Figure 1. 2473-PUB Application of Translational ...€¦ · tis (NASH), although iron has not been...

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INTEGRATED PHYSIOLOGY—INSULIN SECRETION INTEGRATED PHYSIOLOGY—LIVER IN VIVO

2473-PUBApplication of Translational Pharmacokinetic and Pharmacody-namic Modeling in the Development of GPR40 Partial AgonistsDANIEL 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 diabetes. 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 oral glucose tolerance test conditions in single dose and chronic administra-tion were included in the analysis. A model-based in vitro-in vivo correla-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-uated in preclinical experiments and was predictive of the published human dose-response relationship of TAK875. Simulations from the quantitative model were shown to be consistent with the observed dose-response glu-cose data both in the fasted state and following meals in the completed MK-8666 proof of concept study. This model was further used in making quantitative predictions of the dose-response relationship for novel GPR40 agonists in discovery phase, and has been used by the development team as a basis for prioritization and decision making around proposed clinical development programs.

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INTEGRATED PHYSIOLOGY—LIVER

2475-PUBTriple Therapy Utilizing Vitamin E, Milk Thistle, and Carnitine Improves ALT and the Metabolic Abnormalities Associated with NAFLDJOHN POULOS, VALENTIN MILANOV, Fayetteville, NC

Evidence of scientifi c data in peer reviewed journals indicates that anti-oxidant supplementation may improve abnormal liver chemistries, glucose control, and hyperlipidemia, in patients with NAFLD. The primary objective was to determine the effects of Vitamin E 200IU, Silymarin 750mg, L carni-tine 1gm (VSC) on normalization of abnormalities in liver function testing in patients with NAFLD and to determine possible improvements in blood glu-cose, hemoglobin A1c, cholesterol, LDL, triglycerides and CRP. Patients with NAFLD were treated with either VSC (n=15) or placebo (n=17) for a period of 24 weeks. The following laboratory values were assessed AST, ALT, trig-lycerides, HDL, LDL, insulin levels, glucose and CRP. Eleven out of 15 (70%) patients in the VSC group had normalization of ALT whereas 9 of 17 patients (54%) had normalization of ALT in the placebo group (p=0.1). Patients treated with VSC had a 3% reduction in serum glucose levels after 24 weeks of treatment, whereas patients on placebo had a 6% increase in serum glu-cose levels. A 17% increase in serum insulin levels was noted in the placebo 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

Figure 1.

Supported By: National Natural Science Foundation of China (81200630); Natu-ral Science Fund Committee of Zhejiang Province (LQ12H07001); Wenzhou Science and Technology Bureau (H20150001)

INTEGRATED PHYSIOLOGY—INSULIN SECRETION IN VIVO

2471-PUBGPR40 Knockout Rats Have Diminished Lipid-mediated Potentiation of Insulin SecretionTONYA L. MARTIN, JIANYING LIU, MATTHEW M. RANKIN, MEGHAN TOWERS, JENSON QI, LISA D. NORQUAY, ALESSANDRO POCAI, Spring House, PA

Chronic activation of GPR40, a fatty acid sensing G-protein-coupled recep-tor, improves glycemic control in type 2 diabetic humans.

We used zinc fi nger nuclease technology to generate GPR40 null rats in the Sprague-Dawley genetic background with a 2 bp deletion resulting in a trun-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 hyperglycemia when compared to WT rats (118 ± 4.5 vs. 94 ± 3.0 mg/dl, p < 0.05); there were no other differences observed between GPR40 KO and WT rats.

HFD-GPR40 KO rats showed fasting hyperglycemia (121 ± 5.1 vs. 93 ± 2.5 mg/dl, p < 0.05) with decreased fasting insulin (471 ± 124.3 vs. 994 ± 105.2 pg/ml, p < 0.05). HFD-WT rats were hyperinsulinemic compared to WT rats on regular chow (1201 ± 166 pg/ml vs. 517 ± 80.4 pg/ml, p < 0.05). Insulin levels in HF-GPR40 KO rats were similar to GPR40 KO rats on regular chow. After a glucose challenge, the glucose area under the curve (AUC) of HFD-GPR40 KO rats was higher than, but not statistically different from, HFD-WT rats (24411 ± 660 vs. 22224 ± 1237 mg/dl/120 min). However, the insulin AUC was markedly decreased in the HFD-GPR40 KO rats (264,737 ± 25,702 vs. 479,989 ± 40,157 pg/ml/120 min, p < 0.05).

We examined pancreatic islets from the WT and KO rats. WT and KO islets responded similarly to increased concentrations of glucose; however, con-sistent with the in vivo data, when the islets were challenged with glucose and palmitate, the islets from the KO rats showed a diminished insulin secre-tory response.

Taken together, these data demonstrate that GPR40 is required for the maintenance of fasting glycemia and the compensatory response of the β-cell to lipid-induced hyperinsulinemia.

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INTEGRATED PHYSIOLOGY—LIVER

2480-PUBDietary Iron Restriction Prevents the Transition of Fatty Liver to Ste-atohepatitis in Mice Fed a High Fat/High Carbohydrate DietLIPIKA SALAYE, IELIZAVETA BYCHKOVA, DONALD A. MCCLAIN, Winston-Salem, NC, Cleveland, OH

High iron is associated with increased risk for nonalcoholic steatohepati-tis (NASH), although iron has not been implicated causally in its pathogen-esis. We examined progression of NASH in mice fed a model “fast food” diet supplemented with different levels of iron (4, 35, 500, or 2000 ppm). Mice on the 4 ppm iron diet did not become anemic, and the fold-increase in hepatic iron seen at the highest iron was within the normal human range. 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 after initiation of the diet (380±32 IU/L at 6 mo) compared to mice on normal chow (121±40 IU/L, p<0.01). Mice on the 4 ppm diet did not exhibit elevations of ALT (70±15 IU/L at 6 mos). Mice on the 35 pp diet had a delay in the time course of elevation, with elevations of ALT at 6 mos (318±19 IU/L), but not 3 mos (102±22 IU/L). Only mice on the higher iron diets showed up regula-tion of collagen type 2, a marker of liver injury in NASH. We conclude that high tissue iron levels accelerate the transition of NAFLD to NASH and pres-ent an attractive target for risk modifi cation because of the ease of their manipulation.

Supported By: National Institutes of Health; U.S. Department of Veterans Affairs

2481-PUBHigh Olive Oil Intakes Enhance Carbohydrate Stimulation of Lipo-genic Gene Expression in RatsKATHLEEN V. AXEN, KATE RUSSELL, JO ANN BROWN, MARIANNA HARPER, KEERTESHWRYA MISHRA, TASHANNE DISTIN, KENNETH AXEN, Brooklyn, NY

High-fat (HF) diets have been shown to increase hepatic lipogenesis in rodents. To investigate whether this effect may be due to amplifi cation of insulin’s stimulation of lipogenic gene expression, we compared the effects of 1 week’s intake of HF diets on the expression of lipogenic genes and other targets of insulin in rat liver both after a 24 hr fast (baseline) vs. after 18 hr of refeeding with a high carbohydrate diet (80% starch, 0% fat) following the fast. Male Sprague-Dawley rats (N = 40) were fed a HF diet (55% of energy) containing menhaden oil (M-HF, ω-3 PUFA), or olive oil (O-HF, monounsatu-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 (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 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 M-HF rats corresponded to similar % stimulation as in S-HF or LF rats due to 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

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in reducing markers of liver infl ammation, glucose, insulin, and triglycerides indicates that VSC could play an important role in the treatment of nonalco-holic fatty liver disease, diabetes and cardiovascular disease.

2476-PUBPathogenesis of Prediabetes in Asian IndiansSONA VEETTIL, ANANDA BASU, JOHN PORT, RITA BASU, Rochester, MN

The pathophysiology of prediabetes (PD) has not been well explored in Asian Indians (AI) residing in the U.S. The study was conducted to evaluate glucose metabolism and its association with hepatic fat in AI. 10 controls with normal fasting glucose/normal glucose tolerance (NFG/NGT) (7M, age 35 ± 13 yr, FPG 5.1 ± 0.2 mM, 2-hr glucose 5.7 ± 0.4 mM, BMI 24.0 ± 3.4 kg/m2, 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 9.3 ± 2.1 mM, BMI 25.2 ± 3.2 kg/m2, LBM 40.5 ± 6.8 kg, HbA1c 40.0 ± 3.5 mmol/mol) were studied using a [6, 6-2H2 glucose] labeled 75g oral glucose tolerance test (OGTT). The percentage liver fat fraction (% LFF), and total fatty acid (total FA) were measured using magnetic resonance spectros-copy (MRS) with an LC model. Plasma iAUC 0-240 min glucose was signifi -cantly higher in PD vs. control (603.2 ±217.8 vs. 215.3 ± 114.6 mM; p<0.01). Similarly, iAUC 0-240 min insulin (73448.4 ± 44744.9 vs. 39462.0 ± 15632.2 pM; p<0.05); C-peptide (577.1 ± 230.2 vs. 345.3 ± 88.6 nM; p<0.05) were higher in PD vs. control. Plasma HDL concentration (42.4 ± 6.9 vs. 55.9 ± 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 ± 0.0014 IU; p<0.05) were higher in PD vs. controls. Endogenous glucose con-centration calculated with the labeled OGTT was slightly higher (iAUC -799.5 ± 161.5 vs. -715.3 ± 80.0 mM) and hepatic insulin sensitivity (Liver Si) calcu-lated as model independent (iAUC endogenous glucose concentration/iAUC insulin) slightly lower in PD vs. controls (0.017 ± 0.01 vs. 0.022 ± 0.01 mM/pM) but neither reached signifi cance perhaps due to small n’s studied. % LFF was signifi cantly correlated with Liver Si (r2=0.27; p=0.03). We conclude that in AI with prediabetes despite having lower BMI, higher LFF can predict underlying defects in glucose metabolism. Further studies are required to tease out whether there are defects in insulin action vs. secretion by model dependent means.

Supported By: National Center for Advancing Translational Science (R01 DK29953, UL1 TR000135)

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INTEGRATED PHYSIOLOGY—MACRONUTRIENT METABOLISM AND FOOD INTAKE

INTEGRATED PHYSIOLOGY—MACRONUTRIENT METABOLISM AND FOOD INTAKE

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2491-PUBCognitive Performance in Subjects at Risk of Type 2 DiabetesGIAN PIO SORICE, TERESA MEZZA, GIOVANNA MASONE IACOBUCCI, SIMONA MOFFA, FLAVIA IMPRONTA, CAMILLO MARRA, SARA GRIONI, MARILENA VITALE, ANDREA MARI, ANDREA GIACCARI, Rome, Italy, Milan, Italy, Naples, Italy, Padova, Italy

Beyond the calorie amount, other “quality variables” of diet might affect glucose metabolism. Among those, both Glycemic Load (GL) and Glycemic Index (GI) infl uence glucose homeostasis (GH), causing glucose fl uctuations, even in nondiabetic subjects, although in normal range. Since a correlation between GH impairment and cognitive decline has been clearly demon-strated, our aim was to evaluate whether the diet, in people at risk for type 2 diabetes (T2D), could affect cognitive performance (CP). Seventy-one volun-teers (11M, 60F), at risk for T2D, underwent OGTT, neuropsychological tests (to assess verbal learning, memory, visual attention, executive functions and the overall cognitive function) and their eating habits were evaluated using the EPIC food frequency questionnaire. The main anthropometric, metabolic, neuropsychological and nutritional results are summarized in Table 1.Table 1.

mean semAge years 37, 9 1, 4Education anni 13 0, 4BMI kg/m2 24, 9 0, 6

Fasting glucose mg/dl 91, 9 0, 9Fasting insulin mUI/ml 8, 2 0, 5Basal insulin secretion pmol/L 77, 0 3, 4B cell-glucose sensitivity pmol min-1m-2mM-1 135, 4 8, 0Stumvoll umol min-1kg-1 9, 5 0, 2Matsuda umol min-1kg-1 6, 8 0, 4Basal insulin clearance L min-1m-2 1, 7 0, 1OGTT insulin clearance L min-1m-2 1, 4 0, 1

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

TEAC (Trolox Equivalent Antioxidant Capacity) mmol die 1, 5 0, 1TRAP (Total Radical trapping Antioxidant Parameter) mmol die 1, 6 0, 1FRAP (Ferric ion Reducing Antioxidant Parameter) mmol die 3, 9 0, 2

Glycemic Index 40, 3 1, 0Glycemic 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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2485-PUBHepatic microRNAs Profi le in Insulin Receptor Knockout Mice Re -veals Novel Molecules Involved in the Diabetes PathophysiologyBARBARA CAPUANI, DAVID DELLA-MORTE, FRANCESCA PACIFICI, SARA CARA-TELLI, DONATELLA PASTORE, GIULIA DONADEL, ANDREA COPPOLA, ROBERTO ARRIGA, ALFONSO BELLIA, SIMONA FRONTONI, MASSIMO FEDERICI, PAOLO SBRACCIA, GIUSEPPE SCONOCCHIA, DAVIDE LAURO, Rome, Italy

Type 2 diabetes mellitus (T2DM) is characterized by alteration of insulin signaling and defect of insulin-secretion in pancreatic beta cells (β-cells), with subsequent hyperglycemia and prediabetes conditions. Fundamen-tal is discovering early biomarkers to delay or prevent the onset of T2DM. Recently, a novel class of non-coding RNA, microRNA (miRNA), has emerged as important regulators of metabolic cell signaling and with others numer-ous biological functions. MiRNA contribute to the development of chronic infl ammation observed in obese patients with diabetes, pancreatic β-cell dysfunction and increased levels of peripheral insulin resistance. Therefore, we are reaching the goal to reveal new miRNA and mRNA target involved in the onset of diabetes and/or its relative complications. We analyzed miRNA patterns by miRNA arrays in insulin receptor knockout (IR-/-) and heterozy-gous (IR+/-) mice as a model of liver metabolic dysfunction associated with diabetic ketoacidosis and insulin resistance. MiRNAs array identifi ed only 4 miRNA differently expressed between IR+/+, IR+/- and IR-/-: miR-376b, miR-154, miR-543, and miR-199b. Quantitative Real time polymerase reaction confi rmed these results, and bioinformatic analysis reveals interesting mRNA targets involved in metabolic pathways. Particularly, we compared 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 most interesting mRNA target is SIRT1, a deacytetilase involved in modulat-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 early stages of infl ammation in prediabetic conditions. These results provide new insight into pathophysiology of T2DM and nonalcoholic fatty liver dis-ease, and could be useful in identifying novel biomarkers to predict risk for diabetes and its complications.

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INTEGRATED PHYSIOLOGY—MUSCLE INTEGRATED PHYSIOLOGY—OTHER HORMONES

2495-PUBSodium Butyrate Has a Context-dependent Effect on DPP-4 Activity and Metabolism in Cells and TissuesDAE HO LEE, EUN-SOL LEE, DONG-SUNG LEE, Incheon, Republic of Korea, Iksan, Republic of Korea, Chungju, Republic of Korea

Butyric acid, a short chain fatty acid, has various metabolic actions, and a previous study reported that sodium butyrate (SB) enhanced DPP-4 activ-ity at high concentration. We aimed to evaluate the effect of SB on the regulation of DPP-4 and on the other metabolic actions in cells and in high fat diet (HFD)-fed obese mice. We used HepG2 and mouse mesangial cells and 10-week-HFD-induced obese mice. SB treatment was done by supple-menting SB into HFD (5% wt/wt) for additional 15 weeks. In HepG2 cells, SB suppressed DPP-4 activity and expression at sub-molar concentrations, whereas it consistently increased those levels at 1 mM concentration. How-ever, the inhibitory effect of low dose SB on DPP-4 activity was lost in high glucose (30 mM)-exposed HepG2 cells. In HFD-obese mice, SB treatment decreased blood glucose, serum insulin and DPP-4 activity, and suppressed the increase in body weight. On the contrary, various tissues including liver, kidney, and peripheral blood cells showed variable responses to SB. Espe-cially in the kidney, although DPP-4 activity was inhibited by SB treatment in HFD-obese mice, it caused an increase in mRNA expression of TNFα, IL-6, and IL-1β. The pro-infl ammatory actions of SB in the kidney of the HFD-obese mice was supported by cultured mesangial cell experiment in which SB stim-ulated TNFα secretion from the cells. Our results showed that SB has differ-ential actions according to the types of cells and tissues, and its concentra-tion, although it has some metabolically benefi cial effects in whole body.

INTEGRATED PHYSIOLOGY—MUSCLE

2496-PUBDiabetic Myonecrosis: A Rare Diabetes ComplicationMAISARA RAHMAN, TRINA MANSOUR, UNS AL-WAHAB, Murrieta, CA, River-side, CA

Background: Diabetes Myonecrosis is also known as Diabetic muscle 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 presents with a sudden onset of a localized, excruciating, painful swelling of skeletal muscles resulting from a spontaneous ischemic necrosis of the muscle. Many times, the patients will have limited range of motion of the affected limb. The onset of the infarction is acute and last several weeks. MRI confi rms the clinical diagnosis. In some cases of diagnostic uncertainty, a muscle biopsy, which is the gold standard, is needed to diagnose this con-dition. The condition is conservatively managed with pain management and NSAIDS in the acute phase.

Case Presentation: This is a case of a 41-year-old male, with a 20 year history of poorly controlled type 2 DM. Patient presented with 4 days of excruciating pain and limited range of motion from a well demarcated mass and swelling in the left thigh area. The severe pain and palpable mass of the left thigh was suspected to be Myositis, DVT, soft tissue tumor, necrotizing fasciitis or abscess. Work up ruled out all the above possibilities, and the fi nal diagnosis of diabetes myonecrosis was made on the basis of muscle biopsy and MRI fi ndings.

Conclusion: Diabetic myonecrosis is often misdiagnosed and underre-ported. Increasing clinical awareness of this condition is important for early recognition of this rare microvascular complication of uncontrolled diabetes. Diabetes myonecrosis should be included in the differential diagnosis of any diabetic who presents with any painful swelling in any extremity. The more familiar physicians are about this unusual diabetic complication, the more likely that patients will be diagnosed and treated appropriately.

INTEGRATED PHYSIOLOGY—OTHER HORMONES

2497-PUBEffect of Smoking on Postprandial Glucose Excursions in Heavy SmokersMAGNUS F. GRØNDAHL, JONATAN I. BAGGER, ASGER LUND, JENS JUUL HOLST, 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

our data suggest that a diet with a high GI, in people at risk of T2D, may be associated with worse CP, even at subclinical level.

2492-PUBThe Ldb1 Transcriptional Coregulator Mediates Glucose, Lipid, and Energy Homeostasis during Diet-induced ObesityCHRISTINE LOYD, JAMIE GALLOWAY, TEAYOUN KIM, CASSIE HOLLEMAN, YAN-PING LIU, MAIGEN BETHEA, GLENN ROWE, MARTIN YOUNG, KIRK M. HABEG-GER, CHAD S. HUNTER, Birmingham, AL

Mounting evidence indicates that many transcriptional regulators required for β-cell development also mediate postnatal β-cell function or compensatory responses to metabolic stress. The broadly expressed tran-scriptional coregulator, Ldb1, is essential for β-cell development, but it is unclear whether it mediates sustained β-cell responses upon metabolic stress or if it has roles in other metabolic tissues. As germline homozy-gous Ldb1 deletion is embryonically lethal, we investigated inducible β-cell-specifi c (Ldb1Δβ-cell) and global heterozygous (Ldb1+/-) mice that were chal-lenged with a high-fat diet. We found that during diet-induced obesity (DIO), both Ldb1 defi ciency models displayed reduced circulating insulin levels and impaired glucose homeostasis. Regarding potential extra-pancreatic function, we revealed that global Ldb1 heterozygosity reduced food intake, decreased systemic energy expenditure (measured by indirect calorimetry) associated with impaired expression of brown adipose tissue Diodinase 2 and ELOVL Fatty Acid Elongase 3, yet in the absence of effect on adipos-ity. Importantly, the observed changes in Ldb1+/- energy balance during DIO were absent in Ldb1Δβ-cell mice, despite a similar reduction in plasma insulin. 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 regulates glucose, lipid, and energy homeostasis via insulin dependent and independent mechanisms.

Supported By: National Institutes of Health (P30 DK079626)

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2494-PUBAssessment of the Role of Glucose Oxidation and Circulating Fac-tors on Insulin Secretion in Nondiabetic HumansJOSE E. GALGANI, CARMEN GOMEZ, MARIA L. MIZGIER, JOSE L. SANTOS, PABLO OLMOS, ANDREA MARI, Santiago, Chile, Padova, Italy

Glucose-stimulated insulin secretion correlates inversely with the degree of systemic insulin sensitivity suggesting a crosstalk between peripheral organs and endocrine pancreas. Such sensing mechanism might be medi-ated through changes in glucose oxidative disposal in peripheral tissues that may drive the release of circulating factors with action on insulin secretion. We aimed to evaluate the association between whole-body carbohydrate oxidative disposal with insulin secretion to consecutive oral glucose loading in nondiabetic individuals.

Carbohydrate oxidation was measured after an overnight fast and for 6 hours after two 3-h apart 75-g oral glucose tolerance test (OGTT) in 53 participants (24/29 males/females; 34±9 y; 27±4 kg/m2). Insulin secretion was estimated by deconvolution of serum C-peptide concentration, β-cell function by mathematical modelling and insulin sensitivity from glucose and insulin response after OGTT. Circulating lactate, free-fatty acids and candi-date chemokines were assessed before and after OGTT.

Carbohydrate oxidation assessed over the 6-h period did not relate with insulin secretion (r=-0.11; p=0.45) or cell function indexes. Circulating chemokines concentration increased upon oral glucose stimulation, with an average increase between 1.20.3 fold for fractalkine and 5.87.0 fold for RANTES. Insulin secretion rate associated directly with plasma IL8 (r=0.41; p<0.05), IL6 (r=0.35; p<0.05) and RANTES (r=0.30; p<0.05) concentrations determined at 60 min OGTT, even after adjusting for insulin sensitivity. Circu-lating lactate and FFA showed no association with 6-h insulin secretion.

Whole-body carbohydrate oxidative disposal appears to have no infl uence on insulin secretion or putative circulating mediators. IL8 might be a poten-tial factor affecting insulin secretion.

Supported By: FONDECYT (1130217 to J.E.G.); VRA-PUC (to J.E.G.)

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Data were analyzed by standard T test, binary logistic analysis and correla-tion analysis.

Results: Compared with patients with late-onset T2DM, those with young-onset T2DM had a strong family history, more likely to be obese, worse gly-cemic and lipid control. The prevalence of testosterone defi ciency (serum total testosterone <8.7 nmol/L) was 32.47% and 17.70% in young-onset group and late-onset group respectively (p<0.05). Binary logistic regression analysis showed that BMI independently predicted the prevalence of low testosterone in the young-onset group, whereas HbA1c independently pre-dicted the prevalence of low testosterone in the late-onset group. Patients with young-onset T2DM showed signifi cantly lower LH, FSH and testoster-one levels (mean 11.72nmol/L [SD 6.19] vs. 14.60 [6.11]; P=0.001), as com-pared with late-onset individuals. Combining the results of glucose and lipid metabolism in young-onset men, hypogonadism is associated with a signifi -cant increase in the fasting plasma glucose and C-peptide, HbA1c, TC, TG, FFA and LDL . In a correlation analysis, high BMI predicted low testosterone levels (r=-0.313, P=0.007). Binary logistic regression analysis demonstrated that BMI played a pivotal role in regulation of testosterone. In addition, a reduction of HDL and QUICKI in the youth group was also observed.

Conclusion: Testosterone defi ciency is more obvious in patients with young-onset T2DM than that of late-onset T2DM, which would contribute to worse glycemic and lipid control in those patients.

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2502-PUBGuanylin and Uroguanylin mRNA Expression Are Signifi cantly Reg-ulated following Roux-en-Y Gastric Bypass in Humans and Rats, but Are Not Involved in the Regulation of Body Weight and Glucose ControlMARIALUISA FERNANDEZ-CACHON, NICOLAI A. RHEE, SØREN L. PEDERSEN, KRISTOFFER RIGBOLT, CHEN ZHANG, EBBE P. LANGHOLZ, ERIK P. WANDALL, PETER VILMANN, VIGGO B. KRISTIANSEN, MECHTHILDE FALKENHAHN, KAY SCHREITER, KRISTIN BREITSCHOPF, THOMAS HÜBSCHLE, TINA VILSBØLL, FILIP K. KNOP, STEFAN THEIS, JACOB JELSING, Frankfurt, Germany, Hellerup, Denmark, Hørsholm, Denmark, Herlev, Denmark, Hvidovre, Denmark, Hamburg, Germany

Guanylate cyclase activator 2A (GUCA2A) and guanylate cyclase activator 2B (GUCA2B) are prohormones for the peptides guanylin (GN) and uroguany-lin (UGN). Using laser capture microdissection of enteroendocrine cells in obese rats and humans following Roux-en-Y gastric bypass (RYGB), we dem-onstrated that GUCA2A and GUCA2B mRNAs were signifi cantly upregulated post-surgery suggesting a role in the benefi cial metabolic effects observed after RYGB. GUCA2A (700 nmol/kg) and GUCA2B (580 nmol/kg) prohor-mones, as well as GN and UGN peptides (3000 nmol/kg), were administered twice-daily to C57Bl/6 mice for 2.5 days to test their ability to regulate acute food intake. Glucose regulatory effects of GUCA2A and GUCA2B were eval-uated during an oral glucose tolerance test (OGTT) and by in vitro tests in isolated pancreas islets. Finally, C57Bl/6 DIO mice were transfected with adeno-associated viruses (AAV) overexpressing UGN for 4 weeks. Admin-istration with GN, UGN, GUCA2A or GUCA2B showed no effect on acute 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 glucose tolerance during OGTT (2,101±468 GN, 2,169±471 UGN vs. 2,301±374 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-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 or glucose control and appear not to be viable targets for the treatment of obesity or diabetes.

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increases in circulating nicotine levels and activation of nicotinergic recep-tors in the gastrointestinal tract and in the autonomic nervous system would have a detrimental effect on postprandial glucose metabolism and, thus, potentially constitute a link between smoking and risk of type 2 dia-betes. To investigate the above hypothesis, 12 male heavy smokers (age: 26.8±10.3 years; BMI: 25.2±4.0 kg/m2; HbA1c: 30.9±4.5 mmol/mol) under-went two separate 4-hour liquid meal tests with acetaminophen (for evalu-ation of gastric emptying): one with concomitant cigarette smoking (imme-diately before and after meal intake) and one without smoking. Twelve matched non-smokers (age: 26.7±9.08 years; BMI: 25.2±4.5 kg/m2; HbA1c: 31.6±4.27 mmol/mol) underwent an identical meal test without smok-ing. Compared to controls, heavy smokers exhibited similar gastric empty-ing, postprandial plasma glucose excursions (incremental area under curve (iAUC): 94.9±27.2 vs. 47.2±28.9 mmol/L × min, P=0.29) and plasma insulin and C-peptide responses, respectively, when not smoking. Smoking in rela-tion to meal intake signifi cantly lowered the smokers’ postprandial glucose excursions (iAUC: 94.9±27.2 vs. 33.0±12.7 mmol/L × min, P=0.01). Smoking reduced iAUC0-50min for plasma acetaminophen (1.6±0.12 vs. 1.3±0.10 pmol/L × min, P<0.01), but did not affect time-to-peak for acetaminophen signifi -cantly. In conclusion, we show that smoking before and after meal intake reduces postprandial glucose excursions in heavy smokers. Our data sug-gest that this phenomenon may be mediated by smoking-induced delay of gastric emptying, but other yet unclarifi ed mechanisms may also be at play (e.g., smoking-induced changes in the secretion of gut hormones).

2498-PUBDifferent View on Stress-Induced Hyperglycemia in Nondiabetic PopulationONALA TELFORD, DAVID A. D’ALESSIO, MERCEDES FALCIGLIA, Durham, NC, Cin-cinnati, OH

Hyperglycemia is common in patients hospitalized with severe illness. A signifi cant portion of these patients do not have a history of diabetes and regain normal glucose tolerance when they recover. The mechanism of tran-sient hyperglycemia in critically ill patients is generally ascribed to stress but this has not been proven. In this study circulating markers of stress, and regulators of glucose control, were measured in matched groups of non-diabetic ICU patients with and without hyperglycemia. Patients admitted to an ICU were approached for consent and had a blood sample taken. Only subjects with no prior history of diabetes were recruited, and patients with HbA1c diagnostic for diabetes were excluded. Patients were separated into a euglycemic group for those with no glucose readings >120 mg/dl and a hyperglycemic group with either a mean BG > 145, a single value > 200 or eventual treatment with insulin infusion. Forty-six patients were consented and 3 were excluded because of A1c > 7%. By defi nition the peak (113.8 ± 4.1 and 213.0 ± 9.9 mg/dl), and mean (100 ± 3 and 172 ± 12) glucose levels differed in the 20 euglycemic and 23 hyperglycemic (p < 0.0001 for both) subjects, while HbA1c was similar (5.2 ± 0.1, and 5.6 ± 0.1%, p = 0.39). Insu-lin, glucagon and C-peptide did not differ between the eu-and hyper-glyce-mic cohorts, and values of cortisol and epinephrine were also comparable. Hyperglycemic patients had signifi cantly higher circulating levels of GLP-1 and IL-6, but lower endotoxin measures than the euglycemic group. These fi ndings indicate that neither islet nor stress hormones explain nondiabetic hyperglycemia in critical illness, but raise the possibility that gut factors may play a role in this clinical syndrome.

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2500-PUBTestosterone Defi ciency in Male Patients with Young Onset Type 2 Diabetes Contributes to Poor Glycemic and Lipid ControlYAN LI, MANNA ZHANG, JIE ZHE, WENJIE CUI, SHARVAN RAMPERSAD, ZIWEI LIN, PENG YANG, HONG LI, CHUNJUN SHENG, XIAOYUN CHENG, SHEN QU, Shanghai, China

Objective: This study aims to compare the prevalence of testosterone defi ciency between young-onset type 2 diabetes (T2DM) male patients and late-onset ones.

Methods: This cross-sectional study included 102 young-onset T2DM male patients (diagnosis age 35 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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Figure 1. Mice Femoral Reconstruction of Micro-CT.

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-PUBEffects of Heterologous Expression of Human Cyclic Nucleotide Phosphodiesterase 3A (hPDE3A) on Redox Regulation in YeastDONG 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 H2O2, respectively. H2O2-stimulated ROS production was markedly increased in yeast expressing K13R hPDE3A (OxiS1), compared to yeast expressing WT hPDE3A (OxiR1). In OxiR1, YAP1 and YAP1-dependent anti-oxidant genes were upregulated, and accompanied by reduction of thioredoxin peroxidase (Tsa1p). However, in OxiS1, expression of YAP1 and YAP1-dependent genes was impaired, that the thioredoxin system does not function appropriately. H2O2 increased cAMP hydrolyzing activity of WT hPDE3A, but not K13R hPDE3A, through PKA-dependent phosphorylation, which was correlated with its ubiquitinylation. The changes in anti-oxidant gene expression did not directly correlate with differences in cAMP/PKA signaling, since despite differences in their capacities to hydrolyze cAMP, total cAMP levels in the three strains were similar, and PKA activity was lower in OxiS1 than in OxiR1 or mock cells. During exposure to H2O2, however, Sch9p activity, a TORC1-regulated rpS6 kinase and negative regulator of PKA in S. cerevisiae, was rapidly reduced in OxiR1, and Tpk1p, a PKA catalytic subunit, was diffusely spread throughout the cytosol, resulting in PKA activation. On the other hand, in OxiS1, Sch9p activity was unmodulated during exposure to H2O2, 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

2504-PUBExenatide Reduces Cytotoxicity and Proliferation Rate in Differen-tiated SH-SY5Y CellsANARA 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.

2505-PUBAdiponectin Improves Mice Femoral Fracture Healing by Increasing Local BMP-2 ExpressionYANPING GONG, CHUNLIN LI, LIANGCHEN WANG, LIJUAN WAN, Beijing, China

To observe the effect of adiponectin on mice femoral fracture healing and explore the possible mechanisms. Mice were divided into 12 groups by drugs (control, BMP-2, adiponectin), doses (1mg/kg, 2mg/kg) and durations (2 w, 4 w, 6 w). The results revealed that the bone callus formation was faster in adiponectin and BMP-2 groups than control from 2 weeks, with higher elasticity and rigidity in biomechanical analyses (p <0.05). Micro-CT scanning confi rmed better cortical and cancellous micro-structure of adi-ponectin and BMP-2 groups than control (p<0.05, Figure 1= Western Blot-ting revealed that BMP-2 expressions were higher in BMP-2 and adiponec-tin groups. Immunohistochemistry observed linear relationship between the expression of Adiponectin receptor-2 (AdipoR2) and BMP2 at fracture site in adiponectin groups. So adiponectin has signifi cant improving effect on fracture healing by increasing local BMP-2 expression through combining AdipoR2 at fracture site.

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2509-PUBDifferential Effects of the Paracrine-Acting FGF-8 Subfamily in Comparison to Hormone-like FGF Members on Leptin, Adiponectin, and pai-1 Gene Expression Utilizing an Adipocyte Cell ModelDIANA GRÜNDER, MALTE GRÜNDER, SÖREN WESTPHAL, Ulm, Germany

Recent data demonstrate the important role of the FGF family on energy homeostasis and carbohydrate metabolism. Systematic evaluation of whole subfamilies on adipokine biology are lacking. We investigated the effects of the paracrine-acting FGF-8 subfamily (FGF-8, 17, 18) in comparison to the hormone-like FGF members (FGF 19, 21, 23) on leptin (lep), adiponectin (adi) and pai-1 mRNA gene expression. Lep, the prototypic adipocyte-derived hor-mone, induces a negative energy imbalance. Adi inversely correlates with body fat and modulates glucose metabolism and fatty acid oxidation. Pai-1 is increased in obesity and is a risk factor for atherosclerosis. Members of the FGF-8 subfamily concordantly trends to increase lep (FGF-8 2.14-fold, P<0.09; FGF-17 3.04-fold, P<0.13; FGF-18 8.67-fold, P<0.078) and adi (FGF-8 7.23-fold, P<0.05; FGF-17 no signal; FGF-18 2.29-fold, P<0.26), and diminished pai-1 (FGF-8 8.53-fold, P<0.01; FGF-17 12.61-fold, P<0.001; FGF-18 18.02-fold, P<0.01). Within the hormone-like FGF group FGF 21 increased (3.13-fold, P<0.01) whereas others decreased lep (FGF-19 8.6-fold, P<0.001; FGF-23 4.51-fold, P<0.01). With regard to adi no effect could be observed by FGF-19 treatment, upregulation could be detected by FGF-21 (1.64-fold, P<0.01), and downregulation was measured by FGF-23 (1.51-fold, P<0.01). Pai-1 is decreased by FGF-19 and FGF-23 treatment (FGF-19, 58.7-fold, P<0.001; FGF-23, 385-fold, P<0.001) and increased by FGF-21 (15.01-fold, P<0.05). In sum-mary, we systematicely investigated the infl uence of the FGF-8 subfamily (concordant infl uence) in comparison to the hormone-like FGFs (differential effects) on the expression of the prototyptic adipokines lep, adi and pai-1. Our data highlight the importance of the FGF family on adipocyte function. In-depth comprehension of this infl uence may bring to light new potential therapeutic remedies for the treatment of diabetes mellitus.

Supported By: Federal Armed Forces of Germany (28K3-S-201113)

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2512-PUBDissecting Functions of Endotrophin on Different Cell Populations in Adipose TissueYUESHUI ZHAO, XUE GU, KAI SUN, Houston, TX

Endotrophin is a novel adipokine that we recently identifi ed. It is a cleav-age product from collagen 6 in obese adipose tissue. Previously we dem-onstrated that endotrophin serves as a potent stimulator to trigger mas-sive fi brosis and infl ammation locally in adipose tissue which ultimately lead to systemic insulin resistance. However, the detailed molecular mechanism by which endotrophin exerts its functions in adipose tissue remains largely unknown. In the current study, we apply an in vitro system by culturing dif-ferent types of cells from adipose tissue in a conditional medium which con-tains endotrophin and investigate the effects of endotrophin on the cells. Intriguingly, we fi nd that endotrophin activates different pathological rel-evant pathways in different cell types: in 3T3-L1 adipocytes, endotrophin ini-tiates a fi brotic program by up-regulating several collagen proteins, including collagen 3 and collagen 6; whereas in macrophages isolated from white adi-pose tissue, endotrophin stimulates higher expression of pro-infl ammatory genes, i.e., TLR4, IL-1β and IL-18. Collectively, our fi ndings provide a mecha-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.

2507-PUBLong-Term Glycemic Control with Insulin Prevents the Develop-ment of Testicular Interstitial Cell Tumors in Spontaneously Dia-betic Torii RatsTAKESHI OHTA, YUSUKE KEMMOCHI, KATSUHIRO MIYAJIMA, TOMOHIKO SASASE, KENICHI MATSUI, NOBUHISA UEDA, MASAMI SHINOHARA, MUTSU-YOSHI MATSUSHITA, Osaka, Japan, Tokyo, Japan

Leydig cell tumors (LCT) are frequently observed in the Spontaneously Diabetic Torii (SDT) rats, whereas the same tumors rarely occur in Sprague-Dawley (SD) rats though the identical strain origin. The present study was designed to evaluate the preventive effects of glycemic control with insulin on Leydig cell proliferation in SDT rats. The following three groups were used in the study: (i) insulin-treated SDT rats, (ii) untreated SDT rats, and (iii) untreated SD rats. In the insulin-treated group, each SDT rat showing signs of diabetes was treated with subcutaneously implanted sustained-release insulin pellets from 24 weeks of age, and the rats were sacrifi ced at 50 or 68 weeks of age for histological analysis. Untreated SDT and SD rats were sacrifi ced at 32, 50, or 68 weeks of age for histological analysis. Blood glu-cose levels were 400 mg/dl or higher at 24 weeks of age, and increased to approximately 800 mg/dl at 40 weeks of age and thereafter in untreated SDT rats, whereas decreases in blood glucose levels were apparent after treatment, and at 40 weeks of age and thereafter in insulin-treated SDT rats, where levels remained similar to those observed in untreated SD rats. In the testes of all untreated SDT rats, Leydig cell hyperplasia was observed at 50 weeks of age and LCT were observed at 68 weeks of age. In contrast, no Leydig cell proliferation was observed at any week of age in either insulin-treated SDT or untreated SD rats. In summary, long-term glycemic control with insulin markedly prevented the development of Leydig cell prolifera-tive lesions in SDT rats; however, without insulin treatment, proliferative lesions appeared at 50 weeks of age and thereafter (i.e., approximately 30 weeks or more after the onset of diabetes) in almost all SDT rats. This fi nd-ing strongly suggests the association of persistent hyperglycemia with the development of LCT.

2508-PUBCalciotropic Hormones as Predictors of Glycemic Profi le in a Pre-diabetic Elderly CohortKALLIOPI KOTSA, SPYRIDON KARRAS, XANTHIPPI TSEKMEKIDOU, ELENI RAPTI, MARIA GRAMMATIKI, ATHANASIOS C. MOUSIOLIS, MICHAEL DANIILIDIS, Thes-saloniki, Greece

The aim of this cross-sectional study was to investigate the correlation of 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 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 was obtained for fasting plasma glucose (FPG), glycosylated hemoglobin (HbA1c), PTH, 25(OH)D, calcium and phosphorus measurements. Correlation between variables was examined and multiple linear regression analysis was performed to determine the predictive ability of PTH and 25(OH)D on FPG and HbA1c variables. All analyses were carried out using the statistical package SPSS vr 17.00. No statistically signifi cant difference in age, BMI or calcium levels was detected between patients and controls. Both groups were vitD defi cient with controls demonstrating signifi cantly lower 25(OH)D concentrations compared to the prediabetic population [17.88 vs. 19.59 ng/ml respectively (p=0.040)]. There was a non-signifi cant negative correlation of 25(OH)D with both FPG (r=-0.083) and HbA1c (r=-0.203) and a non-signifi -cant positive correlation of PTH (r=0.162) with FPG and HbA1c (r=0.102) in the control group. In the prediabetic population there was a statistically signifi -cant (p=0.017) positive correlation (r=0.212) of PTH with FPG. In the prognos-tic model only PTH had a minor but statistically signifi cant impact on FPG. An increase of 1 pg/dl of PTH resulted in a 0.12 mg/dl increase of FPG. Our results indicate that vitD defi ciency is prevalent in a cohort of elderly non-diabetic subjects in a Mediterranean country. In this cohort PTH is a better predictor than 25(OH)D for FPG in prediabetes.

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MOD-6031 pharmacokinetic (PK) and pharmacodynamic (PD) profi les were assessed in rats and monkeys following administration of single or repeated 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 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 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) were signifi cantly increased compared to reported half-life of OXM (T1/2 ~ 12 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 receptors activation signal was observed at 8 to 12 hours post dose.

Pronounced enhanced PK and PD profi les, elevated exposures and half-life were confi rmed following MOD-6031 administration, providing proper safety exposure margins for the initiation of a phase 1 clinical study.

2519-PUBThe Clinical Characteristics of Obese Patients with Acanthosis Nigricans and Its Independent Risk FactorsYUEYE HUANG, JIAQI CHEN, XINGCHUN WANG, YI ZHANG, SHEN QU, Shang-hai, China

Objective: The aim of the study was to investigate the clinical char acteristics and risk factors for obese patients with acanthosis nigracans (AN).

Methods: Two hundred and eight obese patients were divided into two groups: 80 obese patients without AN (OB group) and 128 obese patients with AN (AN group). The weight, body mass index (BMI), TC (total choles-terol), TG (triglyceride), FFA (free fatty acid), UA (uric acid), free testoster-one, and CRP (C-reactive protein) were measured for each patient. Oral glu-cose tolerance test (OGTT) was performed and insulin levels were measured during OGTT. Serum level of leptin was measured by ELISA.

Results: BMI, UA levels, fasting insulin and the HOMA-IR in AN group were much higher than those of the OB groups (P<0.05). Serum Leptin levels were signifi cantly higher in AN group than that in OB group (34.74±2.95ng/ml, 26.25±2.74ng/ml P<0.001) after adjusting BMI and gender analysis by ANCOVA. For male, AN patients had lower serum levels of testosterone (7.89±3.35nmol/l, 12.72±3.57nmol/l, P<0.001). Serum leptin were correlated with BMI (P<0.001), plasma insulin at 0 min, 30 min, 60 min (P=0.005, 0.001, 0.003), 120 min, and 180 min (P<0.001) and C-peptide at 30 min (P=0.003), 60 min (P<0.001), 120 min (P=0.004), and 180 min (P=0.038). Multiple logis-tic regression analysis indicated that UA (OR 4.627, 95% CI 2.443-8.762, P<0.001) and Leptin (OR 4.098, 95% CI 1.237-13.581, P=0.021) were indepen-dent risk factors for AN in obese patients. In addition, low testosterone level was an independent risk factor for AN in male obese patients (OR 39.062, 95% CI 5.523-283.808, P<0.001).

Conclusion: AN is associated with more severe hyperinsulinemia and hype-ruricemia in obese patients, as well as lower serum of testosterone in male. UA and Leptin are independent risk factors for AN in obese patients. Low testosterone may be a valuable predictor of AN in male obese patients.

2520-PUBReduced Subcutaneous Regional Fat Storage in Insulin-Resistant Females with ObesityTYLER A. BOSCH, ANNE BANTLE, LISA CHOW, Eden Prairie, MN, Minneapolis, MN

Visceral fat (VAT) is an established risk factor for metabolic dysfunc-tion. However, recent data suggests VAT accumulation is a consequence of impaired subcutaneous fat (SAT) storage. We tested the hypothesis that insu-lin resistant (IR) females with obesity have proportionally more VAT storage (relative to SAT) compared to insulin sensitive (IS) females with obesity.

In this cross-sectional study, forty-nine (age 28.6±7.0 yrs.) females (21 IR, 28 IS) with obesity (BMI: 33.8±7.4 kg/m2) were recruited for the TrainMe-UpMN Study. Metabolic status was determined by an OGTT (Matsuda <3.0) and regional fat distribution (including VAT) was measured by dual-energy x-ray absorptiometry. Differences in percent regional fat distribution (rela-tive to total fat mass (TFM)), VAT/abdominal SAT ratio and VAT/Gluteal fat ratio between IS and IR females were assessed by ANOVA.

Figure 1a presents the mean differences in the percent of fat stored in regional depots relative to TFM. Figure 1b presents the ratios of VAT/abdom-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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2517-PUBWhich Anthropometric or Behavioral Factors Contribute to Being Obese among Overweight Children? A Community-based Prospec-tive StudyEUN YOUNG LEE, YEOREE YANG, BORAMI KANG, JIN-HEE LEE, SUN-YOUNG LIM, JOONYUB LEE, HAE KYUNG YANG, HUN-SUNG KIM, SEUNG-HWAN LEE, JAE HYOUNG CHO, YOON-HEE CHOI, BONG-YUN CHA, KUN-HO YOON, Seoul, Republic of Korea

In this study, we investigated which physical or behavioral factors con-tribute to being obesity among overweight children. A community sample of 884 children aged 9-13 years were enrolled from 2014. At the fi rst follow-up examinations in 2015, a total of 833 children completed the measures of anthropometrics, physical fi tness, and questionnaires. Body mass index (BMI, kg/m2) were used to defi ne overweight ( ≥ 85 percentile) and obese (≥ 95 percentile or 25 kg/m2). At baseline, the prevalence of overweight and obesity were 12.0% and 16.4%, respectively. Boys had a higher prevalence of obesity than girls (17.8% vs. 11.7%, P=0.046). After one year follow-up, more than 90% of children with normal weight or obesity at baseline kept their weight unchanged. However, one third of overweight children at base-line became obese, while one third of them became normal weight after one year follow-up. Then, we divided overweight children at baseline into 3 groups according to obesity degree after one year. There were no signifi -cant differences in physical fi tness among 3 groups at baseline. However, overweight children becoming obese after one year showed increased waist circumference and higher BMI percentile at baseline. In terms of behavioral factors, there were no signifi cant differences in physical activities or tele-vision viewing. Meanwhile, overweight children becoming obese after one year eat out more frequently and tended to eat habitually without hunger or overeat compare to other groups. In summary, overweight children becoming obese during follow-up had higher BMI percentile at baseline and showed bad eating habits compared to those keeping or losing weight. Considering that overweight children could change body weight more easily than obese children, a focus on overweight children and further investigation to fi nd contributing factors making these children to become obese may be helpful to prevent obesity among children.

2518-PUBEstablishment of Pharmacokinetic and Pharmacodynamic Profi les of MOD-6031: A Novel, Long-Acting, Dual GLP-1/Glucagon Agonist in Several Toxicological StudiesLITAL ISRAELI YAGEV, AHUVA BAR ILAN, VERED LEV, GILI HART, OREN HERSH-KOVITZ, Nes Ziona, Israel

OPKO Biologics is developing long acting Oxyntomodulin (OXM; MOD-6031) for the indication of weight management and potentially type 2 dia-betes, utilizing reversible PEGylaton technology. The core technology is a spacer that links between the PEG and the peptide. Once injected, a fi rst order hydrolysis slowly releases the intact OXM, enabling a prolonged expo-sure of the peptide while maintaining its biological activity and ability to pass throw the blood brain barrier.

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Table 1. Trajectories of Infl ammatory Markers during Follow-up.

Table 2. Trajectories of Measured Factors during Follow-up.

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2524-PUBRestoration of Beta-Cell Function and Metabolic Flexibility Is Pos-sible in Nondiabetic Asian Individuals with Morbid ObesityHONG 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 may be contributed by early beta-cell dysfunction from rising obesity rates. We compared insulin sensitivity, metabolic fl exibility and beta-cell health in nondiabetic individuals with morbid obesity (n = 9) to lean controls (n =9) and the metabolic changes following surgically induced weight loss (n =4). All subjects underwent oral glucose tolerance testing (OGTT), bio-impedence analysis and hyperinsulinemic euglycemic clamp with indirect calorimetry measurement. Bariatric surgery subjects were studied again at 6-months. Insulin sensitivity index (ISI) was calculated using values from the fi nal 30 minutes of clamp and metabolic fl exibility as changes in respira-tory quotient (RQ) under insulin stimulation. Glucose disposition index (DI) was used to defi ne beta-cell function relative to insulin sensitivity and cal-culated as the product of insulin sensitivity and fi rst phase insulin secretion (insulinogenic index calculated from OGTT). Gender distribution (Female = 22.2%) was similar and obese individuals had a higher body mass index (39.3 +/- 4.8 vs. 23.3 +/- 4.83 kg/m2), lower ISI (2.51 +/- 1.11 vs. 12.84 +/- 5.93, p < 0.001) and DI (4.59 +/- 4.5 vs. 19.22 +/- 7.81 mg/kg/min per uU/mL, p < 0.001), indicating the presence of severe insulin resistance and early beta-cell dysfunction. In 4 individuals after bariatric surgery, there was sig-nifi cant weight loss (115.5 to 90.6 kg) that was contributes mainly by fat mass loss (62% of total weight loss). This was associated with a dramatic improvement in ISI (2.64 +/- 1.11 to 8.05 +/- 3.27, p =0.018), metabolic fl ex-ibility (delta RQ 0.043 +/- 0.038 to 0.085 +/- 0.024, p = 0.016) and DI (5.74 +/- 7.67 to 14.43 +/- 8.39, p 0.034). Beta-cell dysfunction occurs early in the 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

Compared to IS females, IR females have proportionately higher VAT rel-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).

* Indicates a difference between IR and IS p<0.05.Supported By: National Institutes of Health

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2522-PUBChanges in Infl ammatory Markers following Gastric Bypass: A Pro-spective Cohort Study in Chinese Nonmorbidly Obese Adults with DiabetesHONGKAI GAO, MOSHEN MAZIDI, Beijing, China

To report on the changes over time in infl ammatory markers following Roux-en-Y gastric bypass in patients with diabetes and BMI of 28 to 35.This prospective cohort study involved 89 patients who met the indications of bariatric surgery for diabetes with BMI 25-30 kg/m2. Leptin, tumor necro-sis factor α (TNF-α), adiponectin, C-reactive protein (CRP) and interleukin 6 (IL-6) were monitored from baseline to 12 months. BMI steadily decreased from 29.96 kg/m2 at baseline to 25.33 kg/m2 at 12 months following surgical intervention. CRP also decreased from 35.00 mg/dl at baseline to 20.00 mg/dl at 12 months. Leptin, adiponectin and IL-6 steadily decreased from their baseline values down to a nadir at six months, and rose thereafter up to 12 months, resulting in higher 12-months values thanks the baseline ones for adiponectin, but not for leptin and IL-6. A saw tooth pattern was observed for TNF, with however the 12-month and all follow-up values remaining lower than the baseline values. Body weight control following bariatric sur-gery was associated with improved levels of infl ammatory markers during the fi rst 12-month of follow-up of this Chinese cohort. These fi ndings refl ect the control of sub-clinical infl ammation secondary to the reduction of the body fat mass, but also suggest the explanation for improvement of cardio metabolic profi le following bariatric surgery.

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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-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-ing BID may be important to prevent obesity in KIs.

Supported By: Global Korean Nursing Foundation

2528-PUBPredictors of Weight Loss in Diabetics and Nondiabetics Submitted to Bariatric Surgery in Teresopolis, BrazilERIKA C.O. NALIATO, BRUNA M. CRIVANO, BRUNO B. PINTO, JACKSON A. TORRES, MAURO S. PIMENTEL, Teresopolis, Brazil

Bariatric surgery has been proven useful in the treatment of diabetics (DB). Factors such as age, BMI, and surgical technique may infl uence long-term outcome. We compared 20 DB and 57 nondiabetics (ND) submitted to bariatric surgery and investigated predictors of weight loss in these groups. Roux-en-Y bypass (RYBP) was the technique used in 64.3% of DB, while 58.7% of ND were treated with sleeve gastrectomy (p = 0.22). In DB, age at surgery corresponded to 41.2 ± 10.9 years and, in ND, 36.8 ± 9.6 years (p = 0.09) and time elapsed since surgery, 0.9 ± 0.3 years, in DB, and 1.4 ± 1.8 years, in ND (p = 0.64). Most subjects were women (75% of DB vs. 86% of ND, p = 0.30). Prevalence of smokers was 11.8% in DB and 9.3% in ND (p = 0.67). Most DB (55%) and 38.6% of ND had arterial hypertension (p = 0.29). There were no differences between DB and ND when preoperative weight (122.6 ± 6.8 vs. 119.7 ± 2.5 kg, p = 0.62), BMI (44.10 ± 7.13 vs. 45.01 ± 4.91 kg/m², p = 0.37) waist circumference (131.8 ± 23.6 vs. 126.7 ± 12.3 cm, p = 0.40), systolic (130.6 ± 10.6 vs. 135.3 ± 15.9 mmHg, p = 0.38) and diastolic blood pressures (75.6 ± 6.3 vs. 74.5 ± 8.0 mmHg, p = 0.60), total cholesterol (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, 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.

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2530-PUBSerum High-Molecular-Weight Adiponectin Levels Correlate with Various Metabolic Parameters in Special Health Checkup ProgramsHIROSHI HIROSE, KOICHIRO AZUMA, RYOKO SHIMIZU-HIROTA, MICHIYO TAKA -YAMA, YASUSHI IWAO, HIROSHI KAWABE, Tokyo, Japan

Adiponectin (ADPN) is secreted by adipocytes and has been known to reduce blood glucose levels, atherosclerosis, and tumor growth in vitro and in in vivo animal studies. According to recent reports, succination of ADPN contributes to a decrease in high-molecular weight (HMW) ADPN levels in diabetic mice. Moreover, anemia, kidney disease, and high brain natriuretic peptide levels are reportedly associated with elevated serum HMW-ADPN levels in diabetes mellitus and coronary artery disease patients. Therefore, we aimed to further elucidate the relationships between HMW-ADPN levels and various metabolic parameters, including visceral fat area (VFA), subcu-taneous fat area (SFA), and homeostasis model assessments of insulin resis-tance (HOMA-IR) and β-cell function (HOMA-β). Serum HMW-ADPN levels were analyzed in 29- to 92-year-old Japanese men (n = 244) and women (n = 174) who participated in our special health checkup programs during a 3-year period and met our inclusion criteria. VFA and SFA were measured with computed tomography at the umbilical level, while serum insulin and HMW-ADPN concentrations were measured with enzyme immunoassays and chemiluminescent enzyme immunoassays, respectively. We found that the median serum HMW-ADPN levels were 2.42 µg/ml in men and 5.12 µg/ml in women. Moreover, HMW-ADPN levels were positively correlated with high-density lipoprotein cholesterol (HDL-C) and age, and negatively cor-related with body mass index, waist circumference, VFA, SFA, red blood cell (RBC) count, HOMA-IR, and serum triglyceride and C-reactive protein

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2526-PUBDissociation of Glycemic Indices in Obese Dialysis Patients: High HgbA1c and Low Alternative IndicesMARK E. WILLIAMS, NORMA OFSTHUN, NEAL MITTMAN, LIN MA, JULIE BREN-NAN, FRANKLIN MADDUX, Boston, MA, Waltham, MA, Brooklyn, NY, Rockleigh, NJ

Our GIDE (Glycemic Indices in Dialysis Evaluation) study initially reported that obesity associates with high hemoglobin A1c but low alternative gly-cemic indices in hemodialysis (HD) patients in ASN 2015. Now we further examined this association using different cutoffs of indices. A combined cohort of 2,394 active hemodialysis (HD) patients (1,424 with diabetes, 970 without) from 26 U. S. FMCNA facilities had baseline indices [HgbA1c; fruc-tosamine, albumin-adjusted fructosamine (AlbF) and percent glycated albu-min] measured at baseline (Jan-Mar 2013) then monthly until Apr 2015. Obe-sity = BMI≥30kg/m². Glycemic indices of the study populations were then divided into quintiles. Average BMI (kg/m²) by level of glycemic indices (Very low, Low, Med, High, Very high) are shown in Figure below. The means of BMI among the quintiles in each category of indices were signifi cantly dif-ferent, all p < 0.05.

The same trends were obtained from the separated DM and non-DM pop-ulations. Obesity is positively correlated with HgbA1c but negatively corre-lated with other glycemic indices in both diabetic and nondiabetic hemodi-alysis patients. Further studies are needed to explore the mechanisms and assess the relationship of these fi ndings to superior survival outcomes in obese HD patients.Figure. Average BMI by Level of Glycemic Indices in Hemodialysis Patients.

2527-PUBThe Association between Body Image Discrepancy and Body Mass Index in Middle-Aged Korean ImmigrantsCHORONG PARK, SOOHYUN NAM, JANE DIXON, ROBIN WHITTEMORE, Orange, CT

The prevalence of obesity in middle-aged Korean Immigrants (KIs) in the U.S. is increasing at an alarming rate. Body image discrepancy (BID) – the gap between current and ideal body image– may be a risk factor of immigrants’ obesity due to its infl uence on health behaviors. However, little is known about how BID, acculturation, body mass index (BMI) and health behaviors are associated in KIs. The purpose of this study was to identify the associa-tion between BID and acculturation with BMI, physical activity, and eating in KIs. A cross-sectional study was conducted in a national KI sample (N=230; 35.8±5.7 years old, 64% male, 47% overweight/obesity) with an online survey. Data on BID, BMI, physical activity, eating, and Korean/American acculturation were collected with validated measures. First, the association between Korean/American acculturation and BID was explored. Second, the effects of BID and acculturation on BMI, physical activity, and eating were tested with linear regression models. All models controlled for gender, age, socio-economic status and comorbidities. Higher American acculturation was associated with lower BID (β=-.13, p=.05). There was no gender or age effect on BID. The BMI model (adjusted R2=.56, p<.01) showed that higher BID was associated with higher BMI (β=.60, p<.01) but acculturation was not associated with BMI. There was no signifi cant interaction of BID and acculturation in explaining BMI. For eating, higher American acculturation was associated with healthier eating (adjusted R2=.10, p<.01). For physical

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2533-PUBWeight Loss Is Associated with Limited Metabolic Benefi ts in Met-abolically Healthy Obese WomenM. ROSA BERNAL-LOPEZ, SONIA SANTAMARIA-FERNANDEZ, JOSEFINA RUIZ-NAVA, FRANCISCO J. TINAHONES, M. JOSE BUJALANCE, JUAN JOSE BEDOYA, RICADO GOMEZ-HUELGAS, Malaga, Spain

Introduction: A signifi cant percentage of obese subjects, called metaboli-cally healthy obese (MHO), have no metabolic alterations characteristics of obesity. Controversy exists about whether weight loss brings cardiometa-bolic benefi ts in this population.

Aim: Our aim was to assess whether a signifi cant body weight loss induces short-term metabolic benefi ts in MHO individuals.

Material and Methods: We included 115 nondiabetic women (age 35-55 years) with body mass index (BMI) 30-45 kg/m2 and 1 of following criteria: blood pressure 135/85 mmHg, fasting plasma glucose 100 mg/dl, HDL-cholesterol 50 mg/dl and triglycerides 150 mg/dl. After an intensive life-style modifi cation based on Mediterranean diet and exercise, women were classifi ed into three groups according to their body weight loss <5%, ≥5% to <10% and ≥10%. Anthropometric measures, glycemic and lipidic profi le, adipokines, infl ammatory markers and fatty liver index (FLI) were analized at baseline and 3 months.

Results: The fi nal sample, after 11 dropout (9.6%), included 104 women (mean age ± SD: 44.4 ± 3.7 years, BMI mean ± SD: 36.3 ± 4.7 kg/m2), which 47 (45, 2%), 27 (26%) and 30 (28, 8%) lost <5%, ≥5% to <10% and ≥10% of basal body weight, respectively. The lipidic profi le (except triglycerides levels) and FLI improved signifi cantly in all groups. Glycemic parameters (plasmatic insu-lin level, HOMA-R) and infl ammatory biomarkers (hsCRP) only improved in MHO women with body weight loss ≥10%. Adiponectinemia did not change in any group.

Conclusions: A signifi cant weight loss in MHO women induces short-term limited metabolic improvement. The rate of weight loss may infl uence the metabolic response.

Supported By: European Regional Development Fund (PI12/01373, PI14/00696); Research Centres Network (CIBER CB06/03/0018); Ministry of Economy, Innova-tion, Science and Employment (P07-CTS-656, MRBL); Government of Andalusia, Spain (RH-0066-2013)

2534-PUBThe Ameliorating Effect of Gut Microbiota-targeted Clinical Inter-vention on Metabolic Disorders of Impaired Glucose Tolerance Women with PCOSXIAOYING DING, RUI LIU, JIAN SHEN, XUEJIAO WANG, QINGWU YAN, ANDREW S. GREENBERG, LIPING ZHAO, YONGDE PENG, Shanghai, China, Boston, MA

Polycystic ovary syndrome (PCOS) is a common heterogeneous endo-crine disease associated with metabolic disorders. Compared with healthy women, a large proportion of women with PCOS also have obesity, impaired glucose tolerance (IGT), insulin resistance, and dyslipidemia. We investi-gated the ameliorative effect on PCOS characteristics by a gut microbiota-targeted dietary or acarbose intervention. Thirty-four PCOS patients were recruited and randomly assigned into WTP group (intervention with diets based on whole grains, traditional Chinese medicinal foods and prebiotics) and APW group (acarbose plus above intervention). There was signifi cant difference in the serum levels of insulin, ghrelin, spexin, testosterone and LH before and after the twelve-week intervention in APW group. Bacteroi-des, Faecalibacterium, Roseburia, Blautia and Clostridium XlVa were domi-nant genus in pre-intervention PCOS patients. Bacteroides and Clostridium XlVa decreased, while Bifi dobacterium increased after intervention in both groups. 56 key OTUs were clustered into 11 co-abundance groups (CAGs). CAG3 and CAG9 displayed signifi cant correlation with testosterone level in a negative manner, while CAG10 had a signifi cant positive correlation with serun level of LH/FSH throughout the intervention procedure. After inter-vention, butyric acid basically kept steady, while isovaleric acid decreased signifi cantly in both groups. Cytotoxicity of fecal water in both groups sig-nifi cantly decreased after intervention. In general, both simple WTP diet intervention and WTP diet combined with acarbose improved the reproduc-tive and metabolic disorders of PCOS patients, and regulated the gut micro-biota structure and metabolite. These results preliminarily indicated that gut microbiota may participate in the development of metabolic disorders in women with PCOS, which might provide a basis on gut microbiota-targeted clinical intervention.

Supported By: National Natural Science Foundation of China (31330005, 30730005)

levels. Stepwise multiple regression analyses revealed that log-transformed HMW-ADPN levels were independently correlated with HDL-C levels, RBC count, VFA, age, sex, and log [HOMA-IR] in that order (F > 8.0, P < 0.0001, R 2= 0.490). To conclude, serum HMW-ADPN levels were positively correlated with HDL-C levels, age, and female sex, and negatively correlated with VFA, HOMA-IR, and RBC count.

Supported By: JMECSS

2531-PUBGenetic Susceptibility Factor as a Predictor of Type 2 Diabetes Remission and Weight Loss after Bariatric SurgeryANDREEA CIUDIN, OLGA SIMO-SERVAT, ANGEL ORTIZ, ALBERT LECUBE, KEVIN GUILLEN, SARA PICH, ORIOL CASAGRAN, ORIOL CASAGRAN, EDUARDO SALAS, CRISTINA HERNANDEZ, RAMON VILALLONGA, RAFAEL SIMÓ, JORDI MESA, Barcelona, Spain, Lleida, Spain, Esplugues de Llobregat, Spain

Obesity is directly related to an increased risk of diabetes mellitus, cardio-vascular disease, and overall mortality. Weight loss is effective in decreas-ing these risks and to reduce disease severity. Bariatric surgery is an effec-tive therapy for sustained weight loss and type 2 diabetes (T2D) remissions in most of the morbidly obese patients. But there is also a signifi cant number of individuals with an inappropriate response to bariatric surgery. There is some data regarding the genetic load on the outcome of bariatric sur-gery, but its role remains to be elucidated. The aim of this study is to assess whether a selection of genetic variants could identify patients who will have a satisfactory response after bariatric surgery in terms of weight loss and T2D remission. For this purpose a case-control study was designed. This study included 100 women who underwent bariatric surgery (Roux-en-Y lap-aroscopic gastric bypass): 50 patients who were diabetic before surgery (15 cases with less than 40% of the excess weight loss [EWL] and 35 cases with more than 75% EWL), matched with 50 nondiabetic controls (15 patients with less than 40% EWL and 35 with more than 75% EWL). All individu-als were analyzed with a genetic panel (Nutri inCode). The predictive abil-ity was analyzed by discrimination (area under the ROC curve), sensitivity and specifi city and a score was calculated. The results showed a signifi cant discrimination ability with a high sensitivity in identifying individuals who will have a good response to bariatric surgery (more than 75% EWL) or will 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). The panel of genetic variants assessed by Nutri inCode panel has a good sensitivity in identifying individuals who have a good response to bariatric surgery, in terms of weight loss and T2D remission. This genetic approach seems a useful tool in the selection of bariatric surgery in diabetic patients.

2532-PUBBMI and Insulin Resistance According to Vitamin D in Type 2 DMJAE MIN LEE, Daejeon, Republic of Korea

The objective of this study was to investigate the impact of vitamin D con-centration on the relationship of body mass index (BMI) status and insulin resistance in type 2 diabetes. Retrospective study of all patients who had concentrations of vitamin D, fasting glucose, and fasting insulin had been determined (n=257, 44.4% women) between January 1st and July 31th on 2013. We used the BMI for obesity and the HOMA-IR index for insulin resis-tance. The vitamin D status of subjects was categorized into quartiles as a categorical variable: I ( 19 ng/mL), II (19 ng/mL > serum(OH)D 25 ng/mL), III (25 ng/mL > serum(OH)D 31 ng/mL), and IV (>31 ng/mL) The negative cor-relation between serum vitamin D and BMI with type 2 diabetes was sig-nifi cant and the negative correlation between vitamin D and insulin resis-tance in type 2 DM was also remained signifi cant. Multiple regression analysis demonstrated that vitamin D was not associated with BMI (p = 0.681) but associated with insulin resistance (p < 0.042). BMI status and HOMA-IR status were taken out of the analyses investigating the associa-tion between serum vitamin D quartile, separately. It was found that individ-uals with the lowest quartile of 25(OH)D levels had signifi cantly higher rates of unfavorable conditions of BMI and HOMA-IR levels compared to those in the fourth quartile. However, no signifi cant association was found for those in the second vs. those in the fourth quartile or those the in third vs. those in the fourth quartile. As conducting a study of type 2 diabetes, plasma vitamin D has negative correlation with BMI and insulin resistance. Especially, it is more strongly associated with insulin resistance. Therefore, we conclude that vitamin D defi ciency is a valuable attributable risk for type 2 diabetes, especially combined with obesity.

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2540-PUBMelatonin Treatment Improves Insulin Resistance and Pigmenta-tion in Patients with Acanthosis NigricansHANG SUN, SHEN QU, XINGCHUN WANG, JIAQI CHEN, KEXIU SONG, LIANG LI, YUEYE HUANG, HAN CAO, SHANGYU CHAI, Shanghai, China

To investigate the effect of melatonin on insulin resistance in patients of acanthosis nigricans with obesity. A total of 17 obese patients with acan-thosis nigricans and body mass index exceeding 28 kg/m2 were recruited in a 12-week randomized, open-label pilot study. All the participants received melatonin 3 mg/day. Insulin sensitivity, glucose metabolism, infl ammatory factors and other biochemical parameters were measured before and after the treatment course of melatonin. Homeostasis model assessment insu-lin resistance index (7.77±5.2169 vs. 8.99±5.1047, p<0.05) and fasting insulin (32.1018±20.29752uU/ml vs. 37.0935±20.26215uU/ml, p<0.05) were signifi -cantly decreased after the 12-week treatment. There were also statistically signifi cant declines in the AN scores, body weight, body mass index, body fat, visceral index, neck circumference and waist circumference. In conclu-sions, melatonin could improve insulin resistance and reduce insulin levels, help to relieve skin symptom in obese patients with acanthosis nigricans. (NCT02604095).

ISLET BIOLOGY—APOPTOSIS

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2542-PUBThe Effect of Caveolin-1 on the Proliferation and Apoptosis of NIT-1 CellHAICHENG LI, HANGYA PENG, HAIXIA XU, SHUO LIN, KEYI LIN, LONGYI ZENG, Guangzhou, China

Our study aims to access the infl uence of caveolin-1 during the process of proliferation and apoptosis in NIT-1 cell. We knockdown the expression level of caveolin-1 in NIT-1 cell by RNA interference technique which realized by transfer a RNAi vector target caveolin-1 mRNA into the NIT-1 cell through the latent virus infection and purifi ed the positive infection cell by puromycin containing medium. The differences of cell proliferate and apoptosis among the caveolin-1 knockdown cell, the scramble vector infection cell and the wildtype NIT-1 cell were compared, and the effect of caveolin-1 on the cell’s proliferation and apoptosis were analyzed. The results of fl ow cytometry and MTT showed that knockdown the expression level of caveolin-1 in NIT-1 cell could promote proliferation as well as increase the resistance to palm-itic acid’s lipotoxicity. Caveolin-1 may interfere with the pathway of cell’s proliferation and apoptosis. It’s maybe a pro-apoptosis and anti-proliferation factor in NIT-1 cell and a new target for diabetes therapy.Figure 1.

Supported By: National Natural Science Foundation of China (81070661); Novo Nordisk China (2014)

2535-PUBLaparoscopic Sleeve Gastrectomy in Severe Obese Patients with Ancanthosis NigricansYUN HUANG, DONGLEI ZHOU, LIESHENG LU, CUILING ZHU, YI ZHANG, LE BU, SHEN QU, Shanghai, China

Acanthosis nigricans (AN) is the most common dermatologic manifesta-tion of obesity and is considered to be the skin feature of insulin resistance. Those obese individuals with AN are more likely to have abnormal metabolic homeostasis. Bariatric surgery has been proved to be the most effective treatment for obese patients with or without diabetes. However, there are few reports on the effect of bariatric surgery on severe obesity patients with AN. The purpose of our study is to identify the early metabolic responses following laparoscopic sleeve gastrectomy (LSG) in obese individuals with AN. 17 severe obese patients with AN were recruited to undergo LSG from September 2013 through August 2015. They were evaluated preoperatively and 3 months after the surgery for anthropometric parameters, glucose and lipid profi le, hepatic function, and scores of AN. Patients showed a dramatic reduction in body weight (116.43 ± 16.97kg vs. 92.42 ± 14.51kg; P<0.001), BMI (40.96 ± 4.70kg/m2 vs. 32.34 ± 3.69kg/m2; P<0.001) and waist circumference (122.50 ± 8.80cm vs. 106.74 ± 8.17cm; P<0.001). Signifi cant improvements in blood pressure, insulin resistance status, glycemic and hepatic function were achieved. AN scores were signifi cantly decreased from 6.88 ± 1.27 to 4.18 ± 1.67, P<0.001 after surgery. In conclusion, LSG can effectively improve the AN in obese patients and normalize the metabolic status and should be a better choice for severe obese patients with AN.

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2538-PUBExpression of Innate Immune Receptors in Circulating Leukocytes Before and After a Fat Overload and Its Relationship with the Meta-bolic Status of Morbidly Obese PatientsMERCEDES CLEMENTE-POSTIGO, JOSE CARLOS FERNANDEZ-GARCIA, JUAN ALCAIDE-TORRES, FERNANDO CARDONA, FRANCISCO J. TINAHONES, Malaga, Spain

Obesity is characterized by a low-grade infl ammation which leads to the development of insulin resistance and has been associated with high-fat diets. High-fat meals increase the translocation of bacterial products from gut microbiota to the circulation, and bacterial lipopolysaccharide (LPS) has been proposed as one of the factors responsible for this relationship. On the other hand, it has been described that lipids are able to bind and activate receptors of the innate immune system which would also trigger the infl am-matory response. Thus, the aim of this study was to determine the expres-sion of innate immune receptors in circulating leukocytes before and after a fat overload (FO) in morbidly obese (MO) patients and to analyze its relation-ship with lipid and glucose metabolism.

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 high-fat meal in MO patients.

Supported By: Instituto de Salud Carlos III (PI12/02355, CP13/00023, CB06/03/0018); Consejeria de Economia, Innovacion, Ciencia y Empleo (P11-CTS-08181); Fondo Europeo de Desarrollo Regional

Figure 1. 2473-PUB Application of Translational ...€¦ · tis (NASH), although iron has not been...

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