectively. two treatments (9.27±1.02 ng/ml vs. 8.86±2.80 ng/ml, P=0.115). It is sug- Mean (±standard deviation) weight loss at 1 year was less after LSG vs. gested that the circulating ZAG level decreases in PCOS women but can LRYGB: 34.0±13.1kg vs. 39.6±11.6 kg respectively, (p=0.02). LSG and LRYGB

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LB82 LateO Bbesreaikingty—Hum Abstractsan be up-regulated after exenatide or Metformin treatment. These drugs may 325-LB affect the process and development of PCOS by regulating the ZAG level. Changes in SCD1 Promoter DNA Methylation after Bariatric Surgery Supported By: National Natural Science Foundation of China (81200607); Project in Morbid Obese Patients Are Associated with Changes in Insulin of the Key Laboratory for Major Obstetric Diseases of Guangdong Higher Education Resistance Institutes of China (2012Z05) SARA GARCIA-SERRANO, SONSOLES MORCILLO, GRACIA M. MARTÍN-NÚÑEZ, CAROLINA GUTIERREZ-REPISO, FRANCISCA RODRIGUEZ-PACHECO, SERGIO VALDES, 323-LB MONTSERRAT GONZALO, FRANCISCO J. MORENO-RUIZ, ALBERTO RODRIGUEZ- Brown Adipogenic Potential of Brown Adipocytes and Perirenal Adi- CAÑETE, CUSTODIA MONTIEL-CASADO, EDUARDO GARCIA FUENTES, Málaga, pocytes from Human Embryo Spain NAN NAN WU, CHUAN HAI ZHANG, YAN MA, WEI MA, YING MEI FENG, DONG Introduction: Epigenetic is acquiring great importance in complex diseases, ZHAO, Beijing, China providing mechanisms whereby environmental factors can influence complex Brown adipose tissues (BAT) is mainly located in the interscapular region diseases such as obesity and type 2 diabetes. Experimental animal and human and featured as enriched number of mitochondria that mediates heat genera- studies have revealed the association between stearoyl-CoA desaturase 1 tion. It directly regulates whole body energy metabolism and inversely cor- (SCD1) and obesity and insulin resistance. relates with body-mass index. However, the activity of BAT is dramatically Aim: To evaluate whether metabolic changes after intervention are associ- reduced in adults. When stimulated for differentiation, subcutaneous white ated with DNA methylation pattern and if these changes are related to weigh adipose tissue (sWAT) could give rise to “beige cells” that shares functional loss. Methods: The study included 65 subjects with morbid obesity underwent features with the BAT. Therefore, both BAT and beige cells hold therapeutic laparoscopic Roux-en Y gastric by-pass. These subjects were studied before potential for the treatment of metabolic disorders. To investigate the brown and 6 months after bariatric surgery. Serum biochemical and hormone vari- adipogenic potential of WAT in different locations, adipose tissues from inter- ables were measured. The methylation status of the CpG island region of the scapular region (cBAT) and peri-renal adipose tissue (prWAT) were isolated SCD1 gene promoter was determinated. from biopsy of human embryo adipose tissues and cultivated in vitro. After Results: DNA methylation levels of the SCD1 gene promoter increased after 3-5 passages, both culture shower comparable amount of preadipocytes as the intervention (1.54 vs. 2.17, p=0.001). There were no significant differences evidenced by the percentage of CD29+/CD31+/CD11 b-cells by FACS analy- in SCD1 DNA methylation levels between males and females, neither accord- sis. Once stimulated for adipogenic differentiation, the key adipogenic genes ing to age (data not shown). A negative association was observed between including PPARγ2, C/EBPα2 and AP2 expressions were dramatically upregu- changes in SCD1 gene promoter methylation and changes in HOMA-IR (r=- lated in both preadipocytes. Moreover, the expression of BAT and beige cell 0.249; p=0.035). On the opposite, a positive association was found between markers including UCP1, PRDM16, ZIC1 and TBX1 were induced in both preadi- changes in SCD1 gene promoter methylation levels and changes in adiponec- pocytes despite the expression level was higher in preadipocytes from cBAT tin levels (r= 0.389, p=0.019). cells than prWAT. Nevertheless, stimulation of preadipocytes from adult WAT Conclusions: The main finding of our study is that the increase of the SCD1 with the differentiation cocktail had no effect on these marker expression. promoter DNA methylation in morbid obese patients after bariatric surgery is Thereafter, RNASeq was performed using terminally differentiated adipo- associated to the decrease of insulin resistance. cytes from cBAT, prWAT and sWAT. The panel of BAT and beige cell markers Supported By: Consejería de Economía, Innovación, Ciencia y Empresa de la were confirmed increased in prWAC and cBAT. In conclusion, except sWAT, Junta de Andalucía (CTS-8081); FEDER Funds perirenal adipose tissue is an alternative candidate for beige cell production. Supported By: National Natural Science Foundation of China (81470566 to Y.M.F.); 326-LB Beijing Municipal Commission of Health and Family Planning (2014-3-7081 to D.Z.) EndoBarrier Therapy is Associated with Glycemic Improvement, Weight Loss and Safety Issues in Patients with Obesity and Type 2 324-LB Diabetes on Oral Antihyperglycemic Agents A Prospective Study of Visceral Fat, Liver Fat, and the Risk of Devel- LEE M. KAPLAN, JOHN B. BUSE, CHRISTOPHER MULLIN, STEVEN EDMUNDO- oping Type 2 Diabetes in Japanese WICZ, ERIC BASS, PAUL VISINTAINER, PATRICIA KEATING, KENNETH MALOMO, TOMOSHIGE HAYASHI, KYOKO K. SATO, SHINICHIRO UEHARA, MIKIKO SHIBATA, ENDO TRIAL STUDY GROUP, Boston, MA, Chapel Hill, NC, Minneapolis, MN, Denver, YONEZO HIKITA, WILFRED Y. FUJIMOTO, EDWARD J. BOYKO, Osaka, Japan, Sakai, CO, Springfield, MA, Lexington, MA Japan, Seattle, WA EndoBarrier Therapy (EBT) involves the reversible endoscopic placement Visceral adiposity plays a key role in the cardiometabolic diseases, includ- of an impermeable liner that anchors in the duodenum, preventing exposure ing type 2 diabetes. It is not known whether visceral fat and liver fat directly of food to digestive processes and the intestinal mucosa for the first two measured by computed tomography (CT) are independently associated with feet of small bowel. We randomized subjects with obesity, type 2 diabetes incident type 2 diabetes. Study subjects included 1221 nondiabetic Japanese (T2D) and poor glycemic control (HbA1c 7.5-10.0%) on oral antihyperglyce- men and women. Abdominal, thoracic, and thigh fat areas were measured mic agents (Metformin, sulfonylureas, DPP-4 inhibitors and/or thiazolidin- by CT. Visceral fat was measured as intra-abdominal fat area (IAFA) at the ediones) 2:1 to EBT or sham control. Subjects and non-endoscopy study staff umbilicus level. Total fat area (TFA) was the sum of these fat areas. Total were blinded to treatment assignment. Planned enrollment was 500, but the subcutaneous fat area (TSFA) was TFA minus IAFA. Liver fat was assessed trial was stopped early due to the unexpected occurrence of 7 cases of liver by liver-to-spleen (L/S) attenuation ratio measured by CT. Type 2 diabetes abscess. All abscesses resolved with percutaneous drainage and/or antibiotic was defined as fasting plasma glucose ≥126 mg/dL, HbA1c ≥6.5%, or taking therapy. A total of 325 subjects were randomized (n=216 device:109 sham; oral hypoglycemic medication or insulin. The discrete-time hazard model was HbA1c 8.8%; BMI 38.3 kg/m2; average T2D duration 7.5 yr), with only half of used. During the 7047 person-year follow-up period, we confirmed 84 incident EBT subjects permitted to complete the planned 12-month treatment. Of 216 cases of type 2 diabetes. Both greater IAFA and lower L/S ratio were inde- subjects randomized to EBT, 94% were implanted successfully. By the modi- pendently associated with the risk of type 2 diabetes in models that included fied ITT analysis, the mean change in HbA1c was -1.0% for EBT vs. -0.3% for IAFA, L/S ratio, abdominal subcutaneous fat area (ASFA), age, gender, HOMA- the sham group, with a difference between groups of -0.7% in favor of EBT

(95% CI -1.1%, -0.3%). Device-related SAEs requiring early removal occurred I ntegrated

IR, smoking habit, daily alcohol consumption, and regular physical activity. POSTERS Multiple-adjusted hazard odds ratios of type 2 diabetes for tertile 2 and 3 of in 11.7% (7.9%, 16.3%). Among 12-month completers, EBT subjects had a sig-

IAFA were 2.33 (95% CI, 0.85-6.43) and 4.20 (1.43-12.36), respectively, com- nificantly greater rate of achieving (i) HbA1c ≤ 7% (34% EBT vs. 9.4% sham; Physiology/Obesity pared to tertile 1, and those for tertile 2 and 1 of L/S ratio were 2.22 (1.02- Diff [CI] 24.7% [14.08%, 35.3%]) and (ii) total body weight loss ≥ 5% (60.7% 4.83) and 2.25 (1.04-4.88), respectively, compared to tertile 3. Both IAFA and EBT vs. 20.3% sham; Diff [CI] 40.4% [27.3%, 53.5%]. Despite the diminished L/S ratio remained significant predictors of developing type 2 diabetes even sample size, this study nonetheless demonstrated a statistically and clinically after adjustment for ASFA, TFA, TSFA, BMI, or waist circumference, but no significant benefit of EBT over sham for both HbA1c reduction and weight loss. measure of regional or total adiposity other than IAFA or L/S ratio was associ- Efforts are underway to reduce the rate of EBT-associated liver abscess. ated with the risk of developing type 2 diabetes. In conclusion, both greater amounts of visceral and liver fat are independently associated with the risk of type 2 diabetes. This association is independent of other adipose depots and HOMA-IR.

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LB83 Islet Biology— Late Breaking Abstracts Islet Biology—Beta Cell— Apoptosis Development and Postnatal Growth

Islet Biology—Apoptosis out a human IL-1 beta neutralizing monoclonal antibody at 11.1 mmol/L glucose (to potentiate amyloid formation) for 7 days. Progressive amyloid formation 327-LB in human islets during culture closely correlated with increased IL-1 beta release, beta-cell dysfunction, Fas upregulation and apoptosis, as assessed Pancreatic Beta Cell Death Due to Pdx1 Deficiency Requires Bax but by islet insulin response to elevated glucose and quantitative immunolabel- No Bak ing. Also, suppression of amyloid formation in cultured human islets by adeno- DECHENG REN, JUAN SUN, KENNETH S. POLONSKY, Chicago, IL viral prohIAPP-siRNA transduction significantly reduced islet IL-1 beta levels, Pdx1-haploinsufficient mice develop diabetes due to increased -cell death β suggesting that amyloid formation is an important factor in inducing IL-1 beta with reduced -cell mass. To define the molecular link between Pdx1 defi- β production. Treatment with IL-1 beta neutralizing antibody markedly reduced ciency and -cell death, we knock down Pdx1 gene in MIN6 cells. Pdx1KD β beta-cell Fas expression in cultured human islets despite amyloid formation, did not demonstrate a significant increase in Bax and Bak mRNA or protein resulting in lower beta-cell apoptosis, higher beta-cell area to total islet area levels But induced an accumulation of Bax in the mitochondrial fraction and and beta/alpha-cell ratio in treated islets as compared to non-treated cul- no change in Bak. To define the functional effects of Bax on -cell death, β tured islets. Moreover, treated human islets had a greater insulin response to shRNA was used to knock down Bax or Bak. In Bax/Pdx1 double knockdown elevated glucose and higher insulin content than non-treated cultured islets. (DKD) cells the cleaved caspase 3 protein levels were significantly decreased In summary, these data suggest that amyloid-induced beta-cell Fas upregula- by 80% (P<0.001). Bax suppression also inhibited the increase in cytochrome tion is mediated by IL-1 beta in human islets and that neutralizing IL-1 beta c release from mitochondria. Furthermore, only 22.7 ± 1.1% in the Pdx1/Bax may provide a new strategy to protect beta cells from amyloid toxicity in DKD group took up the PI stain compared to 50.2 ± 2.7% in control group type 2 diabetes and clinical islet transplantation. (P<0.001). Bak KD had no effect on β-cell death. To determine the effects of Bax deficiency onβ -cell death in vivo, we used mice in which Bax is condition- ally deleted in islets using MIP-Cre/ERT on a Bak−/− background. The Pdx1+/- BaxF/FBak-/-Cre+ mice showed an increase in β-cell mass by 73% (P<0.01) and Islet Biology—Beta Cell—Development and decrease in TUNEL positive β-cells by 70% (P<0.001). Pdx1+/-BaxF/FBak-/-Cre+ Postnatal Growth mice also exhibited significantly lower fasting blood glucose and improved glucose tolerance and increased insulin secretion (P<0.01). The area under 330-LB the blood glucose curve decreased by 27% in Pdx1+/-BaxF/FBak-/-Cre+ mice Differential Gene Dosage Effect of Diabetes-associated GLIS3 Gene (P<0.001). In conclusion, Bax rather than Bak mediates β-cell apoptosis caused Expression in Pancreatic β-Cell Differentiation and Function by Pdx1 deficiency. Genetic ablation of Bax protects β-cells from apoptosis YISHENG YANG, SEAN P. BUSH, WEI CAO, LAWRENCE C. CHAN, Cleveland, OH, and preserves β-cell mass in Pdx1+/- mice. Houston, TX Mutations of GLI-similar 3 (GLIS3), a Kruppel-like transcription factor, under- 328-LB lie a neonatal diabetes syndrome. Importantly, genome-wide association studies revealed that GLIS3 variants are also associated with common type 1 and Mechanisms of Metabolic Stress-induced β-Cell Death LISETTE A. MADDISON, WENBIAO CHEN, Nashville, TN type 2 diabetes. We previously showed that GLIS3 is a potent transactivator -/- Insulin resistance can be compensated by increased insulin secretion and of the insulin gene. Global GLIS3-deficient (GLIS3 ) mice die of severe diabe- increased β-cell number. However, long-term insulin resistance can lead to tes shortly after birth. GLIS3 controls islet differentiation by transactivating β-cell failure, β-cell death and the development of type 2 diabetes. With its neurogenin 3 (Ngn3). To gain insight into the function of GLIS3 in pancreatic genetic, chemical, and anatomical tractability, zebrafish is poised to help elu- β-cells, we generated β-cell-specific GLIS3-deficient mice using either RIP- fl/fl + fl/fl + cidate the mechanisms that are involved in β-cell failure and death. To this Cre (GLIS3 /RIP-Cre ) or Pdx1-Cre (GLIS3 /Pdx1-Cre ) co-expressing mice. end, we generated a transgenic model with skeletal muscle-specific insulin We observed that, remarkably, neither type of β-cell-specific GLIS3-defi- -/- resistance, zMIR. When challenged with repeated exposure to overnutri- cient mice phenocopied the lethal neonatal diabetes observed in GLIS3 fl/fl + tion, zMIR larvae initially expanded the β-cell number similar to control ani- mice. All GLIS3 /RIP-Cre mice survived to adulthood with normal glucose fl/fl + mals, but underwent a rapid decline in the number of β-cells after the third tolerance. Thirty percent of GLIS3 /Pdx1-Cre mice developed severe dia- exposure. Treatment with antidiabetic drugs protected the zMIR larvae from betes at 3-4 weeks of age, while the others developed mild diabetes with the β-cell loss if the drugs were administered with sufficient duration. We age. In contrast to the >90% reduction of Ngn3 and near-total absence of Ins -/- found that this loss in cells was not through β-cell apoptosis or through de- in the pancreas of neonatal GLIS3 mice, we found only ~50-60% reduction fl/fl + differentiation. Rather, the evidence suggests that necroptosis, an alterna- of Ngn3 and Ins mRNA in the pancreas of GLIS3 /RIP-Cre mice, and ~80% tive pathway of regulated cell death, was involved since inhibitors of this reduction of Ngn3 and Ins mRNA or protein expression in the pancreas of neo- fl/fl + pathway were protective towards the β-cells. Furthermore, genetic ablation natal GLIS3 /Pdx1-Cre mice. By qRT-PCR, we found gene dosage-dependent of ripk3, an effector for necroptosis, also protected the β-cells. Macrophages differences associated with Cre-mediated GLIS3 deletion in the neonatal pan- +/- had a predominant role in the reduction of β-cells in the zMIR animals. Mac- creas: RIP-Cre: ~50-60% of wild-type, a level similar to GLIS3 mice, Pdx1- rophages were found to infiltrate the islet during the time of β-cell reduc- Cre: ~90%, and protamine-Cre (for global knockout): ~100%. The expression tion and depletion of macrophages with clodronate liposomes or by genetic levels of Ngn3 and Ins correlated negatively with the extent of GLIS3 deletion. ablation of irf8 protected β-cells. Furthermore, that macrophage infiltration These mouse models are powerful tools to study GLIS3 gene dosage effects occurred even in the presence of a necroptosis inhibitor suggested a role in β-cells and provide a unique opportunity to decipher the role of GLIS3 muta- upstream of necroptosis. These lines of evidence suggest that β-cells of zMIR tions/variants in a spectrum of β-cell dysfunction in people. fish are more susceptible to metabolic stress, macrophages contribute to Supported By: American Diabetes Association (1-14-MN-01 to L.C.C.); National β-cell death, and β-cells die through necroptosis. Institutes of Health (P30-DK079638); Baylor College of Medicine (T32-HL066991); Supported By: American Diabetes Association (1-13-BS-027 to W.C.); National JDRF (46-2010-752); T.T. and W.F. Chao Global Foundation; Cindy and Frank Liu Fam- Institutes of Health (R01DK088686) ily Foundation; Cunningham Family Foundation; Betty Rutherford Chair in Diabetes Research at Baylor St. Luke’s Medical Center (to L.C.C.); American Heart Association 329-LB (13SDG17090096 to Y.Y.); MetroHealth Medical Center (to Y.Y.) Neutralizing Interleukin (IL)-1 Beta Protects Cultured Human Islets from Amyloid-induced Beta-Cell Death QUEENIE HUI, YOO JIN PARK, ZILIANG AO, NOOSHIN SAFIKHAN, GARTH L. WAR-

NOCK, LUCY MARZBAN, Vancouver, BC, Canada Islet amyloid formation due to aggregation of human islet amyloid polypeptide (hIAPP), contributes to beta-cell dysfunction and death in type 2 diabetes, cultured and transplanted human islets. We previously showed that amyloid formation induces upregulation of the Fas cell death receptor in human islet POSTERS

I slet Biology/ beta cells. Interestingly, most of amyloid forming human islets also had ele-

I nsulin Secretion vated IL-1 beta levels. In this study, we tested if neutralizing IL-1 beta can prevent amyloid-induced Fas upregulation and beta-cell toxicity. Human islets isolated from cadaveric pancreatic donors (n = 6) were cultured with or with-

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LB84 Islet Biology—Beta CellL—Satet Bimurealukings-Secret Abstractsion Coupling and Metabolism

331-LB bilized cells allow for an in depth assessment of chemiosmotic coupling within A Novel Role for Tle3 in Maintaining Beta Cell Identity the β-cells while the intact protocol evaluates a more physiologically relevant SARAH L. ARMOUR, SCOTT J. ANDERSON, MICHAEL G. WHITE, Newcastle, United condition. We have shown that deletions of the Nr4a nuclear receptors clearly Kingdom impact cellular respiration, lowering the oxygen consumption rate in all respi- There is increasing evidence for beta cell plasticity as a potential aetiol- ratory states of intact β-cells between 40-65% and permeabilized β-cells by ogy for diminished insulin and excess glucagon secretion in type 2 diabetes. 23-50% compared to GFP (p<0.05). Our results indicate that knockdown of Underlying mechanisms driving loss of beta cell identity and transition to Nr4a1 and Nr4a3 results in decreased expression of Idh3a, Idh3g, Sdhb, and alpha-like cells remain poorly characterised. Transducin-like enhancer of split Mdh2, which would impede TCA cycle progression, and is consistent with the 3 (Tle3), a member of the Groucho family of co-repressors, is a key regulator of reduction observed in O2 consumption and ultimately glucose stimulated insu- beta cell specification during development. Specifically, through interactions lin secretion. These data demonstrate for the first time that the Nr4a orphan with Nkx6.1, Tle3 acts to suppress glucagon gene activation. Tle1, the human nuclear receptor family members Nr4a1 and Nr4a3 are critical for basal β-cell functional equivalent, is located within a diabetes susceptibility locus, but the mitochondrial function and insulin secretion. role of these proteins in maintaining beta cell identity in the adult and during Supported By: Brigham Young University diabetes development remains relatively unexplored. Aims were to establish an in vitro model of glucotoxicity driven beta cell plasticity and determine the 334-LB impact of Tle3 on beta cell identity. Gene expression and functional studies Heart Failure Causes ER Stress and Mitochondrial Dysfunction in were performed using quantitative rtPCR and insulin/glucagon ELISA in INS1E Pancreatic Beta Cells cells. Following 48 h glucotoxicity (25 mM), expression of beta cell related JESSICA GAMBARDELLA, ALAIN LACAMPAGNE, MARIA SANCHEZ QUINTERO, genes (Ins1, Ins2, Nkx6.1, Pdx1 and Tle3) was significantly reduced compared MICHIO HIRANO, GUIDO IACCARINO, ANDREW MARKS, GAETANO SANTULLI, to cells cultured under normal (11 mM) conditions. These changes were asso- New York, NY, Montpellier, France, Salerno, Italy ciated with reduced insulin storage (60% decrease vs. 11 mM culture) and Cardiovascular disease and diabetes represent major health concerns in beta cell function (glucose stimulated insulin secretion index: 1.9±0.31 (25 U.S. and worldwide. Whereas the increased risk of cardiovascular disease mM) vs. 4.3±0.69 (11 mM); p<0.05). Furthermore, glucagon mRNA expression and heart failure (HF) in diabetic patients has been established, the recipro- and protein content was significantly increased. siRNA mediated knockdown cal relationship, i.e., the augmented risk of glucose intolerance and type 2 of Tle3 (0.33 fold; p<0.05) led to significant reductions in Nkx6.1, Pdx1 and Ins2 diabetes mellitus (TD2M) in patients with cardiovascular disorders, has been gene expression in 11 mM glucose culture. This was coupled to a significant evidenced in the clinical scenario but the underlying mechanisms remain increase in glucagon expression (1.45 fold) and content (1.5 fold). These stud- unclear. In this study we focused on the beta cell function in a murine model ies provide evidence for glucotoxicity driven beta cell dysfunction associated of post-ischemic HF, obtained via ligation of the coronary artery. The HF with loss of beta cell identity and alpha cell transition. Knockdown of Tle3 group exhibited glucose intolerance and impaired glucose-stimulated insulin mimics these glucotoxic effects indicating a novel, activating role for Tle3 in release, with no major differences in islet architecture when comparing HF maintaining beta cell identity/function. and SHAM. Islets isolated from HF mice displayed upregulation of common markers of endoplasmic reticulum (ER) stress, including BiP and spliced XBP. 332-LB Ultrastructural analysis revealed significant mitochondrial dysmorphology (fragmented cristae, swelling, and outer membrane disruption) in HF beta Withdrawn cells. We also found significantly altered mitochondrial dynamics in ex vivo experiments in HF vs. SHAM, including reduced glucose-stimulated and glutamine/leucine-stimulated ATP production, impaired oxygen consumption rate (measured at Seahorse), decreased mtDNA/nDNA, aconitase activity, and NADPH following glucose stimulation, alongside with augmented generation of reactive oxygen species. Strikingly, we demonstrate that during HF beta cells display decreased intracellular calcium stores, and mitochondria exhibit a significantly reduced glucose-stimulated uptake of calcium, known activator of three matrix dehydrogenases in the Krebs cycle. Moreover, the expression of mitochondrial calcium uniporter (MCU) was decreased in HF islets. Taken together, our in vivo and ex vivo data establish that HF induces beta cell failure, characterized by ER stress, mitochondrial dysfunction, and overall impaired fuel-stimulated insulin release. Supported By: National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases

Islet Biology—Beta Cell—Stimulus-Secretion 335-LB Glucose-dependent Stimulation of Insulin Release by INS1E Cells Coupling and Metabolism and Human Islets Induced by a Novel Compound HEATHER L. HAYES, FRANCIS TAVARES, BENJAMIN M. BUEHRER, Research Tri- 333-LB angle Park, NC β-Cell Deletion of Nr4a1 and Nr4a3 Nuclear Receptors Impedes Type 2 diabetes (T2D) results from a decline in beta cell function due to Mitochondrial Respiration and Insulin Secretion a decrease in glucose-stimulated insulin secretion (GSIS) or a loss of beta JEFFERY S. TESSEM, CHAD R. HANCOCK, MERRICK S. REYNOLDS, JASON D. RAY, cell mass. Although considerable progress has been made to understand the KYLE B. KENER, CARRIE DRANEY, JEREMY M. HARDMAN, Provo, UT mechanisms of GSIS in functional beta cells and the dysregulation that occurs Insulin secretion from β-cells is dependent on the glucose stimulation of during the progression of T2D, there are limited options for therapeutics to mitochondrial respiration. The Nr4a family of orphan nuclear receptors are control glucose homeostasis. Several pharmacotherapies exist, but over time essential for fuel utilization and mitochondrial function in liver, muscle and patients experience a loss in their GSIS response to these agents, thus requir- fat. We have demonstrated that overexpression of Nr4a1 or Nr4a3 are suf- ing new therapies to treat T2D. We identified a compound, 033, in an ongoing

ficient to induce pancreatic β-cell proliferation. We examined the impact of small molecule screen that stimulates insulin secretion in a glucose-dependent Nr4a1 and Nr4a3 on pancreatic β-cell mitochondrial function and proliferation manner in INS1E cells. As compared to vehicle control, treatment of INSE cells using lentivirus mediated shRNA knock-down of Nr4a1 and Nr4a3 in INS-1 with 033 results in a 2-fold increase in GSIS without affecting total insulin derived 832/13 rat insulinoma cells. Nr4a1 and Nr4a3 deficient β-cells have content. Moreover, 033 treatment of INS1E cells partially rescues the loss of a 37% reduction in proliferation rates (p<0.05). The reduction in β-cell proinsulin secretion and total insulin content in glucotoxic conditions. Analysis of liferation with Nr4a1 and Nr4a3 deficiency was accompanied by a significant 13 genes that are critical for beta cell function showed that 033 significantly POSTERS decrease in glucose stimulated insulin secretion rates (GSIS) (26% decrease, enhances the expression levels of several genes, including FoxoA2, Glut2, I slet Biology/ I nsulin Secretion p<0.05). High resolution respirometry (Oroboros O2k) was used to evaluate HNF4a, and MafA, in INS1E cells. Importantly, the 033-enhanced effects of mitochondrial respiratory function and capacity with substrate-uncoupler- GSIS translate to primary human islets. Treatment of primary human islets inhibitor titration protocols for both intact and permeabilized β-cells. Permea- from 11 nondiabetic donors (BMI >26) with 033 for 72 h increases GSIS at

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LB85 Islet Biology—Beta CellL—Satet Bimurealukings-Secret Abstractsion Coupling and Metabolism

stimulatory glucose. This effect is not present in primary human islets from Given that the Golgi is pivotal in the formation of secretory granules (and nondiabetic donors with lower BMI values (<26; 5 donors). Interestingly, treat- proinsulin to insulin processing) we propose that this disruption to Golgi ment of islets from T2D subjects with 033 also results in augmented GSIS (4 homeostasis may contribute to the decreased amount of insulin available for donors). Overall, our data demonstrate that 033 increases GSIS in INS1E cells release from pancreatic β-cells in type 2 diabetes. and primary human islets, in part, by upregulating genes responsible for beta cell function. Ongoing studies are underway to identify the molecular targets 338-LB of this compound. Lack of NADPH Oxidase-2 Does Not Improve Pancreatic β-Cell Sur- vival and Function in Male C57BL/6J Mouse Islets Cultured for 3 336-LB Weeks at High Glucose Biomarkers of β-Cell Death in Obese Adolescents with Impaired Glu- ARNALDO H. SOUZA, LAILA R. SANTOS, LETICIA P. ROMA, ANGELO R. CARPINELLI, cose Tolerance (IGT) and Type 2 Diabetes (T2D) JEAN-CHRISTOPHE JONAS, Brussels, Belgium, Heidelberg, Germany, São Paulo, SARAH A. TERSEY, ESTHER BOLANIS, FARAH MEAH, FAROOQ SYED, THOMAS B. Brazil FARB, KARA S. BENNINGER, JENNIFER B. NELSON, KRISTER BOKVIST, KIEREN J. High glucose-induced oxidative stress may contribute to the progressive MATHER, SILVA A. ARSLANIAN, RAGHAVENDRA G. MIRMIRA, Indianapolis, IN, loss of functional β-cell mass in type 2 diabetes. To test whether superoxide Pittsburgh, PA production by NADPH oxidase-2 (NOX2) is involved in β-cell dysfunction and In obese youth, β-cell function worsens with increasing dysglycemia, but it apoptosis under glucotoxic conditions, we characterized the acute and long- is unknown if β-cell death is coincident with this worsening in function. Previ- term effects of glucose on cytosolic glutathione/thiol oxidation (GRX1-roGFP2 ously, we showed elevations in circulating, cell-free methylated and unmethy- and roGFP1 redox-sensitive probes), H2O2 concentration (roGFP2-Orp1 H2O2- lated preproinsulin (INS) DNA in youth with new-onset T1D, indicating that sensitive probe), β-cell stimulus-secretion coupling events and apoptosis in β-cell death is detectable at T1D diagnosis with this measurement. Here we islets from male NOX2 knockout (NOX2-KO) and wild-type (WT) C57BL/6J present studies using this assay to test the hypothesis that β-cell death con- mice cultured for up to 3 weeks in RPMI medium containing 10 or 30 mmol/L tributes to the pathogenesis of dysglycemia in adults and youth. We isolated glucose (G10 or G30). After 1-2 days of culture at G10, the acute glucose stimu- DNA from banked serum from obese normal glucose tolerance (NGT), IGT and lation of insulin secretion (GSIS) was ~1.7-fold higher in NOX2-KO vs. WT islets T2D adults and youth, and assessed differentially methylated INS by droplet despite similar rises in NAD(P)H autofluorescence and intracellular calcium 2+ digital PCR. Among non-dysglycemic controls, values for both methylated and ([Ca ]i) and no differences in cytosolic glutathione oxidation. After long-term unmethylated INS increased with age (P<0.001, R=0.229; P<0.001, R=0.3201), culture at G10, cytosolic thiol oxidation, H2O2 concentration and β-cell apopto- with adults showing 3-30-fold higher levels than youth. Among adults, those sis remained low in both islet types. Also, the glucose-induced rises in NAD(P) 2+ with IGT and T2D exhibited no differences in unmethylated or methylated INS H autofluorescence, [Ca ]i and GSIS were similar to the results obtained after levels compared to controls (P>0.9). Obese youth with NGT and IGT exhibited 1-2 days of culture, except for a progressive reduction of the difference in elevated levels of methylated INS compared to normal weight NGT controls GSIS between NOX2-KO and WT islets. After prolonged culture at G30, cyto- (P<0.001; P<0.01), but showed no differences in unmethylated INS. Youth with solic thiol oxidation and H2O2 concentration increased in parallel with β-cell 2+ phenotypic T2D also showed elevated methylated INS levels compared to apoptosis, the glucose sensitivity of the NAD(P)H, [Ca ]i and insulin secretion 2+ normal weight controls (P<0.01), and a trend to an increased unmethylated responses increased, the maximal [Ca ]i response decreased, but maximal INS (P=0.059). The elevation in methylated INS levels in phenotypic T2D youth GSIS (at G15 and G30) was preserved. These responses were almost identical was driven by a subset with islet autoantibodies (P<0.001). This collaborative in both islet types. In conclusion, NOX2 is confirmed as a negative regulator study demonstrates that while biomarkers coincident with β-cell death are of GSIS in C57BL/6J mouse islets, but it does not detectably contribute to the evident in youth with obesity, dysglycemia and diabetes, these markers are long-term glucotoxic alterations of β-cell function and survival in vitro. not elevated in adults with IGT and T2D. Whereas the different outcomes Supported By: Fundação de Amparo à Pesquisa do Estado de São Paulo, Brazil; in adults and youth may reflect a superior signal-to-noise ratio for the assay Bolsa Estágio de Pesquisa no Exterior, Brazil; “Communauté française de Belgique- in youth, they may also reflect accelerated β-cell death in the pathogenesis Actions de Recherche Concertées,” Belgium F.R.S.-FNRS, Belgium of dysglycemia in childhood in contrast to adults in whom aging-associated β-cell death might overshadow this process. 339-LB Supported By: American Diabetes Association (7-13-JF-56 to S.A.T.); National A Novel Standardized In Vitro Islet Model System for Efficacy and Institutes of Health (UC4 DK104166); Eli Lilly and Company Toxicity Testing in Pancreatic β-Cells BURCAK YESILDAG, APARNA NEELAKANDHAN, SIMON MESSNER, WOLFGANG 337-LB MORITZ, Schlieren, Switzerland Saturated Fatty Acids Induce Golgi Expansion in Pancreatic β-Cells The lack of in vitro models that reliably assess pancreatic islet function for NANCY SUE, EBRU BOSLEM, LE MAY THAI, TREVOR J. BIDEN, Sydney, Australia efficacy and toxicity testing in high-throughput fashion remains a significant We have previously shown that treatment of pancreatic β-cells with satu- challenge in drug development. To address this unmet need, we have devel- rated (palmitate) but not unsaturated (oleate) fatty acid causes endoplasmic oped 3D InSight™ pancreatic microislets, standardized microtissues reaggre- reticulum (ER) stress and a defect in ER-Golgi protein trafficking. Here we gated from dispersed islets and cultured in 96-well-GravityTRAP™ plates at explore whether palmitate also impacts Golgi morphology. a single microislet per well format. We observed robust glucose dependent MIN6 cells were treated for 48 h with 0.4mM lipid: 0.92% [wt/vol] BSA in insulin secretion from microislets across donors, with improved glucose 5mM glucose. Golgi were stained with GM130 antibody and Z-stack images responsiveness, stable viability and size during long-term culture, as well as were taken by confocal microscopy. Golgi volumes (or 2D surface areas) were homogenous size distribution, tissue architecture and cellular composition calculated using LAS X software. allowing high-throughput data acquisition with low intra-assay variability. To Volume and area analysis revealed an expansion of the Golgi in palmitate- evaluate our model for compound risk assessment, 3D InSight™ human and treated cells compared to BSA and oleate treatment. This is distinct from the rat microislets from individual donors were used to assess chronic effects of Golgi fragmentation caused by Brefeldin A. We confirmed this finding in islets marketed drugs previously associated with pancreatic β-cell toxicity. Olan- of diabetic db/db mice compared to nondiabetic controls. ER stress is not zapine (an antipsychotic drug), Tunicamycin (an ER stress inducing antibiotic), sufficient to cause this expansion as it is not replicated with thapsigargin or Tacrolimus and Rapamycin (immunosuppressive agents), were evaluated in tunicamycin (chemical ER stress inducers). Nor was it resolved by treatment a dose-dependent manner for their influence on microislet ATP and insulin with the pan-caspase inhibitor ZVAD arguing against a dependency on cas- content, chronic, basal and glucose stimulated insulin secretion following 14 pase activation or apoptosis. However, overexpression of glucosylceramide days of compound exposure. In human microislets, Tunicamycin treatment

synthase did partially reduce the effects of palmitate, suggesting a role for resulted in decreased ATP (>1 µM) and insulin content (>0.1 µM), impaired sphingolipid metabolism in mediating Golgi expansion. chronic, basal and glucose stimulated insulin secretion (>0.1 µM). Olanzapine We next investigated whether this perturbation in Golgi morphology had decreased insulin content (>10 µM) and impaired chronic insulin secretion (>10 functional consequences. The Golgi plays a central role in the delivery of pro- µM). Tacrolimus and Rapamycin supressed chronic (>10 nM and 0.1 nM), basal teins to the secretory pathway, so we employed Click-iT ManNAz metabolic (>0.01 nM and 0.1 nM) and glucose stimulated insulin secretion (>10 nM and POSTERS I slet Biology/ labeling to track the transport of sialic acid-containing glycoproteins from the 1 nM). Rat microislets displayed similar trends in compound sensitivity. Robust I nsulin Secretion Golgi to the cell surface. We found reduced ManNAz staining at the cell sur- long-term functionality of pancreatic microislets makes them an ideal model face in both palmitate-treated MIN6 cells and db/db islets, indicating a defect for in vitro assessment of compound effects on β-cell viability and function. in Golgi-plasma membrane trafficking.

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LB86 Islet Biology—Beta CellL—Satet Bimurealukings-Secret Abstractsion Coupling and Metabolism

340-LB 342-LB Gastric Bypass Surgery With and Without Exercise Modifies Circu- Serotonin Is a Paracrine Signal that Inhibits Glucagon Secretion in lating miRNAs that Correlate with Improvement in Cardiometabolic Human Pancreatic Islets Risk Factors JOANA ALMACA, JUDITH T. MOLINA, DANUSA MENEGAZ, MADINA MAKHMU- YURY O. NUNEZ LOPEZ, PAUL M. COEN, BRET H. GOODPASTER, ATTILA SEYHAN, TOVA, PER-OLOF BERGGREN, ALEJANDRO CAICEDO, Miami, FL, Stockholm, Swe- Orlando, FL den

Roux-en-Y gastric bypass (RYGB) surgery improves insulin sensitivity (SI) The insulin-secreting pancreatic beta cell has the ability to synthesize, and intrinsic islet β-cell function in obese nondiabetic patients. Exercise store, and release the neurotransmitter serotonin. In the pancreatic islet sero- also improves SI and is an effective adjunct therapy to RYGB surgery. These tonin plays an important role as an autocrine signal that increases beta cell improvements, however, can vary considerably. We investigated whether mass during metabolic challenges. Because serotonin is barely expressed in circulating miRNAs tracked with improvements in SI, acute insulin response rodent islets under normal conditions, it is at present unclear if islet serotonin (AIRg), disposition index (DI), and glucose effectiveness (SG) following 6 months is relevant for regular islet physiology and hormone secretion. Here we show of RYGB surgery-induced weight loss, with (n=11) or without (n=12) an exercise that human beta cells from healthy individuals produce and secrete serotonin training intervention. A panel of miRNAs previously implicated in metabolism when stimulated with increases in glucose concentration. Serotonin secretion were quantified by qRT-PCR. Circulating concentrations of specific miRNAs by beta cells inhibits glucagon secretion from neighboring alpha cells. In the (122, 206, 149) were altered with RYGB and exercise. RYGB alone altered a dif- absence of serotonergic input from beta cells, alpha cells lose their ability to ferent pattern of miRNAs (122, 208, 499). In addition, the change in concentra- regulate glucagon secretion in response to changes in glucose concentration, tion of several miRNAs were significantly correlated with measures of β-cell suggesting that diminished serotonergic control of alpha cells could cause function: AIRg (rmiR-122~AIRg=0.82, FDR=0.01), DI (rmiR-208~Di=-0.87, FDR<0.01); glu- glucose blindness and the uncontrolled glucagon secretion associated with cose uptake: SI (rmiR-208~Si=0.81, FDR=0.01) and SG (rmiR-122~Sg=0.76, FDR=0.04); diabetes. In vivo modulation of serotonin signaling reduced glucagon secre- and other cardiometabolic factors. PCA analysis showed that control and tion and had hypoglycemic effects in healthy and diabetic mice. Modulation exercise groups could be separated based on miR-122, miR-149, and miR-206 of serotonin signaling in the islet thus represents a drug intervention oppor- levels. In summary, our data underscore the potential of circulating miRNAs as tunity. biomarkers of RYGB surgery and exercise responses. Supported By: American Heart Association (14POST20380499) Table 1. MicroRNA Differential Abundance. RGYB + Exercise (Post vs. Pre) Fold Change P. value FDR 343-LB The Mouse Eye as Experimental Platform to Study Human Islet Cell miR.122 0.19 0.00658 0.07240 Biology In Vivo miR.206 0.15 0.03044 0.16527 RAYNER RODRIGUEZ-DIAZ, MIDHAT ABDULREDA, JONATHAN ROBBERT WEITZ, miR.149 9.78 0.04507 0.16527 DAMARIS RUTH MOLANO, ANTONELLO PILEGGI, CAMILO RICORDI, ALEJANDRO RYGB Control (Post vs. Pre) Fold Change P. value FDR CAICEDO, PER-OLOF BERGGREN, Miami, FL, Stockholm, Sweden We have previously described that the anterior chamber of the eye is a miR.122 0.24 0.01181 0.12991 valuable implantation site to study mouse pancreatic islet structure and miR.208 10.93 0.07990 0.34484 function in vivo. Here we transplanted human islets into the eyes of immune- miR.499 4.70 0.09405 0.34484 deficient mice. After transplantation of 500 islets per eye in diabetic mice, normoglycemia was restored for over 150 days. Glucose metabolism in Supported By: Florida Hospital recipient mice was tightly controlled by insulin and glucagon derived from intraocular human islet grafts. The eye acts as a natural window allowing 341-LB for real-time, repeated, noninvasive in vivo imaging of human islet cells in Plasma miRNAs Associate with Progression of Diabetes and vivo. Longitudinal imaging of human islets showed that human islet grafts 1.) Response to Vitamin D in People with Prediabetes preserved most of their native vasculature and resident immune cells and 2.) YURY O. NUNEZ LOPEZ, ANASTASSIOS G. PITTAS, RICHARD E. PRATLEY, ATTILA were re-innervated by autonomic nerves from the mouse eye, but conforming SEYHAN, Orlando, FL, Boston, MA to the human innervation pattern. The effects of drugs topically applied to the Suboptimal vitamin D status is associated with higher risk of type 2 diabe- eye could be measured with local and systemic readouts. Using our model we tes (T2D) in observational studies. Metabolic responses to vitamin D supple- determined that prolonged exposure to liraglutide, a long acting glucagon- mentation vary among people at high risk for T2D. We tested the hypothesis like-peptide-1 receptor agonist, impair human islet function. Currently, we that circulating miRNAs reflect responses to vitamin D supplementation. are evaluating the relevance of the glucagon producing alpha-cells input on We measured plasma levels of metabolically-involved miRNAs in archived the glucose sensitivity of their adjacent insulin producing beta-cells in human samples from subjects with pre-diabetes treated either with placebo (n=21) intraocular islet grafts. Our preliminary results support the relevance of the or vitamin D (n=21) for 4 months in the Calcium and Vitamin D for diabetes paracrine interactions in the human islet in vivo. These results show that our mellitus trial (NCT00436475). miRNA levels at 4 months were compared to experimental platform for imaging and studying human islet cell biology in baseline levels and data adjusted for age, gender, and waist circumference. vivo is a valuable tool to study islet biology in the living organism and screen We found that plasma levels of miR-193b (1.46-fold reduction, p=0.038), miR- drugs for the effects on islet function and glucose metabolism. 125a-5p (1.35-fold increase, p=0.028), miR-130a (1.25-fold increase, p=0.015), and miR-33a (1.51-fold reduction, p=0.041) changed in response to vitamin D and these changes correlated with those in 25(OH)D concentration (r = 344-LB miR-193b Identifying the Genetic Architecture of Insulin Secretion in Pancre- -0.36, r = 0.36, r = 0.31, and r = -0.31, p<0.05). Elevated lev- miR-125a-5p miR-130a miR-33a atic Islets els of miR-28-3p (1.22-fold increase, p=0.013) in vitamin D-treated subjects negatively correlated with changes in HbA1c (r = -0.39, p=0.01). This suggests MARK KELLER, MARY RABAGLIA, KATHY SCHUELER, DONALD STAPLETON, PRA- that miR-28-3p is induced by vitamin D and potentially contributes to the DYUT PAUL, RAHUL DAS, AIMEE BROMAN, BRIAN YANDELL, SUNDUZ KELES, reversal of pre-diabetes. In contrast, reduced plasma levels of miR-324-5p GARY CHURCHILL, KARL BROMAN, ALAN ATTIE, Madison, WI, Bar Harbor, ME The Diversity Outcross (DO) mouse panel is a newly-developed outbred (1.58-fold reduction, p=0.001) and miR-370 (2.18-fold reduction, p=0.004) in mouse stock derived from 5 classical inbred strains (B6, A/J, 129, NOD, NZO) placebo-treated subjects negatively correlated with changes in HbA1c, sug- and 3 wild-derived strains (CAST, PWK, WSB). DO mice carry ~34M SNPs, a gesting that these miRNAs reflect disease progression (r = -0.42 and r = -0.31,

level of genetic diversity present in the human population. To evaluate the p<0.05 respectively). Notably, the change in plasma levels of miR-324-5p also relationship between genetic diversity and islet function, we isolated islets correlated with the change in 25(OH)D (r=0.31, p=0.049). Our results suggest from ~300 DO mice and determined the insulin secretory response to differ- that these miRNAs reflect disease progression and/or metabolic responses to ent insulin secretagogues; glucose, GLP-1, palmitate, amino acids and KCl. In Vitamin D supplementation in patients with pre-diabetes and may be useful addition, a host of other phenotypes were measured, including, body weight, biomarkers in diabetes prevention trials.

fasting and dynamic changes in plasma insulin and glucose, islet number, POSTERS Supported By: Florida Hospital I slet Biology/

and whole-islet RNA-sequencing. Driven by genetic diversity within the DO I nsulin Secretion stock, we observed a large range of values for all phenotypes. Further, due to the unique genetic architecture of every mouse, we observed differential and often specific responsiveness to the secretagogues in our insulin secre-

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LB87 Islet BiLateolo Bgy—Signreaking alAbstracts Transduction

tion assays, consistent with distinct molecular pathways regulating the Islet Biology—Signal Transduction response to each secretagogue. To identify QTLs associated with these phenotypic differences, all DO mice were genotyped at ~150,000 SNP markers 346-LB genome-wide. Distinct QTLs were identified for many of the secretagogues. Elevated Levels of miR-21 in Circulating Extracellular Vesicles Pre- For example, a locus on Chr 3 showed linkage for amino acid-induced insulin date Onset of Type 1 Diabetes Mellitus secretion, whereas a locus on Chr 16 was associated with GLP-1 dependent ALEXANDER J. LAKHTER, FAROOQ SYED, BERNHARD F. MAIER, RAGHAVENDRA insulin secretion. To narrow the list of candidate genes at individual loci, we G. MIRMIRA, CARMELLA EVANS-MOLINA, EMILY K. SIMS, Indianapolis, IN performed single gene queries in human GWAS for associations to diabetes- Early detection of developing type 1 diabetes (T1D), before widespread related phenotypes. This approach takes advantage of the ultra-high genomic destruction of -cell mass, is needed for improved outcomes of T1D preven- resolution in the human studies, without the multiple testing penalty inherent β tion strategies. MicroRNAs (miRNAs) released in extracellular vesicles (EVs) in genome-wide scans. As a validation of our approach, a QTL for islet number have been proposed as ideal biomarkers due to their stability and feasibil- occurred at the Glis3 locus on Chr 19, which has been previously associated ity of detection. Previous work from our lab demonstrated that -cell miR-21 with diabetes in human GWAS, and shown to play a role in islet development. β production is induced by inflammation, and RT-qPCR analysis of diabetic NOD We identified several novel genes not previously linked to diabetes or -cell β mouse islets revealed a ~4-fold increase in miR-21 expression compared to function. NOR controls. We hypothesized that the inflammatory milieu of developing T1D may also increase miR-21 in β-cell EV cargo. EVs released by INS-1 β-cells 345-LB exposed to a cytokine mix of IL-1β, INFγ, and TNFα were isolated using Exo- Insulin Secretion from Clonal MIN6 Sublines Depends on the Dimen- Quick reagent. RT-qPCR revealed an 8-fold increase in EV miR-21. Similarly, a sionality of Culturing 5-fold increase in miR-21 content was observed in EVs from cytokine-treated MATTHEW K. DADDYSMAN, MARTHA H. RENN, ALAN L. HUTCHISON, TOAN human islets. Nanoparticle tracking analysis showed no changes in EV quan- HUYNH, NATALIA TAMARINA, LOUIS H. PHILIPSON, AARON R. DINNER, NORBERT tity or size distribution in response to cytokine exposure, implicating transcript F. SCHERER, Chicago, IL upregulation and changes in EV cargo content as responsible for the increase. The mouse insulinoma-6 (MIN6) cell line is widely used in diabetes research. To assay changes in circulating EV miR-21, we performed longitudinal serum However, we found that MIN6 cells have heterogeneous responses to glu- collections on NOD mice and insulitis resistant NOR controls, starting at 9 cose stimulation. To address this problem, We used flow cytometry to isolate wks of age and until diabetes onset (defined as blood glucose > 250 mg/dL x individual cells from which we established genetically pure clonal sublines of 2, n=7). Starting 3 wks prior to diabetes onset, EV miR-21 levels progressively MIN6. We screened these clonal cell lines for their responsiveness to glucose increased in serum of diabetic NODs compared to age-matched NOR controls, stimulation monitoring insulin secretion and calcium ion uptake. Our mea- peaking at 10-fold over the base level one week prior to the onset of the dis- surements of insulin secretion indicate that we have produced a 3-fold more ease. We propose that EV miR-21 may be a promising marker of insulitis and responsive subline (over basal conditions), which also has intense calcium developing T1D in susceptible individuals. Ongoing studies will further define oscillations following glucose stimulation. Others of our clonal sublines are relationships between EV miR-21 content and β-cell inflammation and death, nonsignificantly responsive for insulin secretion or calcium oscillations. Most and verify our findings in human samples. importantly, unique behaviors are only present when the cells are cultured in Supported By: National Institutes of Health (T32 DK064466 to A.J.L.), 3D islet-like structures (Figure). RNA-seq analysis on these sublines reveals (K08DK103983, P30 DK097512 to E.K.S.); National Institute of Diabetes and epigenetic expression differences in over 4,000 genes between the sublines Digestive and Kidney Diseases at a 99% confidence interval. The number of differentially expressed genes increases to over 6,000 when 2D vs. 3D growth is considered. These epi- 347-LB genetic differences are present in genes throughout the glucose stimulated Autonomic Sensory Innervation of the Pancreatic Islet of Langer- insulin secretion pathways. Our results demonstrate that the widely used hans MIN6 cell line is heterogeneous and should be used with circumspection. MADINA MAKHMUTOVA, RAYNER RODRIGUEZ-DIAZ, JOANA ALMACA, JONA- Figure. THAN WEITZ, ALEJANDRO CAICEDO, Miami, FL Visceral stimuli are detected by free nerve endings and transmitted to the hindbrain via vagal afferent neurons. Vagal neurons respond to various pancreatic stimuli, whoever the quality of islet-specific stimuli as well as higher order projections still remain elusive. Using expression of immediate early gene cFos, in response to Streptozotoxin (STZ) treatment, we identified regions in the Nucleus of the Solitary tract and Parabrachial nucleus that get activated in response to islet stimulation. To further investigate pancreatic sensory innervation, we are using TetTag mouse, where two distinct neural pathways can be traced in the same animal. The TetTag mouse is expressing Tau-LacZ under cFos promoter, which allows labeling of activated neurons throughout neural projections, thus fully tracing neural circuits in response to a first stimulus; it also expresses GFP under cFos promoter, allowing a short term tracing of activated neurons in response to a second stimulus. We are planning to unravel islet-specific innervation using STZ as a first stimulus and compare it to the innervation of the acinar tissue which can be stimulated with Caeruelin. Pathways will be reconstructed and visualized in 3D using two-photon confocal microscopy. In order to determine physiological role of Supported By: University of Chicago; W.M. Keck Foundation the pancreatic sensory innervation on glycaemia, we are planning to use the chemical compound Daun02, which is being converted into a neuronal silencer Daunorubicin by β-galctosidase activity. Thus we have a model where we can trace and manipulate islet-specific neural circuits. Altogether this study will provide insights into pancreatic sensory innervation and its contribution to

glucose metabolism. POSTERS I slet Biology/ I nsulin Secretion

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LB88 SUBJECT Index

8 isoprostane 55‑LB Bone fractures 126‑LB Eating behavior 74‑LB A1c 49‑LB, 312‑LB, 315‑LB Bone marrow adiposity 298‑LB Education 44‑LB, 48‑LB Abscisic acid 121‑LB Brown adipose tissues 323‑LB eGlycemic management systems 101‑LB, 153‑LB Activin 287‑LB Browning 232‑LB, 304‑LB Electrical neuromodulation 288‑LB Adeno associated viral vectors 96‑LB, 246‑LB Camp outcomes 161‑LB Electronegative LDL 34‑LB S U BJECT IN DE X Adherence 117‑LB Canagliflozin 140‑LB Electronic medical records 151‑LB Adipocyte 297‑LB, 318‑LB Cancer 115‑LB Electrophysiology 34‑LB Adipocyte metabolism 229‑LB Carbohydrate counting 64‑LB Empagliflozin 126‑LB, 127‑LB Adipogenesis 302‑LB Cardiometabolic disease 275‑LB EndoBarrier 326‑LB Adipogenic progenitor 298‑LB Cardioprotection 58‑LB Endoplasmic reticulum stress 7‑LB, 334‑LB Adipokine 52‑LB Cardiovascular risk 6‑LB Endothelial dysfunction 176‑LB Adipose tissue 56‑LB, 232‑LB Cardiovascular risk factor control 171‑LB Endotoxin 274‑LB Adipose tissue signaling 309‑LB Carotid intima-media thickness 5‑LB Energy expenditure 278‑LB, 301‑LB Admission 188‑LB Carrageenan 273‑LB Epicardial adipose tissue cross talk 7‑LB Adolescence 71‑LB Case management 46‑LB Epidemiology 184‑LB, 200‑LB, 201‑LB Adrenal 1‑LB CCK administration 253‑LB Epinephrine 2‑LB Advanced glycation end products 172‑LB CD34 109‑LB Epitope 217‑LB Adverse renal outcome 135‑LB Central nucleus of the amygdala 305‑LB Ertugliflozin 125‑LB, 130‑LB African American 147‑LB Characteristics 207‑LB Ethnicity 202‑LB AGEs 5‑LB Childhood obesity 158‑LB Exenatide 86‑LB Agonist 123‑LB Circadian 237‑LB Exendin 4 215‑LB Akt1 245‑LB Citrate 33‑LB Exercise 52‑LB, 53‑LB, 58‑LB, 59‑LB, 103‑LB, Akt2 248‑LB Clinical trial 110‑LB 226‑LB Albuminuria 15‑LB, 17‑LB Clock genes 60‑LB Exercise intolerance 57‑LB Aldosterone 180‑LB Clonal subline 345‑LB Exercise stress test 85‑LB Alzheimer’s Disease 122‑LB Closed loop 104‑LB Exercise training 54‑LB Amino acids 293‑LB Cloud based 84‑LB Exocytosis 247‑LB AMP activated protein kinase 305‑LB CNX 010 710 128‑LB Exosomes 277‑LB AMPK 270‑LB Cohort study 67‑LB Extracellular matrix 281‑LB Amylin 283‑LB Complications 143‑LB Extracellular vesicles 346‑LB Angiopoietin like protein 3 38‑LB Continuous glucose monitor 75‑LB, 169‑LB Eye 343‑LB AnnexinA1 11‑LB Continuous glucose monitoring 163‑LB, 224‑LB Family planning 51‑LB Anti-retroviral therapy 306‑LB Control 145‑LB Fasting plasma glucose 315‑LB ApoA IV 285‑LB Cost savings 152‑LB Fat mass 314‑LB ApoC I 36‑LB Cytokines 214‑LB Fatty liver disease 260‑LB ApoC II 36‑LB Decision support system 82‑LB Fetal programming 239‑LB App 81‑LB Dendritic cells 220‑LB FFAR1 120‑LB ARFRP1 276‑LB Depression 67‑LB, 69‑LB Fibroblast growth factor-21 269‑LB, 284‑LB, Arterial stiffness 155‑LB Dexcom G4 continuous glucose monitoring system 289‑LB Arterial vasoreactivity 176‑LB 79‑LB Food order 62‑LB Artificial pancreas 83‑LB, 103‑LB, 104‑LB, 106‑LB Diabetes 29‑LB, 39‑LB, 65‑LB, 69‑LB, 101‑LB, Fracture 313‑LB AS160 248‑LB 138‑LB, 146‑LB, 174‑LB, 178‑LB, 179‑LB, FTO locus 295‑LB Asian Indians 65‑LB 188‑LB, 199‑LB, 222‑LB, 223‑LB, 283‑LB, Gastric electrical stimulation 141‑LB Atherosclerosis 138‑LB 289‑LB, 308‑LB Gastroparesis 141‑LB Autofluorescence 148‑LB Diabetes alert dog 75‑LB Gene therapy 96‑LB, 246‑LB Autophagy 245‑LB Diabetes complications 184‑LB General control nonderepressible 2 269‑LB Bariatric surgery 28‑LB, 294‑LB, 311‑LB, 317‑LB, Diabetes distress 45‑LB, 50‑LB Genetic architecture 344‑LB 320‑LB Diabetes education 49‑LB, 142‑LB Genetic testing 154‑LB Basal insulin therapy 92‑LB Diabetes monkey 79‑LB Genetics 13‑LB, 19‑LB Bax 327‑LB Diabetes prevalence 183‑LB Genome-wide association studies 212‑LB Behavior change 175‑LB Diabetes self-management 47‑LB, 80‑LB Gestational diabetes 77‑LB, 166‑LB, 167‑LB, Behavioral 160‑LB Diabetes stigma 66‑LB 168‑LB, 170‑LB, 190‑LB, 197‑LB Beige adipocyte 296‑LB Diabetic cardiomyopathy 277‑LB Glargine 300 U/mL 93‑LB Beige cells 323‑LB Diabetic foot infection 42‑LB Glis3 330‑LB Beta adrenergic signaling 296‑LB Diabetic ketoacidosis 127‑LB, 165‑LB Glucagon 39‑LB, 136‑LB, 287‑LB, 290‑LB Beta cell dedifferentiation 227‑LB Diabetic kidney disease 19‑LB Glucagon like peptide 256‑LB Beta cell function 341‑LB Diabetic macular edema 30‑LB Glucagon like peptide-1 35‑LB, 107‑LB, 112‑LB, Beta cell plasticity 331‑LB Diabetic peripheral neuropathy 22‑LB 258‑LB, 282‑LB Bile 262‑LB Dietary fat 275‑LB Glucagon like peptide-1 receptor agonists 6‑LB, Bile acid 311‑LB Dipeptidyl peptidase-4 261‑LB 108‑LB, 110‑LB, 118‑LB, 310‑LB Biomarkers 177‑LB, 336‑LB Dipeptidyl peptidase-4 inhibitor 131‑LB, 133‑LB Glucagon receptor antibody 299‑LB Blood glucose monitoring 76‑LB Discharge algorithm 132‑LB Glucagon secretion 292‑LB Blood glucose monitoring systems 81‑LB Distinguishing type 193‑LB Gluconeogenesis 259‑LB, 267‑LB Blood glucose testing 76‑LB DNA methylation 261‑LB Glucose 78‑LB, 98‑LB BLT1 236‑LB Duration of insulin action 100‑LB Glucose challenge test 182‑LB Body mass index 198‑LB Dyslipidemia 33‑LB, 40‑LB, 272‑LB Glucose excursions 62‑LB Body weight 192‑LB Early life nutrition 191‑LB Glucose metabolism 274‑LB

LB89 Glucose monitoring 70‑LB, 77‑LB Insulin secretion 252‑LB, 255‑LB, 335‑LB, 344‑LB MODY 154‑LB, 213‑LB Glucose transport 3‑LB Insulin sensitivity 134‑LB, 241‑LB, 254‑LB, 255‑LB MODY5 210‑LB Glucose transporter 238‑LB Insulin sensitizer 124‑LB, 240‑LB Monoclonal antibody 240‑LB, 242‑LB Glucose uptake 280‑LB Intensive medication management 142‑LB Monogenic diabetes 213‑LB, 257‑LB Glucose variability 82‑LB, 85‑LB Interesterifed fats 309‑LB Mouse model 291‑LB Glucotoxicity 338‑LB Intervention 25‑LB NASH 260‑LB, 264‑LB, 265‑LB Glycemic 145‑LB Intestinal lipids 268‑LB Necroptosis 328‑LB Glycemic control 64‑LB, 83‑LB, 155‑LB, 203‑LB iPLA2β 216‑LB Neonatal diabetes 207‑LB Glycemic variability 133‑LB Iron 10‑LB Nephropathy 10‑LB, 12‑LB, 13‑LB, 18‑LB S U BJECT IN DE X Golgi 337‑LB Irregular menses 157‑LB Neuron 307‑LB GPR119 119‑LB IRX3 295‑LB Neuropathy 25‑LB, 26‑LB GPR120 280‑LB Islet 330‑LB, 339‑LB, 343‑LB NHANES 181‑LB GPR142 250‑LB Islet alpha cell 292‑LB Niacin 272‑LB GPR40 120‑LB, 252‑LB Islet amyloid and IL-1 beta 329‑LB Nicotinamide adenine dinucleotide 302‑LB GPR40/120 dual agonism 235‑LB Islet auto transplantation 224‑LB Nivolumab 223‑LB Gut microbiota 258‑LB Islet autoantibodies 204‑LB Nocturnal hypoglycemia intervals 91‑LB H. pylori infection and eradication 271‑LB Islet beta cell apoptosis 329‑LB NOD 219‑LB Hair cortisol 162‑LB Islet transplantation 225‑LB, 226‑LB, 227‑LB Nonalcoholic fatty liver disease 146‑LB, 158‑LB, HbA1c 149‑LB KATP channels 122‑LB 263‑LB, 300‑LB Health information technology 80‑LB KCNJ11 257‑LB Noninvasive screening 148‑LB Health related quality of life 149‑LB Ketosis 112‑LB Nopal 63‑LB Heart failure 291‑LB Kidney disease 9‑LB, 16‑LB Novel therapeutics 107‑LB Heart rate 111‑LB Kidney injury 165‑LB Nr4a1 333‑LB Hepatic fat 118‑LB Lactic acidosis 194‑LB Nuclear receptor 241‑LB Hepatic steatosis 137‑LB Lanthionine synthetase C-like 2 121‑LB Obesity 59‑LB, 294‑LB, 297‑LB, 299‑LB, 303‑LB, Hepatitis 139‑LB Leptin 286‑LB 308‑LB, 314‑LB, 321‑LB, 336‑LB Hepatitis B virus 174‑LB Life course epidemiology 198‑LB Obesity pharmacotherapy 310‑LB Hepatocyte insulin sensitivity 244‑LB Linagliptin 17‑LB Omega 3 fatty acids 190‑LB High density lipoprotein 38‑LB Lipid 113‑LB, 254‑LB Oral contraceptives 189‑LB High throughput screening 304‑LB Lipid handling 281‑LB Oral drug 124‑LB Hippo 27‑LB Lipodystrophy 231‑LB, 286‑LB Oral glucose tolerance test 178‑LB HNF 1 beta 210‑LB Lipoprotein lipase 307‑LB Outpatient 84‑LB Hormone 266‑LB Lipotoxicity 337‑LB Oxidation products 172‑LB Human pluripotent stem cells 208‑LB Liraglutide 113‑LB Oxidative stress 338‑LB Hybrid closed loop 99‑LB Liver 179‑LB, 266‑LB Pancreatic islet 342‑LB, 347‑LB Hyperglycemic clamp 253‑LB Liver complications 321‑LB Patient centered medical home 144‑LB Hyperosmolar hyperglycemic state 195‑LB Liver fat 324‑LB Patient engagement 144‑LB Hypertriglyceridemia 37‑LB Lixisenatide 111‑LB Patient level meta-analysis in type two diabetes Hypoglycemia 2‑LB, 3‑LB, 4‑LB, 87‑LB, 90‑LB, Long chain acyl CoA dehydrogenase 41‑LB 91‑LB 136‑LB Long non-coding RNA 259‑LB PCSK9 35‑LB Hypoglycemia associated autonomic failure 1‑LB Lower extremity amputations 187‑LB Pdx1 327‑LB Hypoglycemia cost savings 152‑LB M1 and M2 macrophages 301‑LB Pediatric 156‑LB, 163‑LB, 164‑LB Hypothalamus 54‑LB Macrophage 222‑LB, 306‑LB, 328‑LB Perfluorocarbons 20‑LB Hypoxia 20‑LB Macrophage polarization 216‑LB Persistent organic pollutants 199‑LB iGlarLixi 114‑LB Magnesium 129‑LB Personalized 151‑LB IL 7 218‑LB Magnetic resonance imaging 26‑LB Pharmacist 50‑LB Immunotherapy 218‑LB Mass spectrometry 251‑LB Pharmacodynamics 97‑LB Incident diabetes 180‑LB Mck 276‑LB Pharmacokinetics 97‑LB Incretin 256‑LB Measurement 78‑LB PHD inhibitor 244‑LB Incretin based glucose lowering medications Medicaid 156‑LB Phospholipids 278‑LB, 279‑LB 115‑LB Medical nutrition therapy 61‑LB Physical activity 168‑LB Inflammasome 12‑LB Metabolic assessment 225‑LB Pioglitazone 140‑LB Inflammation 56‑LB, 221‑LB, 236‑LB, 249‑LB, Metabolic effects 271‑LB Pivotal trial 99‑LB 300‑LB Metabolic flux 267‑LB Polycystic ovarian syndrome 322‑LB Inpatient 4‑LB Metabolic syndrome 23‑LB, 173‑LB Polyneuropathy 23‑LB Insight titration algorithm 93‑LB Metabolomics 196‑LB Poorly controlled diabetes 200‑LB, 201‑LB Insulin 98‑LB, 234‑LB, 247‑LB MetAP2 293‑LB Post-prandial blood glucose response 63‑LB Insulin and IGF-1 receptors 231‑LB Metformin 134‑LB, 194‑LB PPAR gamma 2 208‑LB Insulin clearance rate 8‑LB Metreleptin 116‑LB Preconception counseling 51‑LB Insulin degludec 87‑LB, 90‑LB mHealth 68‑LB Prediabetes 316‑LB, 341‑LB Insulin degradation 234‑LB Microislets 339‑LB Predicting type 1 diabetes 206‑LB Insulin gene 206‑LB microRNA 24‑LB Prediction models 186‑LB Insulin Glargine 114‑LB Microvascular 28‑LB, 316‑LB Pregnancy 169‑LB Insulin Glargine 300 U/mL 95‑LB Microvascular complications 31‑LB Prevalence 181‑LB, 189‑LB Insulin like growth factor 1 173‑LB Microvascular events 317‑LB Prevention and control 73‑LB Insulin like growth factor 1 receptor 209‑LB MIN6 345‑LB Progression 204‑LB Insulin like growth factor 2 228‑LB miR-21 346‑LB Proinsulin 251‑LB Insulin lispro 94‑LB miRNAs 340‑LB Prospective study 196‑LB Insulin onset of action 100‑LB Mitochondria 166‑LB, 279‑LB, 334‑LB Psychological factors 74‑LB Insulin receptor 229‑LB, 242‑LB Mitochondrial DNA 55‑LB Psychometrics 66‑LB Insulin resistance 268‑LB, 285‑LB Modulator 123‑LB Quality of life 92‑LB

LB90 Questionnaire validation 70‑LB Sitagliptin 106‑LB, 132‑LB, 214‑LB Treg 215‑LB Rapamycin 228‑LB Skeletal muscle 249‑LB Trends 187‑LB Real world outcomes 117‑LB Slipping slipper sign 22‑LB TRIB3 237‑LB Receptor 230‑LB Smoking 73‑LB Twin pregnancies 167‑LB Red grape cells 60‑LB Social equity 203‑LB Type 1 diabetes 16‑LB, 53‑LB, 105‑LB, 109‑LB, Renal sinus fat 9‑LB Social network 72‑LB 116‑LB, 161‑LB, 164‑LB, 202‑LB, 217‑LB, Reproduction 185‑LB Social stress 270‑LB 290‑LB Reproductive function 157‑LB Sociodemographic factors 143‑LB Type 2 diabetes 18‑LB, 45‑LB, 57‑LB, 86‑LB, Respiration 333‑LB Sodium glucose co-transporter 2 125‑LB, 130‑LB 119‑LB, 159‑LB, 185‑LB, 209‑LB, 212‑LB, Retinal microcirculation 197‑LB Sodium glucose co-transporter 2 inhibitor 129‑LB, 288‑LB, 320‑LB S U BJECT IN DE X Retinal screening 150‑LB 131‑LB, 135‑LB, 137‑LB, 319‑LB Type 2 diabetes and Alzheimer’s Disease 243‑LB Retinopathy 27‑LB, 29‑LB, 31‑LB, 32‑LB Soluble amyloid precursor protein beta 243‑LB Ultra fast-acting insulin 105‑LB Risk reduction 175‑LB Sphingolipids 15‑LB Uridine 262‑LB Risk stratification 150‑LB SREBP 1 211‑LB Urine 21‑LB Risk taking 71‑LB Statin 8‑LB Vaccine 139‑LB RNAseq 21‑LB Stearoyl-CoA desaturase-1 325‑LB Vagus nerve 347‑LB Roux-en-Y gastric bypass 340‑LB Steatohepatitis 264‑LB Variability PK/PD 102‑LB SAR342434 94‑LB Streptozotocin induced diabetes 284‑LB Venous thromboembolism 195‑LB Saroglitazar 37‑LB, 40‑LB Stress 43‑LB Vertical sleeve gastrectomy 282‑LB Screening 30‑LB, 182‑LB Succinate dehydrogenase 41‑LB Veterans 192‑LB Secondary complication 11‑LB Sulfatase 273‑LB Visceral fat 318‑LB, 324‑LB Self-care 147‑LB Survey research 193‑LB Weight loss 312‑LB, 313‑LB Self-management 72‑LB T cell immunology 220‑LB Weight loss surgery 159‑LB Self-monitoring of blood glucose 95‑LB Target HbA1c 186‑LB Weight management 319‑LB Sepsis 153‑LB tDNA 61‑LB Wound dressing 43‑LB Serotonin 342‑LB Technology 46‑LB Wound healing 24‑LB Serum uric acid 263‑LB Telemedicine 32‑LB, 68‑LB Y aminobutyric acid 303‑LB Sex 183‑LB Therapeutic 42‑LB Young children 160‑LB SFRP5 protein 265‑LB Tle3 331‑LB Youth empowering skills 47‑LB Signaling 230‑LB TLR3 219‑LB Zinc a2 glycoprotein 322‑LB Simple titration 88‑LB Transitions 44‑LB

LB91 ABSTRACT Author Index

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

Abd El Aziz, Mirna 115‑LB Auld, Corinth 256‑LB Bhatti, Rahila S. 47‑LB Abderrahmani, Amar 321‑LB Ayuso, Eduard 96‑LB Bian, Lingling 217‑LB Abdulreda, Midhat 343‑LB Azachi, Malkit 60‑LB Biden, Trevor J. 337‑LB Abel, Brent S. 286‑LB Babineaux, Steven M. 186‑LB Billheimer, Dean 36‑LB Abel, E. Dale 245‑LB Baccega, Tania 272‑LB Birnbaum, Yochai 12‑LB Abuaysheh, Sanaa 112‑LB Bacha, Fida 155‑LB Bjerre Knudsen, Lotte 138‑LB Abu-El-Haija, Maisam 224‑LB Backus, Carey 25‑LB Blanc, Evelyn 78‑LB Acharya, Nikhil K. 255‑LB Badia, Rosa M. 212‑LB Block, Bradley 124‑LB Achenbach, Peter 204‑LB Bae, Kwi Hyun 189‑LB Blomster, Hanna 256‑LB Acierno, Ron 69‑LB Baggavalli, Somesh P. 128‑LB Blüher, Matthias 297‑LB Adams, Gregory 280‑LB Bai, Yana 185‑LB Boaz, Mona 60‑LB Adams-Huet, Beverley 116‑LB Baier, Leslie J. 209‑LB Bode, Bruce W. 84‑LB, 99‑LB, 218‑LB Afonso, Milessa Silva 309‑LB Bailey, Timothy S. 81‑LB, 87‑LB, 95‑LB, 99‑LB Bogardus III, Clifton 209‑LB ABSTRACT A U THOR IN DE X Agnew, Thomas P. 295‑LB Bajaj, Mandeep 12‑LB Bokvist, Krister 336‑LB Agoram, Balaji 35‑LB Baker, Nathaniel L. 15‑LB Bolanis, Esther 336‑LB Agrawal, Prabhat Kumar 140‑LB Bakris, George L. 177‑LB Bolli, Geremia B. 91‑LB, 97‑LB Aguilar-Diosdado, Manuel 215‑LB Balicer, Ran 186‑LB Bonàs-Guarch, Sílvia 212‑LB Aharaz, Abdellatif 194‑LB Bandyopadhyay, Gautam 241‑LB Bonaz, Bruno 141‑LB Ahn, Chang Ho 168‑LB Banerjee, Mousumi 23‑LB Bone, Robert N. 216‑LB Ahn, Miwon 211‑LB Bao, Yuqian 92‑LB Booth, Michael 320‑LB Akbar, Arfana 149‑LB Bar-Dayan, Yosefa 60‑LB Booth, Robby 101‑LB, 153‑LB Akella, Lalith 139‑LB Barengolts, Elena 149‑LB Bosch, Fatima 96‑LB, 246‑LB Akriv, Amichay 186‑LB Barquiel, Beatriz 167‑LB Boslem, Ebru 337‑LB Al Asfoor, Shefaa 222‑LB Barquilla García, Alfonso 171‑LB Bottino, Rita 225‑LB Albarado, Diana C. 269‑LB Barshop, Rupert 198‑LB Bouchard, Jonathan 6‑LB Alcaide-Torres, Juan 271‑LB Bartoli, Daniel 55‑LB Boulé, Normand G. 226‑LB Almaca, Joana 342‑LB, 347‑LB Barua, Ankur 61‑LB Bova, Elena V. 176‑LB Aloi, Joseph 152‑LB, 153‑LB Barzilay, Joshua I. 30‑LB Boyko, Edward J. 324‑LB Alonso, G. Todd 164‑LB Bass, Eric 326‑LB Braffett, Barbara H. 157‑LB Altwegg, Romain 141‑LB Bassaganya-Riera, Josep 121‑LB Brandt, Mary 159‑LB Alvarez, Graciela 18‑LB Batra, Manav 112‑LB Brathwaite, Collin E. 294‑LB Amante, Daniel J. 80‑LB Baughman, Robert A. 100‑LB, 102‑LB Brazg, Ron 98‑LB Ambery, Philip 107‑LB Bauman, Janine M. 6‑LB Brazg, Ronald 99‑LB Ambrosi, Thomas H. 298‑LB Baumann, Petra 290‑LB Breton, Marc D. 82‑LB, 103‑LB Ambrosino, Jodie M. 73‑LB Baumeier, Christian 261‑LB Broman, Aimee 344‑LB Amorosa, Louis F. 173‑LB Bautista, Noemi 18‑LB Broman, Karl 344‑LB Ananth, Sudha 10‑LB Bayoumi, Aly Hassan 50‑LB Brown, Janice 33‑LB Andersen, Birgitte 284‑LB Bays, Harold E. 319‑LB Brown, Rebecca J. 286‑LB Andersen, Henning 26‑LB Bazzano, Lydia 198‑LB Browne, Jessica L. 66‑LB Anderson, Barbara J. 71‑LB Beavers, Lisa S. 250‑LB Bruce, David G. 67‑LB Anderson, Pippa 29‑LB Becker, Dorothy J. 51‑LB, 204‑LB Bruce, Kimberley D. 307‑LB Anderson, Scott J. 227‑LB, 331‑LB Becker, Jodie 101‑LB Bruckbauer, Antje 260‑LB Anderson, Stacey 82‑LB, 99‑LB Beck-Nielsen, Henning 194‑LB Bruley des Varannes, Stanislas 141‑LB Andono, Jeselin 62‑LB Beers-Mulroy, Blaire 109‑LB Brunner, Martina 290‑LB Ansah, Eunice Oparebea 188‑LB Beisswenger, Paul J. 5‑LB, 172‑LB Bruno, Elisabeth S. 25‑LB Antebi, Tom 47‑LB Ben Nasr, Moufida 109‑LB Brusko, Todd M. 220‑LB Anthanont, Pimjai 318‑LB Benhamou, Pierre-Yves 141‑LB Bruzzone, Santina 121‑LB Antonacci, Aldana 78‑LB Benite-Ribeiro, Sandra A. 55‑LB Buckingham, Bruce 99‑LB Antunes, Manuel 7‑LB Benninger, Kara S. 336‑LB Bucks, Romola S. 67‑LB Anzola, Isabel 132‑LB Berard, Lori 93‑LB Bucktrout, Samantha L. 218‑LB Ao, Ziliang 329‑LB Bergenstal, Richard 99‑LB Buehrer, Benjamin M. 335‑LB Armian, Haleh 50‑LB Berggren, Per-Olof 342‑LB, 343‑LB Bui, Hai 264‑LB Armour, Sarah L. 227‑LB, 331‑LB Bergman, Richard N. 183‑LB, 255‑LB Bunescu, Razvon 206‑LB Armstrong, David 43‑LB Bergmeier, Stephen 300‑LB Burciu, Camelia 113‑LB Armstrong, Taylor 207‑LB Berishvili, Ekaterine 227‑LB Burgeiro, Ana 7‑LB Arnold, Sue 98‑LB Berkowitz, Theodore S.Z. 200‑LB, 201‑LB Burgess, Shawn C. 267‑LB Aronne, Louis J. 62‑LB Berney, Thierry 227‑LB Burris, Angie 160‑LB Aronson, Ronnie 114‑LB Berria, Rachele 111‑LB Burton, Billy S. 144‑LB Arslanian, Silva A. 157‑LB, 158‑LB, 336‑LB Bertsimas, Dimitris 151‑LB Buse, John B. 326‑LB Arya, Mark 312‑LB Bertuccio, Claudia 18‑LB Bush, Sean P. 330‑LB Ashley, Jason W. 216‑LB Bezy, Olivier 243‑LB Butler, Andrew A. 266‑LB Atkinson, Mark A. 220‑LB Bhamre, Sneha 175‑LB Butler, Deborah A. 163‑LB Attie, Alan 344‑LB Bhargava, Anuj 90‑LB Butterfield, Anthony 264‑LB Augustin, Robert 138‑LB Bhattacharyya, Sumit 273‑LB Byram, Gregory 251‑LB

LB92 Caesar, Emily E. 122‑LB Chellappan Reghuvaran, Anand 41‑LB, 166‑LB Correa-Giannella, Maria L. 21‑LB Cai, Yun 217‑LB Chen, Chu Huang 34‑LB Cortés-Sánchez, Paula 212‑LB Caiazzo, Robert 321‑LB Chen, Heng 217‑LB Corvera, Amanda 49‑LB Caicedo, Alejandro 342‑LB, 343‑LB, 347‑LB Chen, Hongli 243‑LB Coskun, Tamer 308‑LB Calazzo, Robert 141‑LB Chen, Jianmin 11‑LB Coulombe, Benoit 251‑LB Cali, Anna 91‑LB Chen, Keyue 120‑LB Courreges, Maria Cecilia 219‑LB Callaghan, Brian C. 23‑LB Chen, Lin 322‑LB Cowan, Chad 208‑LB, 229‑LB Calle, Alberto 18‑LB Chen, Peili 265‑LB Cox, Jason 280‑LB Callejas, David 96‑LB Chen, Peng 209‑LB Cox, Roger D. 295‑LB Campa, David 150‑LB Chen, Shiuhwei 292‑LB Crowley, Matthew J. 200‑LB, 201‑LB Campbell, James 32‑LB Chen, Shuang 217‑LB Cui, Qiaoli 303‑LB Campbell, Jennifer A. 147‑LB Chen, Wei 198‑LB Cummings, Bethany P. 282‑LB Campodonico-Burnett, William 239‑LB Chen, Wei Yu 34‑LB Cummings, Doyle M. 131‑LB Candeloro, Paola 97‑LB Chen, Wenbiao 328‑LB Curtis, Bradley H. 186‑LB Cannon, Barbara 284‑LB Chen, Yan 86‑LB Cushman, William C. 177‑LB Cannon, Christopher P. 177‑LB Chen, Yang 217‑LB Cutfield, Richard 320‑LB Canouil, Mickael 321‑LB Chen, Yanyun 120‑LB Daddysman, Matthew K. 345‑LB Cao, Marc 293‑LB Chen, Ying 39‑LB, 235‑LB, 280‑LB Dagogo-Jack, Samuel 130‑LB Cao, Wei 330‑LB Chen, Yong 156‑LB Dahmen, Raphael 100‑LB, 102‑LB Cappel, David A. 267‑LB Chen, Yung Tai 174‑LB Dai, Min 185‑LB ABSTRACT A U THOR IN DE X Caprio, Sonia 157‑LB Cheng, John B. 218‑LB Dalgaard, Louise T. 24‑LB Caramori, M. Luiza 13‑LB Cheng, Ning 185‑LB Damm-Frydenberg, Camilla 136‑LB Carbo, Adria 121‑LB Chernavvsky, Daniel R. 82‑LB, 103‑LB Dandona, Paresh 112‑LB Cardona, Guemalli 120‑LB Chesla, Catherine 65‑LB Daneman, Denis 203‑LB Carillo, Juan Jose 264‑LB Cheung, Kitty K.T. 226‑LB Dapoigny, Michel 141‑LB Carls, Ginger S. 117‑LB Chevalier, Soazig 91‑LB D’Aquino, Katharine E. 242‑LB Carlsson, Björn 28‑LB, 316‑LB, 317‑LB Chew, Daniel 288‑LB Darekar, Amanda 130‑LB Carlsson, Lena 28‑LB, 316‑LB, 317‑LB Chima, Ranjit 224‑LB Darsow, Tamara 161‑LB Carmody, David 257‑LB Chiu, Ken C. 179‑LB Das, Rahul 344‑LB Carpinelli, Angelo R. 338‑LB Chiu, Mark L. 242‑LB Davies, Melanie 130‑LB Carreiro, Marina 77‑LB Cho, Nam H. 168‑LB, 178‑LB Davies, Michael J. 129‑LB Carrillo, Juan J. 250‑LB Cho, Young Min 178‑LB Davis, Timothy 67‑LB Carrington, Paul 39‑LB Chodorge, Matthieu 35‑LB Davis, Trent 81‑LB Carroll, Kelley 32‑LB Choi, Sung Hee 168‑LB, 178‑LB Davis, Wendy A. 67‑LB Cartee, Gregory 248‑LB Chong, Yap Seng 197‑LB de la Rosa, Raymond 90‑LB Carvalho, Eugenia 7‑LB, 24‑LB Chou, Hubert S. 119‑LB de Looze, Ferdinandus J. 312‑LB Casana, Estefania 246‑LB Chu, Yvonne 32‑LB DeBoer, Mark 103‑LB Casellas, Alba 246‑LB Chua, Jennifer 49‑LB Deelchand, Dinesh 3‑LB Caspard, Herve 181‑LB Chuang, Lee Ming 179‑LB, 180‑LB DeFronzo, Ralph A. 310‑LB Casper, Anthony 62‑LB Chun, Kevin 65‑LB Deja, Stanislaw 267‑LB Castle, Jessica R. 105‑LB Chung, Choon Hee 124‑LB Delfolie, Astrid 102‑LB Castro, Gisele 305‑LB Church, Tyler 300‑LB Dell, Vanessa 110‑LB Catanozi, Sergio 309‑LB Churchill, Gary 344‑LB Demarest, Keith 79‑LB, 234‑LB, 240‑LB, 242‑LB Cauchi, Stephane 321‑LB Cieniewicz, Anne 240‑LB, 242‑LB Deng, Yingfeng 262‑LB Cavelti-Weder, Claudia 222‑LB Cintra, Dennys E. 309‑LB Deo, Vijaya 175‑LB Cebada-Aleu, Alberto 215‑LB Cinza-Sanjurjo, Sergio 171‑LB Deol, Rupinder 65‑LB Cee-Green, Melanie 134‑LB Cioli, Patrizia 97‑LB Derosa, Giuseppe 130‑LB Cefalu, William T. 124‑LB Clark, Gregory 116‑LB Desai, Mehul 129‑LB Celeste, Anthony 35‑LB Clarke, Antoine B.M. 203‑LB Deuter-Reinhard, Maja 264‑LB Cengiz, Eda 134‑LB Clarke, John G. 84‑LB Devine, Nancy 257‑LB Cercado, Alicia 18‑LB Clarke, Michael 320‑LB Dhaliwal, Noori 45‑LB Cescutti, Jessica 17‑LB Clegg, Deborah J. 183‑LB Dharshi, Anisha S. 161‑LB Cha, Bong Soo 124‑LB Clemente, Romina 78‑LB Díaz, Carlos 212‑LB Chabot, Katherine 251‑LB Clemons, Traci 30‑LB Díaz-Perdigones, Cristina 271‑LB Chagin, Kevin M. 6‑LB Cliff, Phoebe 202‑LB DiCostanza, Sheila 107‑LB Chakkalakal, Rosette J. 170‑LB Clu-Fernández, Carlos 271‑LB Díez Perez, Ma Cruz 171‑LB Chalasani, Naga 118‑LB Coats, Steven 35‑LB Ding, Jiao 185‑LB Chambers, Christina M. 207‑LB Cochran, Elaine 286‑LB Diniz, Susana N. 214‑LB Chan, Juliana C. 19‑LB Coen, Paul M. 340‑LB Dinner, Aaron R. 345‑LB Chan, Lawrence C.B. 330‑LB Coffey, Julie 134‑LB Do, Khoa 54‑LB Chan, Ting Fung 19‑LB Coffin, Benoît 141‑LB Dolan, Larry 159‑LB Chandarana, Keval 88‑LB Cohen, Neale 312‑LB Dong, Fran 207‑LB Chang, Tien Jyun 180‑LB Coín-Aragüez, Leticia 271‑LB Donner, Thomas W. 64‑LB Chao, Jason 95‑LB Collins, Nikki 160‑LB Dopson, Wesley 288‑LB Chao, Jing H. 223‑LB Concepcion, Jr., Nelson 118‑LB Dorval, Etienne 141‑LB Chapman, Simon 47‑LB Conde, Silvia V. 288‑LB Dotzert, Michelle S. 58‑LB Charron-Prochownik, Denise C. 51‑LB Conway, Baqiyyah 20‑LB Dowd, Amy 106‑LB Chaudhary, Kapil 10‑LB Cooper, Jennifer 184‑LB Draney, Carrie 333‑LB Chaudhuri, Ajay 112‑LB Cooper, Mark E. 17‑LB Driver, Emily 109‑LB Chaykin, Louis B. 90‑LB Corkins, Christopher 264‑LB Droz, Brian A. 308‑LB Chee, Winnie S.S. 61‑LB Cornejo-Pareja, Isabel M. 271‑LB Du, Fuyong 240‑LB, 242‑LB

LB93 Duarte, Joao 267‑LB Fonseca, Vivian 198‑LB Gluckman, Peter 197‑LB Ducrotté, Philippe 141‑LB Fontaine, Sébastien 141‑LB Gnana-Prakasam, Jaya P. 10‑LB Dun, Alison 247‑LB Forbes, Angus 47‑LB Goebel, Britta 100‑LB Duncan, Rory R. 247‑LB Forgie, Alison 110‑LB Goetz, Doug 300‑LB Dungan, Kathleen M. 132‑LB Fornoff, Linda 101‑LB Golm, Gregory 125‑LB, 130‑LB Dunstan, Frank D. 29‑LB Forsblom, Carol 16‑LB Gomez, Patricia 132‑LB Duvvuru, Suman 118‑LB Foster, Heather 109‑LB Gonder-Frederick, Linda A. 75‑LB Eberly, Lynn 3‑LB Fouts, Alexandra R. 207‑LB Gong, Yi 322‑LB Eckel, Robert H. 307‑LB Fox, Larry A. 134‑LB González, Santi 212‑LB Edelman, David 200‑LB, 201‑LB Fox, Maura E. 80‑LB Gonzalez, Victor H. 31‑LB Edelman, Steven V. 117‑LB Freitas, Vanessa G. 21‑LB Gonzalo, Montserrat 325‑LB Edmonson, Scott 280‑LB Fretes, Osvaldo 78‑LB Goodpaster, Bret H. 340‑LB Edmundowicz, Steven 326‑LB Frias, Juan 124‑LB, 130‑LB Goodyear, Laurie J. 52‑LB Efanov, Alexander M. 250‑LB Frid, Santiago 78‑LB Gopala, Srinivas 41‑LB, 166‑LB Egede, Leonard E. 46‑LB, 69‑LB, 147‑LB Friesen, Max 229‑LB Gordat, Maud 17‑LB Eiermann, George 280‑LB Fritsche, Andreas 9‑LB Gorden, Phillip 286‑LB Ejskjaer, Niels 26‑LB, 83‑LB Froguel, Philippe 321‑LB Gordillo, Ruth 262‑LB El Ghormli, Laure 155‑LB Frohnert, Brigitte 164‑LB Gorgoglione, Matthew 33‑LB El Ouarrat, Dalila 241‑LB Froy, Oren 60‑LB Gorjão, Renata 214‑LB El Youssef, Joseph 105‑LB Frueh, Chris 69‑LB Gourcerol, Guillaume 141‑LB ABSTRACT A U THOR IN DE X Elasy, Tom A. 170‑LB Frustaci, Mary Ellen 319‑LB Grabman, Jesse H. 75‑LB Elder, Deborah A. 224‑LB Fu, Qi 217‑LB Grandjean, Philippe 199‑LB Eldor, Roy 125‑LB Fu, Xiaorong 267‑LB Grant, Marshall 100‑LB, 102‑LB Elias, Ivet 96‑LB Fujimoto, Wilfred Y. 324‑LB Greeley, Siri Atma W. 154‑LB, 213‑LB, 257‑LB Elofsson, Hampus 256‑LB Fujisaka, Shiho 302‑LB Greenway, Frank 124‑LB Emmerson, Paul J. 308‑LB Funai, Katsuhiko 278‑LB, 279‑LB Gregg, Edward 313‑LB Engel, Samuel S. 125‑LB Fung, Albert 319‑LB Grewal, Gurtej S. 43‑LB Erion, Derek 33‑LB Funk, Deanna R. 226‑LB Griffin, Paul M. 312‑LB Erondu, Ngozi 319‑LB Gabrielsson, Johan 272‑LB Grifoll, Iris 96‑LB Erwin, Patricia J. 72‑LB Gains, T’Keaya L. 232‑LB Grimaud, Jean-Charles 141‑LB Eshghi, Saeed R.T. 226‑LB Galic, Sandra 238‑LB Grimsby, Joseph 35‑LB Eskelinen, Joonas J. 52‑LB Gambardella, Jessica 334‑LB Groleau, Mélanie 93‑LB Espinoza, Daniel 7‑LB Ganguly, Bishu J. 218‑LB Groop, Per-Henrik 16‑LB, 17‑LB Esposito, Virginie 102‑LB Ganz, Tali 60‑LB Grosjean, Philippe 100‑LB Esteves, Brooke 110‑LB Gao, Hong 307‑LB Groth Grunnet, Louise 190‑LB Evans-Molina, Carmella 346‑LB Gao, Leili 23‑LB Grufman, Lisa 256‑LB Evennett, Nicholas 320‑LB Gao, Ying 210‑LB Gu, Haitao 277‑LB Faingold, Maria C. 78‑LB Garcia Fuentes, Eduardo 325‑LB Gu, Lina 108‑LB Fairman, David 35‑LB Garcia, Katelyn R. 313‑LB Gu, Yong 217‑LB Fan, Guo Chang 277‑LB Garcia, Miquel 96‑LB Guadalupe, Mariana 18‑LB Fan, Nengguang 263‑LB Garcia-Serrano, Sara 325‑LB Guarino, Maria P. 288‑LB Fan, Xiaodan 19‑LB Garg, Abhimanyu 116‑LB Gubitosi-Klug, Rose 162‑LB Fanelli, Carmine G. 97‑LB Garg, Manisha 112‑LB Guerci, Bruno 141‑LB Fang, Xiankang 250‑LB Garg, Satish K. 92‑LB, 94‑LB, 99‑LB, 169‑LB Guerrettaz, Lisa 109‑LB Fang, Zhenwei 135‑LB Garibay, Darline 282‑LB Guillén, María A. 167‑LB Farb, Thomas B. 336‑LB Garneau, Pierre 251‑LB Guindo-Martínez, Marta 212‑LB Farias, Ginger 49‑LB Garrett, Valerie 101‑LB Gumbiner, Barry 110‑LB Faubert, Denis 251‑LB Garvey, W. Timothy 237‑LB Gumprecht, Janusz 87‑LB Faucheron, Jean-Luc 141‑LB Garzone, Pamela D. 110‑LB, 218‑LB Gunti, Gowthamraj 128‑LB Feferman, Leo 273‑LB Gastecki, Michelle L. 232‑LB Gupta, Olga T. 160‑LB Feigh, Michael 35‑LB Gautam, Ashish 140‑LB Gupta, Sunil 32‑LB Feldman, Becca 186‑LB Gauthier, Marie Soleil 251‑LB Guralnik, Jack 198‑LB Feldman, Eva 23‑LB, 25‑LB Gazale, Waseem 45‑LB Gurfinkiel, Mirta 78‑LB Fend, Falko 9‑LB Gebregziabher, Mulugeta 147‑LB Gurusamy, Mariappan 10‑LB Feng, Qinghua 18‑LB Geffner, Mitchell 157‑LB Gustat, Jeanette 198‑LB Feng, Wei 179‑LB Genter, Pauline 150‑LB Guth, Lisa M. 56‑LB, 59‑LB Feng, Ying Mei 38‑LB, 323‑LB George, Feba 132‑LB Guthoff, Martina 9‑LB Fenici, Peter 181‑LB Georgopoulos, Lynne 98‑LB Gutierrez-Repiso, Carolina 325‑LB Fernandes, Jyotika 46‑LB Gerety, Gregg 87‑LB Guzman, Cristina B. 118‑LB Fernandez Alonso, Camilo 198‑LB Ghanim, Husam 112‑LB Guzman, Felix 124‑LB Fernandez, Ana 78‑LB Gianchandani, Roma Y. 132‑LB Habegger, Kirk M. 306‑LB Fernandez, Stephen J. 142‑LB Gidding, Sam S. 155‑LB Hadfield, William 47‑LB Ferrara, Patrick J. 278‑LB Gilbert, Richard E. 129‑LB Hadjadj, Samy 141‑LB Ferre, Tura 96‑LB Gilfillan, Christopher 312‑LB Hagay, Yoheved 60‑LB Ferreira, Rita S. 24‑LB GIll, Jasvinder 95‑LB Hajnsek, Martin 290‑LB Ferrer, Jorge 212‑LB Gill, Patricia 76‑LB Hale, Dan 155‑LB Fiorina, Paolo 109‑LB Gillespie, Kathleen M. 204‑LB Hall, Christopher 294‑LB Fisher, Miles 91‑LB Giordano, Dominique 169‑LB Hall, Keneth 294‑LB Flores, Omar 260‑LB Girardet, Clemence 266‑LB Hall, Stephen 312‑LB Florez, Jose C. 212‑LB Giri, Smith 143‑LB, 195‑LB Halladin, Natalie 88‑LB Focht, Kristen 130‑LB Gleisner, John 76‑LB Hallas, Jesper 194‑LB

LB94 Halldorsson, Thorhallur I. 190‑LB Hoang, Vy 238‑LB Jaishy, Bharat 245‑LB Ham, Nina J. 165‑LB Hobbs, Todd M. 6‑LB Jakubowicz, Daniela 60‑LB Hamdouchi, Chafiq 120‑LB Hocher, Berthold 17‑LB Jambrina, Claudia 246‑LB Hamdy, Osama 61‑LB Hodish, Israel 132‑LB James, Merrygay 281‑LB Hames, Kazanna C. 318‑LB Holdych, Janet 145‑LB Jang, Hak C. 168‑LB, 178‑LB Hammad, Samar M. 15‑LB Holinski, Brad 288‑LB Jang, Younghwan 133‑LB Hammar, Niklas 181‑LB Hollander, Priscilla A. 319‑LB Jani, Nisha 187‑LB Hammodat, Hisham 320‑LB Holmes-Truscott, Elizabeth 70‑LB Janssen, Robert 139‑LB Hammond, Craig 264‑LB Holst, Jens Juul 136‑LB Jarolim, Petr 177‑LB Han, Jing 27‑LB Holtzman, David M. 122‑LB Javadi, Pasha 93‑LB Han, Tianshu 191‑LB Hontecillas, Raquel 121‑LB Jayne, Charles 280‑LB Hanaire, Hélène 141‑LB Hornigold, David 35‑LB Jedynasty, Krystyna 94‑LB Hancock, Chad R. 333‑LB Hornung, Lindsey 224‑LB Jenkins, Bonnie 160‑LB Hancock, William D. 216‑LB Horowitz, David A. 44‑LB Jenkins, Todd 159‑LB Handelsman, Yehuda 90‑LB Horowitz, Jeffrey F. 56‑LB, 59‑LB Jenkinson, Lesley 35‑LB Hannon, Tamara S. 134‑LB Horton, Edward S. 313‑LB Jensen, Michael D. 318‑LB Hannukainen, Jarna C. 52‑LB Hoshen, Moshe 186‑LB Jeong, Yoo Mi 85‑LB Hansen, Charlotte T. 87‑LB Hou, Yonyyong 211‑LB Jermutus, Lutz 107‑LB Hansen, Susanne 190‑LB Houlind, Kim 83‑LB Ji, Jiachao 92‑LB Hanson, Robert L. 209‑LB Howard, Andrew 252‑LB Ji, Li 217‑LB ABSTRACT A U THOR IN DE X Hardee, Sandra 4‑LB Howell, Scott K. 5‑LB, 172‑LB Ji, Linong 23‑LB, 92‑LB Hardman, Jeremy M. 333‑LB Howles, Philip 285‑LB Jia, Weiping 92‑LB Hardy, Thomas A. 118‑LB Hsu, Tzu Yu 34‑LB Jiang, Dongdong 303‑LB Hargett, Stefan 274‑LB Hu, Charlie Changzhi 120‑LB Jiang, Guozhi 19‑LB Häring, Hans Ulrich 9‑LB Hu, Frank B. 196‑LB Jiang, Mao 58‑LB Harjutsalo, Valma 16‑LB Hu, Qiong 268‑LB Jideonwo, Victoria N. 211‑LB Harlan, David M. 80‑LB Hu, Xiaobin 185‑LB Jimenez, Veronica 96‑LB, 246‑LB Haro, Heidi 207‑LB Hu, Zhibin 196‑LB Jimenez-Vega, Jose 224‑LB Harper, Wayne L. 124‑LB Huang, Elbert S. 184‑LB Jin, Tianru 301‑LB Harris, Stewart B. 88‑LB, 93‑LB Huang, Hu 54‑LB Joers, James 3‑LB Harrison, Karen 145‑LB Huang, Jingqi 299‑LB Joh, Tenshang 110‑LB, 218‑LB Hart, Matthew 304‑LB Huang, Po Hsun 174‑LB Johnson, Dana 240‑LB, 242‑LB Harville, Emily 198‑LB Huang, Yu 19‑LB Johnson, Jeremy 125‑LB, 130‑LB Hashemi, Nasseh 83‑LB Huang, Zheng 293‑LB Johnson, Jordan M. 278‑LB, 279‑LB Hass, Michael 253‑LB Huang, Zhijiang 292‑LB Johnson, Karen C. 313‑LB Hatab, Sarah 165‑LB Huard, Kim 33‑LB Jonas, Jean-Christophe 338‑LB Hatipoglu, Betul A. 225‑LB Hudak, Carolyn 229‑LB Jones, Bronwen 320‑LB Haurigot, Virginia 96‑LB Huffard, Adrian 221‑LB Jones, Jessica 33‑LB Hayashi, Tomoshige 324‑LB Hughes, Thomas 312‑LB, 315‑LB Jones, Marie 47‑LB Hayes, Heather L. 335‑LB Hui, Queenie 329‑LB Jose, Anju 132‑LB Hayes, John M. 25‑LB Hulme, Maigan A. 220‑LB Joshee, Prakriti 169‑LB Haymond, Mory 159‑LB Hulver, Matthew W. 266‑LB, 274‑LB Joshi, Shashank R. 40‑LB Hazen, Rebecca 162‑LB Hummer, Tim 35‑LB Jung, Chang Hee 133‑LB Hazra, Daya Kishore 140‑LB Hunt, Kelly J. 15‑LB Just, Rasmus 283‑LB He, Jie 185‑LB Hunt, Sharon 146‑LB Kadaria, Dipen 143‑LB, 195‑LB He, Kan 210‑LB Hussain, Azad 198‑LB Kahl, Steven D. 120‑LB He, Xuanyao 186‑LB Hussein, Zanariah 61‑LB Kahle, Melanie 115‑LB Heden, Timothy D. 278‑LB, 279‑LB Hutchison, Alan L. 345‑LB Kahn, Barbara B. 254‑LB Hedgepeth, John 269‑LB Huyck, Susan 125‑LB Kalliokoski, Kari K. 52‑LB Heise, Tim 100‑LB Huynh, Johnny 117‑LB Kallus, Nathan 151‑LB Hejna, Jeanne 112‑LB Huynh, Toan 345‑LB Kammel, Anne 261‑LB Hekmat, Omid 251‑LB Hyde, Craig L. 243‑LB Kamon, Junji 123‑LB Henderson, Amy 101‑LB, 152‑LB, 153‑LB Iaccarino, Guido 334‑LB Kanasaki, Keizo 17‑LB Henriksen, Daniel P. 194‑LB Igel, Leon 62‑LB Kang, Liya 243‑LB Henry, PIerre-Gilles 3‑LB Ignotz, Keith 148‑LB Kang, Minsung 237‑LB Heptulla, Rubina 106‑LB Ilany, Jacob 99‑LB Kaplan, Lee M. 326‑LB Hernández-García, Carmen 271‑LB Imershein, Sarah G. 50‑LB Karasseva, Natalia 232‑LB Herold, Kevan C. 218‑LB Inagaki, Nobuya 119‑LB Kariyawasam, Dulmini 47‑LB Herranz, Lucrecia 167‑LB Inge, Thomas H. 159‑LB Karnatak, Rajendra K. 10‑LB Hesse, Deike 276‑LB Ipp, Eli 150‑LB Karnchanasorn, Rudruidee 179‑LB Hetrick, Byron 221‑LB, 239‑LB Ito, Yusuke 123‑LB Karpati, Tomas 186‑LB Heyward, Bill 139‑LB Jabbour, Serge A. 88‑LB Karter, Andrew J. 184‑LB Higuchi, Takahiro 291‑LB Jackson, Charles Van 308‑LB Karunakaran, Jayakumar 41‑LB, 166‑LB Hijazi, Youssef 100‑LB, 102‑LB Jackson, George L. 200‑LB, 201‑LB Kaspers, Stefan 126‑LB, 127‑LB Hikita, Yonezo 324‑LB Jackson, LaDonya 206‑LB Katikaneni, Ranjitha 106‑LB Hinder, Lucy M. 25‑LB Jackson, Penny 47‑LB Kattan, Michael W. 6‑LB Hinke, Simon A. 240‑LB, 242‑LB Jackson, Sam 139‑LB Katz, Lorraine E.L. 155‑LB Hiraki, Linda T. 13‑LB Jackson, Sandra 182‑LB Katz, Michelle L. 163‑LB Hirano, Michio 334‑LB Jacobs, Peter G. 105‑LB Kaufman, Francine R. 99‑LB Hoag, Tom 145‑LB Jacome-Sosa, Miriam 268‑LB Kavanagh, Deirdre M. 247‑LB Hoang, Linda 49‑LB Jaen, Maria L. 96‑LB Keating, Patricia 326‑LB

LB95 Keles, Sunduz 344‑LB Kusters, Dennis 11‑LB Li, Haidong 86‑LB Keller, Mark 344‑LB Kusunoki, Masataka 137‑LB Li, Haiyan 185‑LB Keller, Susanna 274‑LB Kvist, Kajsa 90‑LB Li, Hung Yuan 180‑LB Kelly-Boruff, Kathleen M. 118‑LB Kwak, Soo Heon 168‑LB Li, Jie 191‑LB Kelsey, Megan M. 157‑LB Kwek, Kenneth 197‑LB Li, Juansheng 185‑LB Kemppainen, Jukka 52‑LB Laber, Samantha 295‑LB Li, Ling Jun 197‑LB Kendall, Heather 145‑LB Lacampagne, Alain 334‑LB Li, Wen Hong 292‑LB Kener, Kyle B. 333‑LB Lackey, Denise 241‑LB Li, Xian 92‑LB Keselowsky, Benjamin 220‑LB Lacy, Eilyn R. 242‑LB Li, Xiaoming 285‑LB Keske, Michelle A. 57‑LB Laeger, Thomas 261‑LB, 269‑LB, 276‑LB Li, Yang 293‑LB Khakharia, Anjali 192‑LB Laffel, Lori M. 159‑LB, 163‑LB Li, Yiming 265‑LB Khanna, Deepika 149‑LB Lai, Chin Hu 34‑LB Li, Ying 191‑LB Khripun, Irina A. 176‑LB Lai, Kevin 109‑LB Li, Yufeng 23‑LB Khunti, Kamlesh 202‑LB Laing, Brenton T. 54‑LB Li, Yutian 277‑LB Kihm, Anthony 240‑LB, 242‑LB Laiteerapong, Neda 184‑LB Li, Zhuo 210‑LB Kilcharan Singh, Harvinder 61‑LB Lakhter, Alexander J. 346‑LB Liang, Feng 299‑LB Kim, Byung Joon 124‑LB Lamb, Stephanie 47‑LB Liang, Yin 79‑LB, 240‑LB, 242‑LB Kim, David 320‑LB Lamoureux, Ecosse 197‑LB Liao, Chen Di 13‑LB Kim, Dennis 312‑LB, 315‑LB Lan, Hui Yao 19‑LB Libby, Andrew 307‑LB Kim, Jae Hyeon 133‑LB Landau, Zohar 60‑LB Libman De Gordon, Ingrid B. 134‑LB, 204‑LB ABSTRACT A U THOR IN DE X Kim, Kook Hwan 289‑LB Lane, Wendy S. 87‑LB Lieberman, Gabriella 310‑LB Kim, Kyoung Min 168‑LB, 178‑LB Lang, Jia Nan 38‑LB Lilleøre, Søren K. 310‑LB Kim, Lee Kyung 178‑LB Lariosa, Samanta 149‑LB Lim, Cadmon K. 19‑LB Kim, Seong Hun 289‑LB Lark, Daniel 281‑LB Lim, Soo 168‑LB, 178‑LB Kim, Sin Gon 124‑LB Larsen, Jane 138‑LB Lin, Chien Te 278‑LB Kim, Sun H. 8‑LB Lassen, Annmarie T. 194‑LB Lin, Hua V. 250‑LB Kim, Sung Woo 189‑LB Lathkar-Pradhan, Sangeeta 132‑LB Lin, James 179‑LB Kim, Sungho 133‑LB Lau, Raymond G. 294‑LB Lin, Shing Jong 174‑LB Kim, Terri 314‑LB Lauring, Brett 125‑LB Lin, Tom 224‑LB Kirchner, Thomas 240‑LB, 242‑LB Lauterbach, B. 148‑LB Lin, Yu Kuei 225‑LB Kirk, Rikke 138‑LB Lavallette, Lucille 264‑LB Lindauer, Katherine 154‑LB Kirkland, Melissa 280‑LB Lavrador, Maria Silvia 309‑LB Lineswala, Jayana P. 120‑LB Klammt, Sebastian 107‑LB Le, Nhan 268‑LB Lingham, Russell 240‑LB, 242‑LB Klein, Richard L. 15‑LB Le, Thuy 109‑LB Lithovius, Raija 16‑LB Kleinman, Nora J. 68‑LB Leal, Ermelindo C. 24‑LB Little, Stuart A. 70‑LB Klingensmith, Georgeanna J. 207‑LB Lee, An Sheng 34‑LB Liu, En 322‑LB Klonoff, David 83‑LB Lee, Byung Wan 133‑LB Liu, Feng 304‑LB Klöting, Nora 297‑LB Lee, Charles 35‑LB Liu, Franklin 236‑LB Knapp, Rebecca G. 69‑LB Lee, Dong Hwa 178‑LB Liu, Jianying 234‑LB Knapp, Rebecca R. 46‑LB Lee, Heung Man 19‑LB Liu, Jin 217‑LB Knocke, Maria 291‑LB Lee, Jennifer 254‑LB Liu, Qian 293‑LB Knowler, William C. 209‑LB Lee, Kwan Woo 124‑LB Liu, Qing 292‑LB Kobes, Sayuko 209‑LB Lee, Moon Kyu 124‑LB Liu, Rui 303‑LB Kocalis, Heidi 275‑LB Lee, Myung Shik 289‑LB Liu, Simin 185‑LB, 191‑LB Kocsis, Gyozo 88‑LB Lee, Scott 99‑LB Liu, Wenjuan 303‑LB Koenigsrainer, Alfred 9‑LB Lee, Seon 282‑LB Liu, Xiaobing 237‑LB Kohler, Sven 126‑LB, 127‑LB Lee, Seung Hwan 124‑LB, 133‑LB Liu, Xilin 293‑LB Koike, Marcia 309‑LB Lee, Seunghun P. 234‑LB Liu, Xin 322‑LB Koitka-Weber, Audrey 17‑LB Lee, Sojung 158‑LB Liu, Yujia 210‑LB Kollar, Laura 82‑LB Lee, Tom 109‑LB Llisterri Caro, José Luis 171‑LB Kong, Alice P. 19‑LB Lee, Verna 61‑LB Lo, Chunmin 253‑LB Kong, Sheldon X. 6‑LB Lee, Woo Je 133‑LB Lockwood, John 264‑LB Konkar, Anish 35‑LB Lee, Yun Sok 244‑LB Lok, Si 19‑LB Koska, Juraj 36‑LB, 113‑LB Lei, Helena 301‑LB Long, Anna E. 204‑LB Kovacs, Peter 297‑LB Lei, Lanyu 177‑LB Long, Qi 182‑LB Kovatchev, Boris P. 82‑LB, 103‑LB, 114‑LB Leibel, Natasha 155‑LB, 159‑LB Long, Tao 322‑LB Kramer, Michael 197‑LB Leibrand, Scott M. 104‑LB Longenecker, Sarah 64‑LB Kramer, William 98‑LB Lemoine, Lori M. 45‑LB Lopes-Virella, Maria F. 15‑LB Krastins, Bryan 251‑LB Leon, Xavier 96‑LB, 246‑LB Lopez, Lizette 113‑LB Kraus, Bettina J. 291‑LB Lerario, Antonio M. 21‑LB Lopez, Mary F. 251‑LB Krishna Reddy, Harsha 128‑LB Leroy, Bruno 91‑LB Lottenberg, Ana Maria 309‑LB Krohn, Knut 297‑LB Lessem, Sarah 193‑LB Loureiro, Marisa 7‑LB Kroon, Tobias 272‑LB Letourneau, Lisa 213‑LB, 257‑LB Lu, Jiahui 322‑LB Kubisiak, Kristine 3‑LB Leventer-Roberts, Maya 186‑LB Lu, Juming 108‑LB Kuhadiya, Nitesh D. 112‑LB Levisetti, Matteo 218‑LB Lu, Mingjian 293‑LB Kumar, Anjali 3‑LB Levitsky, Lynne 157‑LB Lu, Yang 150‑LB Kumar, Rekha 62‑LB Lewis, Anjana Patel 120‑LB Lucidi, Paola 97‑LB Kumar, Sunil 294‑LB Lewis, Cora E. 313‑LB Luk, Andrea O. 19‑LB Kuo, Chin Sung 174‑LB Lewis, Dana M. 104‑LB Lund, Søren 127‑LB Kuo, Ming Shang 264‑LB Lewis, Jamal 220‑LB Lundequist, Anders 256‑LB Kupfer, Stuart 177‑LB Li, Dandan 135‑LB Luo, Xie 304‑LB

LB96 Lutchmansingh, Khama 22‑LB Mayoral, Rafael 235‑LB Morrison, Christopher D. 269‑LB Luzio, Stephen D. 29‑LB McCall, Kelly 206‑LB, 219‑LB, 300‑LB Morró, Meritxell 246‑LB Lv, Dayu 82‑LB McCurdy, Carrie 221‑LB, 239‑LB Morrow, David A. 177‑LB Lv, Tiantian 27‑LB McDonald, Matthew W. 58‑LB Morton, Gregory J. 255‑LB Lv, You 210‑LB McFarland, Raymie 101‑LB, 152‑LB, 153‑LB Mosely, Kylie 66‑LB Lynch, Cheryl P. 147‑LB McGavigan, Anne K. 282‑LB Motiani, Kumail K. 52‑LB Ma, Ronald C. 19‑LB McGee, James 264‑LB Motiani, Piryanka 52‑LB Ma, Wei 323‑LB McGill, Janet B. 218‑LB Mudgett, John 252‑LB Ma, Xiaosu 120‑LB McGill, Margaret J. 53‑LB Muir, Andrew B. 165‑LB Ma, Yan 323‑LB McKay, Siripoom V. 157‑LB Muller, Yunhua 209‑LB Ma, Yunbing 1‑LB McMaster, Christopher 42‑LB Mullin, Christopher 326‑LB Mabus, John 240‑LB, 242‑LB McMillan, Ryan 266‑LB, 274‑LB Muniyappa, Ranganath 286‑LB Macauley, Shannon L. 122‑LB McMullen, William J. 163‑LB Muñoz, Sergio 96‑LB Macdonald, Jennifer 132‑LB Meah, Farah 336‑LB Muñoz-Garach, Araceli 271‑LB Machado, Ubiratan F. 21‑LB Mechanick, Jeffrey I. 61‑LB Murillo Jelsbak, Cristina 171‑LB Machann, Jürgen 9‑LB Meier, Juris J. 115‑LB Murphy, Rinki 320‑LB Macias, Johana 150‑LB Meinicke, Thomas 17‑LB Murray, Michael R. 58‑LB MacKenzie, Marsha 160‑LB Melling, C.W. James 58‑LB Musso, Carla 78‑LB MacLeish, Sarah 162‑LB Melo, Bernardete F. 288‑LB Muta, Kenjiro 255‑LB Madanahalli, Jagannath R. 128‑LB Men, Lichuang 108‑LB Mynatt, Randall L. 266‑LB ABSTRACT A U THOR IN DE X Maddison, Lisette A. 328‑LB Menaged, Miriam 60‑LB Nadalin, Silvio 9‑LB Mader, Julia K. 290‑LB Mende, Christian 129‑LB Nadeau, Kristen J. 134‑LB, 155‑LB Madsbad, Sten 136‑LB, 310‑LB Mendes, Natália Ferreira 305‑LB Nair, Anup K. 209‑LB Magee, Matthew J. 182‑LB Menegaz, Danusa 342‑LB Naito, Takeshi 123‑LB Magee, Michelle F. 142‑LB Meo Guzman, Natalia 78‑LB Najafi, Bijan 43‑LB Maggioni, Luca 96‑LB Mercader, Josep M. 212‑LB Nakagawa, Takashi 302‑LB Mahan, Thomas E. 122‑LB Messner, Simon 339‑LB Nakamura, Katherine 169‑LB Maher, Danielle 76‑LB Mete, Mihriye 142‑LB Nakamura, Takao 137‑LB Maheshwari, Anuj 37‑LB Metro, Sarah 219‑LB Nakandakare, Edna 309‑LB Mahmud, Farid H. 203‑LB Metzger, Daniel 280‑LB Nakatsuka, Yasuhiko 119‑LB Mai, Tingting 322‑LB Miao, Shouwu 280‑LB Nanjunda, Rupesh K. 242‑LB Maier, Bernhard F. 346‑LB Michael, Mervyn D. 282‑LB, 308‑LB Narendran, Parth 202‑LB Makdissi, Antoine 112‑LB Middelbeek, Roeland J.W. 52‑LB Narowski, Tara M. 278‑LB, 279‑LB Makhmutova, Madina 342‑LB, 347‑LB Miguel-Escalada, Irene 212‑LB Nasr, Alexis 158‑LB Makinen, Ville-Petteri 16‑LB Milinovich, Alex 6‑LB Nassar, Carine M. 142‑LB Malatesta, JoAnn 98‑LB Miller, Kellee M. 134‑LB Nathan, Brandon 134‑LB Malgor, Ramiro 300‑LB Milligan, Paul 264‑LB Nathan, Jaimie 224‑LB Mallappa, Onkaramurthy 128‑LB Min, Eun J. 182‑LB Nathow, Thomas 312‑LB Mallol, Cristina 246‑LB Min, Kathryn M. 73‑LB Natsume, Yukie 137‑LB Malloy, Jaret 312‑LB, 314‑LB, 315‑LB Minokoshi, Yasuhiko 270‑LB Nauck, Michael A. 115‑LB Malomo, Kenneth 326‑LB Mion, François 141‑LB Nawroth, Peter 9‑LB Mammen, Anup O. 128‑LB Mireles, Vidal T. 63‑LB Naylor, Jacqui 35‑LB Man, Ryan 197‑LB Mirmira, Raghavendra G. 336‑LB, 346‑LB Naylor, Rochelle N. 154‑LB, 213‑LB, 257‑LB Manandhar, Smriti 143‑LB, 195‑LB Mishra, Shardendu 148‑LB Nedelkov, Dobrin 36‑LB Mancha-Doblas, Isabel 271‑LB Mishriky, Basem M. 131‑LB Nedergaard, Jan 284‑LB Mancuso, James 125‑LB Mogensen, Sofia 256‑LB Neelakandhan, Aparna 339‑LB Mandalapu, Rathna 162‑LB Mohan, Madhu K. 30‑LB Nelson, Alexander 216‑LB Manrique, Camila M. 268‑LB Mohd Ali, Siti Zubaidah 61‑LB Nelson, Andrew N. 254‑LB Manseau, Katherine 207‑LB Moheet, Amir 3‑LB Nelson, Jarrell T. 255‑LB Marcus, Marsha 159‑LB Molano, Damaris Ruth 343‑LB Nelson, Jennifer B. 336‑LB Marie, Suely Kazue 21‑LB Molina, Cesar 175‑LB Nelson, Randall 36‑LB Marikunte, Venkataranganna V. 128‑LB Molina, Judith T. 342‑LB Neufer, P. Darrell 278‑LB Marinelli Andreoli, Anna 97‑LB Molina-Vega, María 271‑LB Nickels, J. Zachary 58‑LB Marks, Andrew 334‑LB Molyneaux, Lynda 53‑LB Nielsen, Thor S.S. 87‑LB Marling, Cindy 206‑LB Monteiro, Maria B. 21‑LB Nikonova, Elena 95‑LB, 111‑LB Marshall, Helen 227‑LB Montgomery, Jazzmyne 154‑LB Nirantharakumar, Krishnarajah 202‑LB Martin, Megan T. 161‑LB Montiel-Casado, Custodia 325‑LB Niswender, Kevin 275‑LB Martin, Tonya 234‑LB Montori, Victor M. 72‑LB Noble, Earl G. 58‑LB Martín-Núñez, Gracia M. 325‑LB Montrose-Rafizadeh, Chahrzad 120‑LB Nolan, Charles E. 243‑LB Martyn-Nemeth, Pamela 74‑LB Moolemath, Yoganand 128‑LB Nørgaard, Kirsten 136‑LB Marwick, Thomas H. 57‑LB Moon, Jae Hoon 168‑LB, 178‑LB Norquay, Lisa 234‑LB Maryniuk, Melinda D. 50‑LB Moon, Min Kyong 124‑LB Norwood, Paul 90‑LB Marzban, Lucy 329‑LB Mora-Navas, Laura 271‑LB Nunes, Valéria Sutti 309‑LB Maslova, Ekaterina 190‑LB Morcillo, Sonsoles 325‑LB Nunez Lopez, Yury O. 340‑LB, 341‑LB Mather, Kieren J. 336‑LB More, Vijay 39‑LB Nuutila, Pirjo 52‑LB Mathieu, Nicolas 141‑LB Moreli, Marcos L. 55‑LB Oakes, Nicholas D. 272‑LB Mathur, Ashish 175‑LB Moreno-Ruiz, Francisco J. 325‑LB Obici, Silvana 253‑LB Matsen, Miles E. 255‑LB Morgan, Claire C. 212‑LB O’Brien, Phillipe D. 25‑LB Matsubara, Tomoko 54‑LB Morin, Robert 81‑LB Odugbesan, Ola 95‑LB Mauer, S. Michael 13‑LB Moritz, Wolfgang 339‑LB Oh, Tae Jung 168‑LB, 178‑LB Maynard, Greg 145‑LB Morral, Nuria 211‑LB Okabe, Keisuke 302‑LB

LB97 Okamoto, Shiki 270‑LB Phillips, Lawrence S. 182‑LB, 192‑LB Ray, Jason D. 333‑LB Olateju, Tolulope O. 226‑LB Piaggi, Paolo 209‑LB Raynel, Sarah 109‑LB Oldfield, Geoffrey S. 312‑LB Pickov, Victor 288‑LB Raz, Itamar 186‑LB Olefsky, Jerrold M. 241‑LB, 244‑LB Pieber, Thomas R. 290‑LB Razjouyan, Javad 43‑LB Oliveira, Denise 55‑LB Pierre, Suzanne 94‑LB Reaume, Andrew G. 124‑LB Olsen, Sjurdur F. 190‑LB Pileggi, Antonello 343‑LB Reaven, Gerald M. 8‑LB O’Neal, David N. 312‑LB Pinheiro, Marcelo M. 214‑LB Reaven, Peter D. 5‑LB, 36‑LB, 113‑LB, 172‑LB Osei, Kwame 132‑LB Piotrowicz, Agata K. 53‑LB Reddivari, Bharathi 149‑LB, 149‑LB Oshida, Yoshiharu 137‑LB Pi-Sunyer, Xavier 313‑LB Reddy, Ravi 105‑LB Otto, Keith A. 120‑LB Pittas, Anastassios G. 341‑LB Reed, Brian 32‑LB Ou, Horng Yih 179‑LB Planas-Fèlix, Mercè 212‑LB Rees, Jordan 226‑LB Overland, Jane 53‑LB Plank, Lindsay 320‑LB Reges, Orna 186‑LB Overton, Rahsaan R. 182‑LB Plum-Morschel, Leona 102‑LB Reid, Timothy 95‑LB Owens, David R. 29‑LB Plutzky, Jorge 111‑LB Reifel Miller, Anne 120‑LB Oz, Gulin 3‑LB Pocai, Alessandro 234‑LB Ren, Decheng 327‑LB Padilla, Jaume 232‑LB Pogach, Leonard 187‑LB Ren, Xiaowei 185‑LB Paez, Vivien Camille 74‑LB Pollock, Benjamin 198‑LB Renn, Martha H. 345‑LB Palaia, Thomas 294‑LB Polonsky, Kenneth S. 327‑LB Resalat, Navid 105‑LB Palermo, Joseph 224‑LB Polonsky, William H. 117‑LB Reutelingsperger, Chris 11‑LB Palyha, Oksana 235‑LB, 252‑LB, 280‑LB Polsky, Sarit 169‑LB Revelo, Xavier 301‑LB ABSTRACT A U THOR IN DE X Pan, An 196‑LB Ponce, Oscar J. 72‑LB Rewers, Marian 204‑LB Pang, Zhen 79‑LB Porcellati, Francesca 97‑LB Rey Aldana, Daniel 171‑LB Pantalone, Kevin M. 6‑LB Pottegaard, Anton 194‑LB Reynolds, Evan 23‑LB Pardo, Scott 81‑LB Pouderoux, Philippe 141‑LB Reynolds, Merrick S. 333‑LB Park, Chang 85‑LB Poulsen, Per L. 26‑LB Rezner, Betsy 109‑LB Park, Cheol Young 133‑LB Powell, Folami L. 10‑LB Rhee, Mary 182‑LB Park, Hanjong 85‑LB Pownall, Henry J. 313‑LB Rhee, Sang Youl 124‑LB Park, Hyeong Kyu 124‑LB Pozzi, Ambra 281‑LB Ribeiro-Oliveira, Antonio 77‑LB Park, Kyong Soo 168‑LB, 178‑LB Prada, Patricia O. 305‑LB Riccardi, Keith 33‑LB Park, Se Eun 133‑LB Prager, Rudolf 88‑LB Rice, Karen 45‑LB Park, Yoo Jin 329‑LB Prakash, Prashant 140‑LB Rickman, Colin 247‑LB Parks, Elizabeth J. 268‑LB Pratley, Richard E. 125‑LB, 341‑LB Ricordi, Camilo 343‑LB Parone, Philippe A. 109‑LB Pratt, Edward John 120‑LB Riddle, Matthew C. 91‑LB Pasquel, Francisco 132‑LB Preiser, Nick 105‑LB Rideout, Drew 294‑LB Passarelli, Marisa 21‑LB Previs, Stephen 39‑LB, 235‑LB, 280‑LB Ridge, Terry 88‑LB Patek, Stephen 82‑LB Price, Olga 280‑LB Ringgaard, Steffen 26‑LB Patel, Dhiren 144-LB Proietto, Joseph 312‑LB, 314‑LB, 315‑LB Riopel, Matthew 241‑LB, 244‑LB Patel, Jaimy 173‑LB Pu, Hongquan 185‑LB Ritzén, Hanna 256‑LB Patel, Raj 149‑LB Pu, Wenji 107‑LB Robbins, Dave 109‑LB Patel, Rajesh 39‑LB Puffing, Adelheid 290‑LB Roberts, Adam 312‑LB Patel, Sonal 288‑LB Purvis, Gareth S.D. 11‑LB Robic, Jessica 82‑LB, 103‑LB Paterson, Andrew D. 13‑LB Pyle, Laura 164‑LB Robinson, Ali 288‑LB Patricio, Miguel 7‑LB Qi, Jenson 234‑LB Robinson, Steven 320‑LB Patton, Ashley 300‑LB Qian, Jinqiao 12‑LB Robshaw, Ashley 243‑LB Pattou, François 321‑LB Qian, Ying 39‑LB Roca-Rodríguez, M. Mar 271‑LB Paul, Pradyut 344‑LB Qian, Yuewei 264‑LB Rodgers Fischl, Andrea 51‑LB Payne, Elizabeth H. 69‑LB Qiao, Jiqiu 79‑LB Rodo, Jordi 96‑LB Pecik, Ilonka 291‑LB Qiao, Wei 79‑LB Rodriguez-Cañete, Alberto 325‑LB Pehmoller, Christian 243‑LB Qiu, Gaokun 196‑LB Rodriguez-Diaz, Rayner 343‑LB, 347‑LB Peltonen, Markku 28‑LB, 316‑LB, 317‑LB Qiu, Yanping 125‑LB Rodríguez-Fos, Elias 212‑LB Pence, Sydney 253‑LB Queiroz, Marcia S. 21‑LB Rodriguez-Gutierrez, Rene 72‑LB Pender, Shiobhan 47‑LB Quinn, Lauretta T. 74‑LB Rodriguez-Pacheco, Francisca 325‑LB Penfornis, Alfred 141‑LB Quinn, Laurie 85‑LB Rogers, Suzanne 238‑LB Peng, Yongde 263‑LB Quintana-Lopez, Laura 215‑LB Rohm, Theresa 222‑LB Perfield, James 264‑LB Quittner, Claudia 116‑LB Rojeski, Maria 94‑LB Perkinson, Robert 240‑LB, 242‑LB Rabaglia, Mary 344‑LB Rolin, Bidda 138‑LB Perkovic, Vlado 17‑LB Rabasa-Lhoret, Remi 251‑LB Roma, Leticia P. 338‑LB Peroni, Odile 254‑LB Radwan, Amr 18‑LB Rondinone, Cristina 35‑LB, 107‑LB Perrin, Laurent 100‑LB Ragolia, Louis 294‑LB Ropert, Alain 141‑LB Pers, Tune 212‑LB Rajappan, Anoopraj 128‑LB Rosenfarb, Johanna 78‑LB Peter, Rajesh 29‑LB Rakipovski, Günaj 138‑LB Rosenstock, Julio 124‑LB, 319‑LB Peterson, Richard G. 308‑LB Ramanadham, Sasanka M. 216‑LB Rosmarin, Melanie 78‑LB Petit, Catherine 141‑LB Ramnarain, Nishan 288‑LB Rothenberg, Richard B. 192‑LB Petrone, Marcella 107‑LB Ranjan, Ajenthen 136‑LB Rothermel, Caitlin 4‑LB Petrov, Aleksandr 235‑LB, 252‑LB Ranjan, Saurabh 10‑LB Ruan, Hai Bin 258‑LB Pfefferkorn, Jeffrey 33‑LB Rankin, Matthew M. 234‑LB Ruan, Xiangbo 259‑LB Pham, Mirko 26‑LB Rao, Ambika 22‑LB Rubin, Daniel J. 132‑LB Phatak, Sanjeev 68‑LB Rasulnia, Mazi 144‑LB Rubin, Gil 186‑LB Philipson, Louis H. 154‑LB, 213‑LB, 257‑LB, 345‑LB Rath, Michaela 276‑LB Ruiz, Rafaela 211‑LB Philipson, Noah 121‑LB Raun, Kirsten 284‑LB Rumpler, Markus 290‑LB Philis-Tsimikas, Athena 87‑LB Ravikumar Jayakumari, Nandini 41‑LB, 166‑LB Ryan, Terence E. 278‑LB

LB98 Saad, Mário José Abdala 305‑LB Sen Ten, En 149‑LB Song, Wei 287‑LB Sabate, Jean-Marc 141‑LB Seng, Thomas 264‑LB Song, Yiqing 135‑LB Saboo, Banshi 37‑LB, 40‑LB Senior, Peter 226‑LB Song, Zhuolun 301‑LB Sabouri, Mohsen 109‑LB Senne-Duff, Beth C. 63‑LB Sørensen, Anja E. 24‑LB Sacks, Harold Scott 232‑LB Sereika, Susan M. 51‑LB Soroka, Orysya 187‑LB Sacramento, Joana F. 288‑LB Serpas, Lilian 150‑LB Sound, Ruby 40‑LB Sacre, Julian W. 57‑LB Seyhan, Attila 340‑LB, 341‑LB Sourij, Harald 290‑LB Sacristan, Victor 246‑LB Sforza, Noelia 78‑LB Souza, Arnaldo H. 338‑LB Safikhan, Nooshin 329‑LB Sha, Sue 129‑LB Speight, Jane 66‑LB, 70‑LB Safo, Sandra E. 182‑LB Shah, Amy S. 155‑LB Spencer Bonilla, Gabriela 72‑LB Saghatelian, Alan 254‑LB Shah, Avani 68‑LB Sprague, Jennifer 157‑LB Sahaf, Newsha 109‑LB Shah, Rachana 157‑LB Stager, William 111‑LB, 114‑LB Sakurada, Brian 6‑LB Shah, Sanjiv 68‑LB Staimez, Lisa R. 182‑LB Saleem, Moin A. 9‑LB Shah, Vinit 280‑LB Stanley, Molly 122‑LB Salsali, Afshin 126‑LB Shang, Jin 235‑LB, 252‑LB Stanton, Robert C. 17‑LB Samoa, Raynald 179‑LB Shankar, R. Ravi 156‑LB Stapleton, Donald 344‑LB Sanchez Quintero, Maria 334‑LB Shankar, Sudha S. 118‑LB Starkstein, Sergio S. 67‑LB Sánchez, Friman 212‑LB Shannon, Megan 218‑LB Steck, Andrea 204‑LB, 207‑LB Santamaria, Jimena 78‑LB Shao, Weijuan 301‑LB Stefano, Leone 149‑LB Santa-Sosa, Eileen 160‑LB Sharma, Kumar 17‑LB Stefanovski, Darko 255‑LB ABSTRACT A U THOR IN DE X Santo González, Armando 171‑LB Shaw, James A.M. 70‑LB, 227‑LB Steineck, Isabelle 136‑LB Santos, Julia M. 55‑LB Sheehan, John J. 181‑LB Stepnaova, Maria 146‑LB Santos, Laila R.B. 338‑LB Shen, Hongbing 196‑LB Stevens, Joseph R. 266‑LB, 274‑LB Santos-Bezerra, Daniele P. 21‑LB Shen, Jie 217‑LB Stevens, Tyler 225‑LB Santulli, Gaetano 334‑LB Shen, Xiaolan 235‑LB Stevenson, Jonathan 32‑LB Sanyoura, May 213‑LB Shepard, Jaclyn A. 75‑LB Stewart, John 93‑LB Saputelli, Raymond J. 144‑LB Sherrod, Julie 160‑LB Stewart, Joshua 220‑LB Saraiva, Luis R. 298‑LB Shi, Leon 98‑LB Stewart, Sunita 160‑LB Saremi, Aramesh 5‑LB, 172‑LB Shi, Yuji 243‑LB Stoppa, Caroline L. 214‑LB Sarfo Kantanka, Osei 188‑LB Shi, Yun 217‑LB Strange, Poul 98‑LB Sarwar, Komil N. 202‑LB Shi, Zhiqing 299‑LB Streetman, Jordan 160‑LB Sasako, Shigetada 123‑LB Shibata, Mikiko 324‑LB Strizek, Alena 186‑LB Sasikala Rajendran, Raji 41‑LB Shin, John 99‑LB Strøm, Marin 190‑LB Sasikaladevi Rajendran, Raji 166‑LB Shin, Myung 252‑LB Stuchlik, Patrick 198‑LB Satapati, Santhosh 39‑LB, 235‑LB Shinjo, Sueli O. 21‑LB Stuckey, Bronwyn G.A. 312‑LB Sathe, Anita 175‑LB Shiosakai, Kazuhito 119‑LB Stumvoll, Michael 297‑LB Sato, Daisuke 137‑LB Shirakawa, Jun 231‑LB Sturla, Laura 121‑LB Sato, Kyoko K. 324‑LB Shoemaker, Daniel 109‑LB Suckow, Arthur T. 35‑LB Sato, Tatsuya 270‑LB Showalter, Aaron D. 282‑LB Sue, Nancy 337‑LB Saur, Didier 130‑LB Shu, Hua 108‑LB Suh, Sunghwan 133‑LB Saussenthaler, Sophie 261‑LB Shu, Tian 198‑LB Sun, Changhao 191‑LB Savolainen, Anna M. 52‑LB Shukla, Alpana P. 62‑LB Sun, Cheng Lin 228‑LB Saw, Seang Mei 197‑LB Siau, Evan 173‑LB Sun, Guofeng 79‑LB Scarazzini, Silvia 78‑LB Siegel, Dionicio R. 254‑LB Sun, Jennifer K. 30‑LB Schenk, Simon 239‑LB Siegel-Axel, Dorothea I. 9‑LB Sun, Jiuru 265‑LB Scherer, Norbert F. 345‑LB Sikes, Kristin 73‑LB Sun, Juan 327‑LB Scherer, Philipp E. 262‑LB Sims, Emily K. 346‑LB Sun, Li Ping 39‑LB Schernthaner, Guntram 17‑LB Sinari, Shripad 36‑LB Sun, Min 217‑LB Schick, Fritz 9‑LB Singh, Vikram 149‑LB Sun, Qi 199‑LB Schleicher, Erwin 9‑LB Singham, Stephanie 47‑LB Sunga, Sheila 125‑LB Schmidt, Signe 136‑LB Sivasailam, Ashok 166‑LB Surendran, Sneha 211‑LB Schmidt, Ulrike 9‑LB Siwakoti, Krishmita 143‑LB, 195‑LB Syed, Farooq 336‑LB, 346‑LB Schmidt, Vanessa 230‑LB Sjöholm, Kajsa 28‑LB, 316‑LB, 317‑LB Syed, Ismail 254‑LB Schmitt, Patricia 51‑LB Skarbaliene, Jolanta 283‑LB Szeto, Cheuk Chun 19‑LB Schneid, Rudi 148‑LB Skarulis, Monica C. 286‑LB Szeto, Daphne 280‑LB Schreiner, Birgit 9‑LB Skelton, Graham S. 209‑LB Tacke, Robert 109‑LB Schueler, Kathy 344‑LB Skinner, Timothy C. 67‑LB Taguchi, Takashi 119‑LB Schulz, Tim J. 298‑LB Skjøth, Trine V. 310‑LB Tajima, Kazuki 231‑LB Schürmann, Annette 261‑LB, 276‑LB Skolnik, Neil 111‑LB Takahashi, Diana 239‑LB Schwanbeck, Maria 256‑LB Slim, Ka 141‑LB Takikawa, Akiko 302‑LB Schwartz, Ann V. 313‑LB Sloop, Kyle W. 282‑LB Talal, Talal K. 43‑LB Schwartz, David D. 71‑LB Slover, Robert 99‑LB Tam, Claudia C. 19‑LB Schwartz, Frank 206‑LB, 219‑LB, 300‑LB Smith, Valerie A. 200‑LB, 201‑LB Tamarina, Natalia 345‑LB Schwartz, Michael W. 255‑LB Sneed, Bria 308‑LB Tamas, Margery J. 192‑LB Schwenk, Robert 261‑LB Snell-Bergeon, Janet K. 169‑LB Tamayo, Raul A. 124‑LB Seaquist, Elizabeth R. 3‑LB So, Wing Yee 19‑LB Tamborlane, William V. 134‑LB Seel, Maureen 64‑LB Solimando, Fernando 127‑LB Tan, Ruo Ding 117‑LB Seemungal, Terence 22‑LB Solito, Egle 11‑LB Tanenberg, Robert J. 4‑LB, 131‑LB Segal, David G. 48‑LB Song, Kelley 49‑LB Tang, Huilin 135‑LB Segundo, Carmen 215‑LB Song, Min 120‑LB Tang, Nelsn 19‑LB Selzer, Sandi 144‑LB Song, Tony 49‑LB Tankisi, H. 26‑LB

LB99 Tansey, Michael 134‑LB Vasandani, Chandna 116‑LB Warnock, Garth L. 329‑LB Tavares, Francis 335‑LB Velayudhan Pillai, Vivek 166‑LB Warren, Curtis R. 208‑LB Taylor, Kristin 312‑LB, 314‑LB Vellanki, Priyathama 132‑LB Warren, Mark 30‑LB, 87‑LB Teelucksingh, Surujpal 22‑LB Venkatesh, Y. Swamy 22‑LB Washio, Takuo 119‑LB Terauchi, Yasuo 231‑LB Venkatraman, Skrikanth 280‑LB Wasserman, David H. 281‑LB Terpstra, Melissa 3‑LB Ventura, Adriana D. 66‑LB Wasserman, Rachel M. 71‑LB Terra, Steven 125‑LB, 130‑LB Vera, Elsa 18‑LB Watkins, Elaine 124‑LB Tersey, Sarah A. 336‑LB Vera, Nicholas 33‑LB Webber, Larry 198‑LB Tessem, Jeffery S. 333‑LB Vergara Martín, Jesús 171‑LB Wei, Jung Nan 180‑LB Thai, Le May 337‑LB Verkerke, Anthony R.P. 278‑LB Weingarten, Anika 297‑LB Tharappel, Anil M. 128‑LB Verma, Narsingh 37‑LB Weinstein, Alexander M. 151‑LB Thayer, Debra W. 142‑LB Vernochet, Cecile 33‑LB Weinstock, Ruth S. 30‑LB Thieme, Karina 21‑LB Veron, Delma 18‑LB Weinzimer, Stuart A. 73‑LB, ;99‑LB Thiemermann, Chris 11‑LB Veron, Dolores 18‑LB Weissmann, Laís 305‑LB Thomas, Catherine 62‑LB Vieira, Pedro M. 254‑LB Weitz, Jonathan 347‑LB Thomas, Rebecca L. 29‑LB Vieira-Potter, Victoria J. 232‑LB Weitz, Jonathan Robbert 343‑LB Thompson, Lisa 65‑LB Vijapurkar, Ujjwala 129‑LB Wellenstein, Kerry 254‑LB Thompson, Michael J. 80‑LB Vijayakumar Sreelatha, Harikrishnan 41‑LB, Wells, Brian J. 6‑LB Thottungal Parambil, Sulfath 41‑LB 166‑LB Welly, Rebecca J. 232‑LB Thuma, Jean 300‑LB Vilà, Laia 96‑LB, 246‑LB Wende, Adam R. 306‑LB ABSTRACT A U THOR IN DE X Tian, Lili 301‑LB Villanueva, Veronica 78‑LB Weng, Christina 32‑LB Timshel, Pascal 212‑LB Viñuela-González, Laura 271‑LB Weng, Jonathan 253‑LB Tinahones, Francisco J. 271‑LB Virella, Gabriel 15‑LB Weng, Wayne 6‑LB Tobacman, Joanne K. 273‑LB Virtanen, Kirsi A. 52‑LB Wentzler, Edward J. 278‑LB, 279‑LB Tobe, Kazuyuki 302‑LB Visintainer, Paul 326‑LB Werner, Rudolf 291‑LB Togashi, Yu 231‑LB Viswanathan, Vijay 68‑LB Wernicke-Panten, Karin 94‑LB Tomlinson, Brian 19‑LB Voelmle, Mary K. 169‑LB Whaley, Jean 79‑LB, 240‑LB, 242‑LB Toppila, Iiro 16‑LB Vogelsang, Maryann 251‑LB Whim, Matthew D. 1‑LB, 2‑LB Torre, Barrett 112‑LB Volkening, Lisa K. 163‑LB White, Michael G. 227‑LB, 331‑LB Torrents, David 212‑LB von Eynatten, Maximilian 17‑LB White, Morris F. 249‑LB Toto, Robert 17‑LB Vorobyev, Sergey V. 176‑LB White, Perrin 160‑LB Touhamy, Samir 62‑LB Voronca, Delia C. 46‑LB, 147‑LB White, William B. 177‑LB Towers, Megan 234‑LB Vuitton, Lucine 141‑LB Whitehouse, Christina R. 44‑LB Trast, Jeniece 106‑LB Wagenknecht, Lynne E. 313‑LB Whittard, Toni 243‑LB Trefts, Elijah 281‑LB Wagner, Robert 9‑LB Whitworth, Stephanie R. 67‑LB Trenchevska, Olgica 36‑LB Wainstein, Julio 60‑LB Wholey, Sarah 161‑LB Trevaskis, James L. 35‑LB Walker, Julie 76‑LB Wiedemann, Monica S. 161‑LB Trikha, Saurabh 249‑LB Walker, Rebekah J. 69‑LB Willemoes, Rie Juul 24‑LB Tripathi, Anand V. 75‑LB Wallace, Jane 81‑LB Williams, Alistair J.K. 204‑LB Troelsen, Lone N. 90‑LB Wallace, Nathaniel 240‑LB, 242‑LB Williams, Ashley 20‑LB Trosclair, Lexie 269‑LB Walsh, R. Matthew 225‑LB Williams, Joni S. 46‑LB, 147‑LB Truong, Christopher 109‑LB Walter, Mary F. 286‑LB Williams, Paul 148‑LB Tryggestad, Jeanie B. 155‑LB Wan, Hong 218‑LB Wilson, Rochelle 160‑LB Tsalikian, Eva 134‑LB Wan, Yun 303‑LB Winer, Daniel 301‑LB Tse, Hubert M. 216‑LB, 306‑LB Wang, Biao 296‑LB Winfield, Thomas G. 29‑LB Tseng, Chin Lin 187‑LB Wang, Bingdi 79‑LB Winn, Nathan C. 232‑LB Tso, Patrick 253‑LB, 285‑LB Wang, Fang 322‑LB Winterberg, Pamela 165‑LB Tsui, Stephen K. 19‑LB Wang, Fei 285‑LB Woerle, Hans J. 17‑LB, 126‑LB Tsukiyama, Shuji 119‑LB Wang, Gui Xia 210‑LB, 228‑LB Wolf, Michael 290‑LB Tsushima, Kensuke 245‑LB Wang, Han 304‑LB Womack, Catherine 313‑LB Turchetti, Lucia 297‑LB Wang, Hong 307‑LB Wong, F. Susan 204‑LB Turkistani, Sarah 50‑LB Wang, Hongliang 27‑LB Wong, Tien Yin 197‑LB Tuttle, Edward 117‑LB Wang, Jiaxin 86‑LB Woo, Minna 301‑LB Twahirwa, Marcel B. 30‑LB Wang, Jingru 250‑LB Woodford, Makenzie L. 232‑LB Twigg, Stephen M. 53‑LB Wang, Liangsu 39‑LB, 235‑LB, 252‑LB Woolcott, Orison O. 183‑LB Udata, Chandrasekhar 110‑LB, 218‑LB Wang, Manqi 2‑LB Woolson, Sandra L. 200‑LB, 201‑LB Uehara, Shinichiro 324‑LB Wang, Pei 304‑LB Wroblewski, Kristen E. 257‑LB Ullal, Jagdeesh 152‑LB Wang, Qian 1‑LB Wu, Jianmin 186‑LB Umpierrez, Guillermo E. 114‑LB, 132‑LB Wang, Qinghua 303‑LB Wu, Nan Nan 323‑LB Underland, Lisa J. 106‑LB Wang, Sheng Ping 252‑LB Wu, Tangchun 196‑LB Urbina, Elaine 155‑LB, 159‑LB Wang, Tiansheng 135‑LB Wu, Yan 27‑LB Usui, Isao 302‑LB Wang, Tongtong 156‑LB Wu, Yangfeng 92‑LB Vaag, Allan A. 190‑LB Wang, Xiaobin 199‑LB Würfel, Josefine 276‑LB Vadali, Gouri 251‑LB Wang, Xiaohong 277‑LB Wysham, Carol H. 90‑LB, 91‑LB Vaeggemose, Michael 26‑LB Wang, Xiaoli 79‑LB Xia, Fang 229‑LB Valdes, Sergio 325‑LB Wang, Xuesong 250‑LB Xiao, Xianchao 210‑LB Valduga, Claudete J. 214‑LB Wang, Yanjun 86‑LB Xiao, Yong Fu 79‑LB Valk, Tim 83‑LB Wang, Yixin (Jim) 79‑LB Xing, Wei 27‑LB Valls Roca, Francisco 171‑LB Wang, Zhao 262‑LB Xu, Jianfeng 293‑LB Van Pelt, Douglas W. 56‑LB, 59‑LB Wang, Zhihong 303‑LB Xu, Kuanfeng 217‑LB Varga, Gabor 264‑LB Wang, Zong Wei 38‑LB Xu, Min 285‑LB

LB100 Xu, Xiangting 217‑LB Yu, Changhong 6‑LB Zhang, Youtao 322‑LB Xu, Xinyu 217‑LB Yu, Haoyong 311‑LB Zhang, Zheng 217‑LB Xu, Yan 292‑LB Yu, Liping 207‑LB Zhao, Dong 38‑LB, 323‑LB Xue, Jiyan 280‑LB Yu, Tian 307‑LB Zhao, Ming 258‑LB Yale, Jean-François 93‑LB Yu, Tse Ya 180‑LB Zhao, Shujie 86‑LB Yan, Hai 299‑LB Yu, Weichuan 19‑LB Zhao, Xiaolong 265‑LB Yan, Jiahe 322‑LB Yuan, Sha Sha 38‑LB Zhao, Ying 86‑LB Yandell, Brian 344‑LB Yue, Dennis 312‑LB Zheng, Jia 52‑LB Yang, Aimin 185‑LB Zannad, Faiez 177‑LB Zheng, Siyuan 322‑LB Yang, Edward H. 223‑LB Zayed, Ahmad 45‑LB Zheng, Tongzhang 185‑LB Yang, Fan 217‑LB Zeitler, Phil 159‑LB Zheng, Xiaohua 248‑LB Yang, Long Yan 38‑LB Zelada, Henry J. 149‑LB Zheng, Xuqin 217‑LB Yang, Nengyu 264‑LB Zeller, Cordula 126‑LB, 127‑LB Zhou, Dan 280‑LB Yang, Tao 217‑LB Zemel, Michael B. 260‑LB Zhou, Hongwen 217‑LB Yang, Yisheng 330‑LB Zeng, Kejing 301‑LB Zhou, Xianghai 23‑LB Yardley, Jane E. 226‑LB Zent, Roy 281‑LB Zhu, Dongshan 92‑LB Yassine, Hussein 36‑LB Zenz, Sabine 290‑LB Zhu, Jing 217‑LB Ye, Weiwei 79‑LB Zerbib, Frank 141‑LB Zhuang, Dongliang 312‑LB, 314‑LB, 315‑LB Ye, Yumei 12‑LB Zhang, Chuan Hai 323‑LB Zhuo, Daisy 151‑LB Yee, John 117‑LB Zhang, Chun 86‑LB Zidon, Terese M. 232‑LB ABSTRACT A U THOR IN DE X Yengo, Loic 321‑LB Zhang, Jianhua 293‑LB Zimmerman, Robert S. 6‑LB Yesildag, Burcak 339‑LB Zhang, Jingjing 135‑LB Zinc, Richard W. 120‑LB Yie, Junming 235‑LB Zhang, Mei 217‑LB Zocchi, Elena 121‑LB Yin, Wu 280‑LB Zhang, Michelle X. 118‑LB Zong, Geng 199‑LB Yip, Kevin Y. 19‑LB Zhang, Nannan 293‑LB Zouhar, Petr 284‑LB Yoo, Hee Won 124‑LB Zhang, Ning 38‑LB Zsombok, Andrea 307‑LB Yoon, Kun Ho 228‑LB Zhang, Puhong 92‑LB Zuluaga Zuluaga, María Clemencia 171‑LB Young, Martin E. 237‑LB Zhang, Quan Jiang 245‑LB Zuñiga, Byron 18‑LB Younossi, Zobair 146‑LB Zhang, Wei 237‑LB Youssef, Gretchen 142‑LB Zhang, Ying 322‑LB

LB101 ABSTRACT Author DISCLOSURE INFORMATION

AUTHOR RELATIONSHIP/COMPANY AUTHOR RELATIONSHIP/COMPANY Abd El Aziz, Mirna �� Disclosed no conflict of interest. Atkinson, Mark A. �� Disclosed no conflict of interest. Abderrahmani, Amar �� Disclosed no conflict of interest. Attie, Alan �� Disclosed no conflict of interest. Abdulreda, Midhat �� Disclosed no conflict of interest. Augustin, Robert �� Employee: Novo Nordisk A/S; Stock/Shareholder: Novo Abel, Brent S. �� Disclosed no conflict of interest. Nordisk A/S. Abel, E. Dale �� Disclosed no conflict of interest. Auld, Corinth �� Disclosed no conflict of interest. Abuaysheh, Sanaa �� Disclosed no conflict of interest. Ayuso, Eduard �� Disclosed no conflict of interest. Abu-El-Haija, Maisam �� Disclosed no conflict of interest. Azachi, Malkit �� Disclosed no conflict of interest. Acharya, Nikhil K. �� Disclosed no conflict of interest. Babineaux, Steven M. �� Employee: Eli Lilly and Company. Achenbach, Peter �� Disclosed no conflict of interest. Baccega, Tania �� Employee: AstraZeneca. Acierno, Ron �� Disclosed no conflict of interest. Bacha, Fida �� Disclosed no conflict of interest. Adams, Gregory �� Disclosed no conflict of interest. Backus, Carey �� Disclosed no conflict of interest. Adams-Huet, Beverley �� Disclosed no conflict of interest. Badia, Rosa M. �� Disclosed no conflict of interest. Afonso, Milessa Silva �� Disclosed no conflict of interest. Bae, Kwi Hyun �� Disclosed no conflict of interest. Agnew, Thomas P. �� Disclosed no conflict of interest. Baggavalli, Somesh P. �� Disclosed no conflict of interest. Agoram, Balaji �� Employee: AstraZeneca. Bai, Yana �� Disclosed no conflict of interest. Agrawal, Prabhat Kumar �� Disclosed no conflict of interest. Baier, Leslie J. �� Disclosed no conflict of interest. Aguilar-Diosdado, Manuel �� Disclosed no conflict of interest. Bailey, Timothy S. �� Consultant: AstraZeneca, Bayer HealthCare, Becton, Aharaz, Abdellatif �� Disclosed no conflict of interest. Dickinson and Company, Eli Lilly and Company, Ahn, Chang Ho �� Disclosed no conflict of interest. Medtronic, Inc., Novo Nordisk Inc., Sanofi U.S.; Ahn, Miwon �� Disclosed no conflict of interest. Research Support: Abbott, ACON Laboratories, Akbar, Arfana �� Disclosed no conflict of interest. Inc., Bayer HealthCare, Dexcom, Inc., Eli Lilly and Akella, Lalith �� Disclosed no conflict of interest. Company, GlaxoSmithKline, Halozyme Therapeutics, Akriv, Amichay �� Disclosed no conflict of interest. Insulet Corporation, Janssen Pharmaceuticals, Al Asfoor, Shefaa �� Disclosed no conflict of interest. Inc., Lexicon Pharmaceuticals, Inc., LifeScan, Albarado, Diana C. �� Disclosed no conflict of interest. Inc., Medtronic, Inc., Novo Nordisk Inc., Orexigen Alcaide-Torres, Juan �� Disclosed no conflict of interest. Therapeutics, Inc., Sanofi U.S.;Speaker’s Bureau: Almaca, Joana �� Disclosed no conflict of interest. Abbott, Insulet Corporation, Novo Nordisk Inc., Sanofi Aloi, Joseph �� Disclosed no conflict of interest. U.S. Alonso, G. Todd �� Disclosed no conflict of interest. Bajaj, Mandeep �� Consultant: Abbott Diabetes Care Inc., Merck & Co., Inc;

A U THOR D I SCLOS RE Altwegg, Romain �� Disclosed no conflict of interest. Research Support: AstraZeneca, Boehringer Ingelheim Alvarez, Graciela �� Disclosed no conflict of interest. Pharmaceuticals, Inc., Eli Lilly and Company, Novo Amante, Daniel J. �� Disclosed no conflict of interest. Nordisk Inc; Speaker’s Bureau: Takeda Pharmaceutical Ambery, Philip �� Employee: MedImmune, LLC.; Stock/Shareholder: Company Limited. AstraZeneca. Baker, Nathaniel L. �� Disclosed no conflict of interest. Ambrosi, Thomas H. �� Disclosed no conflict of interest. Bakris, George L. �� Consultant: AbbVie Inc., Bayer HealthCare, CVRx, Eli Ambrosino, Jodie M. �� Advisory Panel: Insulet Corporation, Medtronic, Inc.; Lilly and Company, GlaxoSmithKline, Janssen Consultant: Insulet Corporation, Medtronic, Inc., Pharmaceuticals, Inc., Medtronic, Inc., Novartis Tandem Diabetes Care, Inc.; Research Support: Pharma AG; Research Support: Medtronic, Inc., Medtronic, Inc.; Stock/Shareholder: Insuline Medical Relypsa, Inc., Takeda Development Center Americas, Ltd. Inc. Amorosa, Louis F. �� Disclosed no conflict of interest. Balicer, Ran �� Disclosed no conflict of interest. Ananth, Sudha �� Disclosed no conflict of interest. Bandyopadhyay, Gautam �� Disclosed no conflict of interest. Andersen, Birgitte �� Employee: Novo Nordisk A/S. Banerjee, Mousumi �� Disclosed no conflict of interest. Andersen, Henning �� Disclosed no conflict of interest. Bao, Yuqian �� Disclosed no conflict of interest. Anderson, Barbara J. �� Disclosed no conflict of interest. Bar-Dayan, Yosefa �� Disclosed no conflict of interest. Anderson, Pippa �� Disclosed no conflict of interest. Barengolts, Elena �� Disclosed no conflict of interest. Anderson, Scott J. �� Disclosed no conflict of interest. Barquiel, Beatriz �� Disclosed no conflict of interest. Anderson, Stacey �� Consultant: Senseonics, Inc; Research Support: Dexcom, Barquilla García, Alfonso �� Disclosed no conflict of interest. Inc., Inspark LLC, Medtronic, Inc., Roche Diagnostics. Barshop, Rupert �� Disclosed no conflict of interest. Andono, Jeselin �� Disclosed no conflict of interest. Bartoli, Daniel �� Disclosed no conflict of interest. Ansah, Eunice Oparebea �� Disclosed no conflict of interest. Barua, Ankur �� Disclosed no conflict of interest. Antebi, Tom �� Disclosed no conflict of interest. Barzilay, Joshua I. �� Disclosed no conflict of interest. Anthanont, Pimjai �� Disclosed no conflict of interest. Bass, Eric �� Disclosed no conflict of interest. Antonacci, Aldana �� Disclosed no conflict of interest. Bassaganya-Riera, Josep �� Disclosed no conflict of interest. Antunes, Manuel �� Disclosed no conflict of interest. Batra, Manav �� Disclosed no conflict of interest. Anzola, Isabel �� Disclosed no conflict of interest. Baughman, Robert A. �� Employee: MannKind Corporation. Ao, Ziliang �� Disclosed no conflict of interest. Bauman, Janine M. �� Research Support: Merck & Co., Inc., Novo Nordisk Inc. Armian, Haleh �� Disclosed no conflict of interest. Baumann, Petra �� Disclosed no conflict of interest. Armour, Sarah L. �� Disclosed no conflict of interest. Baumeier, Christian �� Disclosed no conflict of interest. Armstrong, David �� Disclosed no conflict of interest. Bautista, Noemi �� Disclosed no conflict of interest. Armstrong, Taylor �� Disclosed no conflict of interest. Bayoumi, Aly Hassan �� Disclosed no conflict of interest. Arnold, Sue �� Employee: PhaseBio Pharmaceuticals, Inc. Bays, Harold E. �� Consultant: Akcea, Alnylam, Amgen, AstraZeneca, Aronne, Louis J. �� Disclosed no conflict of interest. Eli Lilly and Company, Ionis, Merck & Co., Inc., Aronson, Ronnie �� Advisory Panel: AstraZeneca, Janssen Pharmaceuticals, Novartis, Pronova, Regeneron, Sanofi, Takeda; Inc., Medtronic, Inc., Novo Nordisk Inc., Sanofi U.S.; Research Support: Amarin, Amgen, Ardea, Arisaph, Consultant: AstraZeneca, Janssen Pharmaceuticals, AstraZeneca, Bristol Myers Squibb, Catabasis, Inc., Medtronic, Inc., Novo Nordisk Inc., Sanofi U.S.; Cymabay, Eisai, Elcelyx, Eli Lilly and Company, Research Support: AbbVie Inc., AstraZeneca, Becton, Esperion, Ferrer/Chiltern, Gilead, GlaxoSmithKline, Dickinson and Company, Covance, Dexcom, Inc., Eli Hanmi, Hisun, Hoffman LaRoche, Home Access, Lilly and Company, Genkyotex, GlaxoSmithKline, ICON Janssen, Johnson and Johnson, Kowa, Merck & Plc., inVentiv Health, Janssen Pharmaceuticals, Inc., Co., Inc., Necktar, Novartis, Novo Nordisk, Omthera, Lexicon Pharmaceuticals, Inc., Medtronic, Inc., Merck Orexigen, Pfizer Inc., Pronova, Regeneron, Sanofi, & Co., Inc., Novo Nordisk Inc., Paraexel International Takeda, TIMI; Speaker’s Bureau: Amarin, Amgen, Corp., Pfizer Inc., Quintiles Inc., Sanofi U.S.;Other AstraZeneca, Eisai, Regeneron, Sanofi, Takeda. Relationship: Sanofi U.S. Bazzano, Lydia �� Disclosed no conflict of interest. Arslanian, Silva A. �� Disclosed no conflict of interest. Beavers, Lisa S. �� Employee: Eli Lilly and Company. Arya, Mark �� Disclosed no conflict of interest. Becker, Dorothy J. �� Disclosed no conflict of interest. Ashley, Jason W. �� Disclosed no conflict of interest. Becker, Jodie �� Disclosed no conflict of interest.

LB102 AUTHOR RELATIONSHIP/COMPANY AUTHOR RELATIONSHIP/COMPANY Beck-Nielsen, Henning �� Other Relationship: Novo Nordisk A/S. Breton, Marc D. �� Advisory Panel: Bayer HealthCare; Consultant: Alere Beers-Mulroy, Blaire �� Disclosed no conflict of interest. Inc., Bayer HealthCare, Roche Diagnostics; Research Beisswenger, Paul J. �� Disclosed no conflict of interest. Support: Abbott Diabetes Care Inc., Bayer HealthCare, Ben Nasr, Moufida �� Disclosed no conflict of interest. BD Technologies, Dexcom, Inc., Roche Diagnostics, Benhamou, Pierre-Yves �� Disclosed no conflict of interest. Tandem Diabetes Care, Inc.; Speaker’s Bureau: Benite-Ribeiro, Sandra A. �� Disclosed no conflict of interest. Dexcom, Inc., Roche Diagnostics; Stock/Shareholder: Benninger, Kara S. �� Disclosed no conflict of interest. Inspark LLC, TypeZero Technologiess LLC. Berard, Lori �� Advisory Panel: Abbott, AstraZeneca, Bayer HealthCare, Broman, Aimee �� Disclosed no conflict of interest. BD Medical-Diabetes Care, Boehringer Ingelheim Broman, Karl �� Disclosed no conflict of interest. Pharmaceuticals, Inc., Eli Lilly Canada Inc., Janssen Brown, Janice �� Employee: Pfizer Inc. Pharmaceuticals, Inc., LifeScan, Inc., Merck & Co., Brown, Rebecca J. �� Disclosed no conflict of interest. Inc., Novo Nordisk Inc., Sanofi;Consultant : Abbott, Browne, Jessica L. �� Advisory Panel: Sanofi ANZ;Consultant : Sanofi ANZ; AstraZeneca, Bayer HealthCare, BD Medical-Diabetes Research Support: Sanofi ANZ;Other Relationship: Care, Boehringer Ingelheim Pharmaceuticals, Inc., AstraZeneca. Eli Lilly Canada Inc., Janssen Pharmaceuticals, Inc., Bruce, David G. �� Disclosed no conflict of interest. LifeScan, Inc., Merck & Co., Inc., Novo Nordisk Inc., Bruce, Kimberley D. �� Disclosed no conflict of interest. Sanofi;Speaker’s Bureau: Abbott, AstraZeneca, Bayer Bruckbauer, Antje �� Employee: NuSirt Biopharma; Stock/Shareholder: NuSirt HealthCare, BD Medical-Diabetes Care, Boehringer Biopharma. Ingelheim Pharmaceuticals, Inc., Eli Lilly Canada Inc., Bruley des Varannes, Stanislas �� Disclosed no conflict of interest. Janssen Pharmaceuticals, Inc., LifeScan, Inc., Merck Brunner, Martina �� Disclosed no conflict of interest. & Co., Inc., Novo Nordisk Inc., Sanofi. Bruno, Elisabeth S. �� Disclosed no conflict of interest. Bergenstal, Richard �� Research Support: Medtronic MiniMed, Inc. Brusko, Todd M. �� Disclosed no conflict of interest. Berggren, Per-Olof �� Disclosed no conflict of interest. Bruzzone, Santina �� Disclosed no conflict of interest. Bergman, Richard N. �� Disclosed no conflict of interest. Buckingham, Bruce �� Research Support: Medtronic MiniMed, Inc. Bergmeier, Stephen �� Disclosed no conflict of interest. Bucks, Romola S. �� Disclosed no conflict of interest. Berishvili, Ekaterine �� Disclosed no conflict of interest. Bucktrout, Samantha L. �� Employee: Pfizer Inc.;Stock/Shareholder : Pfizer Inc. Berkowitz, Theodore S. �� Disclosed no conflict of interest. Buehrer, Benjamin M. �� Disclosed no conflict of interest. Berney, Thierry �� Disclosed no conflict of interest. Bui, Hai �� Employee: Eli Lilly and Company. Berria, Rachele �� Employee: Sanofi. Bunescu, Razvon �� Disclosed no conflict of interest. Bertsimas, Dimitris �� Disclosed no conflict of interest. Burciu, Camelia �� Disclosed no conflict of interest. Bertuccio, Claudia �� Disclosed no conflict of interest. Burgeiro, Ana �� Disclosed no conflict of interest. Bezy, Olivier �� Employee: Pfizer Inc. Burgess, Shawn C. �� Disclosed no conflict of interest. Bhamre, Sneha �� Disclosed no conflict of interest. Burris, Angie �� Disclosed no conflict of interest. Bhargava, Anuj �� Advisory Panel: Abbott, Janssen Pharmaceuticals, Burton, Billy S. �� Disclosed no conflict of interest.

Inc., Sanofi-Aventis Deutschland GmbH;Research Buse, John B. �� Consultant: PhaseBio Pharmaceuticals, Inc.; Other A U THOR D I SCLOS RE Support: AbbVie Inc., Boehringer Ingelheim Relationship: AstraZeneca, Dance Biopharm, GmbH, Bristol-Myers Squibb, Dexcom, Inc., Duke Elcelyx Therapeutics, Inc., Eli Lilly and Company, Clinical Research Institute, Eli Lilly and Company, GI Dynamics, Inc., Lexicon Pharmaceuticals, Inc., GlaxoSmithKline, Hygieia, Jaeb Center for Merck & Co., Inc., Metavention, Novo Nordisk Health Research, Janssen Pharmaceuticals, Inc., A/S, Orexigen Therapeutics, Inc., vTv Therapeutics; Medtronic, Inc., Mylan, Novo Nordisk A/S, Orexigen Research Support: AstraZeneca, Boehringer Ingelheim Therapeutics, Inc., Sanofi-Aventis Deutschland Pharmaceuticals, Inc., Bristol-Myers Squibb Company, GmbH, University of Oxford; Speaker’s Bureau: Eli Lilly and Company, GI Dynamics, Inc., Johnson & Abbott, AstraZeneca, Sanofi U.S. Johnson, Lexicon Pharmaceuticals, Inc., Novo Nordisk Bhattacharyya, Sumit �� Disclosed no conflict of interest. Inc., Orexigen Therapeutics, Inc.; Stock/Shareholder: Bhatti, Rahila S. �� Disclosed no conflict of interest. PhaseBio Pharmaceuticals, Inc. Bian, Lingling �� Disclosed no conflict of interest. Bush, Sean P. �� Disclosed no conflict of interest. Biden, Trevor J. �� Disclosed no conflict of interest. Butler, Andrew A. �� Disclosed no conflict of interest. Billheimer, Dean �� Disclosed no conflict of interest. Butler, Deborah A. �� Disclosed no conflict of interest. Birnbaum, Yochai �� Research Support: AstraZeneca, Boehringer Ingelheim Butterfield, Anthony �� Employee: Eli Lilly and Company. Pharmaceuticals, Inc.; Speaker’s Bureau: AstraZeneca, Byram, Gregory �� Employee: Nuclea Biotechnologies. Daiichi-Sankyo Co., Ltd. Caesar, Emily E. �� Disclosed no conflict of interest. Bjerre Knudsen, Lotte �� Employee: Novo Nordisk A/S; Stock/Shareholder: Novo Cai, Yun �� Disclosed no conflict of interest. Nordisk A/S. Caiazzo, Robert �� Disclosed no conflict of interest. Blanc, Evelyn �� Disclosed no conflict of interest. Caicedo, Alejandro �� Disclosed no conflict of interest. Block, Bradley �� Disclosed no conflict of interest. Calazzo, Robert �� Disclosed no conflict of interest. Blomster, Hanna �� Disclosed no conflict of interest. Cali, Anna �� Employee: Sanofi. Blüher, Matthias �� Disclosed no conflict of interest. Callaghan, Brian C. �� Research Support: Impeto Medical. Boaz, Mona �� Disclosed no conflict of interest. Calle, Alberto �� Disclosed no conflict of interest. Bode, Bruce W. �� Research Support: Medtronic MiniMed, Inc.; Stock/ Callejas, David �� Disclosed no conflict of interest. Shareholder: GLytec LLC. Campa, David �� Disclosed no conflict of interest. Bogardus III, Clifton �� Disclosed no conflict of interest. Campbell, James �� Disclosed no conflict of interest. Bokvist, Krister �� Employee: Eli Lilly and Company. Campbell, Jennifer A. �� Disclosed no conflict of interest. Bolanis, Esther �� Disclosed no conflict of interest. Campodonico-Burnett, William �� Disclosed no conflict of interest. Bolli, Geremia B. �� Speaker’s Bureau: Eli Lilly and Company, Sanofi-Aventis Candeloro, Paola �� Disclosed no conflict of interest. Deutschland GmbH. Cannon, Barbara �� Research Support: Novo Nordisk A/S. Bonàs-Guarch, Sílvia �� Disclosed no conflict of interest. Cannon, Christopher P. �� Consultant: CSL Behring, Essentialis, Inc., Takeda Bonaz, Bruno �� Disclosed no conflict of interest. Development Center Americas, Inc.; Research Bone, Robert N. �� Disclosed no conflict of interest. Support: Accumetrics, Inc., Arisaph Pharmaceuticals, Booth, Michael �� Disclosed no conflict of interest. AstraZeneca Pharmaceuticals LP, Boehringer Booth, Robby �� Employee: Glytec, Inc. Ingelheim Pharmaceuticals, Inc., GlaxoSmithKline, Bosch, Fatima �� Disclosed no conflict of interest. Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Boslem, Ebru �� Disclosed no conflict of interest. Regeneron Pharmaceuticals, Inc., Sanofi U.S., Takeda Bottino, Rita �� Disclosed no conflict of interest. Development Center Americas, Inc. Bouchard, Jonathan �� Employee: Novo Nordisk Inc. Canouil, Mickael �� Disclosed no conflict of interest. Boulé, Normand G. �� Research Support: Medtronic, Inc. Cao, Marc �� Employee: Eli Lilly and Company. Bova, Elena V. �� Disclosed no conflict of interest. Cao, Wei �� Disclosed no conflict of interest. Boyko, Edward J. �� Disclosed no conflict of interest. Cappel, David A. �� Disclosed no conflict of interest. Braffett, Barbara H. �� Disclosed no conflict of interest. Caprio, Sonia �� Disclosed no conflict of interest. Brandt, Mary �� Disclosed no conflict of interest. Caramori, M. Luiza �� Research Support: Bayer HealthCare. Brathwaite, Collin E. �� Disclosed no conflict of interest. Carbo, Adria �� Disclosed no conflict of interest. Brazg, Ron �� Research Support: PhaseBio Pharmaceuticals, Inc. Cardona, Guemalli �� Employee: Eli Lilly and Company. Brazg, Ronald �� Research Support: Medtronic MiniMed, Inc. Carillo, Juan Jose �� Employee: Eli Lilly and Company.

LB103 AUTHOR RELATIONSHIP/COMPANY AUTHOR RELATIONSHIP/COMPANY Carls, Ginger S. �� Consultant: Intarcia Therapeutics, Inc. Chima, Ranjit �� Disclosed no conflict of interest. Carlsson, Björn �� Employee: AstraZeneca; Stock/Shareholder: AstraZeneca. Chiu, Ken C. �� Disclosed no conflict of interest. Carlsson, Lena �� Other Relationship: AstraZeneca, Johnson & Johnson, Chiu, Mark L. �� Employee: Janssen Biotech, Inc.; Stock/Shareholder: Merck Sharp & Dohme Corp. Johnson & Johnson. Carmody, David �� Disclosed no conflict of interest. Cho, Nam H. �� Disclosed no conflict of interest. Carpinelli, Angelo R. �� Disclosed no conflict of interest. Cho, Young Min �� Disclosed no conflict of interest. Carreiro, Marina �� Disclosed no conflict of interest. Chodorge, Matthieu �� Employee: AstraZeneca. Carrillo, Juan J. �� Employee: Eli Lilly and Company. Choi, Sung Hee �� Disclosed no conflict of interest. Carrington, Paul �� Disclosed no conflict of interest. Chong, Yap Seng �� Disclosed no conflict of interest. Carroll, Kelley �� Disclosed no conflict of interest. Chou, Hubert S. �� Employee: Daiichi Sankyo Pharma Development. Cartee, Gregory �� Disclosed no conflict of interest. Chu, Yvonne �� Disclosed no conflict of interest. Carvalho, Eugenia �� Disclosed no conflict of interest. Chua, Jennifer �� Disclosed no conflict of interest. Casana, Estefania �� Disclosed no conflict of interest. Chuang, Lee Ming �� Disclosed no conflict of interest. Casellas, Alba �� Disclosed no conflict of interest. Chun, Kevin �� Disclosed no conflict of interest. Caspard, Herve �� Employee: MedImmune, LLC.; Stock/Shareholder: Chung, Choon Hee �� Disclosed no conflict of interest. AstraZeneca. Church, Tyler �� Disclosed no conflict of interest. Casper, Anthony �� Disclosed no conflict of interest. Churchill, Gary �� Disclosed no conflict of interest. Castle, Jessica R. �� Stock/Shareholder: Pacific Diabetes Technologies, Inc. Cieniewicz, Anne �� Employee: Janssen Pharmaceuticals, Inc.; Stock/ Castro, Gisele �� Disclosed no conflict of interest. Shareholder: Johnson & Johnson. Catanozi, Sergio �� Disclosed no conflict of interest. Cintra, Dennys E. �� Disclosed no conflict of interest. Cauchi, Stephane �� Disclosed no conflict of interest. Cinza-Sanjurjo, Sergio �� Disclosed no conflict of interest. Cavelti-Weder, Claudia �� Disclosed no conflict of interest. Cioli, Patrizia �� Disclosed no conflict of interest. Cebada-Aleu, Alberto �� Disclosed no conflict of interest. Clark, Gregory �� Disclosed no conflict of interest. Cee-Green, Melanie �� Disclosed no conflict of interest. Clarke, Antoine B. �� Disclosed no conflict of interest. Cefalu, William T. �� Disclosed no conflict of interest. Clarke, John G. �� Employee: Glytec LLC; Research Support: Glytec LLC; Celeste, Anthony �� Disclosed no conflict of interest. Stock/Shareholder: Glytec LLC. Cengiz, Eda �� Disclosed no conflict of interest. Clarke, Michael �� Disclosed no conflict of interest. Cercado, Alicia �� Disclosed no conflict of interest. Clegg, Deborah J. �� Disclosed no conflict of interest. Cescutti, Jessica �� Employee: Boehringer Ingelheim France SAS. Clemente, Romina �� Disclosed no conflict of interest. Cha, Bong Soo �� Disclosed no conflict of interest. Clemons, Traci �� Disclosed no conflict of interest. Chabot, Katherine �� Disclosed no conflict of interest. Cliff, Phoebe �� Disclosed no conflict of interest. Chagin, Kevin M. �� Research Support: Merck & Co., Inc., Novo Nordisk Inc. Clu-Fernández, Carlos �� Disclosed no conflict of interest. Chakkalakal, Rosette J. �� Research Support: National Institute of Diabetes and Coats, Steven �� Employee: AstraZeneca. Digestive and Kidney Diseases; Other Relationship: Cochran, Elaine �� Disclosed no conflict of interest.

A U THOR D I SCLOS RE Patient-Centered Outcomes Research Institute. Coen, Paul M. �� Disclosed no conflict of interest. Chalasani, Naga �� Consultant: AbbVie Inc., DS Biopharma, Eli Lilly and Coffey, Julie �� Disclosed no conflict of interest. Company, NuSirt Biopharma, Takeda Pharmaceutical Coffin, Benoît �� Disclosed no conflict of interest. Company Limited, Tobira Therapeutics; Research Cohen, Neale �� Advisory Panel: Abbott, AstraZeneca, Boehringer Support: Eli Lilly and Company, Galectin Therapeutics, Ingelheim GmbH, Lilly Deutschland GmbH, Medtronic, Gilead Sciences, Inc., Intercept Pharmaceuticals. Inc., Merck & Co., Inc.; Research Support: Medtronic, Chambers, Christina M. �� Disclosed no conflict of interest. Inc., Novartis AG, Sanofi U.S.;Speaker’s Bureau: Chan, Juliana C. �� Disclosed no conflict of interest. Abbott, AstraZeneca, Boehringer Ingelheim GmbH, Chan, Lawrence C. �� Disclosed no conflict of interest. Eli Lilly Deutschland GmbH, Grey Innovation, Novartis Chan, Ting Fung �� Disclosed no conflict of interest. AG, Novo Nordisk A/S, Medtronic, Inc., Merck & Co., Chandarana, Keval �� Employee: Novo Nordisk A/S; Stock/Shareholder: Novo Inc., Sanofi U.S., Zosano Pharma. Nordisk A/S. Coín-Aragüez, Leticia �� Disclosed no conflict of interest. Chang, Tien Jyun �� Disclosed no conflict of interest. Collins, Nikki �� Disclosed no conflict of interest. Chao, Jason �� Employee: Xinyi, Inc. Concepcion, Jr., Nelson �� Employee: Eli Lilly and Company; Stock/Shareholder: Eli Chao, Jing H. �� Disclosed no conflict of interest. Lilly and Company. Chapman, Simon �� Disclosed no conflict of interest. Conde, Silvia V. �� Research Support: GlaxoSmithKline. Charron-Prochownik, Denise C. �� Disclosed no conflict of interest. Conway, Baqiyyah �� Disclosed no conflict of interest. Chaudhary, Kapil �� Disclosed no conflict of interest. Cooper, Jennifer �� Disclosed no conflict of interest. Chaudhuri, Ajay �� Disclosed no conflict of interest. Cooper, Mark E. �� Advisory Panel: Boehringer Ingelheim GmbH; Employee: Chaykin, Louis B. �� Speaker’s Bureau: Novo Nordisk A/S. Baker IDI Heart and Diabetes Institute. Chee, Winnie S. �� Disclosed no conflict of interest. Corkins, Christopher �� Employee: Eli Lilly and Company. Chellappan Reghuvaran, Anand �� Disclosed no conflict of interest. Cornejo-Pareja, Isabel M. �� Disclosed no conflict of interest. Chen, Chu Huang �� Disclosed no conflict of interest. Correa-Giannella, Maria L. �� Disclosed no conflict of interest. Chen, Heng �� Disclosed no conflict of interest. Cortés-Sánchez, Paula �� Disclosed no conflict of interest. Chen, Hongli �� Employee: Pfizer Inc. Corvera, Amanda �� Disclosed no conflict of interest. Chen, Jianmin �� Disclosed no conflict of interest. Coskun, Tamer �� Disclosed no conflict of interest. Chen, Keyue �� Employee: Eli Lilly and Company. Coulombe, Benoit �� Disclosed no conflict of interest. Chen, Lin �� Disclosed no conflict of interest. Courreges, Maria Cecilia �� Disclosed no conflict of interest. Chen, Peili �� Disclosed no conflict of interest. Cowan, Chad �� Disclosed no conflict of interest. Chen, Peng �� Disclosed no conflict of interest. Cox, Jason �� Disclosed no conflict of interest. Chen, Shiuhwei �� Disclosed no conflict of interest. Cox, Roger D. �� Disclosed no conflict of interest. Chen, Shuang �� Disclosed no conflict of interest. Crowley, Matthew J. �� Disclosed no conflict of interest. Chen, Wei �� Disclosed no conflict of interest. Cui, Qiaoli �� Disclosed no conflict of interest. Chen, Wei Yu �� Disclosed no conflict of interest. Cummings, Bethany P. �� Research Support: Eli Lilly and Company. Chen, Wenbiao �� Disclosed no conflict of interest. Cummings, Doyle M. �� Disclosed no conflict of interest. Chen, Yan �� Disclosed no conflict of interest. Curtis, Bradley H. �� Employee: Eli Lilly and Company; Stock/Shareholder: Eli Chen, Yang �� Disclosed no conflict of interest. Lilly and Company. Chen, Yanyun �� Employee: Eli Lilly and Company. Cushman, William C. �� Research Support: Eli Lilly and Company, Merck & Co., Inc. Chen, Ying �� Employee: Merck Sharp & Dohme Corp. Cutfield, Richard �� Disclosed no conflict of interest. Chen, Yong �� Employee: Merck & Co., Inc; Stock/Shareholder: Merck & Daddysman, Matthew K. �� Disclosed no conflict of interest. Co., Inc. Dagogo-Jack, Samuel �� Advisory Panel: Amgen Inc., AstraZeneca, Boehringer Chen, Yung Tai �� Disclosed no conflict of interest. Ingelheim Pharmaceuticals, Inc., Janssen Cheng, John B. �� Employee: Pfizer Inc.;Stock/Shareholder : Pfizer Inc. Pharmaceuticals, Inc., Merck & Co., Inc., Novo Cheng, Ning �� Disclosed no conflict of interest. Nordisk Inc., Sanofi U.S.;Consultant : Amgen Inc., Chernavvsky, Daniel R. �� Disclosed no conflict of interest. AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Chesla, Catherine �� Disclosed no conflict of interest. Inc., Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Cheung, Kitty K. �� Disclosed no conflict of interest. Novo Nordisk Inc., Sanofi U.S.;Other Relationship: Chevalier, Soazig �� Employee: Sanofi;Stock/Shareholder : Sanofi. AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Chew, Daniel �� Employee: GlaxoSmithKline. Inc., Novo Nordisk Inc.

LB104 AUTHOR RELATIONSHIP/COMPANY AUTHOR RELATIONSHIP/COMPANY Dahmen, Raphael �� Employee: Sanofi-Aventis Deutschland GmbH. Du, Fuyong �� Employee: Janssen Pharmaceuticals, Inc.; Stock/ Dai, Min �� Disclosed no conflict of interest. Shareholder: Johnson & Johnson. Dalgaard, Louise T. �� Disclosed no conflict of interest. Duarte, Joao �� Disclosed no conflict of interest. Damm-Frydenberg, Camilla �� Disclosed no conflict of interest. Ducrotté, Philippe �� Disclosed no conflict of interest. Dandona, Paresh �� Disclosed no conflict of interest. Dun, Alison �� Disclosed no conflict of interest. Daneman, Denis �� Disclosed no conflict of interest. Duncan, Rory R. �� Disclosed no conflict of interest. Dapoigny, Michel �� Disclosed no conflict of interest. Dungan, Kathleen M. �� Consultant: Eli Lilly and Company, GlaxoSmithKline; D’Aquino, Katharine E. �� Employee: Janssen Pharmaceuticals, Inc.; Stock/ Research Support: AstraZeneca, GlaxoSmithKline, Shareholder: Johnson & Johnson. Merck & Co., Inc., Novo Nordisk Inc., Sanofi U.S. Darekar, Amanda �� Employee: Pfizer Inc. Dunstan, Frank D. �� Disclosed no conflict of interest. Darsow, Tamara �� Disclosed no conflict of interest. Duvvuru, Suman �� Employee: Eli Lilly and Company. Das, Rahul �� Disclosed no conflict of interest. Eberly, Lynn �� Disclosed no conflict of interest. Davies, Melanie �� Advisory Panel: AstraZeneca, Boehringer Ingelheim Eckel, Robert H. �� Disclosed no conflict of interest. Pharmaceuticals, Inc., Eli Lilly and Company, Janssen Edelman, David �� Disclosed no conflict of interest. Pharmaceuticals, Inc., Merck Sharp & Dohme Corp., Edelman, Steven V. �� Consultant: Intarcia Therapeutics, Inc. Novo Nordisk Inc., Sanofi-Aventis Deutschland GmbH; Edmonson, Scott �� Disclosed no conflict of interest. Consultant: AstraZeneca, Boehringer Ingelheim Edmundowicz, Steven �� Disclosed no conflict of interest. Pharmaceuticals, Inc., Eli Lilly and Company, Janssen Efanov, Alexander M. �� Employee: Eli Lilly and Company. Pharmaceuticals, Inc., Merck Sharp & Dohme Corp., Egede, Leonard E. �� Disclosed no conflict of interest. Novo Nordisk Inc., Sanofi-Aventis Deutschland Eiermann, George �� Disclosed no conflict of interest. GmbH; Research Support: Eli Lilly and Company, Novo Ejskjaer, Niels �� Disclosed no conflict of interest. Nordisk Inc., Sanofi-Aventis Deutschland GmbH; El Ghormli, Laure �� Disclosed no conflict of interest. Speaker’s Bureau: AstraZeneca, Boehringer Ingelheim El Ouarrat, Dalila �� Disclosed no conflict of interest. Pharmaceuticals, Inc., Eli Lilly and Company, Janssen El Youssef, Joseph �� Disclosed no conflict of interest. Pharmaceuticals, Inc., Merck Sharp & Dohme Corp., Elasy, Tom A. �� Research Support: National Institute of Diabetes and Mitsubishi Tanabe Pharma Corporation, Novo Nordisk Digestive and Kidney Diseases. Inc., Sanofi-Aventis Deutschland GmbH, Takeda Elder, Deborah A. �� Disclosed no conflict of interest. Pharmaceutical Company Limited. Eldor, Roy �� Employee: Merck & Co., Inc; Stock/Shareholder: Merck & Davies, Michael J. �� Employee: Janssen Scientific Affairs, LLC. Co., Inc. Davis, Timothy �� Disclosed no conflict of interest. Elias, Ivet �� Disclosed no conflict of interest. Davis, Trent �� Advisory Panel: Dexcom; Speaker’s Bureau: Dexcom. Elofsson, Hampus �� Disclosed no conflict of interest. Davis, Wendy A. �� Disclosed no conflict of interest. Emmerson, Paul J. �� Disclosed no conflict of interest. de la Rosa, Raymond �� Research Support: Boehringer Ingelheim Pharmaceuticals, Engel, Samuel S. �� Employee: Merck & Co., Inc; Stock/Shareholder: Merck & Inc., Elcelyx Therapeutics, Inc., GlaxoSmithKline, Co., Inc.

Merck Sharp & Dohme Corp., Novo Nordisk A/S, Erion, Derek �� Employee: Pfizer Inc. A U THOR D I SCLOS RE Sanofi-Aventis Deutschland GmbH;Speaker’s Bureau: Erondu, Ngozi �� Employee: Janssen Research & Development, LLC. AbbVie Inc., Boehringer Ingelheim Pharmaceuticals, Erwin, Patricia J. �� Disclosed no conflict of interest. Inc., Novo Nordisk A/S, Sanofi-Aventis Deutschland Eshghi, Saeed R. �� Disclosed no conflict of interest. GmbH; Stock/Shareholder: Quest Diagnostics. Eskelinen, Joonas J. �� Disclosed no conflict of interest. de Looze, Ferdinandus J. �� Disclosed no conflict of interest. Espinoza, Daniel �� Disclosed no conflict of interest. DeBoer, Mark �� Disclosed no conflict of interest. Esposito, Virginie �� Employee: Sanofi-Aventis Deutschland GmbH. Deelchand, Dinesh �� Disclosed no conflict of interest. Esteves, Brooke �� Disclosed no conflict of interest. DeFronzo, Ralph A. �� Advisory Panel: AstraZeneca, Boehringer Ingelheim Evans-Molina, Carmella �� Disclosed no conflict of interest. Pharmaceuticals, Inc., Intarcia, Janssen, Novo Evennett, Nicholas �� Disclosed no conflict of interest. Nordisk A/S; Consultant: AstraZeneca, Boehringer Faingold, Maria C. �� Advisory Panel: AstraZeneca; Speaker’s Bureau: Ingelheim Pharmaceuticals, Inc., Intarcia, Janssen, AstraZeneca, Novo Nordisk Inc. Novo Nordisk A/S; Research Support: AstraZeneca, Fairman, David �� Disclosed no conflict of interest. Boehringer Ingelheim Pharmaceuticals, Inc., Fan, Guo Chang �� Disclosed no conflict of interest. Janssen; Speaker’s Bureau: AstraZeneca, Novo Fan, Nengguang �� Disclosed no conflict of interest. Nordisk A/S. Fan, Xiaodan �� Disclosed no conflict of interest. Deja, Stanislaw �� Disclosed no conflict of interest. Fanelli, Carmine G. �� Disclosed no conflict of interest. Delfolie, Astrid �� Employee: Sanofi-Aventis Deutschland GmbH. Fang, Xiankang �� Employee: Eli Lilly and Company. Dell, Vanessa �� Disclosed no conflict of interest. Fang, Zhenwei �� Disclosed no conflict of interest. Demarest, Keith �� Employee: Janssen Pharmaceuticals, Inc.; Stock/ Farb, Thomas B. �� Employee: Eli Lilly and Company. Shareholder: Johnson & Johnson. Farias, Ginger �� Disclosed no conflict of interest. Deng, Yingfeng �� Disclosed no conflict of interest. Faubert, Denis �� Disclosed no conflict of interest. Deo, Vijaya �� Disclosed no conflict of interest. Faucheron, Jean-Luc �� Disclosed no conflict of interest. Deol, Rupinder �� Disclosed no conflict of interest. Feferman, Leo �� Disclosed no conflict of interest. Derosa, Giuseppe �� Research Support: Pfizer Inc. Feigh, Michael �� Disclosed no conflict of interest. Desai, Mehul �� Employee: Janssen Research & Development, LLC. Feldman, Becca �� Disclosed no conflict of interest. Deuter-Reinhard, Maja �� Employee: Eli Lilly and Company. Feldman, Eva �� Disclosed no conflict of interest. Devine, Nancy �� Disclosed no conflict of interest. Fend, Falko �� Disclosed no conflict of interest. Dhaliwal, Noori �� Disclosed no conflict of interest. Feng, Qinghua �� Disclosed no conflict of interest. Dharshi, Anisha S. �� Disclosed no conflict of interest. Feng, Wei �� Disclosed no conflict of interest. Díaz, Carlos �� Disclosed no conflict of interest. Feng, Ying Mei �� Disclosed no conflict of interest. Díaz-Perdigones, Cristina �� Disclosed no conflict of interest. Fenici, Peter �� Employee: AstraZeneca; Stock/Shareholder: AstraZeneca. DiCostanza, Sheila �� Employee: MedImmune, LLC.; Stock/Shareholder: Fernandes, Jyotika �� Disclosed no conflict of interest. AstraZeneca. Fernandez Alonso, Camilo �� Disclosed no conflict of interest. Díez Perez, Ma Cruz �� Disclosed no conflict of interest. Fernandez, Ana �� Disclosed no conflict of interest. Ding, Jiao �� Disclosed no conflict of interest. Fernandez, Stephen J. �� Disclosed no conflict of interest. Diniz, Susana N. �� Disclosed no conflict of interest. Ferrara, Patrick J. �� Disclosed no conflict of interest. Dinner, Aaron R. �� Disclosed no conflict of interest. Ferre, Tura �� Disclosed no conflict of interest. Do, Khoa �� Disclosed no conflict of interest. Ferreira, Rita S. �� Disclosed no conflict of interest. Dolan, Larry �� Disclosed no conflict of interest. Ferrer, Jorge �� Disclosed no conflict of interest. Dong, Fran �� Disclosed no conflict of interest. Fiorina, Paolo �� Disclosed no conflict of interest. Donner, Thomas W. �� Disclosed no conflict of interest. Fisher, Miles �� Advisory Panel: AstraZeneca, Boehringer Ingelheim Dopson, Wesley �� Employee: GlaxoSmithKline. Pharmaceuticals, Inc., Eli Lilly and Company, Novo Dorval, Etienne �� Disclosed no conflict of interest. Nordisk, Sanofi;Speaker’s Bureau: Janssen, Merck Dotzert, Michelle S. �� Disclosed no conflict of interest. Sharp & Dohme Corp. Dowd, Amy �� Disclosed no conflict of interest. Flores, Omar �� Employee: NuSirt Biopharma; Stock/Shareholder: NuSirt Draney, Carrie �� Disclosed no conflict of interest. Biopharma. Driver, Emily �� Disclosed no conflict of interest. Florez, Jose C. �� Disclosed no conflict of interest. Droz, Brian A. �� Disclosed no conflict of interest. Focht, Kristen �� Employee: Pfizer Inc.;Stock/Shareholder : Pfizer Inc.

LB105 AUTHOR RELATIONSHIP/COMPANY AUTHOR RELATIONSHIP/COMPANY Fonseca, Vivian �� Disclosed no conflict of interest. Gidding, Sam S. �� Disclosed no conflict of interest. Fontaine, Sébastien �� Disclosed no conflict of interest. Gilbert, Richard E. �� Advisory Panel: AstraZeneca, Boehringer Ingelheim, Forbes, Angus �� Disclosed no conflict of interest. Janssen; Research Support: AstraZeneca, Boehringer Forgie, Alison �� Employee: Pfizer Inc.;Stock/Shareholder : Pfizer Inc. Ingelheim; Speaker’s Bureau: AstraZeneca, Fornoff, Linda �� Disclosed no conflict of interest. Boehringer Ingelheim, Janssen. Forsblom, Carol �� Disclosed no conflict of interest. Gilfillan, Christopher �� Disclosed no conflict of interest. Foster, Heather �� Disclosed no conflict of interest. GIll, Jasvinder �� Employee: Sanofi U.S.;Stock/Shareholder : Sanofi U.S. Fouts, Alexandra R. �� Disclosed no conflict of interest. Gill, Patricia �� Employee: Arkray USA. Fox, Larry A. �� Disclosed no conflict of interest. Gillespie, Kathleen M. �� Disclosed no conflict of interest. Fox, Maura E. �� Disclosed no conflict of interest. Giordano, Dominique �� Disclosed no conflict of interest. Freitas, Vanessa G. �� Disclosed no conflict of interest. Girardet, Clemence �� Disclosed no conflict of interest. Fretes, Osvaldo �� Disclosed no conflict of interest. Giri, Smith �� Disclosed no conflict of interest. Frias, Juan �� Advisory Panel: AstraZeneca, CeQur, Ltd., Johnson & Gleisner, John �� Employee: Arkray USA. Johnson; Research Support: AstraZeneca, Boehringer Gluckman, Peter �� Disclosed no conflict of interest. Ingelheim Pharmaceuticals, Inc., Bristol-Myers Gnana-Prakasam, Jaya P. �� Research Support: American Heart Association. Squibb Company, Eli Lilly and Company, Ionis Goebel, Britta �� Employee: Sanofi-Aventis Deutschland GmbH. Pharmaceuticals, Merck & Co., Inc., Novo Nordisk Goetz, Doug �� Disclosed no conflict of interest. Inc., Pfizer Inc., Sanofi U.S., Takeda Pharmaceutical Golm, Gregory �� Employee: Merck & Co., Inc; Stock/Shareholder: Merck & Company Limited, Theracos, Inc., vTv Therapeutics. Co., Inc. Frid, Santiago �� Disclosed no conflict of interest. Gomez, Patricia �� Disclosed no conflict of interest. Friesen, Max �� Disclosed no conflict of interest. Gonder-Frederick, Linda A. �� Disclosed no conflict of interest. Fritsche, Andreas �� Disclosed no conflict of interest. Gong, Yi �� Disclosed no conflict of interest. Froguel, Philippe �� Disclosed no conflict of interest. González, Santi �� Disclosed no conflict of interest. Frohnert, Brigitte �� Disclosed no conflict of interest. Gonzalez, Victor H. �� Advisory Panel: ACON Laboratories, Inc., Allergan, Inc., Froy, Oren �� Disclosed no conflict of interest. Bayer HealthCare, Genentech, Inc., Regeneron Frueh, Chris �� Disclosed no conflict of interest. Pharmaceuticals, Inc., Valeant Pharmaceuticals; Frustaci, Mary Ellen �� Employee: Janssen Research & Development, LLC. Consultant: Allergan, Inc., Genentech, Inc., Regeneron Fu, Qi �� Disclosed no conflict of interest. Pharmaceuticals, Inc., Valeant Pharmaceuticals; Fu, Xiaorong �� Disclosed no conflict of interest. Research Support: ACON Laboratories, Inc., Allergan, Fujimoto, Wilfred Y. �� Disclosed no conflict of interest. Inc., Regeneron Pharmaceuticals, Inc.; Speaker’s Fujisaka, Shiho �� Disclosed no conflict of interest. Bureau: Allergan, Inc., Bayer HealthCare, Genentech, Funai, Katsuhiko �� Disclosed no conflict of interest. Inc., Regeneron Pharmaceuticals, Inc. Fung, Albert �� Employee: Janssen Research & Development, LLC. Gonzalo, Montserrat �� Disclosed no conflict of interest. Funk, Deanna R. �� Disclosed no conflict of interest. Goodpaster, Bret H. �� Disclosed no conflict of interest.

A U THOR D I SCLOS RE Gabrielsson, Johan �� Disclosed no conflict of interest. Goodyear, Laurie J. �� Disclosed no conflict of interest. Gains, T’Keaya L. �� Disclosed no conflict of interest. Gopala, Srinivas �� Disclosed no conflict of interest. Galic, Sandra �� Disclosed no conflict of interest. Gordat, Maud �� Employee: Boehringer Ingelheim France SAS. Gambardella, Jessica �� Disclosed no conflict of interest. Gorden, Phillip �� Disclosed no conflict of interest. Ganguly, Bishu J. �� Employee: Pfizer Inc.;Stock/Shareholder : Pfizer Inc. Gordillo, Ruth �� Disclosed no conflict of interest. Ganz, Tali �� Disclosed no conflict of interest. Gorgoglione, Matthew �� Employee: Pfizer Inc. Gao, Hong �� Disclosed no conflict of interest. Gorjão, Renata �� Disclosed no conflict of interest. Gao, Leili �� Disclosed no conflict of interest. Gourcerol, Guillaume �� Disclosed no conflict of interest. Gao, Ying �� Disclosed no conflict of interest. Grabman, Jesse H. �� Disclosed no conflict of interest. Garcia Fuentes, Eduardo �� Disclosed no conflict of interest. Grandjean, Philippe �� Disclosed no conflict of interest. Garcia, Katelyn R. �� Disclosed no conflict of interest. Grant, Marshall �� Employee: MannKind Corporation. Garcia, Miquel �� Disclosed no conflict of interest. Greeley, Siri Atma W. �� Disclosed no conflict of interest. Garcia-Serrano, Sara �� Disclosed no conflict of interest. Greenway, Frank �� Disclosed no conflict of interest. Garg, Abhimanyu �� Consultant: Aegerion Pharmaceuticals, Inc., Isis Gregg, Edward �� Disclosed no conflict of interest. Pharmaceuticals, Inc.; Research Support: Aegerion Grewal, Gurtej S. �� Disclosed no conflict of interest. Pharmaceuticals, Inc., Intercept Pharmaceuticals, Isis Griffin, Paul M. �� Disclosed no conflict of interest. Pharmaceuticals, Inc. Grifoll, Iris �� Disclosed no conflict of interest. Garg, Manisha �� Disclosed no conflict of interest. Grimaud, Jean-Charles �� Disclosed no conflict of interest. Garg, Satish K. �� Consultant: Eli Lilly and Company, Lexicon Grimsby, Joseph �� Employee: AstraZeneca. Pharmaceuticals, Inc., Medtronic, Inc., Merck & Co., Groleau, Mélanie �� Employee: Sanofi Canada;Stock/Shareholder : Sanofi Inc., Novo Nordisk Inc., Roche Diagnostics, Sanofi Canada. U.S.; Research Support: Eli Lilly and Company, Groop, Per-Henrik �� Advisory Panel: AbbVie Inc., Boehringer Ingelheim Juvenile Diabetes Research Foundation, Merck & Co., GmbH, Cebix, Inc., Eli Lilly and Company, Janssen Inc., National Institute of Diabetes and Digestive and Pharmaceuticals, Inc., Medscape, Novartis Kidney Diseases, Novo Nordisk A/S, Sanofi U.S. Pharmaceuticals Corporation; Employee: Helsinki Garibay, Darline �� Disclosed no conflict of interest. University Hospital, University of Helsinki; Garneau, Pierre �� Disclosed no conflict of interest. Research Support: Eli Lilly and Company, Roche Garrett, Valerie �� Disclosed no conflict of interest. Pharmaceuticals; Speaker’s Bureau: AstraZeneca, Garvey, W. Timothy �� Disclosed no conflict of interest. Boehringer Ingelheim GmbH, Eli Lilly and Company, Garzone, Pamela D. �� Employee: Pfizer Inc.;Stock/Shareholder : Pfizer Inc. Genzyme Corporation, MSO Finland, Novartis Gastecki, Michelle L. �� Disclosed no conflict of interest. Pharmaceuticals Corporation, Novo Nordisk Inc. Gautam, Ashish �� Disclosed no conflict of interest. Grosjean, Philippe �� Employee: Sanofi-Aventis Deutschland GmbH. Gauthier, Marie Soleil �� Disclosed no conflict of interest. Groth Grunnet, Louise �� Disclosed no conflict of interest. Gazale, Waseem �� Disclosed no conflict of interest. Grufman, Lisa �� Disclosed no conflict of interest. Gebregziabher, Mulugeta �� Disclosed no conflict of interest. Gu, Haitao �� Disclosed no conflict of interest. Geffner, Mitchell �� Disclosed no conflict of interest. Gu, Lina �� Employee: Sanofi Investment Co. Ltd. Genter, Pauline �� Disclosed no conflict of interest. Gu, Yong �� Disclosed no conflict of interest. George, Feba �� Disclosed no conflict of interest. Guadalupe, Mariana �� Disclosed no conflict of interest. Georgopoulos, Lynne �� Employee: PhaseBio Pharmaceuticals, Inc. Guarino, Maria P. �� Research Support: GlaxoSmithKline. Gerety, Gregg �� Consultant: Dexcom, Inc.; Research Support: Boehringer Gubitosi-Klug, Rose �� Disclosed no conflict of interest. Ingelheim Pharmaceuticals, Inc., Lexicon Guerci, Bruno �� Disclosed no conflict of interest. Pharmaceuticals, Inc., Locemia Solutions, LP, Novo Guerrettaz, Lisa �� Disclosed no conflict of interest. Nordisk A/S; Speaker’s Bureau: AstraZeneca, Guillén, María A. �� Disclosed no conflict of interest. Boehringer Ingelheim Pharmaceuticals, Inc., Dexcom, Guindo-Martínez, Marta �� Disclosed no conflict of interest. Inc., Eli Lilly and Company, Janssen Pharmaceuticals, Gumbiner, Barry �� Employee: Pfizer Inc.;Stock/Shareholder : Inc., Novo Nordisk A/S; Stock/Shareholder: Dexcom, GlaxoSmithKline, Pfizer Inc. Inc. Gumprecht, Janusz �� Consultant: Bioton SA, Eli Lilly and Company, Merck Ghanim, Husam �� Disclosed no conflict of interest. Sharp & Dohme Corp., Polpharma SA Pharmaceutical Gianchandani, Roma Y. �� Disclosed no conflict of interest. Works; Speaker’s Bureau: Bioton SA, Eli Lilly and

LB106 AUTHOR RELATIONSHIP/COMPANY AUTHOR RELATIONSHIP/COMPANY Company, Merck Sharp & Dohme Corp., Novo Nordisk Pharmaceuticals, Inc., Novo Nordisk Inc., Sanofi; A/S, Roche Pharmaceuticals, Servier. Speaker’s Bureau: Abbott, AstraZeneca, Boehringer Gunti, Gowthamraj �� Disclosed no conflict of interest. Ingelheim Pharmaceuticals, Inc., Eli Lilly and Gupta, Olga T. �� Disclosed no conflict of interest. Company, Janssen Pharmaceuticals, Inc., Medtronic, Gupta, Sunil �� Disclosed no conflict of interest. Inc., Merck & Co., Inc., Novo Nordisk Inc., Sanofi. Guralnik, Jack �� Disclosed no conflict of interest. Harrison, Karen �� Disclosed no conflict of interest. Gurfinkiel, Mirta �� Disclosed no conflict of interest. Hart, Matthew �� Disclosed no conflict of interest. Gurusamy, Mariappan �� Disclosed no conflict of interest. Harville, Emily �� Disclosed no conflict of interest. Gustat, Jeanette �� Disclosed no conflict of interest. Hashemi, Nasseh �� Disclosed no conflict of interest. Guth, Lisa M. �� Disclosed no conflict of interest. Hass, Michael �� Disclosed no conflict of interest. Guthoff, Martina �� Disclosed no conflict of interest. Hatab, Sarah �� Disclosed no conflict of interest. Gutierrez-Repiso, Carolina �� Disclosed no conflict of interest. Hatipoglu, Betul A. �� Disclosed no conflict of interest. Guzman, Cristina B. �� Employee: Eli Lilly and Company; Stock/Shareholder: Eli Haurigot, Virginia �� Disclosed no conflict of interest. Lilly and Company. Hayashi, Tomoshige �� Disclosed no conflict of interest. Guzman, Felix �� Disclosed no conflict of interest. Hayes, Heather L. �� Disclosed no conflict of interest. Habegger, Kirk M. �� Disclosed no conflict of interest. Hayes, John M. �� Disclosed no conflict of interest. Hadfield, William �� Disclosed no conflict of interest. Haymond, Mory �� Consultant: AstraZeneca, Bristol-Myers Squibb Company, Hadjadj, Samy �� Disclosed no conflict of interest. Daiichi-Sankyo Co., Ltd., National Institutes of Hagay, Yoheved �� Disclosed no conflict of interest. Health, Novo Nordisk Inc.; Stock/Shareholder: Xeris Hajnsek, Martin �� Disclosed no conflict of interest. Pharmaceuticals, Inc. Hale, Dan �� Disclosed no conflict of interest. Hazen, Rebecca �� Disclosed no conflict of interest. Hall, Christopher �� Disclosed no conflict of interest. Hazra, Daya Kishore �� Disclosed no conflict of interest. Hall, Keneth �� Disclosed no conflict of interest. He, Jie �� Disclosed no conflict of interest. Hall, Stephen �� Disclosed no conflict of interest. He, Kan �� Disclosed no conflict of interest. Halladin, Natalie �� Employee: Novo Nordisk A/S. He, Xuanyao �� Employee: Eli Lilly and Company. Hallas, Jesper �� Disclosed no conflict of interest. Heden, Timothy D. �� Disclosed no conflict of interest. Halldorsson, Thorhallur I. �� Disclosed no conflict of interest. Hedgepeth, John �� Disclosed no conflict of interest. Ham, Nina J. �� Disclosed no conflict of interest. Heise, Tim �� Consultant: Profil Institute for Clinical Research, Inc. Hamdouchi, Chafiq �� Employee: Eli Lilly and Company. Hejna, Jeanne �� Disclosed no conflict of interest. Hamdy, Osama �� Disclosed no conflict of interest. Hekmat, Omid �� Disclosed no conflict of interest. Hames, Kazanna C. �� Disclosed no conflict of interest. Henderson, Amy �� Employee: Glytec, Inc. Hammad, Samar M. �� Disclosed no conflict of interest. Henriksen, Daniel P. �� Disclosed no conflict of interest. Hammar, Niklas �� Employee: AstraZeneca; Stock/Shareholder: AstraZeneca. Henry, PIerre-Gilles �� Disclosed no conflict of interest. Hammodat, Hisham �� Disclosed no conflict of interest. Heptulla, Rubina �� Disclosed no conflict of interest.

Hammond, Craig �� Employee: Eli Lilly and Company. Hernández-García, Carmen �� Disclosed no conflict of interest. A U THOR D I SCLOS RE Han, Jing �� Disclosed no conflict of interest. Herold, Kevan C. �� Disclosed no conflict of interest. Han, Tianshu �� Disclosed no conflict of interest. Herranz, Lucrecia �� Disclosed no conflict of interest. Hanaire, Hélène �� Disclosed no conflict of interest. Hesse, Deike �� Disclosed no conflict of interest. Hancock, Chad R. �� Disclosed no conflict of interest. Hetrick, Byron �� Disclosed no conflict of interest. Hancock, William D. �� Disclosed no conflict of interest. Heyward, Bill �� Disclosed no conflict of interest. Handelsman, Yehuda �� Consultant: Amarin Pharma, Inc., Amgen Inc., Amylin Higuchi, Takahiro �� Disclosed no conflict of interest. Pharmaceuticals, LLC., AstraZeneca, Boehringer Hijazi, Youssef �� Employee: Sanofi-Aventis Deutschland GmbH. Ingelheim Pharmaceuticals, Inc., Bristol-Myers Hikita, Yonezo �� Disclosed no conflict of interest. Squibb, diaDexus, Daiichi-Sankyo Co., Ltd., Eisai Hinder, Lucy M. �� Disclosed no conflict of interest. Co., Ltd., Gilead Sciences, Inc., GlaxoSmithKline, Hinke, Simon A. �� Employee: Janssen Pharmaceuticals, Inc.; Stock/ Halozyme Therapeutics, Janssen Pharmaceuticals, Shareholder: Johnson & Johnson. Inc., LipoScience, Inc., Merck Sharp & Dohme Corp., Hiraki, Linda T. �� Disclosed no conflict of interest. Novo Nordisk A/S, Sanofi U.S., Santarus, Inc., Vivus Hirano, Michio �� Disclosed no conflict of interest. Inc.; Research Support: Amgen Inc., AstraZeneca, Hoag, Tom �� Disclosed no conflict of interest. Boehringer Ingelheim Pharmaceuticals, Inc., Bristol- Hoang, Linda �� Disclosed no conflict of interest. Myers Squibb, Gilead Sciences, Inc., GlaxoSmithKline, Hoang, Vy �� Disclosed no conflict of interest. Grifols USA, LLC, Hanmi Pharmaceutical Co., Ltd., Hobbs, Todd M. �� Employee: Novo Nordisk Inc. Intarcia Therapeutics, Inc., Lexicon Pharmaceuticals, Hocher, Berthold �� Advisory Panel: Boehringer Ingelheim GmbH; Employee: Inc., Merck Sharp & Dohme Corp., Novo Nordisk A/S, University of Potsdam; Research Support: Boehringer Sanofi U.S., Takeda Pharmaceutical Company Limited; Ingelheim GmbH. Speaker’s Bureau: Amarin Pharma, Inc., Amylin Hodish, Israel �� Disclosed no conflict of interest. Pharmaceuticals, LLC., AstraZeneca, Boehringer Holdych, Janet �� Disclosed no conflict of interest. Ingelheim Pharmaceuticals, Inc., Daiichi-Sankyo Co., Holinski, Brad �� Employee: GlaxoSmithKline. Ltd., Eli Lilly and Company, GlaxoSmithKline, Janssen Hollander, Priscilla A. �� Advisory Panel: Eli Lilly and Company, Merck & Co., Inc., Pharmaceuticals, Inc., Novo Nordisk A/S, Santarus, Novo Nordisk. Inc., Vivus Inc. Holmes-Truscott, Elizabeth �� Consultant: Abbott Diabetes Care Inc. Hannon, Tamara S. �� Disclosed no conflict of interest. Holst, Jens Juul �� Advisory Panel: AstraZeneca, Boehringer Ingelheim Hannukainen, Jarna C. �� Disclosed no conflict of interest. Pharmaceuticals, Inc., Intarcia Therapeutics, Inc., Hansen, Charlotte T. �� Advisory Panel: AbbVie Inc.; Employee: Novo Nordisk MannKind Corporation, Merck Sharp & Dohme Corp., A/S; Research Support: Johnson & Johnson; Stock/ Novartis Pharma AG, Novo Nordisk A/S, Roche Shareholder: Novo Nordisk A/S. Pharmaceuticals, Sanofi-Aventis Deutschland GmbH, Hansen, Susanne �� Disclosed no conflict of interest. Zealand Pharma A/S; Consultant: Novo Nordisk Hanson, Robert L. �� Disclosed no conflict of interest. A/S; Speaker’s Bureau: AstraZeneca, Bristol-Myers Hardee, Sandra �� Disclosed no conflict of interest. Squibb Company, Eli Lilly and Company, Merck Hardman, Jeremy M. �� Disclosed no conflict of interest. Sharp & Dohme Corp., Novo Nordisk A/S, Roche Hardy, Thomas A. �� Employee: Eli Lilly and Company; Stock/Shareholder: Eli Pharmaceuticals, Sanofi-Aventis Deutschland GmbH. Lilly and Company. Holtzman, David M. �� Disclosed no conflict of interest. Hargett, Stefan �� Disclosed no conflict of interest. Hontecillas, Raquel �� Disclosed no conflict of interest. Häring, Hans Ulrich �� Disclosed no conflict of interest. Hornigold, David �� Employee: AstraZeneca. Harjutsalo, Valma �� Disclosed no conflict of interest. Hornung, Lindsey �� Disclosed no conflict of interest. Harlan, David M. �� Disclosed no conflict of interest. Horowitz, David A. �� Disclosed no conflict of interest. Haro, Heidi �� Disclosed no conflict of interest. Horowitz, Jeffrey F. �� Disclosed no conflict of interest. Harper, Wayne L. �� Disclosed no conflict of interest. Horton, Edward S. �� Disclosed no conflict of interest. Harris, Stewart B. �� Consultant: Abbott, AstraZeneca, Boehringer Ingelheim Hoshen, Moshe �� Disclosed no conflict of interest. Pharmaceuticals, Inc., Eli Lilly Canada Inc., Hou, Yonyyong �� Disclosed no conflict of interest. Janssen Pharmaceuticals, Inc., Novo Nordisk Inc., Houlind, Kim �� Disclosed no conflict of interest. Sanofi;Research Support: Abbott, AstraZeneca, Howard, Andrew �� Employee: Merck & Co., Inc. Boehringer Ingelheim Pharmaceuticals, Inc., Janssen Howell, Scott K. �� Disclosed no conflict of interest.

LB107 AUTHOR RELATIONSHIP/COMPANY AUTHOR RELATIONSHIP/COMPANY Howles, Philip �� Disclosed no conflict of interest. Jani, Nisha �� Disclosed no conflict of interest. Hsu, Tzu Yu �� Disclosed no conflict of interest. Janssen, Robert �� Disclosed no conflict of interest. Hu, Charlie Changzhi �� Employee: Eli Lilly and Company. Jarolim, Petr �� Research Support: Takeda Development Center Americas, Hu, Frank B. �� Disclosed no conflict of interest. Inc. Hu, Qiong �� Disclosed no conflict of interest. Javadi, Pasha �� Employee: Sanofi Canada. Hu, Xiaobin �� Disclosed no conflict of interest. Jayne, Charles �� Disclosed no conflict of interest. Hu, Zhibin �� Disclosed no conflict of interest. Jedynasty, Krystyna �� Other Relationship: Bayer HealthCare, Eli Lilly and Huang, Elbert S. �� Disclosed no conflict of interest. Company, Merck & Co., Inc., Novo Nordisk, Pfizer Inc., Huang, Hu �� Disclosed no conflict of interest. Sanofi. Huang, Jingqi �� Research Support: Pharmaron, Inc. Jenkins, Bonnie �� Disclosed no conflict of interest. Huang, Po Hsun �� Disclosed no conflict of interest. Jenkins, Todd �� Disclosed no conflict of interest. Huang, Yu �� Disclosed no conflict of interest. Jenkinson, Lesley �� Employee: AstraZeneca. Huang, Zheng �� Employee: Eli Lilly and Company. Jensen, Michael D. �� Disclosed no conflict of interest. Huang, Zhijiang �� Disclosed no conflict of interest. Jeong, Yoo Mi �� Disclosed no conflict of interest. Huard, Kim �� Employee: Pfizer Inc. Jermutus, Lutz �� Employee: MedImmune, LLC.; Stock/Shareholder: Hudak, Carolyn �� Disclosed no conflict of interest. AstraZeneca. Huffard, Adrian �� Disclosed no conflict of interest. Ji, Jiachao �� Disclosed no conflict of interest. Hughes, Thomas �� Employee: Zafgen; Stock/Shareholder: Zafgen. Ji, Li �� Disclosed no conflict of interest. Hui, Queenie �� Disclosed no conflict of interest. Ji, Linong �� Consultant: Bayer HealthCare, Boehringer Ingelheim Hulme, Maigan A. �� Disclosed no conflict of interest. Pharmaceuticals, Inc., Eli Lilly and Company, Hulver, Matthew W. �� Disclosed no conflict of interest. Merck & Co., Inc., Novartis Pharmaceuticals Hummer, Tim �� Employee: AstraZeneca. Corporation, Novo Nordisk Inc., Roche Hunt, Kelly J. �� Disclosed no conflict of interest. Pharmaceuticals, Sanofi U.S., Takeda Pharmaceutical Hunt, Sharon �� Disclosed no conflict of interest. Company Limited; Research Support: Roche Hussain, Azad �� Disclosed no conflict of interest. Pharmaceuticals, Sanofi U.S. Hussein, Zanariah �� Disclosed no conflict of interest. Jia, Weiping �� Disclosed no conflict of interest. Hutchison, Alan L. �� Disclosed no conflict of interest. Jiang, Dongdong �� Disclosed no conflict of interest. Huyck, Susan �� Employee: Merck & Co., Inc., Merck & Co., Inc. (Spouse/ Jiang, Guozhi �� Disclosed no conflict of interest. Partner); Stock/Shareholder: Merck & Co., Inc., Merck Jiang, Mao �� Disclosed no conflict of interest. & Co., Inc. (Spouse/Partner). Jideonwo, Victoria N. �� Disclosed no conflict of interest. Huynh, Johnny �� Consultant: Intarcia Therapeutics, Inc. Jimenez, Veronica �� Disclosed no conflict of interest. Huynh, Toan �� Disclosed no conflict of interest. Jimenez-Vega, Jose �� Disclosed no conflict of interest. Hyde, Craig L. �� Employee: Pfizer Inc. Jin, Tianru �� Disclosed no conflict of interest. Iaccarino, Guido �� Disclosed no conflict of interest. Joers, James �� Disclosed no conflict of interest.

A U THOR D I SCLOS RE Igel, Leon �� Disclosed no conflict of interest. Joh, Tenshang �� Employee: Pfizer Inc.;Stock/Shareholder : Pfizer Inc. Ignotz, Keith �� Employee: Freedom Meditech, Inc. Johnson, Dana �� Employee: Janssen Pharmaceuticals, Inc.; Stock/ Ilany, Jacob �� Research Support: Medtronic MiniMed, Inc. Shareholder: Johnson & Johnson. Imershein, Sarah G. �� Disclosed no conflict of interest. Johnson, Jeremy �� Employee: Merck & Co., Inc; Stock/Shareholder: Merck & Inagaki, Nobuya �� Consultant: Arkray Marketing, Inc., Novo Nordisk Inc.; Co., Inc. Research Support: Astellas Pharma Inc., Boehringer Johnson, Jordan M. �� Disclosed no conflict of interest. Ingelheim Japan, Inc., Daiichi-Sankyo Co., Ltd., Johnson, Karen C. �� Disclosed no conflict of interest. Dainippon Sumitomo Pharma Co., Ltd., Eli Lilly Japan Jonas, Jean-Christophe �� Disclosed no conflict of interest. K.K., Fujifilm Pharma Co., Ltd., Japan Tobacco Inc., Jones, Bronwen �� Disclosed no conflict of interest. Kissei Pharmaceutical Co., Ltd., Kyowa Hakko Kirin Jones, Jessica �� Employee: Pfizer Inc. Co., Ltd., Merck Sharp & Dohme Corp., Mitsubishi Jones, Marie �� Disclosed no conflict of interest. Tanabe Pharma Corporation, Novartis Pharma K.K., Jose, Anju �� Disclosed no conflict of interest. Ono Pharmaceutical Co., Ltd., Pfizer Japan Inc., Joshee, Prakriti �� Disclosed no conflict of interest. Sanofi K.K., Sanwa Kagaku Kenkyusho Co., Ltd., Joshi, Shashank R. �� Advisory Panel: Abbott, Novo Nordisk Inc., Roche Shiratori Pharmaceutical Co., Ltd., Taisho Toyama Diagnostics, Sanofi K.K., Takeda Pharmaceutical Pharmaceutical Co., Ltd., Takeda Pharmaceutical Company Limited; Consultant: Bayer Zydus, Franco Company Limited, Tsumura & Co.; Speaker’s Bureau: India, Johnson & Johnson, Marico, Pfizer Inc., Sanofi Arkray Marketing, Inc., Astellas Pharma Inc., K.K., USV, Zydus Cadila; Research Support: Marico; Boehringer Ingelheim Japan, Inc., Daiichi-Sankyo Co., Speaker’s Bureau: Abbott, Alkem, AstraZeneca, Ltd., Dainippon Sumitomo Pharma Co., Ltd., Eisai Co., Boehringer Ingelheim Pharmaceuticals, Inc., Dr. Ltd., Eli Lilly Japan K.K., Japan Tobacco Inc., Johnson Reddys Laboratories, Eli Lilly and Company, Intas, & Johnson, Kowa Pharmaceutical Co. Ltd., Merck Johnson & Johnson, Merck Sharp & Dohme Corp., Sharp & Dohme Corp., Mitsubishi Tanabe Pharma Novartis Pharmaceuticals Corporation, Novo Nordisk Corporation, Novo Nordisk Inc., Ono Pharmaceutical Inc., Serdia, Sun, USV. Co., Ltd., Sanofi K.K., Taisho Toyama Pharmaceutical Jung, Chang Hee �� Disclosed no conflict of interest. Co., Ltd., Takeda Pharmaceutical Company Limited; Just, Rasmus �� Employee: Zealand Pharma A/S; Stock/Shareholder: Other Relationship: Daiichi-Sankyo Co., Ltd. Zealand Pharma A/S. Inge, Thomas H. �� Disclosed no conflict of interest. Kadaria, Dipen �� Disclosed no conflict of interest. Ipp, Eli �� Disclosed no conflict of interest. Kahl, Steven D. �� Employee: Eli Lilly and Company. Ito, Yusuke �� Employee: Nissan Chemical Industries, Ltd. Kahle, Melanie �� Disclosed no conflict of interest. Jabbour, Serge A. �� Consultant: AstraZeneca, Eli Lilly and Company, Janssen Kahn, Barbara B. �� Disclosed no conflict of interest. Pharmaceuticals, Inc.; Speaker’s Bureau: AstraZeneca, Kalliokoski, Kari K. �� Disclosed no conflict of interest. Eli Lilly and Company, Janssen Pharmaceuticals, Inc. Kallus, Nathan �� Disclosed no conflict of interest. Jackson, Charles Van �� Employee: PreClinOmics, A Crown Bioscience Company. Kammel, Anne �� Disclosed no conflict of interest. Jackson, George L. �� Disclosed no conflict of interest. Kamon, Junji �� Employee: Nissan Chemical Industries, Ltd. Jackson, LaDonya �� Disclosed no conflict of interest. Kanasaki, Keizo �� Advisory Panel: Boehringer Ingelheim GmbH; Employee: Jackson, Penny �� Disclosed no conflict of interest. Kanazawa Medical University; Research Support: Jackson, Sam �� Disclosed no conflict of interest. Asteras, Boehringer Ingelheim GmbH, Mitsubishi Jackson, Sandra �� Research Support: Amylin Pharmaceuticals, LLC. Tanabe, Ono Pharmaceutical Co., Sanofi;Speaker’s Jacobs, Peter G. �� Board Member: Pacific Diabetes Technologies, Inc.;Stock/ Bureau: Asteras, Boehringer Ingelheim GmbH, Eli Shareholder: Pacific Diabetes Technologies, Inc. Lilly and Company, Novartis AG, Sanofi, Sumitomo Jacome-Sosa, Miriam �� Disclosed no conflict of interest. Dainippon Pharma. Jaen, Maria L. �� Disclosed no conflict of interest. Kang, Liya �� Employee: Pfizer Inc. Jaishy, Bharat �� Disclosed no conflict of interest. Kang, Minsung �� Disclosed no conflict of interest. Jakubowicz, Daniela �� Disclosed no conflict of interest. Kaplan, Lee M. �� Consultant: GI Dynamics, Inc. Jambrina, Claudia �� Disclosed no conflict of interest. Karasseva, Natalia �� Disclosed no conflict of interest. James, Merrygay �� Disclosed no conflict of interest. Kariyawasam, Dulmini �� Disclosed no conflict of interest. Jang, Hak C. �� Disclosed no conflict of interest. Karnatak, Rajendra K. �� Disclosed no conflict of interest. Jang, Younghwan �� Disclosed no conflict of interest. Karnchanasorn, Rudruidee �� Disclosed no conflict of interest.

LB108 AUTHOR RELATIONSHIP/COMPANY AUTHOR RELATIONSHIP/COMPANY Karpati, Tomas �� Disclosed no conflict of interest. Krastins, Bryan �� Employee: Nuclea Biotechnologies. Karter, Andrew J. �� Disclosed no conflict of interest. Kraus, Bettina J. �� Disclosed no conflict of interest. Karunakaran, Jayakumar �� Disclosed no conflict of interest. Krishna Reddy, Harsha �� Disclosed no conflict of interest. Kaspers, Stefan �� Employee: Boehringer Ingelheim GmbH. Krohn, Knut �� Disclosed no conflict of interest. Katikaneni, Ranjitha �� Disclosed no conflict of interest. Kroon, Tobias �� Disclosed no conflict of interest. Kattan, Michael W. �� Research Support: Merck & Co., Inc., Novo Nordisk Inc. Kubisiak, Kristine �� Disclosed no conflict of interest. Katz, Lorraine E. �� Disclosed no conflict of interest. Kuhadiya, Nitesh D. �� Disclosed no conflict of interest. Katz, Michelle L. �� Disclosed no conflict of interest. Kumar, Anjali �� Disclosed no conflict of interest. Kaufman, Francine R. �� Employee: Medtronic MiniMed, Inc. Kumar, Rekha �� Disclosed no conflict of interest. Kavanagh, Deirdre M. �� Disclosed no conflict of interest. Kumar, Sunil �� Disclosed no conflict of interest. Keating, Patricia �� Disclosed no conflict of interest. Kuo, Chin Sung �� Disclosed no conflict of interest. Keles, Sunduz �� Disclosed no conflict of interest. Kuo, Ming Shang �� Employee: Eli Lilly and Company. Keller, Mark �� Disclosed no conflict of interest. Kupfer, Stuart �� Employee: Takeda Development Center Americas, Inc. Keller, Susanna �� Disclosed no conflict of interest. Kusters, Dennis �� Disclosed no conflict of interest. Kelly-Boruff, Kathleen M. �� Employee: Eli Lilly and Company; Stock/Shareholder: Eli Kusunoki, Masataka �� Other Relationship: Kaken Pharmaceutical Co., Ltd., Lilly and Company. Ono Pharmaceutical Co., Ltd., Taisho Toyama Kelsey, Megan M. �� Disclosed no conflict of interest. Pharmaceutical Co., Ltd. Kemppainen, Jukka �� Disclosed no conflict of interest. Kvist, Kajsa �� Employee: Novo Nordisk A/S. Kendall, Heather �� Disclosed no conflict of interest. Kwak, Soo Heon �� Disclosed no conflict of interest. Kener, Kyle B. �� Disclosed no conflict of interest. Kwek, Kenneth �� Disclosed no conflict of interest. Keselowsky, Benjamin �� Disclosed no conflict of interest. Laber, Samantha �� Disclosed no conflict of interest. Keske, Michelle A. �� Disclosed no conflict of interest. Lacampagne, Alain �� Disclosed no conflict of interest. Khakharia, Anjali �� Disclosed no conflict of interest. Lackey, Denise �� Disclosed no conflict of interest. Khanna, Deepika �� Disclosed no conflict of interest. Lacy, Eilyn R. �� Employee: Janssen Pharmaceuticals, Inc.; Stock/ Khripun, Irina A. �� Disclosed no conflict of interest. Shareholder: Johnson & Johnson. Khunti, Kamlesh �� Advisory Panel: AstraZeneca, Novartis AG, Sanofi U.S.; Laeger, Thomas �� Disclosed no conflict of interest. Research Support: AstraZeneca, Novartis AG, Sanofi Laffel, Lori M. �� Consultant: AstraZeneca, Boehringer Ingelheim U.S.; Speaker’s Bureau: AstraZeneca, Novartis AG, Pharmaceuticals, Inc., Dexcom, Inc., Eli Lilly and Sanofi U.S. Company, Johnson & Johnson, Novo Nordisk Inc., Kihm, Anthony �� Employee: Janssen Pharmaceuticals, Inc.; Stock/ Roche Diagnostics, Sanofi U.S. Shareholder: Johnson & Johnson. Lai, Chin Hu �� Disclosed no conflict of interest. Kilcharan Singh, Harvinder �� Disclosed no conflict of interest. Lai, Kevin �� Disclosed no conflict of interest. Kim, Byung Joon �� Disclosed no conflict of interest. Laing, Brenton T. �� Disclosed no conflict of interest. Kim, David �� Disclosed no conflict of interest. Laiteerapong, Neda �� Disclosed no conflict of interest.

Kim, Dennis �� Employee: Zafgen; Stock/Shareholder: Zafgen. Lakhter, Alexander J. �� Disclosed no conflict of interest. A U THOR D I SCLOS RE Kim, Jae Hyeon �� Disclosed no conflict of interest. Lamb, Stephanie �� Disclosed no conflict of interest. Kim, Kook Hwan �� Disclosed no conflict of interest. Lamoureux, Ecosse �� Disclosed no conflict of interest. Kim, Kyoung Min �� Disclosed no conflict of interest. Lan, Hui Yao �� Disclosed no conflict of interest. Kim, Lee Kyung �� Disclosed no conflict of interest. Landau, Zohar �� Disclosed no conflict of interest. Kim, Seong Hun �� Disclosed no conflict of interest. Lane, Wendy S. �� Advisory Panel: Insulet Corporation, Novo Nordisk A/S; Kim, Sin Gon �� Disclosed no conflict of interest. Consultant: Insulet Corporation, Novo Nordisk A/S; Kim, Sun H. �� Disclosed no conflict of interest. Research Support: Eli Lilly and Company, Novo Kim, Sung Woo �� Disclosed no conflict of interest. Nordisk A/S; Speaker’s Bureau: Novo Nordisk A/S. Kim, Sungho �� Disclosed no conflict of interest. Lang, Jia Nan �� Disclosed no conflict of interest. Kim, Terri �� Employee: Zafgen; Stock/Shareholder: Zafgen. Lariosa, Samanta �� Disclosed no conflict of interest. Kirchner, Thomas �� Employee: Janssen Pharmaceuticals, Inc.; Stock/ Lark, Daniel �� Disclosed no conflict of interest. Shareholder: Johnson & Johnson. Larsen, Jane �� Employee: Novo Nordisk A/S; Stock/Shareholder: Novo Kirk, Rikke �� Employee: Novo Nordisk A/S; Stock/Shareholder: Novo Nordisk A/S. Nordisk A/S. Lassen, Annmarie T. �� Disclosed no conflict of interest. Kirkland, Melissa �� Disclosed no conflict of interest. Lathkar-Pradhan, Sangeeta �� Disclosed no conflict of interest. Klammt, Sebastian �� Disclosed no conflict of interest. Lau, Raymond G. �� Disclosed no conflict of interest. Klein, Richard L. �� Disclosed no conflict of interest. Lauring, Brett �� Employee: Merck & Co., Inc; Stock/Shareholder: Merck & Kleinman, Nora J. �� Employee: Gather Health; Stock/Shareholder: Gather Co., Inc. Health. Lauterbach, B. �� Stock/Shareholder: Saniplus Apotheken B. Lauterbach Klingensmith, Georgeanna J. �� Disclosed no conflict of interest. E.K. Klonoff, David �� Disclosed no conflict of interest. Lavallette, Lucille �� Employee: Eli Lilly and Company. Klöting, Nora �� Disclosed no conflict of interest. Lavrador, Maria Silvia �� Disclosed no conflict of interest. Knapp, Rebecca G. �� Disclosed no conflict of interest. Le, Nhan �� Disclosed no conflict of interest. Knapp, Rebecca R. �� Disclosed no conflict of interest. Le, Thuy �� Disclosed no conflict of interest. Knocke, Maria �� Disclosed no conflict of interest. Leal, Ermelindo C. �� Disclosed no conflict of interest. Knowler, William C. �� Disclosed no conflict of interest. Lee, An Sheng �� Disclosed no conflict of interest. Kobes, Sayuko �� Disclosed no conflict of interest. Lee, Byung Wan �� Disclosed no conflict of interest. Kocalis, Heidi �� Disclosed no conflict of interest. Lee, Charles �� Employee: AstraZeneca. Kocsis, Gyozo �� Advisory Panel: Novo Nordisk A/S; Consultant: Medtronic, Lee, Dong Hwa �� Disclosed no conflict of interest. Inc.; Research Support: Medtronic, Inc. Lee, Heung Man �� Disclosed no conflict of interest. Koenigsrainer, Alfred �� Disclosed no conflict of interest. Lee, Jennifer �� Disclosed no conflict of interest. Kohler, Sven �� Employee: Boehringer Ingelheim GmbH. Lee, Kwan Woo �� Disclosed no conflict of interest. Koike, Marcia �� Disclosed no conflict of interest. Lee, Moon Kyu �� Disclosed no conflict of interest. Koitka-Weber, Audrey �� Employee: Boehringer Ingelheim Pharma GmbH & Co. KG. Lee, Myung Shik �� Disclosed no conflict of interest. Kollar, Laura �� Disclosed no conflict of interest. Lee, Scott �� Employee: Medtronic MiniMed, Inc. Kong, Alice P. �� Disclosed no conflict of interest. Lee, Seon �� Disclosed no conflict of interest. Kong, Sheldon X. �� Employee: Novo Nordisk Inc. Lee, Seung Hwan �� Disclosed no conflict of interest. Konkar, Anish �� Employee: AstraZeneca. Lee, Seunghun P. �� Disclosed no conflict of interest. Koska, Juraj �� Disclosed no conflict of interest. Lee, Sojung �� Disclosed no conflict of interest. Kovacs, Peter �� Disclosed no conflict of interest. Lee, Tom �� Disclosed no conflict of interest. Kovatchev, Boris P. �� Advisory Panel: Dexcom, Inc., Sanofi-Aventis Deutschland Lee, Verna �� Disclosed no conflict of interest. GmbH; Research Support: BD Medical-Diabetes Care, Lee, Woo Je �� Disclosed no conflict of interest. Dexcom, Inc., Roche Diagnostics, Sanofi-Aventis Lee, Yun Sok �� Disclosed no conflict of interest. Deutschland GmbH, Tandem Diabetes Care, Inc.; Lei, Helena �� Disclosed no conflict of interest. Speaker’s Bureau: Dexcom, Inc.; Stock/Shareholder: Lei, Lanyu �� Research Support: Takeda Development Center Americas, Inspark LLC, TypeZero Technologies LLC. Inc. Kramer, Michael �� Disclosed no conflict of interest. Leibel, Natasha �� Disclosed no conflict of interest. Kramer, William �� Consultant: PhaseBio Pharmaceuticals, Inc. Leibrand, Scott M. �� Disclosed no conflict of interest.

LB109 AUTHOR RELATIONSHIP/COMPANY AUTHOR RELATIONSHIP/COMPANY Lemoine, Lori M. �� Disclosed no conflict of interest. Lottenberg, Ana Maria �� Disclosed no conflict of interest. Leon, Xavier �� Disclosed no conflict of interest. Loureiro, Marisa �� Disclosed no conflict of interest. Lerario, Antonio M. �� Disclosed no conflict of interest. Lu, Jiahui �� Disclosed no conflict of interest. Leroy, Bruno �� Employee: Sanofi;Stock/Shareholder : Sanofi. Lu, Juming �� Advisory Panel: Sanofi Investment Co. Ltd.;Consultant : Lessem, Sarah �� Disclosed no conflict of interest. Sanofi Investment Co. Ltd. Letourneau, Lisa �� Disclosed no conflict of interest. Lu, Mingjian �� Employee: Eli Lilly and Company. Leventer-Roberts, Maya �� Disclosed no conflict of interest. Lu, Yang �� Disclosed no conflict of interest. Levisetti, Matteo �� Employee: Mirati Therapeutics; Stock/Shareholder: Mirati Lucidi, Paola �� Disclosed no conflict of interest. Therapeutics. Luk, Andrea O. �� Disclosed no conflict of interest. Levitsky, Lynne �� Disclosed no conflict of interest. Lund, Søren �� Employee: Boehringer Ingelheim GmbH. Lewis, Anjana Patel �� Employee: Eli Lilly and Company. Lundequist, Anders �� Disclosed no conflict of interest. Lewis, Cora E. �� Disclosed no conflict of interest. Luo, Xie �� Disclosed no conflict of interest. Lewis, Dana M. �� Disclosed no conflict of interest. Lutchmansingh, Khama �� Disclosed no conflict of interest. Lewis, Jamal �� Disclosed no conflict of interest. Luzio, Stephen D. �� Disclosed no conflict of interest. Li, Dandan �� Disclosed no conflict of interest. Lv, Dayu �� Disclosed no conflict of interest. Li, Haidong �� Disclosed no conflict of interest. Lv, Tiantian �� Disclosed no conflict of interest. Li, Haiyan �� Disclosed no conflict of interest. Lv, You �� Disclosed no conflict of interest. Li, Hung Yuan �� Disclosed no conflict of interest. Lynch, Cheryl P. �� Disclosed no conflict of interest. Li, Jie �� Disclosed no conflict of interest. Ma, Ronald C. �� Consultant: AstraZeneca, Takeda Pharmaceutical Li, Juansheng �� Disclosed no conflict of interest. Company Limited. Li, Ling Jun �� Disclosed no conflict of interest. Ma, Wei �� Disclosed no conflict of interest. Li, Wen Hong �� Disclosed no conflict of interest. Ma, Xiaosu �� Employee: Eli Lilly and Company. Li, Xian �� Disclosed no conflict of interest. Ma, Yan �� Disclosed no conflict of interest. Li, Xiaoming �� Disclosed no conflict of interest. Ma, Yunbing �� Disclosed no conflict of interest. Li, Yang �� Employee: Eli Lilly and Company. Mabus, John �� Employee: Janssen Pharmaceuticals, Inc.; Stock/ Li, Yiming �� Disclosed no conflict of interest. Shareholder: Johnson & Johnson. Li, Ying �� Disclosed no conflict of interest. Macauley, Shannon L. �� Disclosed no conflict of interest. Li, Yufeng �� Disclosed no conflict of interest. Macdonald, Jennifer �� Disclosed no conflict of interest. Li, Yutian �� Disclosed no conflict of interest. Machado, Ubiratan F. �� Disclosed no conflict of interest. Li, Zhuo �� Disclosed no conflict of interest. Machann, Jürgen �� Disclosed no conflict of interest. Liang, Feng �� Research Support: Pharmaron, Inc. Macias, Johana �� Disclosed no conflict of interest. Liang, Yin �� Employee: Johnson & Johnson. MacKenzie, Marsha �� Disclosed no conflict of interest. Liao, Chen Di �� Disclosed no conflict of interest. MacLeish, Sarah �� Disclosed no conflict of interest. Libby, Andrew �� Disclosed no conflict of interest. Madanahalli, Jagannath R. �� Disclosed no conflict of interest.

A U THOR D I SCLOS RE Libman De Gordon, Ingrid B. �� Disclosed no conflict of interest. Maddison, Lisette A. �� Disclosed no conflict of interest. Lieberman, Gabriella �� Advisory Panel: AstraZeneca, Boehringer Ingelheim, Eli Mader, Julia K. �� Advisory Panel: Boehringer Ingelheim GmbH, Eli Lilly Lilly and Company, Novo Nordisk A/S, Sanofi;Other and Company, Sanofi-Aventis Deutschland GmbH; Relationship: Novo Nordisk A/S. Consultant: BD Medical-Diabetes Care; Speaker’s Lilleøre, Søren K. �� Employee: Novo Nordisk A/S, Novo Nordisk A/S (Spouse/ Bureau: AstraZeneca, Eli Lilly and Company, Roche Partner); Stock/Shareholder: Novo Nordisk A/S. Diagnostics, Sanofi-Aventis Deutschland GmbH, Lim, Cadmon K. �� Disclosed no conflict of interest. Takeda Development Centre Europe Ltd. Lim, Soo �� Disclosed no conflict of interest. Madsbad, Sten �� Advisory Panel: AstraZeneca, Boehringer Ingelheim Lin, Chien Te �� Disclosed no conflict of interest. GmbH, Eli Lilly and Company, Intarcia Therapeutics, Lin, Hua V. �� Employee: Eli Lilly and Company. Inc., Johnson & Johnson, Merck Sharp & Dohme Lin, James �� Disclosed no conflict of interest. Corp., Novo Nordisk A/S, Sanofi-Aventis Deutschland Lin, Shing Jong �� Disclosed no conflict of interest. GmbH; Research Support: Novo Nordisk A/S; Lin, Tom �� Disclosed no conflict of interest. Speaker’s Bureau: AstraZeneca, Boehringer Ingelheim Lin, Yu Kuei �� Disclosed no conflict of interest. GmbH, Bristol-Myers Squibb Company, Eli Lilly and Lindauer, Katherine �� Disclosed no conflict of interest. Company, Merck Sharp & Dohme Corp., Novartis Lineswala, Jayana P. �� Employee: Eli Lilly and Company. Pharmaceuticals Corporation, Novo Nordisk A/S, Lingham, Russell �� Employee: Janssen Pharmaceuticals, Inc.; Stock/ Sanofi-Aventis Deutschland GmbH. Shareholder: Johnson & Johnson. Magee, Matthew J. �� Disclosed no conflict of interest. Lithovius, Raija �� Disclosed no conflict of interest. Magee, Michelle F. �� Consultant: American Diabetes Association, Sanofi U.S.; Little, Stuart A. �� Disclosed no conflict of interest. Research Support: Eli Lilly and Company. Liu, En �� Disclosed no conflict of interest. Maggioni, Luca �� Disclosed no conflict of interest. Liu, Feng �� Disclosed no conflict of interest. Mahan, Thomas E. �� Disclosed no conflict of interest. Liu, Franklin �� Employee: Merck & Co., Inc; Research Support: Merck & Maher, Danielle �� Employee: Arkray USA. Co., Inc. Maheshwari, Anuj �� Disclosed no conflict of interest. Liu, Jianying �� Disclosed no conflict of interest. Mahmud, Farid H. �� Disclosed no conflict of interest. Liu, Jin �� Disclosed no conflict of interest. Mai, Tingting �� Disclosed no conflict of interest. Liu, Qian �� Employee: Eli Lilly and Company. Maier, Bernhard F. �� Disclosed no conflict of interest. Liu, Qing �� Disclosed no conflict of interest. Makdissi, Antoine �� Disclosed no conflict of interest. Liu, Rui �� Disclosed no conflict of interest. Makhmutova, Madina �� Disclosed no conflict of interest. Liu, Simin �� Disclosed no conflict of interest. Makinen, Ville-Petteri �� Disclosed no conflict of interest. Liu, Wenjuan �� Disclosed no conflict of interest. Malatesta, JoAnn �� Employee: PhaseBio Pharmaceuticals, Inc. Liu, Xiaobing �� Disclosed no conflict of interest. Malgor, Ramiro �� Disclosed no conflict of interest. Liu, Xilin �� Employee: Eli Lilly and Company. Mallappa, Onkaramurthy �� Disclosed no conflict of interest. Liu, Xin �� Disclosed no conflict of interest. Mallol, Cristina �� Disclosed no conflict of interest. Liu, Yujia �� Disclosed no conflict of interest. Malloy, Jaret �� Employee: Zafgen; Stock/Shareholder: Zafgen. Llisterri Caro, José Luis �� Disclosed no conflict of interest. Malomo, Kenneth �� Disclosed no conflict of interest. Lo, Chunmin �� Disclosed no conflict of interest. Mammen, Anup O. �� Disclosed no conflict of interest. Lockwood, John �� Employee: Eli Lilly and Company. Man, Ryan �� Disclosed no conflict of interest. Lok, Si �� Disclosed no conflict of interest. Manandhar, Smriti �� Disclosed no conflict of interest. Long, Anna E. �� Disclosed no conflict of interest. Mancha-Doblas, Isabel �� Disclosed no conflict of interest. Long, Qi �� Consultant: Amylin Pharmaceuticals, LLC.; Research Mancuso, James �� Employee: Pfizer Inc., Pfizer Inc.Spouse/Partner ( ); Stock/ Support: American Heart Association, Cystic Fibrosis Shareholder: Pfizer Inc. Spouse/Partner( ). Foundation, National Institutes of Health, National Mandalapu, Rathna �� Disclosed no conflict of interest. Science Foundation. Manrique, Camila M. �� Disclosed no conflict of interest. Long, Tao �� Disclosed no conflict of interest. Manseau, Katherine �� Disclosed no conflict of interest. Longenecker, Sarah �� Disclosed no conflict of interest. Marcus, Marsha �� Advisory Panel: Weight Watchers International, Inc. Lopes-Virella, Maria F. �� Disclosed no conflict of interest. Marie, Suely Kazue �� Disclosed no conflict of interest. Lopez, Lizette �� Disclosed no conflict of interest. Marikunte, Venkataranganna V. �� Disclosed no conflict of interest. Lopez, Mary F. �� Employee: Nuclea Biotechnologies. Marinelli Andreoli, Anna �� Disclosed no conflict of interest.

LB110 AUTHOR RELATIONSHIP/COMPANY AUTHOR RELATIONSHIP/COMPANY Marks, Andrew �� Disclosed no conflict of interest. Molano, Damaris Ruth �� Disclosed no conflict of interest. Marling, Cindy �� Disclosed no conflict of interest. Molina, Cesar �� Disclosed no conflict of interest. Marshall, Helen �� Disclosed no conflict of interest. Molina, Judith T. �� Disclosed no conflict of interest. Martin, Megan T. �� Disclosed no conflict of interest. Molina-Vega, María �� Disclosed no conflict of interest. Martin, Tonya �� Disclosed no conflict of interest. Molyneaux, Lynda �� Disclosed no conflict of interest. Martín-Núñez, Gracia M. �� Disclosed no conflict of interest. Monteiro, Maria B. �� Disclosed no conflict of interest. Martyn-Nemeth, Pamela �� Disclosed no conflict of interest. Montgomery, Jazzmyne �� Disclosed no conflict of interest. Marwick, Thomas H. �� Disclosed no conflict of interest. Montiel-Casado, Custodia �� Disclosed no conflict of interest. Maryniuk, Melinda D. �� Disclosed no conflict of interest. Montori, Victor M. �� Disclosed no conflict of interest. Marzban, Lucy �� Disclosed no conflict of interest. Montrose-Rafizadeh, Chahrzad �� Employee: Eli Lilly and Company. Maslova, Ekaterina �� Disclosed no conflict of interest. Moolemath, Yoganand �� Disclosed no conflict of interest. Mather, Kieren J. �� Research Support: Abbott, Merck & Co., Inc., Novo Moon, Jae Hoon �� Disclosed no conflict of interest. Nordisk Inc., Sanofi U.S. Moon, Min Kyong �� Disclosed no conflict of interest. Mathieu, Nicolas �� Disclosed no conflict of interest. Mora-Navas, Laura �� Disclosed no conflict of interest. Mathur, Ashish �� Disclosed no conflict of interest. Morcillo, Sonsoles �� Disclosed no conflict of interest. Matsen, Miles E. �� Disclosed no conflict of interest. More, Vijay �� Disclosed no conflict of interest. Matsubara, Tomoko �� Disclosed no conflict of interest. Moreli, Marcos L. �� Disclosed no conflict of interest. Mauer, S. Michael �� Research Support: Boehringer Ingelheim GmbH. Moreno-Ruiz, Francisco J. �� Disclosed no conflict of interest. Maynard, Greg �� Disclosed no conflict of interest. Morgan, Claire C. �� Disclosed no conflict of interest. Mayoral, Rafael �� Employee: Merck Sharp & Dohme Corp. Morin, Robert �� Employee: Ascensia Diabetes Care. McCall, Kelly �� Disclosed no conflict of interest. Moritz, Wolfgang �� Employee: InSphero AG. McCurdy, Carrie �� Disclosed no conflict of interest. Morral, Nuria �� Disclosed no conflict of interest. McDonald, Matthew W. �� Disclosed no conflict of interest. Morrison, Christopher D. �� Disclosed no conflict of interest. McFarland, Raymie �� Employee: Glytec, Inc. Morró, Meritxell �� Disclosed no conflict of interest. McGavigan, Anne K. �� Disclosed no conflict of interest. Morrow, David A. �� Consultant: Abbott Laboratories, Inc., AstraZeneca McGee, James �� Employee: Eli Lilly and Company. Pharmaceuticals LP, GlaxoSmithKline, Merck & Co., McGill, Janet B. �� Disclosed no conflict of interest. Inc., Roche Diagnostics; Research Support: Abbott McGill, Margaret J. �� Advisory Panel: Abbott Diabetes Care Inc., Merck Sharp Laboratories, Inc., Amgen Inc., AstraZeneca, Daiichi- & Dohme Corp.; Speaker’s Bureau: Abbott Diabetes Sankyo Co., Ltd., Eisai Co., Ltd., Gilead Sciences, Inc., Care Inc., AstraZeneca, Merck Sharp & Dohme Corp., GlaxoSmithKline, Merck & Co., Inc., Novartis, Roche Roche Pharmaceuticals. Diagnostics, Takeda Development Center Americas, McKay, Siripoom V. �� Disclosed no conflict of interest. Inc. McMaster, Christopher �� Disclosed no conflict of interest. Morton, Gregory J. �� Disclosed no conflict of interest. Mcmillan, Ryan �� Disclosed no conflict of interest. Mosely, Kylie �� Research Support: Abbott Diabetes Care Inc.

McMullen, William J. �� Disclosed no conflict of interest. Motiani, Kumail K. �� Disclosed no conflict of interest. A U THOR D I SCLOS RE Meah, Farah �� Disclosed no conflict of interest. Motiani, Piryanka �� Disclosed no conflict of interest. Mechanick, Jeffrey I. �� Disclosed no conflict of interest. Mudgett, John �� Employee: Merck & Co., Inc. Meier, Juris J. �� Advisory Panel: AstraZeneca, Boehringer Ingelheim Muir, Andrew B. �� Disclosed no conflict of interest. GmbH, Bristol-Myers-Squibb, Merck Sharp & Dohme Muller, Yunhua �� Disclosed no conflict of interest. Corp., Novo Nordisk A/S, Sanofi-Aventis Deutschland Mullin, Christopher �� Disclosed no conflict of interest. GmbH; Research Support: Merck Sharp & Dohme Muniyappa, Ranganath �� Disclosed no conflict of interest. Corp., Novartis Pharma GmbH, Novo Nordisk A/S, Muñoz, Sergio �� Disclosed no conflict of interest. Sanofi-Aventis Deutschland GmbH;Speaker’s Bureau: Muñoz-Garach, Araceli �� Disclosed no conflict of interest. AstraZeneca, Berlin-Chemie, Boehringer Ingelheim Murillo Jelsbak, Cristina �� Disclosed no conflict of interest. GmbH, Bristol-Myers-Squibb, Eli Lilly and Company, Murphy, Rinki �� Disclosed no conflict of interest. Merck Sharp & Dohme Corp., Novartis Pharma GmbH, Murray, Michael R. �� Disclosed no conflict of interest. Novo Nordisk Inc., Roche Pharmaceuticals, Sanofi- Musso, Carla �� Disclosed no conflict of interest. Aventis Deutschland GmbH. Muta, Kenjiro �� Disclosed no conflict of interest. Meinicke, Thomas �� Employee: Boehringer Ingelheim Pharma GmbH & Co. KG. Mynatt, Randall L. �� Disclosed no conflict of interest. Melling, C.W. James �� Disclosed no conflict of interest. Nadalin, Silvio �� Disclosed no conflict of interest. Melo, Bernardete F. �� Research Support: GlaxoSmithKline. Nadeau, Kristen J. �� Disclosed no conflict of interest. Men, Lichuang �� Employee: Sanofi Investment Co. Ltd. Nair, Anup K. �� Disclosed no conflict of interest. Menaged, Miriam �� Disclosed no conflict of interest. Naito, Takeshi �� Employee: Nissan Chemical Industries, Ltd. Mende, Christian �� Advisory Panel: Islet Science; Speaker’s Bureau: Najafi, Bijan �� Disclosed no conflict of interest. AstraZeneca, Forest, Janssen. Nakagawa, Takashi �� Disclosed no conflict of interest. Mendes, Natália Ferreira �� Disclosed no conflict of interest. Nakamura, Katherine �� Employee: Dexcom, Inc. Menegaz, Danusa �� Disclosed no conflict of interest. Nakamura, Takao �� Disclosed no conflict of interest. Meo Guzman, Natalia �� Disclosed no conflict of interest. Nakandakare, Edna �� Disclosed no conflict of interest. Mercader, Josep M. �� Disclosed no conflict of interest. Nakatsuka, Yasuhiko �� Employee: Daiichi-Sankyo Co., Ltd. Messner, Simon �� Employee: InSphero AG. Nanjunda, Rupesh K. �� Employee: Janssen Pharmaceuticals, Inc.; Stock/ Mete, Mihriye �� Disclosed no conflict of interest. Shareholder: Johnson & Johnson. Metro, Sarah �� Disclosed no conflict of interest. Narendran, Parth �� Advisory Panel: AstraZeneca, Novo Nordisk A/S; Metzger, Daniel �� Disclosed no conflict of interest. Speaker’s Bureau: AstraZeneca, Eli Lilly Deutschland Miao, Shouwu �� Disclosed no conflict of interest. GmbH, Sanofi U.S. Michael, Mervyn D. �� Disclosed no conflict of interest. Narowski, Tara M. �� Disclosed no conflict of interest. Middelbeek, Roeland J. �� Disclosed no conflict of interest. Nasr, Alexis �� Disclosed no conflict of interest. Miguel-Escalada, Irene �� Disclosed no conflict of interest. Nassar, Carine M. �� Disclosed no conflict of interest. Milinovich, Alex �� Research Support: Merck & Co., Inc., Novo Nordisk Inc. Nathan, Brandon �� Disclosed no conflict of interest. Miller, Kellee M. �� Disclosed no conflict of interest. Nathan, Jaimie �� Disclosed no conflict of interest. Milligan, Paul �� Employee: Eli Lilly and Company. Nathow, Thomas �� Advisory Panel: Novo Nordisk Inc.; Consultant: Ipswich Min, Eun J. �� Disclosed no conflict of interest. General Hospital, Mater Private Hospital, St. Min, Kathryn M. �� Disclosed no conflict of interest. Andrew’s Private Hospital; Speaker’s Bureau: Abbott, Minokoshi, Yasuhiko �� Disclosed no conflict of interest. AstraZeneca, Novo Nordisk Inc., Janssen Biotech, Inc. Mion, François �� Disclosed no conflict of interest. Natsume, Yukie �� Disclosed no conflict of interest. Mireles, Vidal T. �� Disclosed no conflict of interest. Nauck, Michael A. �� Advisory Panel: Berlin-Chemie, Boehringer Ingelheim Mirmira, Raghavendra G. �� Employee: Eli Lilly and Company (Spouse/Partner); GmbH, GlaxoSmithKline, Intarcia Therapeutics, Research Support: Eli Lilly and Company. Merck Sharp & Dohme Corp., Novo Nordisk A/S, Mishra, Shardendu �� Employee: Freedom Meditech, Inc. Inc.; Consultant: AstraZeneca, Boehringer Ingelheim Mishriky, Basem M. �� Disclosed no conflict of interest. GmbH, Eli Lilly and Company, GlaxoSmithKline, Mogensen, Sofia �� Disclosed no conflict of interest. Intarcia Therapeutics, Inc., Merck Sharp & Dohme Mohan, Madhu K. �� Disclosed no conflict of interest. Corp., Novo Nordisk A/S; Research Support: Mohd Ali, Siti Zubaidah �� Disclosed no conflict of interest. AstraZeneca, Merck Sharp & Dohme Corp., Novo Moheet, Amir �� Disclosed no conflict of interest. Nordisk A/S; Speaker’s Bureau: AstraZeneca, Eli Lilly

LB111 AUTHOR RELATIONSHIP/COMPANY AUTHOR RELATIONSHIP/COMPANY and Company, Medscape, Merck Sharp & Dohme Patek, Stephen �� Stock/Shareholder: TypeZero Technologies LLC. Corp., Novartis Pharma GmbH, PeerVoice. Patel, Dhiren �� Advisory Panel: AstraZeneca, Novo Nordisk Inc., Sanofi Nawroth, Peter �� Disclosed no conflict of interest. U.S.; Consultant: AstraZeneca, Novo Nordisk Inc.; Naylor, Jacqui �� Employee: AstraZeneca. Speaker’s Bureau: Merck & Co., Inc., Novo Nordisk Naylor, Rochelle N. �� Disclosed no conflict of interest. Inc., Sanofi U.S. Nedelkov, Dobrin �� Disclosed no conflict of interest. Patel, Jaimy �� Disclosed no conflict of interest. Nedergaard, Jan �� Research Support: Novo Nordisk A/S. Patel, Raj �� Disclosed no conflict of interest. Neelakandhan, Aparna �� Employee: InSphero AG. Patel, Rajesh �� Disclosed no conflict of interest. Nelson, Alexander �� Disclosed no conflict of interest. Patel, Sonal �� Employee: GlaxoSmithKline. Nelson, Andrew N. �� Disclosed no conflict of interest. Paterson, Andrew D. �� Disclosed no conflict of interest. Nelson, Jarrell T. �� Disclosed no conflict of interest. Patricio, Miguel �� Disclosed no conflict of interest. Nelson, Jennifer B. �� Disclosed no conflict of interest. Patton, Ashley �� Disclosed no conflict of interest. Nelson, Randall �� Disclosed no conflict of interest. Pattou, François �� Disclosed no conflict of interest. Neufer, P. Darrell �� Disclosed no conflict of interest. Paul, Pradyut �� Disclosed no conflict of interest. Nickels, J. Zachary �� Disclosed no conflict of interest. Payne, Elizabeth H. �� Disclosed no conflict of interest. Nielsen, Thor S. �� Employee: Novo Nordisk A/S; Stock/Shareholder: Novo Pecik, Ilonka �� Disclosed no conflict of interest. Nordisk A/S. Pehmoller, Christian �� Employee: Pfizer Inc. Nikonova, Elena �� Employee: Artech Information Systems, LLC., Sanofi. Peltonen, Markku �� Disclosed no conflict of interest. Nirantharakumar, Krishnarajah �� Disclosed no conflict of interest. Pence, Sydney �� Disclosed no conflict of interest. Niswender, Kevin �� Disclosed no conflict of interest. Pender, Shiobhan �� Disclosed no conflict of interest. Noble, Earl G. �� Disclosed no conflict of interest. Penfornis, Alfred �� Disclosed no conflict of interest. Nolan, Charles E. �� Employee: Pfizer Inc. Peng, Yongde �� Disclosed no conflict of interest. Nørgaard, Kirsten �� Advisory Panel: Abbott, Medtronic, Inc., Novo Nordisk Perfield, James �� Employee: Eli Lilly and Company. A/S; Research Support: Novo Nordisk A/S, Zealand Perkinson, Robert �� Employee: Janssen Pharmaceuticals, Inc.; Stock/ Pharma A/S; Speaker’s Bureau: Medtronic, Inc., Novo Shareholder: Johnson & Johnson. Nordisk A/S, Roche Diagnostics, Sanofi-Aventis Perkovic, Vlado �� Advisory Panel: AbbVie Inc., AstraZeneca, Boehringer Deutschland GmbH, Zealand Pharma A/S. Ingelheim GmbH, Eli Lilly and Company, Janssen Norquay, Lisa �� Disclosed no conflict of interest. Pharmaceuticals, Inc., Merck KGaA; Consultant: Norwood, Paul �� Research Support: Eli Lilly and Company, Novo Nordisk AbbVie Inc.; Employee: The George Institute for A/S, Sanofi-Aventis Deutschland GmbH. Global Health; Research Support: Abbvie, Janssen. Nunes, Valéria Sutti �� Disclosed no conflict of interest. Peroni, Odile �� Disclosed no conflict of interest. Nunez Lopez, Yury O. �� Disclosed no conflict of interest. Perrin, Laurent �� Employee: Sanofi-Aventis Deutschland GmbH. Nuutila, Pirjo �� Disclosed no conflict of interest. Pers, Tune �� Disclosed no conflict of interest. Oakes, Nicholas D. �� Employee: AstraZeneca. Peter, Rajesh �� Disclosed no conflict of interest.

A U THOR D I SCLOS RE Obici, Silvana �� Disclosed no conflict of interest. Peterson, Richard G. �� Consultant: PreClinOmics. O’Brien, Phillipe D. �� Disclosed no conflict of interest. Petit, Catherine �� Disclosed no conflict of interest. Odugbesan, Ola �� Speaker’s Bureau: Boehringer Ingelheim Pharmaceuticals, Petrone, Marcella �� Employee: MedImmune, LLC.; Stock/Shareholder: Inc., Eli Lilly and Company, Janssen Pharmaceuticals, AstraZeneca, GlaxoSmithKline. Inc., Merck & Co., Inc., Novo Nordisk Inc., Sanofi U.S. Petrov, Aleksandr �� Employee: Merck & Co., Inc. Oh, Tae Jung �� Disclosed no conflict of interest. Pfefferkorn, Jeffrey �� Employee: Pfizer Inc. Okabe, Keisuke �� Disclosed no conflict of interest. Pham, Mirko �� Disclosed no conflict of interest. Okamoto, Shiki �� Disclosed no conflict of interest. Phatak, Sanjeev �� Disclosed no conflict of interest. Olateju, Tolulope O. �� Disclosed no conflict of interest. Philipson, Louis H. �� Disclosed no conflict of interest. Oldfield, Geoffrey S. �� Disclosed no conflict of interest. Philipson, Noah �� Disclosed no conflict of interest. Olefsky, Jerrold M. �� Disclosed no conflict of interest. Philis-Tsimikas, Athena �� Advisory Panel: Dexcom, Inc., Eli Lilly and Company, Oliveira, Denise �� Disclosed no conflict of interest. Voluntis; Consultant: Novo Nordisk A/S, Sanofi U.S.; Olsen, Sjurdur F. �� Disclosed no conflict of interest. Research Support: Amylin Pharmaceuticals, LLC., O’Neal, David N. �� Advisory Panel: Abbott, Firefly Bioworks, Inc., Medtronic, AstraZeneca, Eli Lilly and Company, Genentech, Inc., Inc., Sanofi U.S.;Research Support: Firefly Bioworks, Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Inc., Medtronic, Inc., Sanofi U.S.;Speaker’s Novo Nordisk A/S, Pfizer Inc., Sanofi U.S. Bureau: Medtronic, Inc., Novo Nordisk Inc.; Other Phillips, Lawrence S. �� Advisory Panel: Boehringer Ingelheim Pharmaceuticals, Inc.; Relationship: Novo Nordisk Inc. Research Support: AbbVie Inc., Amylin Pharmaceuticals, Osei, Kwame �� Disclosed no conflict of interest. LLC., Cabernet Pharmaceuticals, Eli Lilly and Company, Oshida, Yoshiharu �� Disclosed no conflict of interest. GlaxoSmithKline, Janssen Pharmaceuticals, Inc., Otto, Keith A. �� Employee: Eli Lilly and Company. Merck & Co., Inc., Novo Nordisk Inc., PhaseBio Ou, Horng Yih �� Disclosed no conflict of interest. Pharmaceuticals, Inc., Roche Pharmaceuticals, Overland, Jane �� Disclosed no conflict of interest. Vascular Pharmaceuticals; Speaker’s Bureau: Amylin Overton, Rahsaan R. �� Disclosed no conflict of interest. Pharmaceuticals, LLC., Novo Nordisk Inc. Owens, David R. �� Disclosed no conflict of interest. Piaggi, Paolo �� Disclosed no conflict of interest. Oz, Gulin �� Disclosed no conflict of interest. Pickov, Victor �� Employee: GlaxoSmithKline. Padilla, Jaume �� Disclosed no conflict of interest. Pieber, Thomas R. �� Advisory Panel: AstraZeneca, Bristol-Myers Squibb Paez, Vivien Camille �� Disclosed no conflict of interest. Company, Eli Lilly and Company, Novo Nordisk A/S, Palaia, Thomas �� Disclosed no conflict of interest. Roche Diagnostics; Employee: CBmed-Center for Palermo, Joseph �� Disclosed no conflict of interest. Biomarker Research in Medicine; Research Support: Palyha, Oksana �� Employee: Merck Sharp & Dohme Corp. Novo Nordisk A/S. Pan, An �� Disclosed no conflict of interest. Pierre, Suzanne �� Employee: Sanofi;Stock/Shareholder : Sanofi. Pang, Zhen �� Employee: Crown Bioscience, Inc. Pileggi, Antonello �� Disclosed no conflict of interest. Pantalone, Kevin M. �� Consultant: Eli Lilly and Company, Merck & Co., Inc., Novo Pinheiro, Marcelo M. �� Speaker’s Bureau: Merck Sharp & Dohme Corp. Nordisk Inc.; Research Support: Merck & Co., Inc., Piotrowicz, Agata K. �� Disclosed no conflict of interest. Novo Nordisk Inc.; Speaker’s Bureau: AstraZeneca, Pi-Sunyer, Xavier �� Disclosed no conflict of interest. Merck & Co., Inc., Novo Nordisk Inc., Sanofi U.S. Pittas, Anastassios G. �� Disclosed no conflict of interest. Pardo, Scott �� Employee: Ascensia Diabetes Care. Planas-Fèlix, Mercè �� Disclosed no conflict of interest. Park, Chang �� Disclosed no conflict of interest. Plank, Lindsay �� Disclosed no conflict of interest. Park, Cheol Young �� Disclosed no conflict of interest. Plum-Morschel, Leona �� Employee: Profil Institute for Clinical Research, Inc. Park, Hanjong �� Disclosed no conflict of interest. Plutzky, Jorge �� Consultant: Amylin Pharmaceuticals, AstraZeneca, Bristol- Park, Hyeong Kyu �� Disclosed no conflict of interest. Myers Squibb, Daiichi Sankyo, Eli Lilly and Company, Park, Kyong Soo �� Disclosed no conflict of interest. Ember Therapeutics, GlaxoSmithKline, Merck & Co., Park, Se Eun �� Disclosed no conflict of interest. Inc., NovoNordisk, Pfizer Inc., Roche/Genentech, Park, Yoo Jin �� Disclosed no conflict of interest. Takeda, Vivus; Research Support: Bristol-Myers Parks, Elizabeth J. �� Disclosed no conflict of interest. Squibb, GlaxoSmithKline. Parone, Philippe A. �� Disclosed no conflict of interest. Pocai, Alessandro �� Disclosed no conflict of interest. Pasquel, Francisco �� Consultant: Merck & Co., Inc. Pogach, Leonard �� Disclosed no conflict of interest. Passarelli, Marisa �� Disclosed no conflict of interest. Pollock, Benjamin �� Disclosed no conflict of interest.

LB112 AUTHOR RELATIONSHIP/COMPANY AUTHOR RELATIONSHIP/COMPANY Polonsky, Kenneth S. �� Disclosed no conflict of interest. Reges, Orna �� Disclosed no conflict of interest. Polonsky, William H. �� Consultant: Abbott, AstraZeneca, Boehringer Ingelheim Reid, Timothy �� Speaker’s Bureau: Boehringer Ingelheim Pharmaceuticals, Pharmaceuticals, Inc., Dexcom, Inc., Eli Lilly and Inc., Eli Lilly and Company, Janssen Pharmaceuticals, Company, Intarcia Therapeutics, Inc., Johnson & Inc., Novo Nordisk Inc., Sanofi U.S. Johnson, Merck & Co., Inc., Novo Nordisk Inc., Roche Reifel Miller, Anne �� Employee: Eli Lilly and Company. Pharmaceuticals, Sanofi U.S. Ren, Decheng �� Disclosed no conflict of interest. Polsky, Sarit �� Research Support: Dexcom, Inc. Ren, Xiaowei �� Disclosed no conflict of interest. Ponce, Oscar J. �� Disclosed no conflict of interest. Renn, Martha H. �� Disclosed no conflict of interest. Porcellati, Francesca �� Disclosed no conflict of interest. Resalat, Navid �� Disclosed no conflict of interest. Pottegaard, Anton �� Disclosed no conflict of interest. Reutelingsperger, Chris �� Disclosed no conflict of interest. Pouderoux, Philippe �� Disclosed no conflict of interest. Revelo, Xavier �� Disclosed no conflict of interest. Poulsen, Per L. �� Disclosed no conflict of interest. Rewers, Marian �� Disclosed no conflict of interest. Powell, Folami L. �� Disclosed no conflict of interest. Rey Aldana, Daniel �� Disclosed no conflict of interest. Pownall, Henry J. �� Disclosed no conflict of interest. Reynolds, Evan �� Disclosed no conflict of interest. Pozzi, Ambra �� Disclosed no conflict of interest. Reynolds, Merrick S. �� Disclosed no conflict of interest. Prada, Patricia O. �� Disclosed no conflict of interest. Rezner, Betsy �� Disclosed no conflict of interest. Prager, Rudolf �� Advisory Panel: Boehringer Ingelheim Pharmaceuticals, Inc., Rhee, Mary �� Disclosed no conflict of interest. Eli Lilly and Company, Merck Sharp & Dohme Corp., Rhee, Sang Youl �� Disclosed no conflict of interest. Novo Nordisk A/S, Sanofi-Aventis Deutschland GmbH. Ribeiro-Oliveira, Antonio �� Disclosed no conflict of interest. Prakash, Prashant �� Disclosed no conflict of interest. Riccardi, Keith �� Employee: Pfizer Inc. Pratley, Richard �� Consultant: AstraZeneca, Boehringer Ingelheim Rice, Karen �� Disclosed no conflict of interest. Pharmaceuticals, Inc., Eli Lilly and Company, Rickman, Colin �� Disclosed no conflict of interest. GlaxoSmithKline, Hanmi Pharmaceutical Co., Ricordi, Camilo �� Disclosed no conflict of interest. Ltd., Janssen Pharmaceuticals, Inc., Ligand Riddle, Matthew C. �� Consultant: AstraZeneca, Biodel, Elcelyx, Pharmaceuticals, Inc., Merck & Co., Inc., Novo GlaxoSmithKline, Sanofi, Valeritas;Research Support: Nordisk Inc., Takeda; Research Support: Eli Lilly AstraZeneca, Eli Lilly and Company, Novo Nordisk, and Company, Merck & Co., Inc., Novo Nordisk Inc., Sanofi. Sanofi-Aventis U.S., LLC, Takeda;Speaker’s Bureau: Rideout, Drew �� Disclosed no conflict of interest. AstraZeneca, Novo Nordisk Inc; Other Relationship: Ridge, Terry �� Advisory Panel: Novo Nordisk A/S, Sanofi-Aventis Novo Nordisk Inc. Deutschland GmbH; Research Support: Eisai Co., Pratt, Edward John �� Employee: Eli Lilly and Company. Ltd., Eli Lilly and Company, Merck Sharp & Dohme Preiser, Nick �� Disclosed no conflict of interest. Corp., Novartis AG, Novo Nordisk A/S, Sanofi- Previs, Stephen �� Employee: Merck Sharp & Dohme Corp. Aventis Deutschland GmbH, Takeda Development Price, Olga �� Disclosed no conflict of interest. Center Americas, Inc.; Speaker’s Bureau: Janssen

Proietto, Joseph �� Consultant: AstraZeneca, iNova, Novo Nordisk Inc., Pharmaceuticals, Inc., Novo Nordisk A/S. A U THOR D I SCLOS RE Zafgen; Other Relationship: Zafgen. Ringgaard, Steffen �� Disclosed no conflict of interest. Pu, Hongquan �� Disclosed no conflict of interest. Riopel, Matthew �� Disclosed no conflict of interest. Pu, Wenji �� Employee: MedImmune, LLC.; Stock/Shareholder: Ritzén, Hanna �� Disclosed no conflict of interest. AstraZeneca. Robbins, Dave �� Disclosed no conflict of interest. Puffing, Adelheid �� Disclosed no conflict of interest. Roberts, Adam �� Disclosed no conflict of interest. Purvis, Gareth S. �� Disclosed no conflict of interest. Robic, Jessica �� Disclosed no conflict of interest. Pyle, Laura �� Disclosed no conflict of interest. Robinson, Ali �� Employee: GlaxoSmithKline. Qi, Jenson �� Disclosed no conflict of interest. Robinson, Steven �� Disclosed no conflict of interest. Qian, Jinqiao �� Disclosed no conflict of interest. Robshaw, Ashley �� Disclosed no conflict of interest. Qian, Ying �� Disclosed no conflict of interest. Roca-Rodríguez, M. Mar �� Disclosed no conflict of interest. Qian, Yuewei �� Employee: Eli Lilly and Company. Rodgers Fischl, Andrea �� Disclosed no conflict of interest. Qiao, Jiqiu �� Employee: Crown Bioscience, Inc. Rodo, Jordi �� Disclosed no conflict of interest. Qiao, Wei �� Employee: Crown Bioscience, Inc. Rodriguez Diaz, Rayner �� Disclosed no conflict of interest. Qiu, Gaokun �� Disclosed no conflict of interest. Rodriguez-Cañete, Alberto �� Disclosed no conflict of interest. Qiu, Yanping �� Employee: Merck Sharp & Dohme Corp. Rodriguez-Diaz, Rayner �� Disclosed no conflict of interest. Queiroz, Marcia S. �� Disclosed no conflict of interest. Rodríguez-Fos, Elias �� Disclosed no conflict of interest. Quinn, Lauretta T. �� Disclosed no conflict of interest. Rodriguez-Gutierrez, Rene �� Disclosed no conflict of interest. Quinn, Laurie �� Disclosed no conflict of interest. Rodriguez-Pacheco, Francisca �� Disclosed no conflict of interest. Quintana-Lopez, Laura �� Disclosed no conflict of interest. Rogers, Suzanne �� Disclosed no conflict of interest. Quittner, Claudia �� Disclosed no conflict of interest. Rohm, Theresa �� Disclosed no conflict of interest. Rabaglia, Mary �� Disclosed no conflict of interest. Rojeski, Maria �� Employee: Sanofi;Stock/Shareholder : Sanofi. Rabasa-Lhoret, Remi �� Disclosed no conflict of interest. Rolin, Bidda �� Employee: Novo Nordisk A/S; Stock/Shareholder: Novo Radwan, Amr �� Disclosed no conflict of interest. Nordisk A/S. Ragolia, Louis �� Disclosed no conflict of interest. Roma, Leticia P. �� Disclosed no conflict of interest. Rajappan, Anoopraj �� Disclosed no conflict of interest. Rondinone, Cristina �� Employee: MedImmune, LLC.; Stock/Shareholder: Rakipovski, Günaj �� Employee: Novo Nordisk A/S; Stock/Shareholder: Novo AstraZeneca. Nordisk A/S. Ropert, Alain �� Disclosed no conflict of interest. Ramanadham, Sasanka M. �� Disclosed no conflict of interest. Rosenfarb, Johanna �� Disclosed no conflict of interest. Ramnarain, Nishan �� Employee: GlaxoSmithKline. Rosenstock, Julio �� Disclosed no conflict of interest. Ranjan, Ajenthen �� Research Support: Danish Diabetes Academy. Rosmarin, Melanie �� Disclosed no conflict of interest. Ranjan, Saurabh �� Disclosed no conflict of interest. Rothenberg, Richard B. �� Disclosed no conflict of interest. Rankin, Matthew M. �� Disclosed no conflict of interest. Rothermel, Caitlin �� Consultant: Monarch Medical Technologies. Rao, Ambika �� Disclosed no conflict of interest. Ruan, Hai Bin �� Disclosed no conflict of interest. Rasulnia, Mazi �� Disclosed no conflict of interest. Ruan, Xiangbo �� Disclosed no conflict of interest. Rath, Michaela �� Disclosed no conflict of interest. Rubin, Daniel J. �� Research Support: AstraZeneca, National Institute Raun, Kirsten �� Employee: Novo Nordisk A/S. of Diabetes and Digestive and Kidney Diseases, Ravikumar Jayakumari, Nandini �� Disclosed no conflict of interest. National Institutes of Health. Ray, Jason D. �� Disclosed no conflict of interest. Rubin, Gil �� Employee: Eli Lilly and Company; Stock/Shareholder: Eli Raynel, Sarah �� Disclosed no conflict of interest. Lilly and Company. Raz, Itamar �� Advisory Panel: Eli Lilly and Company. Ruiz, Rafaela �� Disclosed no conflict of interest. Razjouyan, Javad �� Disclosed no conflict of interest. Rumpler, Markus �� Disclosed no conflict of interest. Reaume, Andrew G. �� Disclosed no conflict of interest. Ryan, Terence E. �� Disclosed no conflict of interest. Reaven, Gerald M. �� Disclosed no conflict of interest. Saad, Mário José Abdala �� Disclosed no conflict of interest. Reaven, Peter D. �� Research Support: Novo Nordisk A/S. Sabate, Jean-Marc �� Disclosed no conflict of interest. Reddivari, Bharathi �� Disclosed no conflict of interest. Saboo, Banshi �� Disclosed no conflict of interest. Reddy, Ravi �� Disclosed no conflict of interest. Sabouri, Mohsen �� Disclosed no conflict of interest. Reed, Brian �� Disclosed no conflict of interest. Sacks, Harold Scott �� Disclosed no conflict of interest. Rees, Jordan �� Disclosed no conflict of interest. Sacramento, Joana F. �� Research Support: GlaxoSmithKline.

LB113 AUTHOR RELATIONSHIP/COMPANY AUTHOR RELATIONSHIP/COMPANY Sacre, Julian W. �� Disclosed no conflict of interest. Shah, Sanjiv �� Advisory Panel: Boehringer Ingelheim Pharmaceuticals, Sacristan, Victor �� Disclosed no conflict of interest. Inc., Eli Lilly and Company, Eris Lifesciences, Gather Safikhan, Nooshin �� Disclosed no conflict of interest. Health, Sanofi-Aventis Deutschland GmbH, Torrent Safo, Sandra E. �� Disclosed no conflict of interest. Pharmaceuticals Ltd, USV India; Speaker’s Bureau: Saghatelian, Alan �� Disclosed no conflict of interest. AstraZeneca, Bayer HealthCare, Boehringer Ingelheim Sahaf, Newsha �� Disclosed no conflict of interest. Pharmaceuticals, Inc., Eli Lilly and Company, Sanofi- Sakurada, Brian �� Employee: Novo Nordisk Inc. Aventis Deutschland GmbH, USV India; Stock/ Saleem, Moin A. �� Disclosed no conflict of interest. Shareholder: Gather Health. Salsali, Afshin �� Employee: Boehringer Ingelheim Pharmaceuticals, Inc. Shah, Vinit �� Disclosed no conflict of interest. Samoa, Raynald �� Disclosed no conflict of interest. Shang, Jin �� Employee: Merck & Co., Inc. Sanchez Quintero, Maria �� Disclosed no conflict of interest. Shankar, R. Ravi �� Employee: Merck & Co., Inc; Stock/Shareholder: Merck & Sánchez, Friman �� Disclosed no conflict of interest. Co., Inc. Santamaria, Jimena �� Disclosed no conflict of interest. Shankar, Sudha S. �� Employee: Eli Lilly and Company, Merck & Co., Inc. Santa-Sosa, Eileen �� Disclosed no conflict of interest. (Spouse/Partner); Stock/Shareholder: Eli Lilly and Santo González, Armando �� Disclosed no conflict of interest. Company, Merck & Co., Inc. (Spouse/Partner). Santos, Julia M. �� Disclosed no conflict of interest. Shannon, Megan �� Employee: Pfizer Inc.;Stock/Shareholder : Pfizer Inc. Santos, Laila R. �� Disclosed no conflict of interest. Shao, Weijuan �� Disclosed no conflict of interest. Santos-Bezerra, Daniele P. �� Disclosed no conflict of interest. Sharma, Kumar �� Advisory Panel: Boehringer Ingelheim GmbH; Employee: Santulli, Gaetano �� Disclosed no conflict of interest. University of California; Research Support: Boehringer Sanyoura, May �� Disclosed no conflict of interest. Ingelheim GmbH, Merck & Co., Inc; Speaker’s Bureau: Saputelli, Raymond J. �� Disclosed no conflict of interest. Merck & Co., Inc. Saraiva, Luis R. �� Disclosed no conflict of interest. Shaw, James A. �� Disclosed no conflict of interest. Saremi, Aramesh �� Disclosed no conflict of interest. Sheehan, John J. �� Employee: AstraZeneca. Sarfo Kantanka, Osei �� Disclosed no conflict of interest. Shen, Hongbing �� Disclosed no conflict of interest. Sarwar, Komil N. �� Disclosed no conflict of interest. Shen, Jie �� Disclosed no conflict of interest. Sasako, Shigetada �� Employee: Nissan Chemical Industries, Ltd. Shen, Xiaolan �� Employee: Merck Sharp & Dohme Corp. Sasikala Rajendran, Raji �� Disclosed no conflict of interest. Shepard, Jaclyn A. �� Disclosed no conflict of interest. Sasikaladevi Rajendran, Raji �� Disclosed no conflict of interest. Sherrod, Julie �� Disclosed no conflict of interest. Satapati, Santhosh �� Disclosed no conflict of interest. Shi, Leon �� Disclosed no conflict of interest. Sathe, Anita �� Disclosed no conflict of interest. Shi, Yuji �� Employee: Pfizer Inc. Sato, Daisuke �� Disclosed no conflict of interest. Shi, Yun �� Disclosed no conflict of interest. Sato, Kyoko K. �� Disclosed no conflict of interest. Shi, Zhiqing �� Employee: REMD Biotherapeutics, Inc. Sato, Tatsuya �� Disclosed no conflict of interest. Shibata, Mikiko �� Disclosed no conflict of interest. Saur, Didier �� Employee: Pfizer Inc. Shin, John �� Employee: Medtronic MiniMed, Inc.

A U THOR D I SCLOS RE Saussenthaler, Sophie �� Disclosed no conflict of interest. Shin, Myung �� Employee: Merck & Co., Inc. Savolainen, Anna M. �� Disclosed no conflict of interest. Shinjo, Sueli O. �� Disclosed no conflict of interest. Saw, Seang Mei �� Disclosed no conflict of interest. Shiosakai, Kazuhito �� Employee: Daiichi-Sankyo Co., Ltd. Scarazzini, Silvia �� Disclosed no conflict of interest. Shirakawa, Jun �� Disclosed no conflict of interest. Schenk, Simon �� Disclosed no conflict of interest. Shoemaker, Daniel �� Disclosed no conflict of interest. Scherer, Norbert F. �� Disclosed no conflict of interest. Showalter, Aaron D. �� Employee: Eli Lilly and Company. Scherer, Philipp E. �� Disclosed no conflict of interest. Shu, Hua �� Disclosed no conflict of interest. Schernthaner, Guntram �� Advisory Panel: Boehringer Ingelheim GmbH; Employee: Shu, Tian �� Disclosed no conflict of interest. Rudolfstiftung Hospital Vienna. Shukla, Alpana P. �� Disclosed no conflict of interest. Schick, Fritz �� Disclosed no conflict of interest. Siau, Evan �� Disclosed no conflict of interest. Schleicher, Erwin �� Disclosed no conflict of interest. Siegel, Dionicio R. �� Disclosed no conflict of interest. Schmidt, Signe �� Advisory Panel: Roche Diagnostics; Consultant: Novo Siegel-Axel, Dorothea I. �� Disclosed no conflict of interest. Nordisk A/S, Unomedical; Speaker’s Bureau: Roche Sikes, Kristin �� Disclosed no conflict of interest. Diagnostics, Sanofi U.S.;Other Relationship: Sims, Emily K. �� Disclosed no conflict of interest. Medtronic, Inc., Novo Nordisk A/S, Roche Sinari, Shripad �� Disclosed no conflict of interest. Diagnostics. Singh, Vikram �� Disclosed no conflict of interest. Schmidt, Ulrike �� Disclosed no conflict of interest. Singham, Stephanie �� Disclosed no conflict of interest. Schmidt, Vanessa �� Disclosed no conflict of interest. Sivasailam, Ashok �� Disclosed no conflict of interest. Schmitt, Patricia �� Disclosed no conflict of interest. Siwakoti, Krishmita �� Disclosed no conflict of interest. Schneid, Rudi �� Consultant: Freedom Meditech, Inc. Sjöholm, Kajsa �� Stock/Shareholder: Pfizer Inc. Schreiner, Birgit �� Disclosed no conflict of interest. Skarbaliene, Jolanta �� Employee: Zealand Pharma A/S; Stock/Shareholder: Schueler, Kathy �� Disclosed no conflict of interest. Zealand Pharma A/S. Schulz, Tim J. �� Disclosed no conflict of interest. Skarulis, Monica C. �� Disclosed no conflict of interest. Schürmann, Annette �� Disclosed no conflict of interest. Skelton, Graham S. �� Disclosed no conflict of interest. Schwanbeck, Maria �� Disclosed no conflict of interest. Skinner, Timothy C. �� Disclosed no conflict of interest. Schwartz, Ann V. �� Disclosed no conflict of interest. Skjøth, Trine V. �� Employee: Novo Nordisk A/S; Stock/Shareholder: Schwartz, David D. �� Disclosed no conflict of interest. Novo Nordisk A/S, Novo Nordisk A/S (Spouse/ Schwartz, Frank �� Research Support: Medtronic MiniMed, Inc. Partner). Schwartz, Michael W. �� Research Support: Novo Nordisk Inc. Skolnik, Neil �� Advisory Panel: AstraZeneca, Boehringer Ingelheim Schwenk, Robert �� Disclosed no conflict of interest. Pharmaceuticals, Inc., Eli Lilly and Company, Novartis, Seaquist, Elizabeth R. �� Advisory Panel: Medtronic; Consultant: Locemia, Novo Sanofi, Teva. Nordisk; Research Support: Eli Lilly and Company. Slim, Ka �� Disclosed no conflict of interest. Seel, Maureen �� Disclosed no conflict of interest. Sloop, Kyle W. �� Employee: Eli Lilly and Company. Seemungal, Terence �� Disclosed no conflict of interest. Slover, Robert �� Research Support: Medtronic MiniMed, Inc. Segal, David G. �� Other Relationship: Novo Nordisk A/S. Smith, Valerie A. �� Disclosed no conflict of interest. Segundo, Carmen �� Disclosed no conflict of interest. Sneed, Bria �� Disclosed no conflict of interest. Selzer, Sandi �� Disclosed no conflict of interest. Snell-Bergeon, Janet K. �� Disclosed no conflict of interest. Sen Ten, En �� Disclosed no conflict of interest. So, Wing Yee �� Disclosed no conflict of interest. Seng, Thomas �� Employee: Eli Lilly and Company. Solimando, Fernando �� Employee: Boehringer Ingelheim GmbH. Senior, Peter �� Disclosed no conflict of interest. Solito, Egle �� Disclosed no conflict of interest. Senne-Duff, Beth C. �� Stock/Shareholder: Gilead Sciences, Inc. (Spouse/ Song, Kelley �� Disclosed no conflict of interest. Partner), Johnson & Johnson. Song, Min �� Employee: Eli Lilly and Company. Sereika, Susan M. �� Disclosed no conflict of interest. Song, Tony �� Disclosed no conflict of interest. Serpas, Lilian �� Disclosed no conflict of interest. Song, Wei �� Disclosed no conflict of interest. Seyhan, Attila �� Disclosed no conflict of interest. Song, Yiqing �� Disclosed no conflict of interest. Sforza, Noelia �� Disclosed no conflict of interest. Song, Zhuolun �� Disclosed no conflict of interest. Sha, Sue �� Employee: Janssen Research & Development, LLC. Sørensen, Anja E. �� Disclosed no conflict of interest. Shah, Amy S. �� Disclosed no conflict of interest. Soroka, Orysya �� Disclosed no conflict of interest. Shah, Rachana �� Disclosed no conflict of interest. Sound, Ruby �� Disclosed no conflict of interest.

LB114 AUTHOR RELATIONSHIP/COMPANY AUTHOR RELATIONSHIP/COMPANY Sourij, Harald �� Advisory Panel: Amgen Inc., AstraZeneca Takahashi, Diana �� Disclosed no conflict of interest. Pharmaceuticals LP, Boehringer Ingelheim GmbH, Takikawa, Akiko �� Disclosed no conflict of interest. Eli Lilly and Company, Merck Sharp & Dohme Corp., Talal, Talal K. �� Disclosed no conflict of interest. Novartis Pharma AG, Novo Nordisk A/S; Employee: Tam, Claudia C. �� Disclosed no conflict of interest. Center for Biomarker Research in Medicine, Sanofi- Tamarina, Natalia �� Disclosed no conflict of interest. Aventis Deutschland GmbH; Research Support: Tamas, Margery J. �� Employee: Institute for Medical and Nursing Education; AstraZeneca Pharmaceuticals LP, Boehringer Stock/Shareholder: General Electric, Google. Ingelheim GmbH, Merck Sharp & Dohme Corp.; Tamayo, Raul A. �� Disclosed no conflict of interest. Speaker’s Bureau: AstraZeneca Pharmaceuticals LP, Tamborlane, William V. �� Disclosed no conflict of interest. Bayer HealthCare, Boehringer Ingelheim GmbH, Eli Tan, Ruo Ding �� Consultant: Intarcia Therapeutics, Inc. Lilly and Company, Merck Sharp & Dohme Corp., Tanenberg, Robert J. �� Disclosed no conflict of interest. Novartis AG, Novo Nordisk A/S, Sanofi-Aventis Tang, Huilin �� Disclosed no conflict of interest. Deutschland GmbH, Takeda Pharmaceutical Tang, Nelsn �� Disclosed no conflict of interest. Company Limited. Tankisi, H. �� Disclosed no conflict of interest. Souza, Arnaldo H. �� Disclosed no conflict of interest. Tansey, Michael �� Disclosed no conflict of interest. Speight, Jane �� Advisory Panel: Roche Diagnostics; Consultant: Abbott Tavares, Francis �� Disclosed no conflict of interest. Diabetes Care Inc., Janssen Pharmaceuticals, Inc., Taylor, Kristin �� Employee: Zafgen; Stock/Shareholder: Zafgen. Roche Diagnostics, Sanofi ANZ;Research Support: Teelucksingh, Surujpal �� Disclosed no conflict of interest. Medtronic, Inc., Sanofi ANZ;Speaker’s Bureau: Abbott Terauchi, Yasuo �� Disclosed no conflict of interest. Diabetes Care Inc., Johnson & Johnson Diabetes Terpstra, Melissa �� Disclosed no conflict of interest. Institute, Roche Diagnostics, Sanofi ANZ;Other Terra, Steven �� Employee: Pfizer Inc.;Stock/Shareholder : Pfizer Inc. Relationship: Eli Lilly and Company, Medtronic, Inc., Tersey, Sarah A. �� Disclosed no conflict of interest. Merck Sharp & Dohme Corp., Novo Nordisk Inc., Tessem, Jeffery S. �� Disclosed no conflict of interest. Roche Diagnostics, Sanofi ANZ. Thai, Le May �� Disclosed no conflict of interest. Spencer Bonilla, Gabriela �� Disclosed no conflict of interest. Tharappel, Anil M. �� Disclosed no conflict of interest. Sprague, Jennifer �� Disclosed no conflict of interest. Thayer, Debra W. �� Disclosed no conflict of interest. Stager, William �� Employee: Sanofi U.S. Thieme, Karina �� Disclosed no conflict of interest. Staimez, Lisa R. �� Disclosed no conflict of interest. Thiemermann, Chris �� Disclosed no conflict of interest. Stanley, Molly �� Disclosed no conflict of interest. Thomas, Catherine �� Disclosed no conflict of interest. Stanton, Robert C. �� Advisory Panel: Boehringer Ingelheim GmbH; Employee: Thomas, Rebecca L. �� Disclosed no conflict of interest. Harvard Medical Schoo, Joslin Diabetes Center. Thompson, Lisa �� Disclosed no conflict of interest. Stapleton, Donald �� Disclosed no conflict of interest. Thompson, Michael J. �� Disclosed no conflict of interest. Starkstein, Sergio S. �� Disclosed no conflict of interest. Thottungal Parambil, Sulfath �� Disclosed no conflict of interest. Steck, Andrea �� Disclosed no conflict of interest. Thuma, Jean �� Disclosed no conflict of interest.

Stefano, Leone �� Disclosed no conflict of interest. Tian, Lili �� Disclosed no conflict of interest. A U THOR D I SCLOS RE Stefanovski, Darko �� Disclosed no conflict of interest. Timshel, Pascal �� Disclosed no conflict of interest. Steineck, Isabelle �� Research Support: Danish Diabetes Academy, Zealand Tinahones, Francisco J. �� Disclosed no conflict of interest. Pharma A/S; Speaker’s Bureau: Roche Diagnostics, Tobacman, Joanne K. �� Disclosed no conflict of interest. Rubin Medical. Tobe, Kazuyuki �� Disclosed no conflict of interest. Stepnaova, Maria �� Disclosed no conflict of interest. Togashi, Yu �� Disclosed no conflict of interest. Stevens, Joseph R. �� Disclosed no conflict of interest. Tomlinson, Brian �� Disclosed no conflict of interest. Stevens, Tyler �� Disclosed no conflict of interest. Toppila, Iiro �� Disclosed no conflict of interest. Stevenson, Jonathan �� Disclosed no conflict of interest. Torre, Barrett �� Disclosed no conflict of interest. Stewart, John �� Employee: Sanofi;Stock/Shareholder : Sanofi. Torrents, David �� Disclosed no conflict of interest. Stewart, Joshua �� Disclosed no conflict of interest. Toto, Robert �� Advisory Panel: Boehringer Ingelheim GmbH; Employee: Stewart, Sunita �� Disclosed no conflict of interest. University of Texas Southwestern Medical Center. Stoppa, Caroline L. �� Disclosed no conflict of interest. Touhamy, Samir �� Disclosed no conflict of interest. Strange, Poul �� Consultant: PhaseBio Pharmaceuticals, Inc. Towers, Megan �� Disclosed no conflict of interest. Streetman, Jordan �� Disclosed no conflict of interest. Trast, Jeniece �� Disclosed no conflict of interest. Strizek, Alena �� Employee: Eli Lilly and Company. Trefts, Elijah �� Disclosed no conflict of interest. Strøm, Marin �� Disclosed no conflict of interest. Trenchevska, Olgica �� Disclosed no conflict of interest. Stuchlik, Patrick �� Disclosed no conflict of interest. Trevaskis, James L. �� Employee: AstraZeneca. Stuckey, Bronwyn G. �� Research Support: Bayer HealthCare, Eli Lilly and Trikha, Saurabh �� Disclosed no conflict of interest. Company. Tripathi, Anand V. �� Disclosed no conflict of interest. Stumvoll, Michael �� Disclosed no conflict of interest. Troelsen, Lone N. �� Employee: Novo Nordisk A/S. Sturla, Laura �� Disclosed no conflict of interest. Trosclair, Lexie �� Disclosed no conflict of interest. Suckow, Arthur T. �� Employee: AstraZeneca. Truong, Christopher �� Disclosed no conflict of interest. Sue, Nancy �� Disclosed no conflict of interest. Tryggestad, Jeanie B. �� Disclosed no conflict of interest. Suh, Sunghwan �� Disclosed no conflict of interest. Tsalikian, Eva �� Disclosed no conflict of interest. Sun, Changhao �� Disclosed no conflict of interest. Tse, Hubert M. �� Disclosed no conflict of interest. Sun, Cheng Lin �� Disclosed no conflict of interest. Tseng, Chin Lin �� Disclosed no conflict of interest. Sun, Guofeng �� Employee: Crown Bioscience, Inc. Tso, Patrick �� Disclosed no conflict of interest. Sun, Jennifer K. �� Advisory Panel: Allergan, Inc., Eleven Biotherapeutics, Tsui, Stephen K. �� Disclosed no conflict of interest. Novartis Pharmaceuticals Corporation, Regeneron Tsukiyama, Shuji �� Employee: Daiichi Sankyo Development Ltd. Pharmaceuticals, Inc.; Consultant: Kowa Company, Tsushima, Kensuke �� Disclosed no conflict of interest. Ltd.; Research Support: Boston Micromachines, Turchetti, Lucia �� Disclosed no conflict of interest. Genentech, Inc., Optovue; Other Relationship: Bayer Turkistani, Sarah �� Disclosed no conflict of interest. HealthCare. Tuttle, Edward �� Consultant: Intarcia Therapeutics, Inc. Sun, Jiuru �� Disclosed no conflict of interest. Twahirwa, Marcel B. �� Disclosed no conflict of interest. Sun, Juan �� Disclosed no conflict of interest. Twigg, Stephen M. �� Advisory Panel: Abbott Diabetes Care Inc., AstraZeneca, Sun, Li Ping �� Disclosed no conflict of interest. Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly Sun, Min �� Disclosed no conflict of interest. and Company, Novo Nordisk Inc., Sanofi-Aventis Sun, Qi �� Disclosed no conflict of interest. Deutschland GmbH, Takeda Pharmaceutical Company Sunga, Sheila �� Employee: Merck & Co., Inc; Stock/Shareholder: Merck & Limited; Speaker’s Bureau: AstraZeneca, Merck Co., Inc. Sharp & Dohme Corp., Novartis Pharmaceuticals Surendran, Sneha �� Disclosed no conflict of interest. Corporation, Novo Nordisk Inc., Sanofi-Aventis Syed, Farooq �� Disclosed no conflict of interest. Deutschland GmbH, Servier, Takeda Pharmaceutical Syed, Ismail �� Disclosed no conflict of interest. Company Limited. Szeto, Cheuk Chun �� Disclosed no conflict of interest. Udata, Chandrasekhar �� Employee: Pfizer Inc.;Stock/Shareholder : Pfizer Inc. Szeto, Daphne �� Disclosed no conflict of interest. Uehara, Shinichiro �� Disclosed no conflict of interest. Tacke, Robert �� Disclosed no conflict of interest. Ullal, Jagdeesh �� Disclosed no conflict of interest. Taguchi, Takashi �� Employee: Daiichi-Sankyo Co., Ltd. Umpierrez, Guillermo E. �� Advisory Panel: AstraZeneca, Boehringer Ingelheim Tajima, Kazuki �� Disclosed no conflict of interest. Pharmaceuticals, Inc., Merck & Co., Inc., Novo

LB115 AUTHOR RELATIONSHIP/COMPANY AUTHOR RELATIONSHIP/COMPANY Nordisk Inc., Regeneron Pharmaceuticals, Inc., Sanofi Wang, Xiaobin �� Disclosed no conflict of interest. U.S.; Consultant: AstraZeneca, Boehringer Ingelheim Wang, Xiaohong �� Disclosed no conflict of interest. Pharmaceuticals, Inc., Merck & Co., Inc., Novo Wang, Xiaoli �� Employee: Crown Bioscience, Inc. Nordisk Inc., Regeneron Pharmaceuticals, Inc., Sanofi Wang, Xuesong �� Employee: Eli Lilly and Company. U.S.; Research Support: AstraZeneca, Boehringer Wang, Yanjun �� Disclosed no conflict of interest. Ingelheim Pharmaceuticals, Inc., Merck & Co., Inc., Wang, Yixin (Jim) �� Employee: Crown Bioscience, Inc. Novo Nordisk Inc., Sanofi U.S. Wang, Zhao �� Disclosed no conflict of interest. Underland, Lisa J. �� Disclosed no conflict of interest. Wang, Zhihong �� Disclosed no conflict of interest. Urbina, Elaine �� Other Relationship: Atcor Medical. Wang, Zong Wei �� Disclosed no conflict of interest. Usui, Isao �� Disclosed no conflict of interest. Warnock, Garth L. �� Disclosed no conflict of interest. Vaag, Allan A. �� Disclosed no conflict of interest. Warren, Curtis R. �� Disclosed no conflict of interest. Vadali, Gouri �� Employee: Nuclea Biotechnologies. Warren, Mark �� Advisory Panel: Eli Lilly and Company, Novo Nordisk Vaeggemose, Michael �� Disclosed no conflict of interest. Inc.; Research Support: Boehringer Ingelheim Valdes, Sergio �� Disclosed no conflict of interest. Pharmaceuticals, Inc., Bristol-Myers Squibb, Valduga, Claudete J. �� Disclosed no conflict of interest. Daiichi-Sankyo Co., Ltd., Eli Lilly and Company, Valk, Tim �� Consultant: Admetsys; Stock/Shareholder: Admetsys. Janssen Pharmaceuticals, Inc., Mylan, Novartis Valls Roca, Francisco �� Disclosed no conflict of interest. Pharmaceuticals Corporation, Novo Nordisk Inc., Pfizer Van Pelt, Douglas W. �� Disclosed no conflict of interest. Inc., Sanofi-Aventis Deutschland GmbH, Shire, VPI; Varga, Gabor �� Employee: Eli Lilly and Company. Speaker’s Bureau: AstraZeneca, Eli Lilly and Company, Vasandani, Chandna �� Disclosed no conflict of interest. Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Velayudhan Pillai, Vivek �� Disclosed no conflict of interest. Novo Nordisk Inc., Sanofi-Aventis Deutschland GmbH, Vellanki, Priyathama �� Consultant: Merck & Co., Inc. Shire. Venkatesh, Y. Swamy �� Disclosed no conflict of interest. Washio, Takuo �� Employee: Daiichi-Sankyo Co., Ltd. Venkatraman, Skrikanth �� Disclosed no conflict of interest. Wasserman, David H. �� Disclosed no conflict of interest. Ventura, Adriana D. �� Disclosed no conflict of interest. Wasserman, Rachel M. �� Disclosed no conflict of interest. Vera, Elsa �� Disclosed no conflict of interest. Watkins, Elaine �� Disclosed no conflict of interest. Vera, Nicholas �� Employee: Pfizer Inc. Webber, Larry �� Disclosed no conflict of interest. Vergara Martín, Jesús �� Disclosed no conflict of interest. Wei, Jung Nan �� Disclosed no conflict of interest. Verkerke, Anthony R. �� Disclosed no conflict of interest. Weingarten, Anika �� Disclosed no conflict of interest. Verma, Narsingh �� Disclosed no conflict of interest. Weinstein, Alexander M. �� Disclosed no conflict of interest. Vernochet, Cecile �� Employee: Pfizer Inc. Weinstock, Ruth S. �� Research Support: Calibra Medical, Intarcia Therapeutics, Veron, Delma �� Disclosed no conflict of interest. Inc., Medtronic, Inc., Mylan, Novo Nordisk Inc., Sanofi Veron, Dolores �� Disclosed no conflict of interest. U.S. Vieira, Pedro M. �� Disclosed no conflict of interest. Weinzimer, Stuart A. �� Advisory Panel: Insulet Corporation, Medtronic, Inc.;

A U THOR D I SCLOS RE Vieira-Potter, Victoria J. �� Disclosed no conflict of interest. Consultant: Insulet Corporation, Medtronic, Inc., Vijapurkar, Ujjwala �� Employee: Janssen Research & Development, LLC. Tandem Diabetes Care, Inc.; Research Support: Vijayakumar Sreelatha, Harikrishnan �� Disclosed no conflict of interest. Medtronic, Inc.; Stock/Shareholder: Insulet Vilà, Laia �� Disclosed no conflict of interest. Corporation. Villanueva, Veronica �� Disclosed no conflict of interest. Weissmann, Laís �� Disclosed no conflict of interest. Viñuela-González, Laura �� Disclosed no conflict of interest. Weitz, Jonathan �� Disclosed no conflict of interest. Virella, Gabriel �� Disclosed no conflict of interest. Weitz, Jonathan Robbert �� Disclosed no conflict of interest. Virtanen, Kirsi A. �� Disclosed no conflict of interest. Wellenstein, Kerry �� Disclosed no conflict of interest. Visintainer, Paul �� Disclosed no conflict of interest. Wells, Brian J. �� Research Support: Merck & Co., Inc., Novo Nordisk Inc. Viswanathan, Vijay �� Disclosed no conflict of interest. Welly, Rebecca J. �� Disclosed no conflict of interest. Voelmle, Mary K. �� Disclosed no conflict of interest. Wende, Adam R. �� Disclosed no conflict of interest. Vogelsang, Maryann �� Employee: Nuclea Biotechnologies. Weng, Christina �� Disclosed no conflict of interest. Volkening, Lisa K. �� Disclosed no conflict of interest. Weng, Jonathan �� Disclosed no conflict of interest. von Eynatten, Maximilian �� Employee: Boehringer Ingelheim GmbH. Weng, Wayne �� Employee: Novo Nordisk Inc. Vorobyev, Sergey V. �� Disclosed no conflict of interest. Wentzler, Edward J. �� Disclosed no conflict of interest. Voronca, Delia C. �� Disclosed no conflict of interest. Werner, Rudolf �� Disclosed no conflict of interest. Vuitton, Lucine �� Disclosed no conflict of interest. Wernicke-Panten, Karin �� Employee: Sanofi. Wagenknecht, Lynne E. �� Disclosed no conflict of interest. Whaley, Jean �� Employee: Janssen Pharmaceuticals, Inc.; Stock/ Wagner, Robert �� Disclosed no conflict of interest. Shareholder: Johnson & Johnson. Wainstein, Julio �� Disclosed no conflict of interest. Whim, Matthew D. �� Disclosed no conflict of interest. Walker, Julie �� Employee: Arkray USA. White, Michael G. �� Disclosed no conflict of interest. Walker, Rebekah J. �� Disclosed no conflict of interest. White, Morris F. �� Disclosed no conflict of interest. Wallace, Jane �� Employee: Ascensia Diabetes Care. White, Perrin �� Disclosed no conflict of interest. Wallace, Nathaniel �� Employee: Janssen Pharmaceuticals, Inc.; Stock/ White, William B. �� Consultant: Ardea Biosciences, AstraZeneca, Shareholder: Johnson & Johnson. Dendreon Group, Forest Research Institute, Walsh, R. Matthew �� Disclosed no conflict of interest. Roche Pharmaceuticals, St. Jude Medical, Takeda Walter, Mary F. �� Disclosed no conflict of interest. Development Center Americas, Inc., Inc., Teva Wan, Hong �� Employee: Alexo Therapeutics; Stock/Shareholder: Alexo Pharmaceutical Industries Ltd. Therapeutics. Whitehouse, Christina R. �� Disclosed no conflict of interest. Wan, Yun �� Disclosed no conflict of interest. Whittard, Toni �� Employee: Pfizer Inc. Wang, Biao �� Disclosed no conflict of interest. Whitworth, Stephanie R. �� Disclosed no conflict of interest. Wang, Bingdi �� Employee: Crown Bioscience, Inc. Wholey, Sarah �� Disclosed no conflict of interest. Wang, Fang �� Disclosed no conflict of interest. Wiedemann, Monica S. �� Disclosed no conflict of interest. Wang, Fei �� Disclosed no conflict of interest. Willemoes, Rie Juul �� Disclosed no conflict of interest. Wang, Gui Xia �� Disclosed no conflict of interest. Williams, Alistair J. �� Disclosed no conflict of interest. Wang, Han �� Disclosed no conflict of interest. Williams, Ashley �� Disclosed no conflict of interest. Wang, Hong �� Disclosed no conflict of interest. Williams, Joni S. �� Disclosed no conflict of interest. Wang, Hongliang �� Disclosed no conflict of interest. Williams, Paul �� Employee: Freedom Meditech, Inc. Wang, Jiaxin �� Disclosed no conflict of interest. Wilson, Rochelle �� Disclosed no conflict of interest. Wang, Jingru �� Employee: Eli Lilly and Company. Winer, Daniel �� Disclosed no conflict of interest. Wang, Liangsu �� Disclosed no conflict of interest. Winfield, Thomas G. �� Disclosed no conflict of interest. Wang, Manqi �� Disclosed no conflict of interest. Winn, Nathan C. �� Disclosed no conflict of interest. Wang, Pei �� Disclosed no conflict of interest. Winterberg, Pamela �� Disclosed no conflict of interest. Wang, Qian �� Disclosed no conflict of interest. Woerle, Hans J. �� Employee: Boehringer Ingelheim GmbH. Wang, Qinghua �� Disclosed no conflict of interest. Wolf, Michael �� Disclosed no conflict of interest. Wang, Sheng Ping �� Employee: Merck & Co., Inc. Womack, Catherine �� Disclosed no conflict of interest. Wang, Tiansheng �� Disclosed no conflict of interest. Wong, F. Susan �� Disclosed no conflict of interest. Wang, Tongtong �� Employee: Merck & Co., Inc; Stock/Shareholder: Merck & Wong, Tien Yin �� Disclosed no conflict of interest. Co., Inc. Woo, Minna �� Disclosed no conflict of interest.

LB116 AUTHOR RELATIONSHIP/COMPANY AUTHOR RELATIONSHIP/COMPANY Woodford, Makenzie L. �� Disclosed no conflict of interest. Young, Martin E. �� Disclosed no conflict of interest. Woolcott, Orison O. �� Disclosed no conflict of interest. Younossi, Zobair �� Disclosed no conflict of interest. Woolson, Sandra L. �� Disclosed no conflict of interest. Youssef, Gretchen �� Disclosed no conflict of interest. Wroblewski, Kristen E. �� Disclosed no conflict of interest. Yu, Changhong �� Research Support: Merck & Co., Inc., Novo Nordisk Inc. Wu, Jianmin �� Employee: Eli Lilly and Company. Yu, Haoyong �� Disclosed no conflict of interest. Wu, Nan Nan �� Disclosed no conflict of interest. Yu, Liping �� Disclosed no conflict of interest. Wu, Tangchun �� Disclosed no conflict of interest. Yu, Tian �� Disclosed no conflict of interest. Wu, Yan �� Disclosed no conflict of interest. Yu, Tse Ya �� Disclosed no conflict of interest. Wu, Yangfeng �� Disclosed no conflict of interest. Yu, Weichuan �� Disclosed no conflict of interest. Würfel, Josefine �� Disclosed no conflict of interest. Yuan, Sha Sha �� Disclosed no conflict of interest. Wysham, Carol H. �� Advisory Panel: AstraZeneca, Boehringer Ingelheim Yue, Dennis �� Disclosed no conflict of interest. Pharmaceuticals, Inc., Eli Lilly and Company, Zannad, Faiez �� Consultant: Air Liquide, Biotronik, Boston Scientific, Janssen, Sanofi;Consultant : AstraZeneca, Eli Lilly Cardiorenal Diagnostics, Pfizer Inc., St. Jude Medical, and Company, Janssen, Sanofi;Research Support: Takeda Development Center Americas, Inc. AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Zayed, Ahmad �� Disclosed no conflict of interest. Inc., Eli Lilly and Company, Janssen, Merck & Zeitler, Phil �� Consultant: AstraZeneca, Boehringer Ingelheim Co., Inc., Novo Nordisk, Sanofi;Speaker’s Bureau: Pharmaceuticals, Inc., Daiichi-Sankyo Co., Ltd., Eli AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Lilly and Company, Merck & Co., Inc., Takeda. Inc., Eli Lilly and Company, Janssen, Novo Nordisk, Zelada, Henry J. �� Disclosed no conflict of interest. Sanofi. Zeller, Cordula �� Employee: Boehringer Ingelheim GmbH. Xia, Fang �� Disclosed no conflict of interest. Zemel, Michael B. �� Board Member: NuSirt Biopharma; Employee: NuSirt Xiao, Xianchao �� Disclosed no conflict of interest. Biopharma; Stock/Shareholder: NuSirt Biopharma. Xiao, Yong Fu �� Employee: Crown Bioscience, Inc. Zeng, Kejing �� Disclosed no conflict of interest. Xing, Wei �� Disclosed no conflict of interest. Zent, Roy �� Disclosed no conflict of interest. Xu, Jianfeng �� Employee: Eli Lilly and Company. Zenz, Sabine �� Disclosed no conflict of interest. Xu, Kuanfeng �� Disclosed no conflict of interest. Zerbib, Frank �� Disclosed no conflict of interest. Xu, Min �� Disclosed no conflict of interest. Zhang, Chuan Hai �� Disclosed no conflict of interest. Xu, Xiangting �� Disclosed no conflict of interest. Zhang, Chun �� Disclosed no conflict of interest. Xu, Xinyu �� Disclosed no conflict of interest. Zhang, Jianhua �� Employee: Eli Lilly and Company. Xu, Yan �� Disclosed no conflict of interest. Zhang, Jingjing �� Disclosed no conflict of interest. Xue, Jiyan �� Disclosed no conflict of interest. Zhang, Mei �� Disclosed no conflict of interest. Yale, Jean-François �� Advisory Panel: Abbott, AstraZeneca, Boehringer Zhang, Michelle X. �� Employee: Eli Lilly Canada Inc.; Stock/Shareholder: Eli Lilly Ingelheim Pharmaceuticals, Inc., Eli Lilly Canada Canada Inc. Inc., Janssen Pharmaceuticals, Inc., Medtronic, Inc., Zhang, Nannan �� Employee: Eli Lilly and Company.

Merck & Co., Inc., Novo Nordisk Inc., Sanofi, Takeda Zhang, Ning �� Disclosed no conflict of interest. A U THOR D I SCLOS RE Pharmaceutical Company Limited; Research Support: Zhang, Puhong �� Disclosed no conflict of interest. AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Zhang, Quan Jiang �� Disclosed no conflict of interest. Inc., Eli Lilly Canada Inc., Janssen Pharmaceuticals, Zhang, Wei �� Disclosed no conflict of interest. Inc., Medtronic, Inc., Merck & Co., Inc., Mylan, Sanofi; Zhang, Ying �� Disclosed no conflict of interest. Speaker’s Bureau: AstraZeneca, Bayer HealthCare, Zhang, Youtao �� Disclosed no conflict of interest. Boehringer Ingelheim Pharmaceuticals, Inc., Eli Zhang, Zheng �� Disclosed no conflict of interest. Lilly Canada Inc., Janssen Pharmaceuticals, Inc., Zhao, Dong �� Disclosed no conflict of interest. Medtronic, Inc., Merck & Co., Inc., Novo Nordisk Inc., Zhao, Ming �� Disclosed no conflict of interest. Sanofi, Takeda Pharmaceutical Company Limited. Zhao, Shujie �� Disclosed no conflict of interest. Yan, Hai �� Board Member: REMD Biotherapeutics, Inc.; Employee: Zhao, Xiaolong �� Disclosed no conflict of interest. REMD Biotherapeutics, Inc. Zhao, Ying �� Disclosed no conflict of interest. Yan, Jiahe �� Disclosed no conflict of interest. Zheng, Jia �� Disclosed no conflict of interest. Yandell, Brian �� Disclosed no conflict of interest. Zheng, Siyuan �� Disclosed no conflict of interest. Yang, Aimin �� Disclosed no conflict of interest. Zheng, Tongzhang �� Disclosed no conflict of interest. Yang, Edward H. �� Disclosed no conflict of interest. Zheng, Xiaohua �� Disclosed no conflict of interest. Yang, Fan �� Disclosed no conflict of interest. Zheng, Xuqin �� Disclosed no conflict of interest. Yang, Long Yan �� Disclosed no conflict of interest. Zhou, Dan �� Disclosed no conflict of interest. Yang, Nengyu �� Employee: Eli Lilly and Company. Zhou, Hongwen �� Disclosed no conflict of interest. Yang, Tao �� Disclosed no conflict of interest. Zhou, Xianghai �� Disclosed no conflict of interest. Yang, Yisheng �� Disclosed no conflict of interest. Zhu, Dongshan �� Disclosed no conflict of interest. Yardley, Jane E. �� Research Support: Medtronic, Inc.; Speaker’s Bureau: Zhu, Jing �� Disclosed no conflict of interest. Animas Corporation. Zhuang, Dongliang �� Employee: Zafgen; Stock/Shareholder: Zafgen. Yassine, Hussein �� Disclosed no conflict of interest. Zhuo, Daisy �� Disclosed no conflict of interest. Ye, Weiwei �� Employee: Crown Bioscience, Inc. Zidon, Terese M. �� Disclosed no conflict of interest. Ye, Yumei �� Research Support: AstraZeneca, Boehringer Ingelheim Zimmerman, Robert S. �� Consultant: Novo Nordisk Inc.; Research Support: Merck & Pharmaceuticals, Inc. Co., Inc., Novo Nordisk Inc.; Speaker’s Bureau: Merck Yee, John �� Employee: Intarcia Therapeutics, Inc. & Co., Inc. Yengo, Loic �� Disclosed no conflict of interest. Zinc, Richard W. �� Employee: Eli Lilly and Company. Yesildag, Burcak �� Employee: InSphero AG. Zocchi, Elena �� Disclosed no conflict of interest. Yie, Junming �� Employee: Merck Sharp & Dohme Corp. Zong, Geng �� Disclosed no conflict of interest. Yin, Wu �� Disclosed no conflict of interest. Zouhar, Petr �� Research Support: Novo Nordisk A/S. Yip, Kevin Y. �� Disclosed no conflict of interest. Zsombok, Andrea �� Disclosed no conflict of interest. Yoo, Hee Won �� Disclosed no conflict of interest. Zuluaga Zuluaga, María Clemencia �� Disclosed no conflict of interest. Yoon, Kun Ho �� Disclosed no conflict of interest. Zuñiga, Byron �� Disclosed no conflict of interest.

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