INTEGRATED PHYSIOLOGY— SECRETION INTEGRATED PHYSIOLOGY—LIVER IN VIVO CATEGORY Figure 1. 2473-PUB Application of Translational Pharmacokinetic and Pharmacody- namic Modeling in the Development of GPR40 Partial Agonists DANIEL A. TATOSIAN, OSKAR ALSKAER, MARIA E. TRUJILLO, GEORGE EIER- MANN, LENA E. FRIBERG, MARIA KJELLSON, KUMAR K. MURALIDHARAN, HUBERT JOSIEN, ADAM WEINGLASS, JERRY DI SALVO, XIAOYAN N. LI, MICHAEL MILLER, PAVAN VADDADY, PRAJAKTI KOTHARE, Kenilworth, NJ, Upp- sala, Sweden, Rahway, NJ, Boston, MA Partial GPR40 agonists have been clinically validated as a mechanism for glucose lowering in patients with type 2 . A prior GPR40 partial agonist TAK-875 by Takeda was discontinued in Phase 3 due to liver toxic- ity with unknown mechanism. Discovery efforts for identifying novel GPR40 partial agonists have since focused on compounds with low anticipated clinical dose as a mitigation strategy. Given the critical nature of human dose projection for this target, a translational pharmacokinetic and phar- macodynamic model was developed to enhance predictions of clinical dose- response for novel chemical matter. A semi-physiologic glucose and insulin model was developed based on a human model published by Jauslin et al. [J Clin Pharmacol 2007;47:1244– 55]. This compartmental model was allometrically scaled and applied to glu- cose and insulin data observed in man and in Goto-Kakizaki rats. Published and internal data from human trials and rodent experiments under fasted or Supported By: National Natural Science Foundation of China (81200630); Natu- oral conditions in single dose and chronic administra- ral Science Fund Committee of Zhejiang Province (LQ12H07001); Wenzhou Science tion were included in the analysis. A model-based in vitro-in vivo correla- and Technology Bureau (H20150001) tion relating potency from a cell-based inositol phosphatase 1 accumulation assay to in vivo response was established to enable predictions. The translational model adequately described data for 5 compounds eval- INTEGRATED PHYSIOLOGY—INSULIN SECRETION uated in preclinical experiments and was predictive of the published human IN VIVO dose-response relationship of TAK875. Simulations from the quantitative model were shown to be consistent with the observed dose-response glu- 2471-PUB cose data both in the fasted state and following meals in the completed GPR40 Knockout Rats Have Diminished Lipid-mediated Potentiation MK-8666 proof of concept study. This model was further used in making of Insulin Secretion quantitative predictions of the dose-response relationship for novel GPR40 TONYA L. MARTIN, JIANYING LIU, MATTHEW M. RANKIN, MEGHAN TOWERS, agonists in discovery phase, and has been used by the development team JENSON QI, LISA D. NORQUAY, ALESSANDRO POCAI, Spring House, PA as a basis for prioritization and decision making around proposed clinical Chronic activation of GPR40, a fatty acid sensing G-protein-coupled recep- development programs. tor, improves glycemic control in type 2 diabetic humans. We used zinc fi nger nuclease technology to generate GPR40 null rats in the 2474-PUB Sprague-Dawley genetic background with a 2 bp deletion resulting in a trun- WITHDRAWN cated GPR40 protein. GPR40 Knockout (GPR40 KO) rats and their wild type (WT) littermates were fed either high fat (HFD, Research Diets 12492, 60% kcals fat) or regular chow (LabDiets 5001, 13% kcals fat) for ten weeks. On regular chow, GPR40 KO rats showed fasting when compared to WT rats (118 ± 4.5 vs. 94 ± 3.0 mg/dl, p < 0.05); there were no INTEGRATED PHYSIOLOGY—LIVER other differences observed between GPR40 KO and WT rats. HFD-GPR40 KO rats showed fasting hyperglycemia (121 ± 5.1 vs. 93 ± 2.5 2475-PUB mg/dl, p < 0.05) with decreased fasting insulin (471 ± 124.3 vs. 994 ± 105.2 Triple Therapy Utilizing Vitamin E, Milk Thistle, and Carnitine pg/ml, p < 0.05). HFD-WT rats were hyperinsulinemic compared to WT rats Improves ALT and the Metabolic Abnormalities Associated with on regular chow (1201 ± 166 pg/ml vs. 517 ± 80.4 pg/ml, p < 0.05). Insulin NAFLD levels in HF-GPR40 KO rats were similar to GPR40 KO rats on regular chow. JOHN POULOS, VALENTIN MILANOV, Fayetteville, NC After a glucose challenge, the glucose area under the curve (AUC) of HFD- Evidence of scientifi c data in peer reviewed journals indicates that anti- GPR40 KO rats was higher than, but not statistically different from, HFD-WT oxidant supplementation may improve abnormal liver chemistries, glucose rats (24411 ± 660 vs. 22224 ± 1237 mg/dl/120 min). However, the insulin AUC control, and hyperlipidemia, in patients with NAFLD. The primary objective was markedly decreased in the HFD-GPR40 KO rats (264,737 ± 25,702 vs. was to determine the effects of Vitamin E 200IU, Silymarin 750mg, L carni- 479,989 ± 40,157 pg/ml/120 min, p < 0.05). tine 1gm (VSC) on normalization of abnormalities in liver function testing in We examined pancreatic islets from the WT and KO rats. WT and KO islets patients with NAFLD and to determine possible improvements in blood glu- responded similarly to increased concentrations of glucose; however, con- cose, hemoglobin A1c, cholesterol, LDL, triglycerides and CRP. Patients with sistent with the in vivo data, when the islets were challenged with glucose NAFLD were treated with either VSC (n=15) or placebo (n=17) for a period and palmitate, the islets from the KO rats showed a diminished insulin secre- of 24 weeks. The following laboratory values were assessed AST, ALT, trig- tory response. lycerides, HDL, LDL, insulin levels, glucose and CRP. Eleven out of 15 (70%) Taken together, these data demonstrate that GPR40 is required for the patients in the VSC group had normalization of ALT whereas 9 of 17 patients Integrated maintenance of fasting glycemia and the compensatory response of the (54%) had normalization of ALT in the placebo group (p=0.1). Patients treated β-cell to lipid-induced hyperinsulinemia.

with VSC had a 3% reduction in serum glucose levels after 24 weeks of Physiology/Obesity treatment, whereas patients on placebo had a 6% increase in serum glu- PUBLISHED ONLY 2472-PUB cose levels. A 17% increase in serum insulin levels was noted in the placebo WITHDRAWN group, while a 18% reduction in insulin was seen in the VSC group. Serum triglycerides were reduced by 12% at week 24 in the VSC treated subjects whereas a 18% increase in serum triglycerides were seen in the placebo group. A trend in the reduction of serum cholesterol, HDL, LDL and CRP was seen in the VSC treated patients in comparison to the placebo treated group. In this 24 week study patients treated with VSC had normalization of ALT and signifi cant reductions in serum glucose, insulin and triglycerides in com- parison to the placebo group. Also noted in this study were reductions in AST, cholesterol, HDL and LDL and CRP levels. The ability of this compound

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A617 INTEGRATEDCATEGORY PHYSIOLOGY—LIVER

in reducing markers of liver infl ammation, glucose, insulin, and triglycerides 2480-PUB indicates that VSC could play an important role in the treatment of nonalco- Dietary Iron Restriction Prevents the Transition of Fatty Liver to Ste- holic fatty liver disease, diabetes and cardiovascular disease. atohepatitis in Mice Fed a High Fat/High Carbohydrate Diet LIPIKA SALAYE, IELIZAVETA BYCHKOVA, DONALD A. MCCLAIN, Winston-Salem, 2476-PUB NC, Cleveland, OH Pathogenesis of in Asian Indians High iron is associated with increased risk for nonalcoholic steatohepati- SONA VEETTIL, ANANDA BASU, JOHN PORT, RITA BASU, Rochester, MN tis (NASH), although iron has not been implicated causally in its pathogen- The pathophysiology of prediabetes (PD) has not been well explored in esis. We examined progression of NASH in mice fed a model “fast food” Asian Indians (AI) residing in the U.S. The study was conducted to evaluate diet supplemented with different levels of iron (4, 35, 500, or 2000 ppm). glucose metabolism and its association with hepatic fat in AI. 10 controls Mice on the 4 ppm iron diet did not become anemic, and the fold-increase with normal fasting glucose/normal glucose tolerance (NFG/NGT) (7M, age in hepatic iron seen at the highest iron was within the normal human range. 35 ± 13 yr, FPG 5.1 ± 0.2 mM, 2-hr glucose 5.7 ± 0.4 mM, BMI 24.0 ± 3.4 kg/m2, All mice developed similar steatosis. Mice on the 500 and 2000 ppm iron diets developed elevations in serum alanine transaminase (ALT) 3 and 6 mos LBM 43.4 ± 9.2 kg, HbA1c 34.6 ± 2.5 mmol/mol) and 10 subjects with PD (per current ADA guidelines) (4M, 43.4 ± 12.3 yr, FPG 6.3 ± 1.0 mM, 2-hr glucose after initiation of the diet (380±32 IU/L at 6 mo) compared to mice on normal 2 chow (121±40 IU/L, p<0.01). Mice on the 4 ppm diet did not exhibit elevations 9.3 ± 2.1 mM, BMI 25.2 ± 3.2 kg/m , LBM 40.5 ± 6.8 kg, HbA1c 40.0 ± 3.5 2 of ALT (70±15 IU/L at 6 mos). Mice on the 35 pp diet had a delay in the time mmol/mol) were studied using a [6, 6- H2 glucose] labeled 75g oral glucose tolerance test (OGTT). The percentage liver fat fraction (% LFF), and total course of elevation, with elevations of ALT at 6 mos (318±19 IU/L), but not fatty acid (total FA) were measured using magnetic resonance spectros- 3 mos (102±22 IU/L). Only mice on the higher iron diets showed up regula- copy (MRS) with an LC model. Plasma iAUC 0-240 min glucose was signifi - tion of collagen type 2, a marker of liver injury in NASH. We conclude that cantly higher in PD vs. control (603.2 ±217.8 vs. 215.3 ± 114.6 mM; p<0.01). high tissue iron levels accelerate the transition of NAFLD to NASH and pres- Similarly, iAUC 0-240 min insulin (73448.4 ± 44744.9 vs. 39462.0 ± 15632.2 ent an attractive target for risk modifi cation because of the ease of their pM; p<0.05); C-peptide (577.1 ± 230.2 vs. 345.3 ± 88.6 nM; p<0.05) were manipulation. higher in PD vs. control. Plasma HDL concentration (42.4 ± 6.9 vs. 55.9 ± Supported By: National Institutes of Health; U.S. Department of Veterans Affairs 14.5 vs. mg/dl; p<0.05) was lower in PD vs. control. % LFF (4.7 ± 4.2 vs. 1.6 ± 0.9; p=0.049) and total FA concentrations (0.0077 ± 0.0063 vs. 0.0020 ± 2481-PUB 0.0014 IU; p<0.05) were higher in PD vs. controls. Endogenous glucose con- High Olive Oil Intakes Enhance Carbohydrate Stimulation of Lipo- centration calculated with the labeled OGTT was slightly higher (iAUC -799.5 ± genic Gene Expression in Rats 161.5 vs. -715.3 ± 80.0 mM) and hepatic insulin sensitivity (Liver Si) calcu- KATHLEEN V. AXEN, KATE RUSSELL, JO ANN BROWN, MARIANNA HARPER, lated as model independent (iAUC endogenous glucose concentration/iAUC KEERTESHWRYA MISHRA, TASHANNE DISTIN, KENNETH AXEN, Brooklyn, NY insulin) slightly lower in PD vs. controls (0.017 ± 0.01 vs. 0.022 ± 0.01 mM/ High-fat (HF) diets have been shown to increase hepatic lipogenesis in pM) but neither reached signifi cance perhaps due to small n’s studied. % rodents. To investigate whether this effect may be due to amplifi cation of LFF was signifi cantly correlated with Liver Si (r2=0.27; p=0.03). We conclude insulin’s stimulation of lipogenic gene expression, we compared the effects that in AI with prediabetes despite having lower BMI, higher LFF can predict of 1 week’s intake of HF diets on the expression of lipogenic genes and other underlying defects in glucose metabolism. Further studies are required to targets of insulin in rat liver both after a 24 hr fast (baseline) vs. after 18 hr of tease out whether there are defects in insulin action vs. secretion by model refeeding with a high carbohydrate diet (80% starch, 0% fat) following the dependent means. fast. Male Sprague-Dawley rats (N = 40) were fed a HF diet (55% of energy) Supported By: National Center for Advancing Translational Science (R01 containing menhaden oil (M-HF, ω-3 PUFA), or olive oil (O-HF, monounsatu- DK29953, UL1 TR000135) rated fat), or saffl ower oil (S-HF, ω-6 PUFA); control rats were fed a 15% fat (LF) diet. M-HF rats had lower % body fat (p< 0.02) and hepatic lipid levels 2477-PUB (p< 0.01) than O-HF or S-HF rats. M-HF rats exhibited lower fasting and feed- ing-stimulated expression of SREBP-1c, a major regulator of lipogenesis, as WITHDRAWN well as its lipogenic targets Fatty Acid Synthase, Glycerol Phosphate Acyl Transferase, and Stearoyl Desaturase than O-HF, S-HF or LF rats. In contrast, O-HF rats showed markedly higher fasting SREBP-1c expression and greater % stimulated expression (fed x 100%/fasted) of these lipogenic targets than S-HF or LF rats. O-HF rats also showed greater suppression by refeeding of: 1.) expression of Carnitine Palmitoyl Transferase 1 (which promotes fat oxidation) compared with M-HF, S-HF and LF rats (80% vs. 50%), and 2.) expression of the insulin-regulated genes for Insig-2 and Phosphoenolpyru- vate Carboxykinase than M-HF, S-HF, and LF rats, indicating high insulin sen- sitivity in O-HF rats. The low lipogenic gene expression after refeeding in 2478-PUB M-HF rats corresponded to similar % stimulation as in S-HF or LF rats due to WITHDRAWN low baseline expression in the M-HF group. In contrast, the high responses to refeeding in the O-HF rats refl ected greater % stimulation than the other three groups. These fi ndings suggest that high olive oil intakes may amplify insulin’s effect, beyond a general increase in lipogenic gene expression. Supported By: City University of New York

2482-PUB

Integrated WITHDRAWN Physiology/Obesity

PUBLISHED ONLY 2479-PUB WITHDRAWN

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A618 INTEGRATED PHYSIOLOGY—MACRONUTRIENTCATEGORY METABOLISM AND FOOD INTAKE

2483-PUB INTEGRATED PHYSIOLOGY—MACRONUTRIENT WITHDRAWN METABOLISM AND FOOD INTAKE 2489-PUB 2484-PUB WITHDRAWN WITHDRAWN 2490-PUB 2485-PUB WITHDRAWN Hepatic microRNAs Profi le in Insulin Receptor Knockout Mice Re - veals Novel Molecules Involved in the Diabetes Pathophysiology BARBARA CAPUANI, DAVID DELLA-MORTE, FRANCESCA PACIFICI, SARA CARA- 2491-PUB TELLI, DONATELLA PASTORE, GIULIA DONADEL, ANDREA COPPOLA, ROBERTO Cognitive Performance in Subjects at Risk of ARRIGA, ALFONSO BELLIA, SIMONA FRONTONI, MASSIMO FEDERICI, PAOLO GIAN PIO SORICE, TERESA MEZZA, GIOVANNA MASONE IACOBUCCI, SIMONA SBRACCIA, GIUSEPPE SCONOCCHIA, DAVIDE LAURO, Rome, Italy MOFFA, FLAVIA IMPRONTA, CAMILLO MARRA, SARA GRIONI, MARILENA Type 2 diabetes mellitus (T2DM) is characterized by alteration of insulin VITALE, ANDREA MARI, ANDREA GIACCARI, Rome, Italy, Milan, Italy, Naples, signaling and defect of insulin-secretion in pancreatic beta cells ( -cells), β Italy, Padova, Italy with subsequent hyperglycemia and prediabetes conditions. Fundamen- Beyond the calorie amount, other “quality variables” of diet might affect tal is discovering early biomarkers to delay or prevent the onset of T2DM. glucose metabolism. Among those, both Glycemic Load (GL) and Glycemic Recently, a novel class of non-coding RNA, microRNA (miRNA), has emerged Index (GI) infl uence glucose homeostasis (GH), causing glucose fl uctuations, as important regulators of metabolic cell signaling and with others numer- even in nondiabetic subjects, although in normal range. Since a correlation ous biological functions. MiRNA contribute to the development of chronic between GH impairment and cognitive decline has been clearly demon- infl ammation observed in obese patients with diabetes, pancreatic β-cell strated, our aim was to evaluate whether the diet, in people at risk for type 2 dysfunction and increased levels of peripheral . Therefore, diabetes (T2D), could affect cognitive performance (CP). Seventy-one volun- we are reaching the goal to reveal new miRNA and mRNA target involved in teers (11M, 60F), at risk for T2D, underwent OGTT, neuropsychological tests the onset of diabetes and/or its relative complications. We analyzed miRNA (to assess verbal learning, memory, visual attention, executive functions and patterns by miRNA arrays in insulin receptor knockout (IR-/-) and heterozy- +/- the overall cognitive function) and their eating habits were evaluated using gous (IR ) mice as a model of liver metabolic dysfunction associated with the EPIC food frequency questionnaire. The main anthropometric, metabolic, and insulin resistance. MiRNAs array identifi ed only neuropsychological and nutritional results are summarized in Table 1. 4 miRNA differently expressed between IR+/+, IR+/- and IR-/-: miR-376b, miR- 154, miR-543, and miR-199b. Quantitative Real time polymerase reaction Table 1. confi rmed these results, and bioinformatic analysis reveals interesting mean sem mRNA targets involved in metabolic pathways. Particularly, we compared Age years 37, 9 1, 4 mRNA targets to protein profi le previously identifi ed in our later proteomic study performed in the same samples. This analysis revealed that one of the Education anni 13 0, 4 most interesting mRNA target is SIRT1, a deacytetilase involved in modulat- BMI kg/m2 24, 9 0, 6 ing the activation of infl ammatory state mediated by HMGB1. The inhibition of SIRT1 expression mediated by one of identifi ed miRNAs, can activate the Fasting glucose mg/dl 91, 9 0, 9 early stages of infl ammation in prediabetic conditions. These results provide new insight into pathophysiology of T2DM and nonalcoholic fatty liver dis- Fasting insulin mUI/ml 8, 2 0, 5 ease, and could be useful in identifying novel biomarkers to predict risk for Basal insulin secretion pmol/L 77, 0 3, 4 diabetes and its complications. B cell-glucose sensitivity pmol min-1m-2mM-1 135, 4 8, 0 Stumvoll umol min-1kg-1 9, 5 0, 2 2486-PUB Matsuda umol min-1kg-1 6, 8 0, 4 WITHDRAWN Basal insulin clearance L min-1m-2 1, 7 0, 1 OGTT insulin clearance L min-1m-2 1, 4 0, 1

MMSE seconds 28, 2 0, 2 RAVLT: RI seconds 34, 1 0, 9 RAVLT: RD seconds 9, 9 4, 0 Multiple Features seconds 43, 9 2, 4 2487-PUB Trail Making test-A seconds 32, 7 1, 8 WITHDRAWN Tail Making Test-B seconds 91, 2 7, 9 Stroop Colour Word Test seconds 23, 8 0, 8

TEAC (Trolox Equivalent Antioxidant Capacity) mmol die 1, 5 0, 1 Integrated TRAP (Total Radical trapping Antioxidant Parameter) mmol die 1, 6 0, 1 Physiology/Obesity FRAP (Ferric ion Reducing Antioxidant Parameter) mmol die 3, 9 0, 2 PUBLISHED ONLY 2488-PUB Glycemic Index 40, 3 1, 0 WITHDRAWN Glycemic Load 115, 1 6, 3 The results of neuropsychological tests were then normalized by age and education; each test was standardized on a scale from 0 (worst) to 4 (best performance). The equivalent scores of each test were added to obtain a composite endpoint (Cognitive Performance Index), from 0 to 16, from poor- est to better CP. Data analysis showed a signifi cant inverse correlation (R2: 0.051; p=0.05) between GI and Cognitive Performance Index. In conclusion,

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A619 INTEGRATED PHYSIOLOGY—MUSCLE CATEGORY INTEGRATED PHYSIOLOGY—OTHER HORMONES

our data suggest that a diet with a high GI, in people at risk of T2D, may be 2495-PUB associated with worse CP, even at subclinical level. Sodium Butyrate Has a Context-dependent Effect on DPP-4 Activity and Metabolism in Cells and Tissues 2492-PUB DAE HO LEE, EUN-SOL LEE, DONG-SUNG LEE, Incheon, Republic of Korea, Iksan, The Ldb1 Transcriptional Coregulator Mediates Glucose, Lipid, and Republic of Korea, Chungju, Republic of Korea Energy Homeostasis during Diet-induced Obesity Butyric acid, a short chain fatty acid, has various metabolic actions, and CHRISTINE LOYD, JAMIE GALLOWAY, TEAYOUN KIM, CASSIE HOLLEMAN, YAN- a previous study reported that sodium butyrate (SB) enhanced DPP-4 activ- PING LIU, MAIGEN BETHEA, GLENN ROWE, MARTIN YOUNG, KIRK M. HABEG- ity at high concentration. We aimed to evaluate the effect of SB on the GER, CHAD S. HUNTER, Birmingham, AL regulation of DPP-4 and on the other metabolic actions in cells and in high Mounting evidence indicates that many transcriptional regulators fat diet (HFD)-fed obese mice. We used HepG2 and mouse mesangial cells required for β-cell development also mediate postnatal β-cell function or and 10-week-HFD-induced obese mice. SB treatment was done by supple- compensatory responses to metabolic stress. The broadly expressed tran- menting SB into HFD (5% wt/wt) for additional 15 weeks. In HepG2 cells, scriptional coregulator, Ldb1, is essential for β-cell development, but it is SB suppressed DPP-4 activity and expression at sub-molar concentrations, unclear whether it mediates sustained β-cell responses upon metabolic whereas it consistently increased those levels at 1 mM concentration. How- stress or if it has roles in other metabolic tissues. As germline homozy- ever, the inhibitory effect of low dose SB on DPP-4 activity was lost in high gous Ldb1 deletion is embryonically lethal, we investigated inducible β-cell- glucose (30 mM)-exposed HepG2 cells. In HFD-obese mice, SB treatment specifi c (Ldb1Δβ-cell) and global heterozygous (Ldb1+/-) mice that were chal- decreased blood glucose, serum insulin and DPP-4 activity, and suppressed lenged with a high-fat diet. We found that during diet-induced obesity (DIO), the increase in body weight. On the contrary, various tissues including liver, both Ldb1 defi ciency models displayed reduced circulating insulin levels kidney, and peripheral blood cells showed variable responses to SB. Espe- and impaired glucose homeostasis. Regarding potential extra-pancreatic cially in the kidney, although DPP-4 activity was inhibited by SB treatment function, we revealed that global Ldb1 heterozygosity reduced food intake, in HFD-obese mice, it caused an increase in mRNA expression of TNFα, IL-6, decreased systemic energy expenditure (measured by indirect calorimetry) and IL-1β. The pro-infl ammatory actions of SB in the kidney of the HFD-obese associated with impaired expression of brown adipose tissue Diodinase 2 mice was supported by cultured mesangial cell experiment in which SB stim- and ELOVL Fatty Acid Elongase 3, yet in the absence of effect on adipos- ulated TNFα secretion from the cells. Our results showed that SB has differ- ity. Importantly, the observed changes in Ldb1+/- energy balance during DIO ential actions according to the types of cells and tissues, and its concentra- were absent in Ldb1Δβ-cell mice, despite a similar reduction in plasma insulin. tion, although it has some metabolically benefi cial effects in whole body. Ldb1+/- mice were also protected from diet-induced dyslipidemia and hepatic steatosis, a characteristic not observed in Ldb1Δβ-cell mice. These data sug- gest that Ldb1 expressed in the pancreatic cell and other metabolic tissues INTEGRATED PHYSIOLOGY—MUSCLE regulates glucose, lipid, and energy homeostasis via insulin dependent and independent mechanisms. 2496-PUB Supported By: National Institutes of Health (P30 DK079626) Diabetic Myonecrosis: A Rare Diabetes Complication MAISARA RAHMAN, TRINA MANSOUR, UNS AL-WAHAB, Murrieta, CA, River- 2493-PUB side, CA Background: Diabetes Myonecrosis is also known as Diabetic muscle WITHDRAWN infarction. Diabetes Myonecrosis is a rare complication of diabetes mellitus (DM) and affects both type 1 and type 2 DM patients with long-standing uncontrolled diabetes. The clinical presentation of diabetes myonecrosis 2494-PUB presents with a sudden onset of a localized, excruciating, painful swelling Assessment of the Role of Glucose Oxidation and Circulating Fac- of skeletal muscles resulting from a spontaneous ischemic of the tors on Insulin Secretion in Nondiabetic Humans muscle. Many times, the patients will have limited range of motion of the JOSE E. GALGANI, CARMEN GOMEZ, MARIA L. MIZGIER, JOSE L. SANTOS, affected limb. The onset of the infarction is acute and last several weeks. PABLO OLMOS, ANDREA MARI, Santiago, Chile, Padova, Italy MRI confi rms the clinical diagnosis. In some cases of diagnostic uncertainty, Glucose-stimulated insulin secretion correlates inversely with the degree a muscle , which is the gold standard, is needed to diagnose this con- of systemic insulin sensitivity suggesting a crosstalk between peripheral dition. The condition is conservatively managed with pain management and organs and endocrine pancreas. Such sensing mechanism might be medi- NSAIDS in the acute phase. ated through changes in glucose oxidative disposal in peripheral tissues that Case Presentation: This is a case of a 41-year-old male, with a 20 year may drive the release of circulating factors with action on insulin secretion. history of poorly controlled type 2 DM. Patient presented with 4 days of We aimed to evaluate the association between whole-body carbohydrate excruciating pain and limited range of motion from a well demarcated mass oxidative disposal with insulin secretion to consecutive oral glucose loading and swelling in the left thigh area. The severe pain and palpable mass of the in nondiabetic individuals. left thigh was suspected to be Myositis, DVT, soft tissue tumor, necrotizing Carbohydrate oxidation was measured after an overnight fast and for fasciitis or . Work up ruled out all the above possibilities, and the 6 hours after two 3-h apart 75-g oral glucose tolerance test (OGTT) in 53 fi nal diagnosis of diabetes myonecrosis was made on the basis of muscle participants (24/29 males/females; 34±9 y; 27±4 kg/m2). Insulin secretion biopsy and MRI fi ndings. Conclusion: Diabetic myonecrosis is often misdiagnosed and underre- was estimated by deconvolution of serum C-peptide concentration, β-cell function by mathematical modelling and insulin sensitivity from glucose and ported. Increasing clinical awareness of this condition is important for early insulin response after OGTT. Circulating lactate, free-fatty acids and candi- recognition of this rare microvascular complication of uncontrolled diabetes. date chemokines were assessed before and after OGTT. Diabetes myonecrosis should be included in the differential diagnosis of any Carbohydrate oxidation assessed over the 6-h period did not relate diabetic who presents with any painful swelling in any extremity. The more with insulin secretion (r=-0.11; p=0.45) or cell function indexes. Circulating familiar physicians are about this unusual diabetic complication, the more likely that patients will be diagnosed and treated appropriately.

Integrated chemokines concentration increased upon oral glucose stimulation, with an average increase between 1.20.3 fold for fractalkine and 5.87.0 fold for

Physiology/Obesity RANTES. Insulin secretion rate associated directly with plasma IL8 (r=0.41; PUBLISHED ONLY p<0.05), IL6 (r=0.35; p<0.05) and RANTES (r=0.30; p<0.05) concentrations INTEGRATED PHYSIOLOGY—OTHER HORMONES determined at 60 min OGTT, even after adjusting for insulin sensitivity. Circu- lating lactate and FFA showed no association with 6-h insulin secretion. 2497-PUB Whole-body carbohydrate oxidative disposal appears to have no infl uence Effect of Smoking on Postprandial Glucose Excursions in Heavy on insulin secretion or putative circulating mediators. IL8 might be a poten- Smokers tial factor affecting insulin secretion. MAGNUS F. GRØNDAHL, JONATAN I. BAGGER, ASGER LUND, JENS JUUL HOLST, Supported By: FONDECYT (1130217 to J.E.G.); VRA-PUC (to J.E.G.) ANNESOFIE FAURSCHOU, TINA VILSBØLL, FILIP K. KNOP, Hellerup, Denmark, Copenhagen, Denmark Epidemiological studies suggest that smoking increases the risk of type 2 diabetes, but little is known about the physiological effects of smoking on postprandial glucose metabolism. We hypothesized that smoking-induced

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A620 INTEGRATED PHYSIOLOGY—OTHERCATEGORY HORMONES increases in circulating nicotine levels and activation of nicotinergic recep- Data were analyzed by standard T test, binary logistic analysis and correla- tors in the gastrointestinal tract and in the autonomic nervous system tion analysis. would have a detrimental effect on postprandial glucose metabolism and, Results: Compared with patients with late-onset T2DM, those with young- thus, potentially constitute a link between smoking and risk of type 2 dia- onset T2DM had a strong family history, more likely to be obese, worse gly- betes. To investigate the above hypothesis, 12 male heavy smokers (age: cemic and lipid control. The prevalence of testosterone defi ciency (serum 26.8±10.3 years; BMI: 25.2±4.0 kg/m2; HbA1c: 30.9±4.5 mmol/mol) under- total testosterone <8.7 nmol/L) was 32.47% and 17.70% in young-onset went two separate 4-hour liquid meal tests with acetaminophen (for evalu- group and late-onset group respectively (p<0.05). Binary logistic regression ation of gastric emptying): one with concomitant cigarette smoking (imme- analysis showed that BMI independently predicted the prevalence of low diately before and after meal intake) and one without smoking. Twelve testosterone in the young-onset group, whereas HbA1c independently pre- matched non-smokers (age: 26.7±9.08 years; BMI: 25.2±4.5 kg/m2; HbA1c: dicted the prevalence of low testosterone in the late-onset group. Patients 31.6±4.27 mmol/mol) underwent an identical meal test without smok- with young-onset T2DM showed signifi cantly lower LH, FSH and testoster- ing. Compared to controls, heavy smokers exhibited similar gastric empty- one levels (mean 11.72nmol/L [SD 6.19] vs. 14.60 [6.11]; P=0.001), as com- ing, postprandial plasma glucose excursions (incremental area under curve pared with late-onset individuals. Combining the results of glucose and lipid (iAUC): 94.9±27.2 vs. 47.2±28.9 mmol/L × min, P=0.29) and plasma insulin metabolism in young-onset men, hypogonadism is associated with a signifi - and C-peptide responses, respectively, when not smoking. Smoking in rela- cant increase in the fasting plasma glucose and C-peptide, HbA1c, TC, TG, tion to meal intake signifi cantly lowered the smokers’ postprandial glucose FFA and LDL . In a correlation analysis, high BMI predicted low testosterone excursions (iAUC: 94.9±27.2 vs. 33.0±12.7 mmol/L × min, P=0.01). Smoking levels (r=-0.313, P=0.007). Binary logistic regression analysis demonstrated reduced iAUC0-50min for plasma acetaminophen (1.6±0.12 vs. 1.3±0.10 pmol/L that BMI played a pivotal role in regulation of testosterone. In addition, a × min, P<0.01), but did not affect time-to-peak for acetaminophen signifi - reduction of HDL and QUICKI in the youth group was also observed. cantly. In conclusion, we show that smoking before and after meal intake Conclusion: Testosterone defi ciency is more obvious in patients with reduces postprandial glucose excursions in heavy smokers. Our data sug- young-onset T2DM than that of late-onset T2DM, which would contribute gest that this phenomenon may be mediated by smoking-induced delay of to worse glycemic and lipid control in those patients. gastric emptying, but other yet unclarifi ed mechanisms may also be at play (e.g., smoking-induced changes in the secretion of gut hormones). 2501-PUB 2498-PUB WITHDRAWN Different View on Stress-Induced Hyperglycemia in Nondiabetic Population ONALA TELFORD, DAVID A. D’ALESSIO, MERCEDES FALCIGLIA, Durham, NC, Cin- 2502-PUB cinnati, OH Guanylin and Uroguanylin mRNA Expression Are Signifi cantly Reg- Hyperglycemia is common in patients hospitalized with severe illness. A ulated following Roux-en-Y Gastric Bypass in Humans and Rats, signifi cant portion of these patients do not have a and but Are Not Involved in the Regulation of Body Weight and Glucose regain normal glucose tolerance when they recover. The mechanism of tran- Control sient hyperglycemia in critically ill patients is generally ascribed to stress MARIALUISA FERNANDEZ-CACHON, NICOLAI A. RHEE, SØREN L. PEDERSEN, but this has not been proven. In this study circulating markers of stress, and KRISTOFFER RIGBOLT, CHEN ZHANG, EBBE P. LANGHOLZ, ERIK P. WANDALL, regulators of glucose control, were measured in matched groups of non- PETER VILMANN, VIGGO B. KRISTIANSEN, MECHTHILDE FALKENHAHN, KAY diabetic ICU patients with and without hyperglycemia. Patients admitted SCHREITER, KRISTIN BREITSCHOPF, THOMAS HÜBSCHLE, TINA VILSBØLL, FILIP to an ICU were approached for consent and had a blood sample taken. Only K. KNOP, STEFAN THEIS, JACOB JELSING, Frankfurt, Germany, Hellerup, Denmark, subjects with no prior history of diabetes were recruited, and patients with Hørsholm, Denmark, Herlev, Denmark, Hvidovre, Denmark, Hamburg, Germany HbA1c diagnostic for diabetes were excluded. Patients were separated into Guanylate cyclase activator 2A (GUCA2A) and guanylate cyclase activator a euglycemic group for those with no glucose readings >120 mg/dl and a 2B (GUCA2B) are prohormones for the peptides guanylin (GN) and uroguany- hyperglycemic group with either a mean BG > 145, a single value > 200 or lin (UGN). Using laser capture microdissection of enteroendocrine cells in eventual treatment with insulin infusion. Forty-six patients were consented obese rats and humans following Roux-en-Y gastric bypass (RYGB), we dem- and 3 were excluded because of A1c > 7%. By defi nition the peak (113.8 ± onstrated that GUCA2A and GUCA2B mRNAs were signifi cantly upregulated 4.1 and 213.0 ± 9.9 mg/dl), and mean (100 ± 3 and 172 ± 12) glucose levels post-surgery suggesting a role in the benefi cial metabolic effects observed differed in the 20 euglycemic and 23 hyperglycemic (p < 0.0001 for both) after RYGB. GUCA2A (700 nmol/kg) and GUCA2B (580 nmol/kg) prohor- subjects, while HbA1c was similar (5.2 ± 0.1, and 5.6 ± 0.1%, p = 0.39). Insu- mones, as well as GN and UGN peptides (3000 nmol/kg), were administered lin, glucagon and C-peptide did not differ between the eu-and hyper-glyce- twice-daily to C57Bl/6 mice for 2.5 days to test their ability to regulate acute mic cohorts, and values of cortisol and epinephrine were also comparable. food intake. Glucose regulatory effects of GUCA2A and GUCA2B were eval- Hyperglycemic patients had signifi cantly higher circulating levels of GLP-1 uated during an oral glucose tolerance test (OGTT) and by in vitro tests in and IL-6, but lower endotoxin measures than the euglycemic group. These isolated pancreas islets. Finally, C57Bl/6 DIO mice were transfected with fi ndings indicate that neither islet nor stress hormones explain nondiabetic adeno-associated viruses (AAV) overexpressing UGN for 4 weeks. Admin- hyperglycemia in critical illness, but raise the possibility that gut factors may istration with GN, UGN, GUCA2A or GUCA2B showed no effect on acute play a role in this clinical syndrome. cumulative food intake (9.11±0.82 to 10.26±0.71 g vs. 9.23±0.39 g vehicle at 68 hrs, p>0.05). Similarly, GUCA2B and GUCA2B prohormones did not affect 2499-PUB glucose tolerance during OGTT (2,101±468 GN, 2,169±471 UGN vs. 2,301±374 WITHDRAWN min×mmol/L vehicle, p>0.05), and had no effect on glucose-stimulated insulin secretion in isolated rat pancreas islets. Finally, chronic AVV-mediated over- expression of UGN did not lead to any differences in body weight (46.2±1.1 UGN vs. 47.5±0.9 g vehicle) or glucose homeostasis (2008, 2±497 UGN vs. 2291, 1±472 min×mmol/L vehicle, p>0.05). In conclusion, these data demon-

2500-PUB Integrated Testosterone Defi ciency in Male Patients with Young Onset Type 2 strate that GUCA2A and GUCA2B prohormones, and GN and UGN peptides, do not play a signifi cant role in the powerful effects of RYGB on body weight Diabetes Contributes to Poor Glycemic and Lipid Control Physiology/Obesity YAN LI, MANNA ZHANG, JIE ZHE, WENJIE CUI, SHARVAN RAMPERSAD, ZIWEI or glucose control and appear not to be viable targets for the treatment of PUBLISHED ONLY LIN, PENG YANG, HONG LI, CHUNJUN SHENG, XIAOYUN CHENG, SHEN QU, obesity or diabetes. Shanghai, China Objective: This study aims to compare the prevalence of testosterone 2503-PUB defi ciency between young-onset type 2 diabetes (T2DM) male patients and WITHDRAWN late-onset ones. Methods: This cross-sectional study included 102 young-onset T2DM male patients (diagnosis age ɖ35 years) and 237 male patients with late- onset T2DM (diagnosis age >35 years). Serum FSH, LH, testosterone, lipid profi le, HbA1c and beta-cell function were determined in blood samples.

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A621 INTEGRATED PHYSIOLOGY—OTHERCATEGORY HORMONES

2504-PUB Figure 1. Mice Femoral Reconstruction of Micro-CT. Exenatide Reduces Cytotoxicity and Proliferation Rate in Differen- tiated SH-SY5Y Cells ANARA KARACA, UMIDAHAN DJAKBAROVA, NESE ERSOZ GULCELIK, Ankara, Turkey, Istanbul, Turkey Recent data showed a link between diabetes and Alzheimer’s disease (AD). GLP-1R agonists exert cytoprotective effects on islets. Few cases reported that GLP-1R agonists improved cognitive function in AD patients with diabetes. We aimed to reveal the impact of exenatide on cytotoxicity and cell proliferation in AB Oligomer differentiated SH-SY5Y cells; AD model cells. Cytotoxicity was analyzed via level of lactate dehydrogenase release and proliferation rate by bromodeoxyuridine incorporation assay. Addition of exenatide to AB Oligomer treated cells signifi cantly decreased cytotoxicity, cell proliferation rate compared to AB oligomer only treated cells (p=0.005 and p=0.01, respectively). Briefl y, exenatide has neuroprotective effects in AB oligomer treated cells, suggesting a potential role in treatment of AD. Figure 1. % Proliferation Rate.

Figure 2. % Cytotoxicity. A: The new bone calluses of adiponectin and BMP - 2 groups were better than control at 2 weeks. Cortical continuity and cancellous bone structure of adi- ponectin and BMP-2 groups were better than control from 4 weeks. B C: BMD, BV/TV of mice femoral Micro-CT index. * compared with 2 weeks, P < 0.05; ** compared with 2 weeks, P < 0.01; # compared with control, P < 0.05. Supported By: Army Logistics Scientifi c Research Subject (CWS13J054)

2506-PUB Effects of Heterologous Expression of Human Cyclic Nucleotide Phosphodiesterase 3A (hPDE3A) on Redox Regulation in Yeast DONG KEUN RHEE, JUNG CHAE LIM, STEVEN C. HOCKMAN, FAIYAZ AHMAD, DONG HO WOO, YOUN WOOK CHUNG, SHIWEI LIU, ALLISON L. HOCKMAN, VIN- CENT C. MANGANIELLO, Bethesda, MD Oxidative stress plays a pivotal role in pathogenesis of cardiovascular diseases and diabetes, however the role of PKA-PDE3A remains unknown. Here we show that yeast expressing WT hPDE3A or K13R hPDE3A (putative ubiquitinylation site mutant) exhibited resistance or sensitivity to exogenous 2505-PUB H2O2, respectively. H2O2-stimulated ROS production was markedly increased Adiponectin Improves Mice Femoral Fracture Healing by Increasing in yeast expressing K13R hPDE3A (OxiS1), compared to yeast expressing WT Local BMP-2 Expression hPDE3A (OxiR1). In OxiR1, YAP1 and YAP1-dependent anti-oxidant genes YANPING GONG, CHUNLIN LI, LIANGCHEN WANG, LIJUAN WAN, Beijing, China were upregulated, and accompanied by reduction of thioredoxin peroxidase To observe the effect of adiponectin on mice femoral fracture healing (Tsa1p). However, in OxiS1, expression of YAP1 and YAP1-dependent genes and explore the possible mechanisms. Mice were divided into 12 groups by was impaired, that the thioredoxin system does not function appropriately. drugs (control, BMP-2, adiponectin), doses (1mg/kg, 2mg/kg) and durations H2O2 increased cAMP hydrolyzing activity of WT hPDE3A, but not K13R (2 w, 4 w, 6 w). The results revealed that the bone callus formation was hPDE3A, through PKA-dependent phosphorylation, which was correlated faster in adiponectin and BMP-2 groups than control from 2 weeks, with with its ubiquitinylation. The changes in anti-oxidant gene expression did higher elasticity and rigidity in biomechanical analyses (p <0.05). Micro-CT not directly correlate with differences in cAMP/PKA signaling, since despite scanning confi rmed better cortical and cancellous micro-structure of adi- differences in their capacities to hydrolyze cAMP, total cAMP levels in the ponectin and BMP-2 groups than control (p<0.05, Figure 1= Western Blot- three strains were similar, and PKA activity was lower in OxiS1 than in OxiR1 ting revealed that BMP-2 expressions were higher in BMP-2 and adiponec- or mock cells. During exposure to H2O2, however, Sch9p activity, a TORC1- tin groups. Immunohistochemistry observed linear relationship between the regulated rpS6 kinase and negative regulator of PKA in S. cerevisiae, was

Integrated expression of Adiponectin receptor-2 (AdipoR2) and BMP2 at fracture site rapidly reduced in OxiR1, and Tpk1p, a PKA catalytic subunit, was diffusely in adiponectin groups. So adiponectin has signifi cant improving effect on spread throughout the cytosol, resulting in PKA activation. On the other

Physiology/Obesity fracture healing by increasing local BMP-2 expression through combining hand, in OxiS1, Sch9p activity was unmodulated during exposure to H2O2, PUBLISHED ONLY AdipoR2 at fracture site. consistent with reduced activation of PKA and reduced phosphorylation of PKA substrates. These results suggest that, during oxidative stress, TOR- Sch9 signaling might regulate PKA activity, and that post-translational modi- fi cations of hPDE3A are critical in its regulation of cellular recovery from oxidative stress. Supported By: National Heart, Lung, and Blood Institute

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A622 OBESITY—ANIMALCATEGORY

2507-PUB 2509-PUB Long-Term Glycemic Control with Insulin Prevents the Develop- Differential Effects of the Paracrine-Acting FGF-8 Subfamily in ment of Testicular Interstitial Cell Tumors in Spontaneously Dia- Comparison to Hormone-like FGF Members on Leptin, Adiponectin, betic Torii Rats and pai-1 Gene Expression Utilizing an Adipocyte Cell Model TAKESHI OHTA, YUSUKE KEMMOCHI, KATSUHIRO MIYAJIMA, TOMOHIKO DIANA GRÜNDER, MALTE GRÜNDER, SÖREN WESTPHAL, Ulm, Germany SASASE, KENICHI MATSUI, NOBUHISA UEDA, MASAMI SHINOHARA, MUTSU- Recent data demonstrate the important role of the FGF family on energy YOSHI MATSUSHITA, Osaka, Japan, Tokyo, Japan homeostasis and carbohydrate metabolism. Systematic evaluation of whole Leydig cell tumors (LCT) are frequently observed in the Spontaneously subfamilies on adipokine biology are lacking. We investigated the effects Diabetic Torii (SDT) rats, whereas the same tumors rarely occur in Sprague- of the paracrine-acting FGF-8 subfamily (FGF-8, 17, 18) in comparison to the Dawley (SD) rats though the identical strain origin. The present study was hormone-like FGF members (FGF 19, 21, 23) on leptin (lep), adiponectin (adi) designed to evaluate the preventive effects of glycemic control with insulin and pai-1 mRNA gene expression. Lep, the prototypic adipocyte-derived hor- on Leydig cell proliferation in SDT rats. The following three groups were mone, induces a negative energy imbalance. Adi inversely correlates with used in the study: (i) insulin-treated SDT rats, (ii) untreated SDT rats, and (iii) body fat and modulates glucose metabolism and fatty acid oxidation. Pai-1 untreated SD rats. In the insulin-treated group, each SDT rat showing signs is increased in obesity and is a risk factor for atherosclerosis. Members of of diabetes was treated with subcutaneously implanted sustained-release the FGF-8 subfamily concordantly trends to increase lep (FGF-8 2.14-fold, insulin pellets from 24 weeks of age, and the rats were sacrifi ced at 50 or P<0.09; FGF-17 3.04-fold, P<0.13; FGF-18 8.67-fold, P<0.078) and adi (FGF-8 68 weeks of age for histological analysis. Untreated SDT and SD rats were 7.23-fold, P<0.05; FGF-17 no signal; FGF-18 2.29-fold, P<0.26), and diminished sacrifi ced at 32, 50, or 68 weeks of age for histological analysis. Blood glu- pai-1 (FGF-8 8.53-fold, P<0.01; FGF-17 12.61-fold, P<0.001; FGF-18 18.02-fold, cose levels were 400 mg/dl or higher at 24 weeks of age, and increased to P<0.01). Within the hormone-like FGF group FGF 21 increased (3.13-fold, approximately 800 mg/dl at 40 weeks of age and thereafter in untreated P<0.01) whereas others decreased lep (FGF-19 8.6-fold, P<0.001; FGF-23 SDT rats, whereas decreases in blood glucose levels were apparent after 4.51-fold, P<0.01). With regard to adi no effect could be observed by FGF-19 treatment, and at 40 weeks of age and thereafter in insulin-treated SDT rats, treatment, upregulation could be detected by FGF-21 (1.64-fold, P<0.01), where levels remained similar to those observed in untreated SD rats. In the and downregulation was measured by FGF-23 (1.51-fold, P<0.01). Pai-1 is testes of all untreated SDT rats, Leydig cell hyperplasia was observed at 50 decreased by FGF-19 and FGF-23 treatment (FGF-19, 58.7-fold, P<0.001; FGF- weeks of age and LCT were observed at 68 weeks of age. In contrast, no 23, 385-fold, P<0.001) and increased by FGF-21 (15.01-fold, P<0.05). In sum- Leydig cell proliferation was observed at any week of age in either insulin- mary, we systematicely investigated the infl uence of the FGF-8 subfamily treated SDT or untreated SD rats. In summary, long-term glycemic control (concordant infl uence) in comparison to the hormone-like FGFs (differential with insulin markedly prevented the development of Leydig cell prolifera- effects) on the expression of the prototyptic adipokines lep, adi and pai-1. tive lesions in SDT rats; however, without insulin treatment, proliferative Our data highlight the importance of the FGF family on adipocyte function. lesions appeared at 50 weeks of age and thereafter (i.e., approximately 30 In-depth comprehension of this infl uence may bring to light new potential weeks or more after the onset of diabetes) in almost all SDT rats. This fi nd- therapeutic remedies for the treatment of diabetes mellitus. ing strongly suggests the association of persistent hyperglycemia with the Supported By: Federal Armed Forces of Germany (28K3-S-201113) development of LCT. 2510-PUB 2508-PUB WITHDRAWN Calciotropic Hormones as Predictors of Glycemic Profi le in a Pre- diabetic Elderly Cohort KALLIOPI KOTSA, SPYRIDON KARRAS, XANTHIPPI TSEKMEKIDOU, ELENI RAPTI, MARIA GRAMMATIKI, ATHANASIOS C. MOUSIOLIS, MICHAEL DANIILIDIS, Thes- 2511-PUB saloniki, Greece The aim of this cross-sectional study was to investigate the correlation of WITHDRAWN 25-hydroxyvitamin D [25(OH)D] and parathyroid hormone (PTH) levels with glycemic biomarkers in a cohort of elderly nondiabetic subjects in order to incorporate 25(OH)D and PTH in a prognostic model for prediabetes in daily clinical practice. A total of 180 prediabetic patients (age >65 years) and 81 OBESITY—ANIMAL healthy age-matched controls were included. Anthropometric parameters [age, body mass index (BMI), waist circumference] and dietary intake of cal- cium and vitamin D (vitD) were recorded. A morning fasting plasma sample 2512-PUB was obtained for fasting plasma glucose (FPG), glycosylated hemoglobin Dissecting Functions of Endotrophin on Different Cell Populations (HbA1c), PTH, 25(OH)D, calcium and phosphorus measurements. Correlation in Adipose Tissue between variables was examined and multiple linear regression analysis YUESHUI ZHAO, XUE GU, KAI SUN, Houston, TX was performed to determine the predictive ability of PTH and 25(OH)D on Endotrophin is a novel adipokine that we recently identifi ed. It is a cleav- FPG and HbA1c variables. All analyses were carried out using the statistical age product from collagen 6 in obese adipose tissue. Previously we dem- package SPSS vr 17.00. No statistically signifi cant difference in age, BMI or onstrated that endotrophin serves as a potent stimulator to trigger mas- calcium levels was detected between patients and controls. Both groups sive fi brosis and infl ammation locally in adipose tissue which ultimately lead were vitD defi cient with controls demonstrating signifi cantly lower 25(OH)D to systemic insulin resistance. However, the detailed molecular mechanism concentrations compared to the prediabetic population [17.88 vs. 19.59 ng/ by which endotrophin exerts its functions in adipose tissue remains largely ml respectively (p=0.040)]. There was a non-signifi cant negative correlation unknown. In the current study, we apply an in vitro system by culturing dif- of 25(OH)D with both FPG (r=-0.083) and HbA1c (r=-0.203) and a non-signifi - ferent types of cells from adipose tissue in a conditional medium which con- cant positive correlation of PTH (r=0.162) with FPG and HbA1c (r=0.102) in the tains endotrophin and investigate the effects of endotrophin on the cells. control group. In the prediabetic population there was a statistically signifi - Intriguingly, we fi nd that endotrophin activates different pathological rel- cant (p=0.017) positive correlation (r=0.212) of PTH with FPG. In the prognos- evant pathways in different cell types: in 3T3-L1 adipocytes, endotrophin ini- Integrated tic model only PTH had a minor but statistically signifi cant impact on FPG. tiates a fi brotic program by up-regulating several collagen proteins, including collagen 3 and collagen 6; whereas in macrophages isolated from white adi- Physiology/Obesity An increase of 1 pg/dl of PTH resulted in a 0.12 mg/dl increase of FPG. Our PUBLISHED ONLY results indicate that vitD defi ciency is prevalent in a cohort of elderly non- pose tissue, endotrophin stimulates higher expression of pro-infl ammatory diabetic subjects in a Mediterranean country. In this cohort PTH is a better genes, i.e., TLR4, IL-1β and IL-18. Collectively, our fi ndings provide a mecha- predictor than 25(OH)D for FPG in prediabetes. nistic insight into the adverse effects of endotrophin in unhealthy adipose tissue and further establish this novel adipokine as a potential target to treat obesity and other metabolic dysfunctions.

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A623 OBESITY—HUMANCATEGORY

2513-PUB MOD-6031 pharmacokinetic (PK) and pharmacodynamic (PD) profi les were assessed in rats and monkeys following administration of single or repeated WITHDRAWN doses of SC injection up to 300mg/kg and 250 mg/kg, respectively. The PK parameters of MOD-6031 and its hydrolyzed subproducts (OXM peptide and PEG-linker) were quantitated utilizing sensitive LC-MS-MS method. The PD 2514-PUB profi le of MOD-6031, which is mainly derived by the activity of the released OXM, was measured by luminescence detection of cAMP stimulation in WITHDRAWN GLP-1R overexpressing cell line upon agonist binding. The results of PK analysis conducted in rats and monkeys consistently demonstrated a dose-dependent exposure for MOD-6031 and its hydrolyzed subproducts. The half-life of MOD-6031 and hydrolyzed OXM (T1/2~ 8-11 h) 2515-PUB were signifi cantly increased compared to reported half-life of OXM (T1/2 ~ 12 WITHDRAWN m). In the PD analysis, all treated animals demonstrated an increase in cAMP stimulating, confi rming GLP-1R activation. The activity profi les were compa- rable in their pattern to the MOD-6031 and its hydrolyzed OXM PK profi les. Similar Tmax were obtained in the PK and PD analysis, while the maximal 2516-PUB receptors activation signal was observed at 8 to 12 hours post dose. Pronounced enhanced PK and PD profi les, elevated exposures and half- WITHDRAWN life were confi rmed following MOD-6031 administration, providing proper safety exposure margins for the initiation of a phase 1 clinical study.

2519-PUB OBESITY—HUMAN The Clinical Characteristics of Obese Patients with Acanthosis Nigricans and Its Independent Risk Factors 2517-PUB YUEYE HUANG, JIAQI CHEN, XINGCHUN WANG, YI ZHANG, SHEN QU, Shang- Which Anthropometric or Behavioral Factors Contribute to Being hai, China Obese among Overweight Children? A Community-based Prospec- Objective: The aim of the study was to investigate the clinical char acteristics tive Study and risk factors for obese patients with acanthosis nigracans (AN). EUN YOUNG LEE, YEOREE YANG, BORAMI KANG, JIN-HEE LEE, SUN-YOUNG Methods: Two hundred and eight obese patients were divided into two LIM, JOONYUB LEE, HAE KYUNG YANG, HUN-SUNG KIM, SEUNG-HWAN LEE, groups: 80 obese patients without AN (OB group) and 128 obese patients JAE HYOUNG CHO, YOON-HEE CHOI, BONG-YUN CHA, KUN-HO YOON, Seoul, with AN (AN group). The weight, body mass index (BMI), TC (total choles- Republic of Korea terol), TG (triglyceride), FFA (free fatty acid), UA (uric acid), free testoster- In this study, we investigated which physical or behavioral factors con- one, and CRP (C-reactive protein) were measured for each patient. Oral glu- tribute to being obesity among overweight children. A community sample cose tolerance test (OGTT) was performed and insulin levels were measured of 884 children aged 9-13 years were enrolled from 2014. At the fi rst follow- during OGTT. Serum level of leptin was measured by ELISA. up examinations in 2015, a total of 833 children completed the measures Results: BMI, UA levels, fasting insulin and the HOMA-IR in AN group of anthropometrics, physical fi tness, and questionnaires. Body mass index were much higher than those of the OB groups (P<0.05). Serum Leptin levels (BMI, kg/m2) were used to defi ne overweight ( ≥ 85 percentile) and obese were signifi cantly higher in AN group than that in OB group (34.74±2.95ng/ (≥ 95 percentile or 25 kg/m2). At baseline, the prevalence of overweight and ml, 26.25±2.74ng/ml P<0.001) after adjusting BMI and gender analysis by obesity were 12.0% and 16.4%, respectively. Boys had a higher prevalence ANCOVA. For male, AN patients had lower serum levels of testosterone of obesity than girls (17.8% vs. 11.7%, P=0.046). After one year follow-up, (7.89±3.35nmol/l, 12.72±3.57nmol/l, P<0.001). Serum leptin were correlated more than 90% of children with normal weight or obesity at baseline kept with BMI (P<0.001), plasma insulin at 0 min, 30 min, 60 min (P=0.005, 0.001, their weight unchanged. However, one third of overweight children at base- 0.003), 120 min, and 180 min (P<0.001) and C-peptide at 30 min (P=0.003), line became obese, while one third of them became normal weight after 60 min (P<0.001), 120 min (P=0.004), and 180 min (P=0.038). Multiple logis- one year follow-up. Then, we divided overweight children at baseline into tic regression analysis indicated that UA (OR 4.627, 95% CI 2.443-8.762, 3 groups according to obesity degree after one year. There were no signifi - P<0.001) and Leptin (OR 4.098, 95% CI 1.237-13.581, P=0.021) were indepen- cant differences in physical fi tness among 3 groups at baseline. However, dent risk factors for AN in obese patients. In addition, low testosterone level overweight children becoming obese after one year showed increased waist was an independent risk factor for AN in male obese patients (OR 39.062, circumference and higher BMI percentile at baseline. In terms of behavioral 95% CI 5.523-283.808, P<0.001). factors, there were no signifi cant differences in physical activities or tele- Conclusion: AN is associated with more severe hyperinsulinemia and hype- vision viewing. Meanwhile, overweight children becoming obese after one ruricemia in obese patients, as well as lower serum of testosterone in male. year eat out more frequently and tended to eat habitually without hunger or UA and Leptin are independent risk factors for AN in obese patients. Low overeat compare to other groups. In summary, overweight children becoming testosterone may be a valuable predictor of AN in male obese patients. obese during follow-up had higher BMI percentile at baseline and showed bad eating habits compared to those keeping or losing weight. Considering 2520-PUB that overweight children could change body weight more easily than obese Reduced Subcutaneous Regional Fat Storage in Insulin-Resistant children, a focus on overweight children and further investigation to fi nd Females with Obesity contributing factors making these children to become obese may be helpful TYLER A. BOSCH, ANNE BANTLE, LISA CHOW, Eden Prairie, MN, Minneapolis, MN to prevent obesity among children. Visceral fat (VAT) is an established risk factor for metabolic dysfunc- tion. However, recent data suggests VAT accumulation is a consequence of 2518-PUB impaired subcutaneous fat (SAT) storage. We tested the hypothesis that insu- Integrated Establishment of Pharmacokinetic and Pharmacodynamic Profi les lin resistant (IR) females with obesity have proportionally more VAT storage (relative to SAT) compared to insulin sensitive (IS) females with obesity. Physiology/Obesity of MOD-6031: A Novel, Long-Acting, Dual GLP-1/Glucagon Agonist PUBLISHED ONLY in Several Toxicological Studies In this cross-sectional study, forty-nine (age 28.6±7.0 yrs.) females (21 IR, 2 LITAL ISRAELI YAGEV, AHUVA BAR ILAN, VERED LEV, GILI HART, OREN HERSH- 28 IS) with obesity (BMI: 33.8±7.4 kg/m ) were recruited for the TrainMe- KOVITZ, Nes Ziona, Israel UpMN Study. Metabolic status was determined by an OGTT (Matsuda <3.0) OPKO Biologics is developing long acting Oxyntomodulin (OXM; MOD- and regional fat distribution (including VAT) was measured by dual-energy 6031) for the indication of weight management and potentially type 2 dia- x-ray absorptiometry. Differences in percent regional fat distribution (rela- betes, utilizing reversible PEGylaton technology. The core technology is a tive to total fat mass (TFM)), VAT/abdominal SAT ratio and VAT/Gluteal fat spacer that links between the PEG and the peptide. Once injected, a fi rst ratio between IS and IR females were assessed by ANOVA. order hydrolysis slowly releases the intact OXM, enabling a prolonged expo- Figure 1a presents the mean differences in the percent of fat stored in sure of the peptide while maintaining its biological activity and ability to regional depots relative to TFM. Figure 1b presents the ratios of VAT/abdom- pass throw the blood brain barrier. inal SAT and VAT/gluteal SAT. We observed signifi cant differences (p<0.05) in proportional fat storage between IR and IS females with obesity.

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A624 OBESITY—HUMANCATEGORY

Compared to IS females, IR females have proportionately higher VAT rel- Table 1. Trajectories of Infl ammatory Markers during Follow-up. ative to total fat as well as regional SAT depots; suggesting the need to investigate impairments in SAT storage capacity as a potential mechanism for obesity induced IR. Figure 1a presents the percent of fat (relative to total fat mass) in the visceral, subcutaneous abdominal and subcutaneous gluteal regions for IR and IS females. Figure 1b presents the ratio of VAT to abdominal SAT and VAT to gluteal fat. Figure. Percent Fat (Relative to Total Fat). Table 2. Trajectories of Measured Factors during Follow-up.

2523-PUB WITHDRAWN

* Indicates a difference between IR and IS p<0.05. Supported By: National Institutes of Health 2524-PUB Restoration of Beta-Cell Function and Metabolic Flexibility Is Pos- 2521-PUB sible in Nondiabetic Asian Individuals with Morbid Obesity WITHDRAWN HONG CHANG TAN, PHONG CHING LEE, ALVIN ENG, SHANKER PASUPATHY, SONALI GANGULY, WENG HOONG CHAN, CHIN HOONG LIM, KWANG WEI THAM, Singapore, Singapore The disproportionately higher burden of type 2 diabetes (T2D) in Asians 2522-PUB may be contributed by early beta-cell dysfunction from rising obesity rates. Changes in Infl ammatory Markers following Gastric Bypass: A Pro- We compared insulin sensitivity, metabolic fl exibility and beta-cell health spective Cohort Study in Chinese Nonmorbidly Obese Adults with in nondiabetic individuals with morbid obesity (n = 9) to lean controls (n Diabetes =9) and the metabolic changes following surgically induced weight loss HONGKAI GAO, MOSHEN MAZIDI, Beijing, China (n =4). All subjects underwent oral glucose tolerance testing (OGTT), bio- To report on the changes over time in infl ammatory markers following impedence analysis and hyperinsulinemic euglycemic clamp with indirect Roux-en-Y gastric bypass in patients with diabetes and BMI of 28 to 35.This calorimetry measurement. Bariatric surgery subjects were studied again prospective cohort study involved 89 patients who met the indications of at 6-months. Insulin sensitivity index (ISI) was calculated using values from bariatric surgery for diabetes with BMI 25-30 kg/m2. Leptin, tumor necro- the fi nal 30 minutes of clamp and metabolic fl exibility as changes in respira- sis factor α (TNF-α), adiponectin, C-reactive protein (CRP) and interleukin 6 tory quotient (RQ) under insulin stimulation. Glucose disposition index (DI) (IL-6) were monitored from baseline to 12 months. BMI steadily decreased was used to defi ne beta-cell function relative to insulin sensitivity and cal- from 29.96 kg/m2 at baseline to 25.33 kg/m2 at 12 months following surgical culated as the product of insulin sensitivity and fi rst phase insulin secretion intervention. CRP also decreased from 35.00 mg/dl at baseline to 20.00 mg/ (insulinogenic index calculated from OGTT). Gender distribution (Female = 22.2%) was similar and obese individuals had a higher body mass index dl at 12 months. Leptin, adiponectin and IL-6 steadily decreased from their Integrated 2 baseline values down to a nadir at six months, and rose thereafter up to 12 (39.3 +/- 4.8 vs. 23.3 +/- 4.83 kg/m ), lower ISI (2.51 +/- 1.11 vs. 12.84 +/- months, resulting in higher 12-months values thanks the baseline ones for 5.93, p < 0.001) and DI (4.59 +/- 4.5 vs. 19.22 +/- 7.81 mg/kg/min per uU/mL, Physiology/Obesity PUBLISHED ONLY adiponectin, but not for leptin and IL-6. A saw tooth pattern was observed p < 0.001), indicating the presence of severe insulin resistance and early for TNF, with however the 12-month and all follow-up values remaining beta-cell dysfunction. In 4 individuals after bariatric surgery, there was sig- lower than the baseline values. Body weight control following bariatric sur- nifi cant weight loss (115.5 to 90.6 kg) that was contributes mainly by fat gery was associated with improved levels of infl ammatory markers during mass loss (62% of total weight loss). This was associated with a dramatic the fi rst 12-month of follow-up of this Chinese cohort. These fi ndings refl ect improvement in ISI (2.64 +/- 1.11 to 8.05 +/- 3.27, p =0.018), metabolic fl ex- the control of sub-clinical infl ammation secondary to the reduction of the ibility (delta RQ 0.043 +/- 0.038 to 0.085 +/- 0.024, p = 0.016) and DI (5.74 +/- body fat mass, but also suggest the explanation for improvement of cardio 7.67 to 14.43 +/- 8.39, p 0.034). Beta-cell dysfunction occurs early in the metabolic profi le following bariatric surgery. pathogenesis of T2D is evident even in nondiabetic obese individuals. Weight loss improves insulin sensitivity, metabolic fl exibility and reverses early beta-cell dysfunction. Supported By: SingHealth Foundation

ADA-Supported Research For author disclosure information, see page A696.

A625 OBESITY—HUMANCATEGORY

2525-PUB activity, acculturation and BID were not associated with physical activity (adjusted R2=.026, all p>.05). The fi ndings indicate that higher levels of Amer- WITHDRAWN ican acculturation in middle-aged KI immigrants was associated with lower BID, which does not occur in blacks or Hispanics. In addition, BID appears to have a strong infl uence on obesity in KIs, regardless of their gender. Reduc- 2526-PUB ing BID may be important to prevent obesity in KIs. Supported By: Global Korean Nursing Foundation Dissociation of Glycemic Indices in Obese Dialysis Patients: High HgbA1c and Low Alternative Indices MARK E. WILLIAMS, NORMA OFSTHUN, NEAL MITTMAN, LIN MA, JULIE BREN- 2528-PUB NAN, FRANKLIN MADDUX, Boston, MA, Waltham, MA, Brooklyn, NY, Rockleigh, Predictors of Weight Loss in Diabetics and Nondiabetics Submitted NJ to Bariatric Surgery in Teresopolis, Brazil Our GIDE (Glycemic Indices in Dialysis Evaluation) study initially reported ERIKA C.O. NALIATO, BRUNA M. CRIVANO, BRUNO B. PINTO, JACKSON A. that obesity associates with high hemoglobin A1c but low alternative gly- TORRES, MAURO S. PIMENTEL, Teresopolis, Brazil cemic indices in hemodialysis (HD) patients in ASN 2015. Now we further Bariatric surgery has been proven useful in the treatment of diabetics examined this association using different cutoffs of indices. A combined (DB). Factors such as age, BMI, and surgical technique may infl uence long- cohort of 2,394 active hemodialysis (HD) patients (1,424 with diabetes, 970 term outcome. We compared 20 DB and 57 nondiabetics (ND) submitted to without) from 26 U. S. FMCNA facilities had baseline indices [HgbA1c; fruc- bariatric surgery and investigated predictors of weight loss in these groups. tosamine, albumin-adjusted (AlbF) and percent glycated albu- Roux-en-Y bypass (RYBP) was the technique used in 64.3% of DB, while min] measured at baseline (Jan-Mar 2013) then monthly until Apr 2015. Obe- 58.7% of ND were treated with sleeve gastrectomy (p = 0.22). In DB, age sity = BMI≥30kg/m². Glycemic indices of the study populations were then at surgery corresponded to 41.2 ± 10.9 years and, in ND, 36.8 ± 9.6 years divided into quintiles. Average BMI (kg/m²) by level of glycemic indices (Very (p = 0.09) and time elapsed since surgery, 0.9 ± 0.3 years, in DB, and 1.4 ± low, Low, Med, High, Very high) are shown in Figure below. The means of 1.8 years, in ND (p = 0.64). Most subjects were women (75% of DB vs. 86% BMI among the quintiles in each category of indices were signifi cantly dif- of ND, p = 0.30). Prevalence of smokers was 11.8% in DB and 9.3% in ND ferent, all p < 0.05. (p = 0.67). Most DB (55%) and 38.6% of ND had arterial (p = The same trends were obtained from the separated DM and non-DM pop- 0.29). There were no differences between DB and ND when preoperative ulations. Obesity is positively correlated with HgbA1c but negatively corre- weight (122.6 ± 6.8 vs. 119.7 ± 2.5 kg, p = 0.62), BMI (44.10 ± 7.13 vs. 45.01 ± lated with other glycemic indices in both diabetic and nondiabetic hemodi- 4.91 kg/m², p = 0.37) waist circumference (131.8 ± 23.6 vs. 126.7 ± 12.3 cm, p = alysis patients. Further studies are needed to explore the mechanisms and 0.40), systolic (130.6 ± 10.6 vs. 135.3 ± 15.9 mmHg, p = 0.38) and diastolic assess the relationship of these fi ndings to superior survival outcomes in blood pressures (75.6 ± 6.3 vs. 74.5 ± 8.0 mmHg, p = 0.60), total cholesterol obese HD patients. (179.5 ± 31.3 vs. 194.7 ± 38.4 mg/dL, p = 0.17), LDL (104.9 ± 27.3 vs. 112.1 ± 32.3 mg/dL, p = 0.45), and triglycerides (174.2 ± 92.8 vs. 170.7 ± 82.8 mg/dL, Figure. Average BMI by Level of Glycemic Indices in Hemodialysis Patients. p = 0.89) were compared. DB had higher fasting glucose levels (132.9 ± 58.2 vs. 93.0 ± 11.7 mg/dL, p < 0.01) and lower HDL levels (40.4 ± 8.1 vs. 47.8 ± 11.2 mg/dL, p = 0.02). Mean weight loss corresponded to 31.2 ± 14.6 kg in DB and 33.7 ± 14.9 kg in ND (p = 0.30) and mean BMI loss, to 11.38 ± 5.14 vs. 12.24 ± 5.30 kg/m², respectively (p = 0.33). In the multivariate analysis, preoperative BMI, diastolic blood pressure and RYBP were the predictors of weight loss in the present study (r² = 91.04%, p < 0.01). In conclusion, DB and ND had a similar weight loss as a result of bariatric surgery, with greater probability of weight decrease for those with higher BMI, lower diastolic blood pressure, and submitted to a RYBP.

2529-PUB WITHDRAWN

2530-PUB 2527-PUB Serum High-Molecular-Weight Adiponectin Levels Correlate with The Association between Body Image Discrepancy and Body Mass Various Metabolic Parameters in Special Health Checkup Programs Index in Middle-Aged Korean Immigrants HIROSHI HIROSE, KOICHIRO AZUMA, RYOKO SHIMIZU-HIROTA, MICHIYO TAKA- CHORONG PARK, SOOHYUN NAM, JANE DIXON, ROBIN WHITTEMORE, Orange, YAMA, YASUSHI IWAO, HIROSHI KAWABE, Tokyo, Japan CT Adiponectin (ADPN) is secreted by adipocytes and has been known to The prevalence of obesity in middle-aged Korean Immigrants (KIs) in the reduce blood glucose levels, atherosclerosis, and tumor growth in vitro and U.S. is increasing at an alarming rate. Body image discrepancy (BID) – the gap in in vivo animal studies. According to recent reports, succination of ADPN between current and ideal body image– may be a risk factor of immigrants’ contributes to a decrease in high-molecular weight (HMW) ADPN levels in obesity due to its infl uence on health behaviors. However, little is known diabetic mice. Moreover, anemia, , and high brain natriuretic about how BID, acculturation, body mass index (BMI) and health behaviors peptide levels are reportedly associated with elevated serum HMW-ADPN are associated in KIs. The purpose of this study was to identify the associa- levels in diabetes mellitus and coronary artery disease patients. Therefore, tion between BID and acculturation with BMI, physical activity, and eating in we aimed to further elucidate the relationships between HMW-ADPN levels

Integrated KIs. A cross-sectional study was conducted in a national KI sample (N=230; and various metabolic parameters, including visceral fat area (VFA), subcu- 35.8±5.7 years old, 64% male, 47% overweight/obesity) with an online taneous fat area (SFA), and homeostasis model assessments of insulin resis-

Physiology/Obesity survey. Data on BID, BMI, physical activity, eating, and Korean/American tance (HOMA-IR) and β-cell function (HOMA-β). Serum HMW-ADPN levels PUBLISHED ONLY acculturation were collected with validated measures. First, the association were analyzed in 29- to 92-year-old Japanese men (n = 244) and women between Korean/American acculturation and BID was explored. Second, the (n = 174) who participated in our special health checkup programs during a effects of BID and acculturation on BMI, physical activity, and eating were 3-year period and met our inclusion criteria. VFA and SFA were measured tested with linear regression models. All models controlled for gender, age, with computed tomography at the umbilical level, while serum insulin and socio-economic status and comorbidities. Higher American acculturation HMW-ADPN concentrations were measured with enzyme immunoassays was associated with lower BID (β=-.13, p=.05). There was no gender or age and chemiluminescent enzyme immunoassays, respectively. We found that effect on BID. The BMI model (adjusted R2=.56, p<.01) showed that higher the median serum HMW-ADPN levels were 2.42 µg/ml in men and 5.12 µg/ BID was associated with higher BMI (β=.60, p<.01) but acculturation was ml in women. Moreover, HMW-ADPN levels were positively correlated with not associated with BMI. There was no signifi cant interaction of BID and high-density lipoprotein cholesterol (HDL-C) and age, and negatively cor- acculturation in explaining BMI. For eating, higher American acculturation related with body mass index, waist circumference, VFA, SFA, red blood was associated with healthier eating (adjusted R2=.10, p<.01). For physical cell (RBC) count, HOMA-IR, and serum triglyceride and C-reactive protein

For author disclosure information, see page A696. ADA-Supported Research

A626 OBESITY—HUMANCATEGORY levels. Stepwise multiple regression analyses revealed that log-transformed 2533-PUB HMW-ADPN levels were independently correlated with HDL-C levels, RBC Weight Loss Is Associated with Limited Metabolic Benefi ts in Met- count, VFA, age, sex, and log [HOMA-IR] in that order (F > 8.0, P < 0.0001, R 2= abolically Healthy Obese Women 0.490). To conclude, serum HMW-ADPN levels were positively correlated M. ROSA BERNAL-LOPEZ, SONIA SANTAMARIA-FERNANDEZ, JOSEFINA RUIZ- with HDL-C levels, age, and female sex, and negatively correlated with VFA, NAVA, FRANCISCO J. TINAHONES, M. JOSE BUJALANCE, JUAN JOSE BEDOYA, HOMA-IR, and RBC count. RICADO GOMEZ-HUELGAS, Malaga, Spain Supported By: JMECSS Introduction: A signifi cant percentage of obese subjects, called metaboli- cally healthy obese (MHO), have no metabolic alterations characteristics of 2531-PUB obesity. Controversy exists about whether weight loss brings cardiometa- Genetic Susceptibility Factor as a Predictor of Type 2 Diabetes bolic benefi ts in this population. Remission and Weight Loss after Bariatric Surgery Aim: Our aim was to assess whether a signifi cant body weight loss induces ANDREEA CIUDIN, OLGA SIMO-SERVAT, ANGEL ORTIZ, ALBERT LECUBE, KEVIN short-term metabolic benefi ts in MHO individuals. GUILLEN, SARA PICH, ORIOL CASAGRAN, ORIOL CASAGRAN, EDUARDO SALAS, Material and Methods: We included 115 nondiabetic women (age 35-55 CRISTINA HERNANDEZ, RAMON VILALLONGA, RAFAEL SIMÓ, JORDI MESA, years) with body mass index (BMI) 30-45 kg/m2 and ɖ1 of following criteria: Barcelona, Spain, Lleida, Spain, Esplugues de Llobregat, Spain blood pressure ɖ135/85 mmHg, fasting plasma glucose ɖ100 mg/dl, HDL- Obesity is directly related to an increased risk of diabetes mellitus, cardio- cholesterol ɖ50 mg/dl and triglycerides ɖ150 mg/dl. After an intensive life- vascular disease, and overall mortality. Weight loss is effective in decreas- style modifi cation based on Mediterranean diet and exercise, women were ing these risks and to reduce disease severity. Bariatric surgery is an effec- classifi ed into three groups according to their body weight loss <5%, ≥5% tive therapy for sustained weight loss and type 2 diabetes (T2D) remissions to <10% and ≥10%. Anthropometric measures, glycemic and lipidic profi le, in most of the morbidly obese patients. But there is also a signifi cant number adipokines, infl ammatory markers and fatty liver index (FLI) were analized at of individuals with an inappropriate response to bariatric surgery. There baseline and 3 months. is some data regarding the genetic load on the outcome of bariatric sur- Results: The fi nal sample, after 11 dropout (9.6%), included 104 women gery, but its role remains to be elucidated. The aim of this study is to assess (mean age ± SD: 44.4 ± 3.7 years, BMI mean ± SD: 36.3 ± 4.7 kg/m2), which 47 whether a selection of genetic variants could identify patients who will have (45, 2%), 27 (26%) and 30 (28, 8%) lost <5%, ≥5% to <10% and ≥10% of basal a satisfactory response after bariatric surgery in terms of weight loss and body weight, respectively. The lipidic profi le (except triglycerides levels) and T2D remission. For this purpose a case-control study was designed. This FLI improved signifi cantly in all groups. Glycemic parameters (plasmatic insu- study included 100 women who underwent bariatric surgery (Roux-en-Y lap- lin level, HOMA-R) and infl ammatory biomarkers (hsCRP) only improved in aroscopic gastric bypass): 50 patients who were diabetic before surgery (15 MHO women with body weight loss ≥10%. Adiponectinemia did not change cases with less than 40% of the excess weight loss [EWL] and 35 cases with in any group. more than 75% EWL), matched with 50 nondiabetic controls (15 patients Conclusions: A signifi cant weight loss in MHO women induces short-term with less than 40% EWL and 35 with more than 75% EWL). All individu- limited metabolic improvement. The rate of weight loss may infl uence the als were analyzed with a genetic panel (Nutri inCode). The predictive abil- metabolic response. ity was analyzed by discrimination (area under the ROC curve), sensitivity Supported By: European Regional Development Fund (PI12/01373, PI14/00696); and specifi city and a score was calculated. The results showed a signifi cant Research Centres Network (CIBER CB06/03/0018); Ministry of Economy, Innova- discrimination ability with a high sensitivity in identifying individuals who tion, Science and Employment (P07-CTS-656, MRBL); Government of Andalusia, will have a good response to bariatric surgery (more than 75% EWL) or will Spain (RH-0066-2013) achieve T2D remission (81, 81% and 98, 82% respectively; AUC-ROC 0.72, CI 95% [0.46-0.67] and AUC-ROC 0.94, CI 95% [0,872-0,978] respectively). 2534-PUB The panel of genetic variants assessed by Nutri inCode panel has a good The Ameliorating Effect of Gut Microbiota-targeted Clinical Inter- sensitivity in identifying individuals who have a good response to bariatric vention on Metabolic Disorders of Impaired Glucose Tolerance surgery, in terms of weight loss and T2D remission. This genetic approach Women with PCOS seems a useful tool in the selection of bariatric surgery in diabetic patients. XIAOYING DING, RUI LIU, JIAN SHEN, XUEJIAO WANG, QINGWU YAN, ANDREW S. GREENBERG, LIPING ZHAO, YONGDE PENG, Shanghai, China, Boston, MA 2532-PUB Polycystic ovary syndrome (PCOS) is a common heterogeneous endo- BMI and Insulin Resistance According to Vitamin D in Type 2 DM crine disease associated with metabolic disorders. Compared with healthy JAE MIN LEE, Daejeon, Republic of Korea women, a large proportion of women with PCOS also have obesity, impaired The objective of this study was to investigate the impact of vitamin D con- glucose tolerance (IGT), insulin resistance, and dyslipidemia. We investi- centration on the relationship of body mass index (BMI) status and insulin gated the ameliorative effect on PCOS characteristics by a gut microbiota- resistance in type 2 diabetes. Retrospective study of all patients who had targeted dietary or acarbose intervention. Thirty-four PCOS patients were concentrations of vitamin D, fasting glucose, and fasting insulin had been recruited and randomly assigned into WTP group (intervention with diets determined (n=257, 44.4% women) between January 1st and July 31th on based on whole grains, traditional Chinese medicinal foods and prebiotics) 2013. We used the BMI for obesity and the HOMA-IR index for insulin resis- and APW group (acarbose plus above intervention). There was signifi cant tance. The vitamin D status of subjects was categorized into quartiles as a difference in the serum levels of insulin, ghrelin, spexin, testosterone and categorical variable: I (ɖ19 ng/mL), II (19 ng/mL > serum(OH)Dɖ25 ng/mL), LH before and after the twelve-week intervention in APW group. Bacteroi- III (25 ng/mL > serum(OH)Dɖ31 ng/mL), and IV (>31 ng/mL) The negative cor- des, Faecalibacterium, Roseburia, Blautia and Clostridium XlVa were domi- relation between serum vitamin D and BMI with type 2 diabetes was sig- nant genus in pre-intervention PCOS patients. Bacteroides and Clostridium nifi cant and the negative correlation between vitamin D and insulin resis- XlVa decreased, while Bifi dobacterium increased after intervention in both tance in type 2 DM was also remained signifi cant. Multiple regression groups. 56 key OTUs were clustered into 11 co-abundance groups (CAGs). analysis demonstrated that vitamin D was not associated with BMI (p = CAG3 and CAG9 displayed signifi cant correlation with testosterone level in 0.681) but associated with insulin resistance (p < 0.042). BMI status and a negative manner, while CAG10 had a signifi cant positive correlation with HOMA-IR status were taken out of the analyses investigating the associa- serun level of LH/FSH throughout the intervention procedure. After inter- tion between serum vitamin D quartile, separately. It was found that individ- vention, butyric acid basically kept steady, while isovaleric acid decreased Integrated uals with the lowest quartile of 25(OH)D levels had signifi cantly higher rates signifi cantly in both groups. Cytotoxicity of fecal water in both groups sig- Physiology/Obesity of unfavorable conditions of BMI and HOMA-IR levels compared to those in nifi cantly decreased after intervention. In general, both simple WTP diet PUBLISHED ONLY the fourth quartile. However, no signifi cant association was found for those intervention and WTP diet combined with acarbose improved the reproduc- in the second vs. those in the fourth quartile or those the in third vs. those in tive and metabolic disorders of PCOS patients, and regulated the gut micro- the fourth quartile. As conducting a study of type 2 diabetes, plasma vitamin biota structure and metabolite. These results preliminarily indicated that D has negative correlation with BMI and insulin resistance. Especially, it is gut microbiota may participate in the development of metabolic disorders in more strongly associated with insulin resistance. Therefore, we conclude women with PCOS, which might provide a basis on gut microbiota-targeted that vitamin D defi ciency is a valuable attributable risk for type 2 diabetes, clinical intervention. especially combined with obesity. Supported By: National Natural Science Foundation of China (31330005, 30730005)

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A627 ISLET BIOLOGY—APOPTOSISCATEGORY

2535-PUB 2539-PUB Laparoscopic Sleeve Gastrectomy in Severe Obese Patients with WITHDRAWN Ancanthosis Nigricans YUN HUANG, DONGLEI ZHOU, LIESHENG LU, CUILING ZHU, YI ZHANG, LE BU, SHEN QU, Shanghai, China Acanthosis nigricans (AN) is the most common dermatologic manifesta- 2540-PUB tion of obesity and is considered to be the skin feature of insulin resistance. Melatonin Treatment Improves Insulin Resistance and Pigmenta- Those obese individuals with AN are more likely to have abnormal metabolic tion in Patients with Acanthosis Nigricans homeostasis. Bariatric surgery has been proved to be the most effective HANG SUN, SHEN QU, XINGCHUN WANG, JIAQI CHEN, KEXIU SONG, LIANG LI, treatment for obese patients with or without diabetes. However, there are YUEYE HUANG, HAN CAO, SHANGYU CHAI, Shanghai, China few reports on the effect of bariatric surgery on severe obesity patients with To investigate the effect of melatonin on insulin resistance in patients of AN. The purpose of our study is to identify the early metabolic responses acanthosis nigricans with obesity. A total of 17 obese patients with acan- following laparoscopic sleeve gastrectomy (LSG) in obese individuals with thosis nigricans and body mass index exceeding 28 kg/m2 were recruited in AN. 17 severe obese patients with AN were recruited to undergo LSG from a 12-week randomized, open-label pilot study. All the participants received September 2013 through August 2015. They were evaluated preoperatively melatonin 3 mg/day. Insulin sensitivity, glucose metabolism, infl ammatory and 3 months after the surgery for anthropometric parameters, glucose and factors and other biochemical parameters were measured before and after lipid profi le, hepatic function, and scores of AN. Patients showed a dramatic the treatment course of melatonin. Homeostasis model assessment insu- reduction in body weight (116.43 ± 16.97kg vs. 92.42 ± 14.51kg; P<0.001), BMI lin resistance index (7.77±5.2169 vs. 8.99±5.1047, p<0.05) and fasting insulin 2 2 (40.96 ± 4.70kg/m vs. 32.34 ± 3.69kg/m ; P<0.001) and waist circumference (32.1018±20.29752uU/ml vs. 37.0935±20.26215uU/ml, p<0.05) were signifi - (122.50 ± 8.80cm vs. 106.74 ± 8.17cm; P<0.001). Signifi cant improvements cantly decreased after the 12-week treatment. There were also statistically in blood pressure, insulin resistance status, glycemic and hepatic function signifi cant declines in the AN scores, body weight, body mass index, body were achieved. AN scores were signifi cantly decreased from 6.88 ± 1.27 to fat, visceral index, neck circumference and waist circumference. In conclu- 4.18 ± 1.67, P<0.001 after surgery. In conclusion, LSG can effectively improve sions, melatonin could improve insulin resistance and reduce insulin levels, the AN in obese patients and normalize the metabolic status and should be help to relieve skin symptom in obese patients with acanthosis nigricans. a better choice for severe obese patients with AN. (NCT02604095). 2536-PUB WITHDRAWN ISLET BIOLOGY—APOPTOSIS 2541-PUB 2537-PUB WITHDRAWN WITHDRAWN 2542-PUB The Effect of Caveolin-1 on the Proliferation and Apoptosis of NIT-1 2538-PUB Cell Expression of Innate Immune Receptors in Circulating Leukocytes HAICHENG LI, HANGYA PENG, HAIXIA XU, SHUO LIN, KEYI LIN, LONGYI ZENG, Before and After a Fat Overload and Its Relationship with the Meta- Guangzhou, China bolic Status of Morbidly Obese Patients Our study aims to access the infl uence of caveolin-1 during the process of MERCEDES CLEMENTE-POSTIGO, JOSE CARLOS FERNANDEZ-GARCIA, JUAN proliferation and apoptosis in NIT-1 cell. We knockdown the expression level ALCAIDE-TORRES, FERNANDO CARDONA, FRANCISCO J. TINAHONES, Malaga, of caveolin-1 in NIT-1 cell by RNA interference technique which realized by Spain transfer a RNAi vector target caveolin-1 mRNA into the NIT-1 cell through Obesity is characterized by a low-grade infl ammation which leads to the the latent virus infection and purifi ed the positive infection cell by puromycin development of insulin resistance and has been associated with high-fat containing medium. The differences of cell proliferate and apoptosis among diets. High-fat meals increase the translocation of bacterial products from the caveolin-1 knockdown cell, the scramble vector infection cell and the gut microbiota to the circulation, and bacterial lipopolysaccharide (LPS) has wildtype NIT-1 cell were compared, and the effect of caveolin-1 on the cell’s been proposed as one of the factors responsible for this relationship. On the proliferation and apoptosis were analyzed. The results of fl ow cytometry other hand, it has been described that lipids are able to bind and activate and MTT showed that knockdown the expression level of caveolin-1 in NIT-1 receptors of the innate immune system which would also trigger the infl am- cell could promote proliferation as well as increase the resistance to palm- matory response. Thus, the aim of this study was to determine the expres- itic acid’s lipotoxicity. Caveolin-1 may interfere with the pathway of cell’s sion of innate immune receptors in circulating leukocytes before and after a proliferation and apoptosis. It’s maybe a pro-apoptosis and anti-proliferation fat overload (FO) in morbidly obese (MO) patients and to analyze its relation- factor in NIT-1 cell and a new target for diabetes therapy. ship with lipid and glucose metabolism. Figure 1. For this purpose, leukocyte Toll-like Receptor (TLR) 2, TLR4 and CD14 expression was measured by fl ow cytometry before and at 3 h after a FO in 14 MO patients classifi ed according to their baseline triglyceride (TG) and glucose levels in non-hypertriglyceridemic, normoglycemic patients (NTG), hypertriglyceridemic, normoglycemic patients (HTG), and diabetic patients without hypertriglyceridemia (DM). Plasma LPS levels as well as biochemical and anthropometric variables were determined. Monocyte TLR2 expression at 0 h and 3 h as well as monocyte CD14 expression at 3 h after the FO were higher in both HTG and DM compared to NTG patients. Monocyte TLR2 expression correlated positively with TG levels and negatively with HDL-C levels. Monocyte TLR2 and CD14 expres- sion decreased at 3 h after the FO compared to baseline in NTG patients. However, the expression of these markers was not signifi cantly modifi ed by the FO in HTG and DM patients. In conclusion, hypertriglyceridemia and diabetes imply a higher monocyte TLR2 and CD14 expression and modify the response of these receptors to a

Islet Biology/ high-fat meal in MO patients. Insulin Secretion Supported By: Instituto de Salud Carlos III (PI12/02355, CP13/00023,

PUBLISHED ONLY Supported By: National Natural Science Foundation of China (81070661); Novo CB06/03/0018); Consejeria de Economia, Innovacion, Ciencia y Empleo (P11- Nordisk China (2014) CTS-08181); Fondo Europeo de Desarrollo Regional

For author disclosure information, see page A696. ADA-Supported Research

A628