INTEGRATED PHYSIOLOGY—INSULINCATEGORY SECRETION IN VIVO

the elevated blood glucose and oral glucose challenge induced hyperglycemia in HFD+STZ rats. Interestingly, GLP-1 analogue but not sitagliptin signifi cantly reduced the body weight/fat mass and fasted plasma insulin. The major mechanism of action for GLP-1 analogue and DPPIV inhibitor in treatment of diabetes is to improve the pancreatic β-cell function and promotion of β-cell regeneration. Consistent to the observations in humans, the present study demonstrated the effi cacy differences on effect of pancreatic β-cell function and mass with GLP-1 analogue and DPPIV inhibitor. These results showed that we have established a sensitive model for the evaluation of novel drugs on pancreatic β-cell function and mass.

2847-PO Ketosis-Onset Type 2 Diabetes Had Better Islet β-Cell Function and More Serious Insulin Resistance LINGLING ZOU, HONGYUN LU, YINGJUAN ZENG, SHUNKUI LUO, YING SUN, HONG LIU, LIAO SUN, Guangzhou, China This case control study was aimed to investigate the clinical characteristics INTEGRATED PHYSIOLOGY—INSULIN SECRETION and β-cell function of ketosis-onset type 2 diabetes, and provide evidence for IN VIVO treatment selection. 122 cases of newly diagnosed type 2 diabetic patients were divided into two groups based on the presence of urine acetone bodies 2845-PO (51cases) or not (71cases). We collected their clinical and C-peptide (CP) data, WITHDRAWN calculated the area under the curve(AUC)during CP release test. Insulin resis- tance index (HOMA-IR) and β-cell function index (HOMA-β) were used to estimate insulin sensitivity and β-cell function.We found that compared with non-ketosis group, Fasting CP, 0.5hCP, 3hCP, AUC of ketosis group were sig- nifi cantly higher (P<0.05) [Fig.1].Insulin resistance in ketosis group was more obvious (HOMA-IR, ketosis vs. non-ketosis group: 3.04±0.19 vs. 2.58±0.10, P<0.05) and β-cell function injury was less slight than non-ketosis group (HOMA-β, ketosis vs. non-ketosis group: 35.89±4.62 vs. 25.16±2.71, P<0.05). Plasma triglyceride level in ketosis group was signifi cantly higher than non- ketosis group (2.34±0.23mmol/L vs.1.86±0.11mmol/L, P<0.05), and the percent- age complicated with fatty liver was also higher (ketosis vs. non-ketosis group 54.90% vs. 36.62%, P<0.01). In conclusion, compared with non-ketosis onset type 2 diabetic patients, ketosis-onset patients had better islet β-cell function and more serious insulin resistance which may be caused by liptoxicity.

2846-PO 2848-PO A Rat Model for Later Phase Diabetes—Effi cacy Assessments of WITHDRAWN DPPIV Inhibitor and GLP-1 Analogue HONG LI, ZHAOHONG WANG, WENLING YIN, JISONG CUI, Beijing, China The present study was aimed to establish a rat model that refl ects the later phase T2DM in humans, especially in patients with decreased pancreatic β-cell function and mass. Effects of a GLP-1 analogue and sitagliptin on the improvement of impaired β-cell function/mass and other diabetic parameters Obesity were assessed in this model. SD rats were divided into 4 groups: (1) healthy control (HC) fed by chow; (2) rats fed by high fat diet (HFD) followed a single PUBLISHED ONLY dose of Streptozotocin (STZ), designated as HFD+STZ then treated with Integrated Physiology/ vehicle; (3) HFD+STZ treated with GLP-1 analogue 1mg/kg; or (4) with sita- gliptin 450 mg/kg once daily for 14 days. Pancreatic β-cell function and mass were evaluated by hyperglycemia clamp and insulin/Ki67 immunohistochem- ical staining. OGTT, body weight & composition, food & water intake, blood glucose and plasma insulin levels were measured. By 2-steps hyperglycemia clamp, the maximal insulin secretion (ng/ml) in HC rats (group 1) was 3.5±0.9, which was decreased to 0.9±0.3 in group 2 rats. The impaired insulin secretion was recovered to 3.5±0.7 in the rats given GLP-1 analogue (group 3) and 2.2±0.1 in the rats given sitagliptin (group 4), respectively. Histology fi ndings confi rmed the functional evaluation. Additionally, both medicines signifi cantly decreased

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A723 INTEGRATEDCATEGORY PHYSIOLOGY—LIVER

2851-PO Research on Insulin Resistance and the Function of Islet α,β-Cells in Elderly Patients With Type 2 Diabetes Mellitus and the Reaction of DDP-IV Inhibitors Before and After Treatment REN MIN, CHEN SHU, ZHANG MIN, WANG JUNKANG, Chengdu, China Methods: Fasting plasma glucose( FPG) ,fasting serum insulin( FNS) , C- peptide and glucagon were measured in 30 elderly patients 2 DM (Group A) respectively. Homeostasis model assessment- insulin resistance index (HOMA- IR) and insulin sensitivity index ( ISI) were applied to assess the status of insulin resistance, HOM A-βwas used to assess the basic function of islet βcells. Glucagon was used to assess the basic function of islet αcells. These values were compared with 30 healthy seniors (Group B),30 IGT 2849-PO (Impaired Glucose Tolerance) seniors (Group C),30 newly diagnosed patients A Cross-Discipline Survey Study: After the Wen Chuan Mega-Quake (Group D). Then give the treatment of DPP-IV inhibitors (sitagliptin 100mg qd) 3 Years the Infl uence of the Local Residents’ Stress on Pancreatic to patients in Group A for 3 months, observe the reaction of DPP-IV inhibitors Cell Function before and after treatment, include serum insulin,glucagon and C-peptide WANG JUN KANG, CHEN SHU, ZHANG XUE JUN, Chengdu, China levels. Results: The level of C-peptide and ISI and HOMA-βin Group A were Objective: To observe the infl uence of stress to mega-quakes on pancreatic lower than in other groups. But the level of glucagon was higher than in other cell function of the people in the 5.12 earthquake area after 3 years. Methods: groups. There were very signifi cant differences between T2DM group and The G1 group (1000) people lived in the Wenchuan area for over 3 years after other groups ( P< 0. 05) . In patients treated with DPP-IV inhibitors showed the earthquake. G2 group (1000) people lived in the temporary board rooms that the level of serum glucagon ascent and the level of C-peptide and ISI and in the Wen chuan area for over six months after the earthquake. G3 group HOMA-βdescent. Conclusion: Elderly patients 2DM have obvious insulin (800) was the residents of Chengdu city. Understanding stress condition by resistance and islet cells dysfunction and high-level glucagon. Hyperisuline- self-made meter.Fasting blood glucose (FPG), Fasting insulin (FIns), proinsulin, mia with low C- peptide level may exist in elderly patients with type 2 diabe- C-peptide, glucagon and glucocorticoid were measured. The insulin resistance tes mellitus. This study suggests that insulin resistance and islet cells dysfunc- was evaluated by HOMA-IR. The β-cell function was assessed by HOMA-β. tion may play a key role in glycometabolism disorder in elderly patient with Results: In the G1 group, 81 examples were diagnosed with diabetes mel- type 2 diabetes mellitus. DPP-IV inhibitors may play an important part in the litus, the morbidity is 10.12%; In the G2 group, 104 examples were diagnosed treatment of elderly patients 2DM. with diabetes mellitus, the morbidity is 10.40%. In the G3 group, 102 examples were diagnosed with diabetes mellitus, the morbidity is 10.20%. G2 group were higher than the prevalence rates of G3 group, (P<0.05). Risk factor INTEGRATED PHYSIOLOGY—LIVER analysis in the G3 Group found that obesity (OR 1.24) glucagon (OR2.13), glu- cocorticoid (OR 1.67), stress (OR1.32) were risk factors for insulin resistance 2852-PO (P<0.05). Age, (OR1.24) obesity (OR2.13), glucocorticoid (OR1.67), stress Multiple Nuclear Receptors Regulate Hepatic Gck Expression (OR1.32) were the islet secretion functions to reduce risk factors (P<0.05). through the Retinoic Acid Responsive Element in its Promoter Conclusions: The earthquake stress causes the island of Alpha cell secretion RUI LI, YANG LI, RUI ZHANG, GUOXUN CHEN, Knoxville, TN dysfunction, the Beta cell secretion decrease, the insulin resistance increases. The hepatic glucokinase (gene, Gck) plays a critical role in glucose homeo- Relieve stress and intervention may prevent diabetes and development. stasis. We have reported that retinoids synergize with insulin to induce Gck expression in primary rat hepatocytes. Here, we determine the retinoic acid 2850-PO responsive element (RARE) in the hepatic Gck promoter, and the transcription Restoration of the First-Phase Insulin Secretion and a Decline in Fat factors binding to it. A series of Gck promoter reporter gene constructs were Mass are Predictors for Achieving Long-Term Glycemic Control after made. Their responses to retinoic acid (RA) were analyzed using dual luciferase Early Intensive Insulin Therapy in Patients With Newly Diagnosed assay. Electrophoretic mobility shift (EMSA) and super-shift assays were used Type 2 Diabetes to analyze the protein binding activities in rat liver nuclear extract (NE). The JANG WON SON, HEE SUN KWON, SEONG SU LEE, SUNG RAE KIM, SOON JIB effects of these nuclear receptors on Gck expression were determined using YOO, Bucheon, Republic of Korea recombinant adenovirus-mediated over-expression in the absence or presence Recently, early intensive insulin therapy (IIT) was reported to improve β-cell of RA and insulin. We observed that RA and RA + insulin, not insulin, activated function and induce long-term remission in patients with newly diagnosed the reporter gene constructs containing 1 to 0.2 kb of the Gck promoter frag- type 2 diabetes. However, the possible mechanisms responsible for this ments in primary hepatocytes. Co-transfection of the reporter gene constructs disease-modifying effect are still unclear. We evaluated clinical characteris- with expression vectors of rat retinoic acid receptor α (RARα)/retinoid X recep- tics of patients with newly diagnosed type 2 diabetes, who achieved a long- tor γ (RXRγ) introduced and improved the RA responses in INS-1 cells and hepa- term glycemic control after early IIT. A total of 59 subjects with newly diag- tocytes, respectively. One RARE overlapping with a HNF4α binding site was nosed diabetes participated in a 12 week course of IIT and followed up for 1 identifi ed and confi rmed using reporter gene constructs containing linker-scan year. and single nucleotide mutations. The interactions of 32P-labeled oligo nucleotide According to post-insulin therapy oral glucose tolerance test, patients were probes and proteins in NE produced multiple bands in EMSA assay. The inten- categorized diabetes group (n = 31) and non-diabetes group (n = 28). At 1 year sities of some of them were signifi cantly reduced by the specifi c antibodies to follow up, all patients with diabetes group was received either insulin or oral RARα, RXRγ, HNF4α, and COUP-TFII. The RARE mutations altering the RA hypoglycemic agents. Among patients with non-diabetes group, excluding 2 responses also changed the binding patterns. Over-expression of RARα poten- patients lost to follow up, 11 patients achieved long-term glycemic control tiated the synergy between RA and insulin to induce Gck expression, whereas without pharmacologic therapy, but remaining 15 patients were maintained over-expressions of HNF4a and COUP-TFII impaired it. We conclude that one

Obesity pharmacologic therapy at 1 year follow up. There is no signifi cant difference RARE in the hepatic Gck promoter binds to multiple nuclear receptors which in clinical characteristics at baseline between patients with or without main- positively or negatively modulate its responses to RA and insulin. taining pharmacologic therapy. Compared to a total of 46 patients with main- Supported by: AHA PUBLISHED ONLY Integrated Physiology/ taining pharmacologic therapy, β-cell function as identifi ed by the insulino- genic index was improved signifi cantly after IIT in those patients with 2853-PO achieving long-term glycemic control without pharmacologic therapy. In addi- Standard Clamp Technique Underestimates the Role of the Liver in tion, the increment of the insulinogenic index and a loss of fat mass were Insulin (INS) Regulation of Glucose Homeostasis signifi cant before and after IIT in this subgroup. TIFFANY D. FARMER, ERIN C. HEALEY, TRACY P. O’BRIEN, GREGORY A. MCCOY, In conclusion, the improvement of early-phase insulin secretion could be MASAKAZU SHIOTA, Nashville, TN an important mechanism for the maintaining long-term glycemic control with- INS clamp studies in rats and mice are generally performed with INS infu- out anti-diabetic medication after early IIT in patients with newly diagnosed sion into the systemic circulation (SC) via the jugular vein (JV), while INS type 2 diabetes. secreted from the pancreas fl ows into the portal vein (PV) and passes through the liver prior to reaching the SC. We compared the effect of SC vs PV INS delivery in 6h-fasted conscious SD rats.

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A724 INTEGRATEDCATEGORY PHYSIOLOGY—LIVER

INS clamps were performed under euglycemic and hyperglycemic condi- 2855-PO tions using chronic catheterization [the carotid artery (CA) and PV, JV, and ileal vein (ILV)] and tracer ([3-3H]-glucose) methods. During the clamp, soma- WITHDRAWN tostatin (5 µg/kg/min) was infused into the JV, and glucagon (1.6 ng/kg/min) was infused into PV via ILV to maintain basal levels. INS was infused at 1, 2 or 5 mU/kg/min into SC or PV. Blood was collected from CA and PV. Under basal conditions, arterial (A) INS was <50% of that in PV (Table). With INS-PV, PV>A INS concentrations were maintained, while A>PV con- centrations with INS-SC. INS-SC vs INS-PV resulted in higher rates of glucose disappearance rate (Rd) and muscle glycogen synthesis, less inhibition of endogenous glucose production (EGP), and lower liver glycogen synthesis at any given INS infusion rate and A INS concentration. In comparison to SC delivery, PV infusion of INS is the preferred (more physiologic) technique when assessing glucose homeostasis under clamp conditions.

2856-PO Hepatic SILAC Proteomic Analysis of the PANDER Transgenic Mouse Supported by: NIDDK (2R01DK60667 to M.S.) Reveals Network of Enhanced Triacylglycerol Production MARK G. ATHANASON, BRANT R. BURKHARDT, Tampa, FL 2854-PO PANcreatic DERived factor (PANDER) or FAM3B is a novel secreted protein WITHDRAWN that is highly expressed and secreted from the endocrine pancreas. Previous studies have revealed that PANDER impacts glycemic regulation via interac- tion with the liver and potentially insulin signaling but the precise mechanism is unknown. The complex nature of insulin signaling and multiple molecules involved with this process warranted an approach such as high throughput mass spectrometry based proteomic analysis using Stable Isotope Labeling of Amino Acids in Cell Culture (SILAC) to accurately quantify and compare our PANDER transgenic (TG) overexpressing mouse model to wild type B6SJLF (WT) to measure global changes in hepatic signaling. Six TG and matched WT were evaluated by SILAC. The “spike-in” process was employed by equal addition of labeled liver derived AML12 cell line protein lysate to the mice liver protein lysate for relative quantitative analysis. Upon acquisition of the datasets by use of high performance liquid chromatography tandem mass spectrometry (HPLC MS/MS, LTQ Orbitrap) differential proteomic networks were identifi ed. Ingenuity Pathway Analysis (IPA) revealed six differentially expressed proteins (ENTPD5, ACSL1, SCP2, PEPCK, PRKAR2B, and FABP1) in the TG that were estimated to function in concert to increase quantities of tria- cylglycerol (z-score of 2.4). The most highly upregulated protein of the six identifi ed was ENTPD5 (ectonucleoside triphosphate diphosphohydrolase 5) which was increased eight fold in the TG. This enzyme is a known regulator of triacylglycerol in the liver. These proteomic results are very concordant with the hepatic steatosis observed phenotypically in the TG. Overall, our SILAC approach has revealed a PANDER-induced selective hepatic insulin resistant lipogenic and gluconeogenic pathway that demonstrates the utility of this method to elucidate novel mechanistic proteomic networks involved Obesity in hepatic signaling. PUBLISHED ONLY Integrated Physiology/ 2857-PO Study of Clinical and Biochemical Profi le of Non-Alcoholic Fatty Liver Disease in Patients With Diabetes Mellitus SUNNY GARG, AWADHESH K. ARYA, AWANINDRA DWIVEDI, RICHIK TRIPATHI, KAMLAKAR TRIPATHI, Varanasi, India NAFLD represents a condition that occurs in those who do not consume alcohol in amount considered to be harmful to liver and in absence of known toxin, drug or viral disease. Obesity and insulin resistance are the key patho- genic factors associated with NAFLD, and thus it is a very common condition among patients with type 2 diabetes mellitus (T2DM). Importantly, the risk

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A725 INTEGRATEDCATEGORY PHYSIOLOGY—LIVER

of liver-related death in patients with T2DM is 2.5-fold higher than that of insulin-stimulated glucose disposal rate (IS-GDR) was no signifi cant change the general population. between two groups. On the other hand, in the NCD fed rats, the GIR, IS-GDR, For this study, we recruited 100 patients of non-alcoholic fatty liver disease. and HGO were no signifi cant change between two groups. Consistent with Other causes of liver disease were diligently ruled out by optimum history of the clamp data, the insulin stimulated phosphorylation of Akt (Ser473) was alcohol intake, and other laboratory tests like viral markers (using miropar- signifi cantly decreased in liver of HFD fed rats injected with Ad-G0S2. Fur- ticle enzyme immunoassay kits from ABBOTT Labs, Chicago), autoimmune thermore, the oil-red stain indicated that overexpression of G0S2 protein in markers (using ELISA method), serum ferritin, alpha 1 antitrypsin levels, and liver promoted hepatic steatosis by 2.5-fold in HFD fed rats. other relevant investigations. Liver biopsy was done to confi rm the diagnosis. In conclusion, these results indicate that hepatic G0S2 protein might pro- These patients were further divided in two groups, 38 with diabetes mellitus mote hepatic insulin resistance by the exacerbation of hepatic steatosis. (Group A) and 62 without diabetes mellitus (Group B). These two groups were compared on the basis of lipid profi le (Beckman-US- Synchron CX 5 system), 2860-PO fasting plasma glucose, serum insulin levels (using kit supplied by the Bhaba Serum MicroRNA 122 Levels Correlate Positively With Alanine Ami- Atomic Research Center, Mumbai), and insulin resistance (calculated by notransferase Levels and Insulin Resistance in Chinese Young HOMA-IR method). Adults On comparison between group A and B, no signifi cant difference was found RUI WANG, JIE HONG, YANAN CAO, JUAN SHI, WEIQIONG GU, YIFEI ZHANG, in the anthropometric profi le and lipid profi le. On the other hand, fasting plasma WEIQING WANG, GUANG NING, Shanghai, China glucose, serum insulin levels, and insulin resistance were signifi cantly lower MicroRNA 122 (miR-122), an abundant liver-specifi c microRNA(miRNA), in Group B as compared to Group A (p<0.001). Statistically signifi cant higher regulates cholesterol metabolism, promotes hepatitis C virus replication and values of metabolic variables in Group A as compared to Group B indicated was reduced in hepatocellular carcinoma. Nevertheless, its role in insulin greater severity of insulin resistance in the diabetic group. However, non- resistance remains inconclusive. In this study, microRNAs were isolated from signifi cant differences in the anthropometric and lipid profi le in the two groups serum of 123 obese and 107 normal-weight Chinese young adults using the could be attributed to some degree of insulin resistance in Group B, albeit miRNeasy kit (Qiagen). We identifi ed that the miR-122 relative expression lesser than Group A. levels in obese patients were signifi cantly higher than normal-weight subjects (P < 0.001) and were closely related to adiposity, liver enzymes and insulin 2858-PO sensitivity (all P < 0.01). Multiple stepwise regression analysis showed an Human Liver Gene Expression in Early Stage Hepatic Steatosis independent association of miR-122 with alanine aminotransferase (ALT) (P KAIDA MU, YUNXIA ZHU, SHIHONG WANG, CHEN WANG, WEIPING JIA, Shang- < 0.001). miR-122 remained an independent risk factor of insulin resistance hai, China assessed by binary HOMA-IR (OR = 3.379 per SD unit, 95% CI [1.141 - 10.007], Nonalcoholic fatty liver disease (NAFLD) has emerged as a growing public P = 0.028) after controlling for age, sex, BMI, WHR, systolic blood pressure, health problem and is associated with obesity and type 2 diabetes. The patho- diastolic blood pressure, lipid profi le and liver enzymes. We conclude that genesis of the disorder is not fully clarifi ed. The aim of present study was to serum miR-122 correlates positively with ALT and insulin resistance but not evaluate the gene expression in the early stage of NAFLD. obesity in Chinese young adults. These fi ndings reveal a new promising target To this end, Affymatrix GeneChip Human Genome U133 Plus 2.0 Array was for the treatment of type 2 diabetes. used to investigate the gene expression in human liver of subjects with early stage liver steatosis (15-25% of hepatocytes with fat) and controls without 2861-PO fatty liver (<5% of hepatocytes with fat). Real-time PCR was used for the Different Changes of Serum Fibroblast Growth Factor 21 in Patients confi rmation. With Acute and Chronic Liver Injury With a threshold of P<0.05 and fold change (fatty liver group/control HUATING LI, YONGNING SUN, MI ZHOU, YUQIAN BAO, AIMIN XU, WEIPING JIA, group)>1.4 or <0.7, we identifi ed 162 probes which represent 128 dif-genes. Shanghai, China, Hong Kong, China Among them, 53 genes were involved in metabolic process by Gene ontology Fibroblast growth factor (FGF) 21, abundantly expressed in the liver, is an analysis. Pathway analysis showed that genes involved in triglyceride syn- endocrine hormone involving in metabolic regulation. It has been demon- thesis (AGPAT2, GK) and fatty acid transport (CD36) were upregulated, while strated to have a close relationship with nonalcoholic fatty liver disease and genes involved in de novo fatty acid synthesis (ACACA, FASN, ELOVL6) were its related liver injuries. However, the relevance of FGF21 with acute and down-regulated in subjects with fatty liver. No changes could be found in chronic liver injuries caused by hepatitis B virus is unknown. In this study, genes responsible for β-oxidation (CPT-1) and VLDL secretion (MTP). serum FGF21 levels were measured by enzyme-linked immunosorbent assay Our data showed that increased fatty acid transport and triglyceride syn- in 18 patients with acute hepatitis B, 53 patients with chronic hepatitis B and thesis might be the earlier step in the development of NAFLD. 78 control subjects, and their association with metabolic parameters, levels of liver injury markers and Hepatitis B Virus (HBV)-DNA was investigated. 2859-PO After adjustment for age and gender, serum FGF21 concentrations in the Overexpression of Hepatic G0S2 Protein Promotes Hepatic Insulin patients with acute hepatitis B (452.43 pg/ml [196.51-723.81]) were signifi - Resistance in High-Fat-Fed Male Wistar Rats cantly higher than those in control subjects (234.83 pg/ml [139.37-473.81]) YOSHIYUKI SUGAYA, HIROAKI SATOH, TSUYOSHI WATANABE, Fukushima, (P<0.05). By contrast, serum concentrations of FGF21 were signifi cantly lower Japan in patients with chronic hepatitis B (94.42 pg/ml [36.86-166.65]) than those Fatty liver is strongly associate with insulin resistance. Recently it has been in control subjects (P<0.01). In acute and chronic hepatitis B, a positive and reported that G0S2 inhibited the lipolysis activity of adipose triglyceride negative association of serum FGF21 levels with liver enzymes and HBV-DNA lipase. Moreover, we confi rmed that G0S2 protein content were increased in was observed respectively. Different changes of serum FGF21 in patients with the liver of high fat diet (HFD) fed rat. However, the precise physiological role acute and chronic hepatitis B may refl ect the pathophysiological roles of FGF21 of hepatic G0S2 is still unknown. in acute and chronic liver injury. In the current studies, we investigated the effect of hepatic G0S2 on insu- lin sensitivity in normal chow diet (NCD) or HFD fed male Wistar rats by

Obesity overexpressing G0S2 protein using an adenovirus (Ad) encoding mouse G0S2. Male Wistar rats were fed NCD or 60% HFD diet for a total of 4 weeks. PUBLISHED ONLY Integrated Physiology/ After 3 weeks feeding, they were injected with control Ad-GFP or Ad-G0S2. On day 7 post injection, glucose tolerance test (GTT) and euglycemic-hyper- insulinemic clamp studies (at 25 mU/kg/min insulin infusion rate) were per- formed after a 8-hour fast. The body weight and fasting glucose levels were no signifi cant changes between Ad-GFP and Ad-G0S2 groups. In the HFD fed rats, during the clamp studies, the glucose infusion rate (GIR) required to euglycemia was signifi - cantly decreased from 34.9 ± 2.3 to 29.4 ± 0.8 mg/kg/min (p < 0.05) in Ad-GFP and Ad-G0S2 group. Insulin suppressed hepatic glucose output (HGO) was increased from 5.1 ± Supported by: National Basic Research Program (2011CB504001); NSFC 0.6 to 6.7 ± 0.5 mg/kg/min (p < 0.05) in Ad-GFP and Ad-G0S2 group, but (81170379), (81200292)

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A726 INTEGRATED PHYSIOLOGY—MACRONUTRIENTCATEGORY METABOLISM AND FOOD INTAKE

2862-PO activity was detected after 24h. The Luciferase activity of R-PNPLA3-1 (-279/- Profi ling the Dynamic Proteome of Hepatic Lipid Droplet Associated 19bp) which contains a putative sterol regulatory element (SRE) (-91/-100bp) Proteins during High-Fat Feeding were increased 51.1 folds in LO2 cells (P<0.01). Almost no Luciferase activities SALMAAN AHMED KHAN, TODD W. MARKOWSKI, LEEANN HIGGINS, DOUGLAS were detected in R-PNPLA3-2 (-699/-264bp) and R-PNPLA3-3 (-956/-696bp). G. MASHEK, St. Paul, MN, Minneapolis, MN Cotransfecting with SREBP-1c, the luciferase activity of R-PNPLA3-1 was Elevated levels of circulating free fatty acids (FFA) in obese individuals are elevated 2.6 folds (P<0.05), while the luciferase activity of R-PNPLA3-2 and thought to be causative agents in the development of insulin resistance (IR) R-PNPLA3-2 did not changed. After mutating the putative SRE in R-PNPLA3-1, and type 2 diabetes. These circulating FFA may be stored as TAG in cellular the effect of SREBP-1c on PNPLA3 was completely abolished (P<0.01). Taken lipid droplets (LD) and accumulation of these stores lead to hepatic steatosis together, SREBP-1c tranactivates rat PNPLA3 mediated by a SRE between and non-alcoholic fatty liver disease (NAFLD). NAFLD is the most common nucleotides -91 and -100 of the rat PNPLA3 promoter. form of liver disease in the US and is considered a manifestation of the Supported by: NSFC (30900506) metabolic syndrome in the liver. Highlighting an instrumental role for LDs in the pathogenesis of NAFLD, research has shown that an increase in liver LDs 2865-PO in obesity is linked to IR. Rather than serving as an inert fat store, studies State of Histostructure of Liver in Animals With Diabetes Induced by have demonstrated that LD are dynamic, participate in metabolism, traffi ck- Xanturenic Acid ing, and communicate with other organelles. At present research into the GABIT G. MEYRAMOV, AISULU A. KIKIMBAEVA, FARIDA A. MINDUBAEVA, dynamic nature of LD proteins in the liver has been limited. Further investiga- AIZHAN G. MEYRAMOVA, Karaganda, Kazakhstan, Astana, Kazakhstan tion into the role of hepatic LD and fat accumulation in the development of IR Selective destruction of B-cells within 20-30 min caused by chelat active is required. In this study we profi le the hepatic LD proteome in mice fed a chemicals result developing of artifi cial diabetes without primary alterations chow or high-fat (60%) diet for 9 weeks. LD were isolated from mouse liver of other tissues including liver. Meanwhile type 2 diabetes in human deve- tissues, proteins were extracted and processed for an iTRAQ-based quantita- loped not as artifi cial chemical diabetes. Aim of work: to study state of his- tion method using an LTQ Orbitrap Velos for MS analysis. 1255 proteins were tostructure of liver in animals contained on diet stimulated endogene synthe- identifi ed. We performed functional analysis to identify sets of proteins and sis of Xanturenic acid (DXA), a diabetogenic metabolit of Tryptophan, that pathways that were differentially regulated between chow and high-fat fed more approached to conditions developing diabetes in human. 22 rats were groups. Based on this analysis the oxidative phosphorylation pathway was contained 116 days on DXA. Blood glucose (BG) control weekly, XA in the urine signifi cantly up-regulated in the high-fat fed group. Carbohydrate metabolism (XAU)-1 time per 2 weeks; histology: SHIFF-method staining of glycogen with and glutathione metabolism pathways were signifi cantly down-regulated measuring of absorbance (AB), haematoxylin and eosin (HE), staining of RNA upon high-fat feeding. These data demonstrate that increase in dietary fat by pyronine. Results: BG: before-4.2±0.4mM; 108th-114th-10.7±2.3mM; XAU: can greatly infl uence the profi le of proteins associated with the LD in the liver. before-0,045±0.009 mcg/ml; 112nd-114th day-0.339±0.041 mcg/ml. Histology: Pathways identifi ed to be dysregulated upon high fat feeding could provide 1) distrophya of paracentral and peripheral zones lobules of liver (in 22±6.7% future targets for mechanistic studies to better understand the development lobules); 2) partial destruction of central veins (18±3.5% number of veins on hepatic IR and NAFLD. sections); 3) destruction of main part endothelium of veins (12±4.6% veins); Supported by: NIH (DK090364 to D.G.M.) 4) lysis of erytrocites (in 21±5.5% of investigated capilla- res); 5) stasis of leicocytes (in 28±4.2% capillares) with infi ltration in tissue (17.6±2.7%); 6) 2863-PO necrosis of pre-located hepatocytes with pycnosis or fragme-ntation of nuclei; WITHDRAWN 7) partial lipid infi ltration in peripherical part of liver’s globules (in 21.2±3.4% globules); 8) hydropic and vacuolar distrophya of hepatocytes with destruction of nuclei (16± 5.3%);9)not marked inhibition synthesis of albumen. Arterial vessels: 1) destruction and fi brinoid changes; 2) partial alteration of endothe- lium of interglobular arteries. Decreasing of glycogen content in cytoplasm of 24±5.6% of hepatocytes: 0.31±0.04 (intact hepa- tocytes-1.00±0.07).In conclusions, contrary diabetes provoked by chelat active chemicals diabetes caused by XA accom panied by multiple histo- logical changes in the tissue of liver. Supported by: Family of Professor G. Meyramov

INTEGRATED PHYSIOLOGY—MACRONUTRIENT METABOLISM AND FOOD INTAKE

2866-PO Weight Loss, Glucose and Lipids after a Worksite Wellness Interven- tion in African American and Caucasian Women BERNARD V. MILLER, BEN LEON, KONG CHEN, ANNE E. SUMNER, RICHARD O. CANNON, Bethesda, MD Weight loss is often less in African Americans (AA) than Caucasians (CC) during bodyweight reducing interventions. The effect of racial difference in weight loss on glucose and lipid metabolism has not been investigated. We 2864-PO hypothesized that AA women lose body fat at a slower rate than CC women, SREBP-1c Transactivates Rat PNPLA3 Gene Mediated by a SRE resulting in less weight loss. 94 women, 55 AA and 39 CC, who completed a between Nucleotides -91 and -100 of the Rat PNPLA3 Promoter in worksite wellness intervention at the NIH with initial BMI (AA=34±1, Obesity Human Normal Liver Cell Lines LO2 CC=32±1kg/m2, P=0.50), percent body fat (AA=44±1, CC=45±1%, P=0.62) and HUA LIANG, JING XU, HONGXIA LIU, JIANPING WENG, Guangzhou, China fat mass (AA=39±2, CC=37±2kg, P=0.43) were studied. Participants were PUBLISHED ONLY Patatin-like phospholipase domain protein 3 (PNPLA3) is a non-secreted randomly selected to complete a 6-mo program that included web-based Integrated Physiology/ protein expressed in human and rat liver and adipose tissue, and function nutritional information and access to convenient onsite exercise rooms, with mainly to regulate triglyceride synthesis. It is therefore hypothesized that (intervention) or without (control) dietitian counseling. After baseline assess- PNPLA3 could be involved in the pathogenesis of disorders of energy metab- ment, all participants were instructed to decrease caloric intake by 500 kcal/d olism, such as obesity, type 2 diabetes and non-alcoholic fatty liver disease. and increase physical activity by 5,000 pedometer steps/d. We measured Given that the regulatory mechanism of PNPAL3 gene is largely unknown, the bodyweight, body fat, glucose, insulin, insulin sensitivity index (SI) by the current study aims to explore the effect of the sterol regulatory element minimal model, A1C (AA n=23, CC n=20), triglycerides (TG), and lipoprotein binding protein 1c (SREBP-1c) on the transactivation of rat PNPLA3 gene. The cholesterols. All data had normal distribution. Two-way repeated measures 1000bp upstream of the rat PNPLA3 promoter was tested. Three overlapped ANOVA was used to determine within and between group differences. Weight PNPLA3 report plasmids and PNPLA3 mutating report plasmid were respec- loss was slower in AA (-0.28±0.08) than CC (-0.62±0.15kg/mo, P<0.05) women. tively cotransfected with pcDNA3.1-SREBP-1c into LO2 cells. The luciferase There was no difference in weight loss by condition. The reductions in fat

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A727 INTEGRATED PHYSIOLOGY—MACRONUTRIENTCATEGORY METABOLISM AND FOOD INTAKE

mass (AA=-1.4±0.4, CC=-2.9±0.8kg, P<0.05) and truncal fat (AA=-0.6±0.3, secretion of GLP-17-36 and PYY. Gx by itself results in a signifi cant nutrient- CC=-2.2±0.6kg, P<0.05) were lower in AA than CC women. Percent body fat stimulated incretin secretion, but not in post-prandial energy expenditure. changed similarly in AA (0.1±0.9) and CC (-1.5±0.5%, P=0.20) women. Changes in glucose, insulin, SI, A1C and lipids were not different by race. Despite one- 2869-PO half the reduction of total bodyweight mostly due to less reduction in fat WITHDRAWN mass, AA women showed similar improvement in glucose, insulin and lipids compared with CC women. AA and CC women likely benefi t metabolically from wellness intervention in the workplace to a similar degree. Supported by: NIH

2867-PO Dietary Betaine Supplementation Improves Systemic Metabolism in HFD-Fed Mice ASMA EJAZ, ELIZABETH LI, ALLISON B. GOLDFINE, CARLES LERIN, MIRANDA LIANG, ROBERT GERSZTEN, MARY-ELIZABETH PATTI, Boston, MA Betaine is an important dietary nutrient and methylated derivative of glycine which serves as a methyl donor in the methionine cycle, an osmolyte, and a precursor for glutathione biosynthesis. Our prior metabolomics analysis of human plasma demonstrated that betaine levels are correlated with insulin sensitivity (r=0.55, p<0.05). To determine whether betaine might improve systemic metabolism, we supplemented betaine (1% w/v in water) prior to initiation of high-fat diet (45% HFD). Betaine was well tolerated, and after 20 weeks, plasma levels were 29% higher in supplemented mice (p= 0.06). Betaine supplementation increased energy expenditure (6% increase, p<0.01) despite no effects on food or water consumption, body weight, or body composition. Betaine supplementation tended to reduce hepatic triglyceride content (49%, p=0.1) and signifi cantly reduced hepatic cholesterol by 39% (p=0.05). We extended our studies to a larger cohort of mice across a spectrum of fat intake (10%, 45%, and 60%) in order to assess the impact of betaine on glucose metabolism. Body weight was signifi cantly reduced in betaine-treated mice fed either the 10 or 60% fat diet (7 and 9%, respectively, p<0.01), despite no change in food or water intake. Fasting glucose tended to be reduced with betaine supplementation in mice fed a 60% HFD (208 vs. 162 mg/dl, p=0.08). Strikingly, there was a marked effect of betaine to reduce plasma insulin levels in mice fed a 60% HFD, with a 56% reduction in insulin in the fasting state, 56% in the refed state, and 28% reduction after an IP glucose load (p<0.01 for all). Together, our data demonstrate that betaine supplementation improves 2870-PO systemic energy metabolism. We hypothesize that improvements in hepatic lipid metabolism may contribute mechanistically to improvements in fasting WITHDRAWN glucose, fasting insulin, and refed insulin. Supported by: Ajinomoto Group

2868-PO Glucose Metabolism Improvements Following Biliopancreatic Diver- sion in Rat are Associated With GLP-1 and PYY ELENA-DANA BARABOI, WEI LI, SÉBASTIEN LABBÉ, MARIE-CLAUDE ROY, CYN- THIA BOUCHARD, PIERRE SAMSON, FADY MOUSTARAH, LAURENT BIERTHO, DENIS RICHARD, Quebec, QC, Canada Mechanisms underlying the benefi cial effects of the bariatric surgery on body weight and glucose metabolism remain to be delineated. Three different bariatric procedures (biliopancreatic diversion with duode- nal switch, BPD; sleeve gastrectomy, Gx and duodenal switch, DS) or sham surgery were performed on high-fat (HF) fed, insulin resistant, male Wistar rats. Sham operated animals were either HF ad libitum fed or pair-weighted with the BPD rats (PW shams). Body weight and food intake were measured daily for 9 weeks following surgery. IPGTT tests were performed pre- and post-operatively. At 7 weeks after surgery, all rats were fasted and then allowed to eat a standardized meal. Oxygen consumption and locomotor activ- ity were measured and blood samples were collected in fasting state and

Obesity during refeeding period. Plasma levels of incretins (GLP-17-36, PYY, GIP), insu- lin and glucose were determined. BPD, DS and Gx resulted in a transitory reduction of food intake. BPD and PUBLISHED ONLY Integrated Physiology/ DS led to a noticeable reduction in body weight and fat gain. Gx rats showed only a trend toward decrease in body weight gain compared to shams. Eight weeks after surgery, HOMA-IR index and data from IPGTT showed a signifi cant amelioration of insulin resistance in BPD, DS and PW shams, while Gx and HF-fed sham rats still showed high fasting levels of plasma insulin. Signifi cant elevations of basal levels of GLP-17-36 and PYY along with a hypertrophy of the pancreas were noticed in BPD and DS rats. Ingestion of a standardized meal led to a signifi cant increase in plasma GLP-17-36 and PYY in Gx animals and plasma GIP in Gx, DS and BPD rats. Post-prandial energy expenditure was not changed independent of bariatric procedure.Our data suggest that ame- lioration of insulin sensitivity following BPD is potentially mediated by hyper-

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A728 INTEGRATED PHYSIOLOGY—MACRONUTRIENTCATEGORY METABOLISM AND FOOD INTAKE

2871-PO 2873-PO Gastric Bypass Surgery Enhances Ghrelin Suppression and Improves Biliopancreatic Diversion With Duodenal Switch Reduces Fat Gain Beta-Cell Function and Central Obesity at 24 Months in Moderately Through a Reduction in Digestible Energy Intake Obese Adults With Type 2 Diabetes ELENA-DANA BARABOI, WEI LI, SÉBASTIEN LABBÉ, MARIE-CLAUDE ROY, CYN- STEVEN K. MALIN, AASHISH SAMAT, KATHY WOLSKI, BETH ABOOD, CLAIRE THIA BOUCHARD, PIERRE SAMSON, FADY MOUSTARAH, LAURENT BIERTHO, POTHIER, DEEPAK L. BHATT, STEVEN E. NISSEN, PHILIP SCHAUER, JOHN P. KIR- DENIS RICHARD, Quebec, QC, Canada WAN, SANGEETA R. KASHYAP, Cleveland, OH Bariatric surgery represents a very effective therapy for obesity and type Previously we reported that Roux-en-Y gastric bypass (RYGB) improved 2 diabetes. The mechanisms underlying body weight loss are still not com- β-cell function and central adiposity to a greater extent than Sleeve gastrec- pletely understood. tomy (SG) or intensive medical therapy (IMT). The relationship between ghre- High fat-fed Wistar rats underwent 3 types of bariatric surgery (biliopancreatic lin, a gluco-regulatory and appetite hormone, and β-cell function or fat mass diversion with duodenal swith, BPD/DS; sleeve gastrectomy, Gx and duodenal at 24 months following bariatric surgery is unknown in moderately obese switch, DS) or sham surgery. An additional group of sham rats were body weight adults with type 2 diabetes (T2D). Methods: STAMPEDE was a prospective, matched with the BPD rats (pair-weighted, PW shams). Body weight, food and randomized controlled trial. 53 moderately obese subjects (BMI: 36±3kg/m2, water intake were measured daily following surgery. Body composition and energy Age: 49±9y) with T2D (HbA1c: 9.7±2%) were randomized to IMT, IMT+RYGB, content of feces were also determined pre- and post-operatively. Oxygen consump- or IMT+SG. Subjects underwent a mixed-meal tolerance test, whereby fast- tion and locomotor activity were measured at 8 weeks after the surgery during ing ghrelin levels and ghrelin suppression (60 min post-prandial - fasting) were basal and fasting states. At the end of the experimental period, blood samples assessed at baseline, 12 and 24 months. β-cell function (oral disposition index) were taken after a 16-h fast and intestine, fat, muscle samples were collected and body fat (DXA) was also assessed. Results: At 24 months, body fat reduced and weighted. Plasma levels of incretins (GLP-17-36 and PYY) were determined. by 10.6 ±7% after RYGB and 7.7±3% after SG, while IMT had no effect. β-cell BPD and DS led to a noticeable reduction in body weight gain, fat-weight function increased 5.8 fold in RYGB from baseline and was greater than IMT (white and brown adipose tissue depots) and -volume along with a higher per- at 24 months (P<0.001), and there were no difference between SG vs. IMT centage of lean mass compared to sham rats and Gx. BPD, DS and Gx resulted (P=0.32). After 24 months, ghrelin suppression improved following RYGB, but in reduced food intake for the fi rst 3-weeks post-operatively. BPD and DS also not SG or IMT (p<0.05 vs. SG, p = 0.09 vs. IMT). Fasting ghrelin levels reduced led to intestinal malbsorption inducing a signifi cant reduction in digestible 4-fold 12 and 24 months after SG but enhanced ghrelin suppression was not energy intake compared to other groups. A larger pool of gut secretory cells present. At 24 months, low fasting ghrelin levels correlated with enhanced β was associated with elevation of plasma levels of GLP-17-36 and PYY in BPD and cell function (r=-0.29, p=0.03), and enhanced ghrelin suppression was associ- DS rats. Basal energy expenditure was decreased in rats presenting a similar ated with GLP-1 rise (r=-0.42, p<0.01) and android body fat (r=0.36; p<0.01) reduction of body weight (BPD, DS and PW shams) compared to other groups. (N= 53). Conclusion. Ghrelin suppression is sustained 24 months after RYGB However, in basal and fasting state, BPD and DS rats showed higher oxygen and is related to decreased central obesity and improved incretin mediated consumption along with lower locomotor activity compared to PW shams. insulin secretion. These fi ndings suggest that ghrelin suppression after RYGB Our data suggest that the effects of BPD-DS on energy balance are in adults with type 2 diabetes contributes to improved glucose homeostasis explained by a reduction in digestible energy intake largely due to nutrient via attenuating the negative effect of ghrelin on β-cell function. malabsorption. Supported by: Ethicon Endo-Surgery, Inc. (EESIIS19900); NIH (R01-DK089547) 2874-PO Caloric Restriction Alone Decreases Glucose Production and Insulin 2872-PO Resistance in Obese Adolescents Fatty Acid Transporter CD36 Mediates Hypothalamic Effect of Fatty DANIEL S. HSIA, STEPHANIE T. CHUNG, SHAJI K. CHACKO, MOREY W. HAYMOND, Acids on Food Intake but Not on Insulin Sensitivity in Rats Houston, TX VALENTINE S. MOULLÉ, ERWANN PHILIPPE, CHRISTELLE LE FOLL, NADIM KASSIS, Diabetes control improves after bariatric surgery. After Roux-en-Y gastric CLAUDE ROUCH, ANNE LORSIGNOL, AMBROSE DUNN-MEYEL, LUC PÉNICAUD, bypass surgery and prior to weight loss, adults exhibit improved insulin resis- BARRY E. LEVIN, CÉLINE CRUCIANI-GUGLIELMACCI, CHRISTOPHE MAGNAN, Paris, tance (HOMA-IR) similar to caloric-restricted controls. Whether this improve- France, East Orange, NJ, Toulouse, France, Dijon, France ment results from decreased total energy expenditure (TEE), changes in fatty Energy balance is controlled by different peripheral signals like nutrients acid (FFA) metabolism, or related to changes in glucose production rate (GPR), and hormones. Variation of their concentrations is detected in specifi c brain gluconeogenesis (GNG), and glycogenolysis (GLY) is unknown. areas such as the hypothalamus, where fatty acid (FA) sensitive neurons can To address these questions, 4 obese adolescents (age 15.5 ± 0.4 yrs and sense FA concentrations variations. These neurons play a physiological role BMI 43.7 ± 1.3 kg/m2, mean ± SE) were studied at baseline and after a 4-day in the control of food intake and the regulation of hepatic glucose production. caloric restriction (~300 kcal/day) mimicking a post-bariatric surgery diet. GPR Mechanisms which mediate FA effects in these neurons are still a matter of 13 2 ([1- C]glucose) and GNG ( H2O) were measured via stable isotope dilution debate. Le Foll et al. showed in vitro that at least 50% of the FA sensing in technique and mass spectrometry; GLY was GPR minus GNG. TEE was mea- ventromedial hypothalamic (VMH) neurons is attributable to the interaction sured using 24-hour indirect room calorimetry. of long chain FA with CD36, while only ~20% is due to intracellular metabolism After caloric restriction, HOMA-IR improved by ~75% and was associated of FA. We aimed at studying whether in vivo effects of hypothalamic FA with a greater decline in fasting insulin than glucose (Table 1). GLY declined sensing may be partly related to their interaction with CD36 or intracellular by 75% and GNG increased by 35% resulting in a 25% decline in overall GPR. events such as β-oxidation. TEE and plasma FFA remained unchanged. A catheter was implanted in the carotid artery toward the brain in male In conclusion, improvement in HOMA-IR could not be accounted for by a Wistar rats to infuse different solutions. After recovery, animals were food- change in TEE or FFA availability. Assuming brain utilization of glucose deprived for 5 hours then 10 min infusions of triglycerides emulsion, Intralipid remained constant; the non-brain insulin dependent glucose utilization (ILH) or saline/heparin (SH) were carried out and food intake was assessed decreased after 4 days of caloric restriction, and may contribute to improved over the next 5h. Insulin sensitivity was studied during insulin tolerance test. glucose homeostasis immediately post bariatric surgery. These parameters were measured in two different series of animals: 1) Eto-

moxir (CPT1 inhibitor) was co-infused with ILH or SH; and 2) Rats were previously Table 1 Baseline After Caloric Restriction p-value Obesity injected in VMH with shRNA against CD36 or scrambled RNA before infu- (mean ± SE) (mean ± SE) sions. HOMA-IR 5.40 ± 1.38 1.41 ± 0.60 0.04 PUBLISHED ONLY

IL signifi cantly decreased food intake during refeeding compared to S Integrated Physiology/ H H Fasting insulin (uU/mL) 24.21 ± 2.17 7.58 ± 1.19 <0.001 (50% reduction, p<0.001). Etomoxir did not affect this inhibitory effect of ILH on food intake while VMH CD36 depletion almost totally reduced this effect. Fasting glucose (mmol/L) 4.90 ± 0.11 3.98 ± 0.11 <0.001 ILH decreased insulin sensitivity compared to SH. Neither Etomoxir nor VMH GPR (mg/kgLBM/min) 2.35 ± 0.06 1.75 ± 0.05 <0.001 CD36 depletion altered this effect. GLY (mg/kgLBM/min) 1.28 ± 0.06 0.32 ± 0.05 <0.001 In conclusion, the inhibitory effect of FA on food intake is dependent on GNG (mg/kgLBM/min) 1.07 ± 0.04 1.44 ± 0.06 <0.001 VMH CD36 expression, whereas FA effects on insulin sensitivity are not dependent of CD36. TEE (kcal/kg/day) 21.1 ± 0.98 19.5 ± 1.35 0.35 FFA (mmol/L) 0.9 ± 0.09 0.73 ± 0.07 0.19 Supported by: Endocrine Fellows Foundation

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A729 INTEGRATED PHYSIOLOGY—MACRONUTRIENTCATEGORY METABOLISM AND FOOD INTAKE

2875-PO Two days after the insulin analogue was started, the fasting glycaemia Neurogenetic Basis for Circadian Control of Behavior and Glucose improved (INS: -65±41 mg/dL, GLP-1: -29±48, diet: -31±46, p<0.05), the REE Metabolism decreased (INS:-162±241 kcal/24H, GLP-1: 0±141, diet: -41±154, p<0.05), and WENYU HUANG, KATHRYN M. RAMSEY, LEI CHENG, BILIANA MARCHEVA, CHIAKI the RQ increased (from 0.76±0.04 to 0.80±0.04, p<0.01), whereas it decreased OMURA, YUMIKO KOBAYASHI, RAVINDRA DHIR, REXFORD S. AHIMA, JOSEPH T. with diet (from 0.79±0.05 to 0.76±0.04, p<0.05), and was unchanged with BASS, Chicago, IL, Philadelphia, PA GLP-1 (p<0.005 for the comparison of ΔRQ between treatments). Thirty-three The central nervous system (CNS) programs 24 hr circadian cycles of behav- patients were examined 3 months later. Their HbA1C improved (INS, n=16: ior and metabolism to maintain energy constancy across the daily sleep-wake/ -1.7±1.4%, GLP-1, n=12: -2.1±1.4, diet, n=5: -1.7±2.8,NS), with differing weight fasting-feeding period. At the molecular level, the clock is driven by a tran- changes (INS: +1.5±4.3 kg, GLP-1: -2.8±2.8, diet: -2.2±2.7, p<0.005). The weight scription-translation feedback loop. However, the role of hypothalamic clock changes after 3 months correlated to the early changes of REE (r=-0.37, p<0.05) in the integration of behavior with peripheral tissue metabolism has not been and RQ (r=+0.43, p<0.01); these relations persisted when both changes were determined. Here, we demonstrate that the hypothalamic clock gene Bmal1 included in a multivariate regression analysis (r=0.58, p<0.005). coordinates glucose homeostasis across the sleep-wake/feeding-fasting In uncontroled patients with T2D, two days after the introduction of a cycle. Hypothalamic clock ablation shifts feeding to the light period, when bed-time insulin analogue, the REE decreases by -9%, and the Respiratory mice are normally sleeping, and results in hyperglycemia due to increased Quotient increases by +5%, pointing to a reduction of lipid oxidation. These hepatic gluconeogenesis and reduced peripheral glucose disposal. Surpris- changes predict later weight gain. ingly, the effects of hypothalamic clock on peripheral insulin resistance can be corrected by temporal restriction of feeding to nighttime, suggesting that 2878-PO circadian misalignment is a primary cause of peripheral insulin resistance. The Effect of Naringenin on Macronutrients Induced Oxidative Stress These results provide evidence for genetic interconnections between central and Infl ammation and peripheral clocks in the pathogenesis of metabolic disorders arising from NISSRIN ALAZZAM, HUSAM GHANIM, PARESH DANDONA, Buffalo, NY circadian disruption. We have previously demonstrated that oxidative and infl ammatory stress is induced by macronutrient intake while the intake of orange juice containing 2876-PO fl avonoids or a preparation containing resveratrol and polyphenol prevents such increases. We, therefore, hypothesized that naringenin, a citrus fl a- WITHDRAWN vonoid, inhibits oxidative stress and infl ammation induced by glucose or saturated fat in cells involved in atherogenesis, the monocyte (THP-1 cell line) and the human arterial endothelial cell (HAEC). THP-1 and HAEC cells were challenged with 15 mM of glucose or 50mg/ml cream (saturated fat) in the presence or absence of 100µM of naringenin. The mRNA expression of several genes such as IL-1β, HO-1, MCP-1, CCR-2, TLR-4 and VCAM-1 were measured using Real-Time PCR. Data are presented as mean±SD, n=6. Naringenin sup- pressed glucose and cream induced increases in expression of IL-1β (by 60±12% and 21±4%), CCR-2 (by 41±6% and 36±19%) and MCP-1 (by 40±22% and 48±22%) in THP-1 cells (p<0.05). In HAEC, naringenin suppressed glucose and cream induced TLR-4 (by 53±9% and 62±11%) and MCP-1(by 58±8% and 35±24%). Naringenin also suppressed cream, but not glucose, induced increase in VCAM-1 expression (by 25±10%) in HAEC. On the other hand, naringenin signifi cantly increased HO-1 expression (antioxidant enzyme gen- erating carbon monoxide which is also a vasodilator) in both THP-1 (by 44±24%) and HAEC (by 101±39%) cells. Naringenin has neutralizing effects on glucose and saturated fat (cream) induced oxidative stress and infl ammation and may, therefore, have potential insulin sensitizing and anti-atherogenic effects which need to be confi rmed, in vivo.

2879-PO Hyperphagia Exacerbate Negative Effects of OVX on Muscle and Bone RANA SAMADFAM, SUSAN Y. SMITH, Senneville, QC, Canada Ovariectomy (OVX) in rats is associated with weight gain and loss of bone mass and strength. Increased body weight is in part attributed to increases in growth, consistent with OVX-induced hyperphagia. We compared the effects of OVX-induced hyperphagia on body composition in aged rats (over 6 months of age) fed ad libitum with OVX rats placed on restricted diet. PMI Nutrition International diet was provided to all animals, with restricted diet groups receiving 21 g/day. Body composition was evaluated at baseline and 4, 8, 12 and 19/20 weeks post surgery using DXA (Dual Energy X-ray Absorp- tiometry) and/or pQCT (Peripheral Quantitative Computed Tomography). Overall, BMD for OVX groups were comparable to baseline whereas increases up to 2 and 6% were noted for sham controls respectively on the restricted

Obesity 2877-PO and fed ad libitum. Signifi cant increases were noted over the study period in Early Modifi cations of Respiratory Exchanges Predict Later Weight muscle mass for rats on restricted diet, with trends for increases in fat mass. in Patients Treated for Uncontrolled Type 2 Diabetes For ad libitum fed rats, although an increase in muscle mass was noted 4 PUBLISHED ONLY Integrated Physiology/ CONCEPCION GONZALEZ, ELISA MAURY, BLANDINE CHERIFI, CÉDRIC FAGOUR, weeks following surgery compared to shams, muscle mass gradually declined SOPHIE SALANDINI, AUDREY PIERREISNARD, PAULINE MASQUEFA-GIRAUD, over the remaining study period with lower values 20 weeks post surgery. Fat HENRI GIN, VINCENT RIGALLEAU, Pessac, France mass increased for this group. Adjusting muscle mass and fat mass for body Do early changes of Resting Energy Expenditure (REE) and Respiratory weight, no signifi cant differences were noted between OVX and sham controls Quotient (RQ) relate to later weight course in patients with Type 2 Diabetes for animals on the restricted diet, indicating that the increased body weight (T2D) starting insulin or GLP-1 analogues? is the result of proportional increases in muscle and fat mass, likely related Sixty-seven patients (age 57±9yrs, BMI 33.7±5.0, HbA1C 9.9±1.5%) started to the effect of OVX on skeletal growth. For animals fed ad libitum, signifi cant a bed-time insulin analogue (n=28, Glargine® or Detemir®, initial dose 0.2UI/ decreases in lean mass with signifi cant increases in fat mass were noted kg), or a GLP-1 analogue (n=23, Exenatide ® or Liraglutide®), or a dietary interven- when adjusted for body weight, compared to shams, indicating negative tion (n=16, carbohydrate and caloric restriction). Their respiratory exchanges effects on soft tissue composition. Bone strength was evaluated using com- were monitored at day 0,1,and 2 during 30 minutes before breakfast. pression test on excised L3 vertebral body at 12 months of age. Vertebral

For author disclosure information, see page 829. ADA-Funded Research

A730 INTEGRATED CATEGORYPHYSIOLOGY—MUSCLE bodies on the restricted diet were stronger compared to ad libitum fed animals. breakfast menu included 5 choices containing 40-45g of CHO. All patients on These data suggest that calorie restriction dampens OVX- induced negative Ward A (with and without diabetes) were given the intervention breakfast effects on body composition. for the fi rst 4 weeks of the study, while those on Ward B received standard menus (60-75g CHO in NCS meals). After 4 weeks, the standard and interven- 2880-PO tion wards were switched. Data were collected only on patients with diabe- Use of Modeling to Decipher Key Questions on GOAT/Ghrelin Process- tes who were able to consume meals. ing In Vivo The diabetic patients on Ward A (N=71) who received the intervention HSIU-CHIUNG YANG, MING-SHANG KUO, JENNY TONG, VIRGINIA LUCAITES, showed a smaller rise in pre-breakfast to pre-lunch BG (146 to 155 mg/dL) TRAVIS SHOCKLEY, NICHOLE REYNOLDS, YANYUN CHEN, MARIAN K. MOSIOR, than those who received the standard hospital breakfast (N= 47;152 to 180 Indianapolis, IN, Cincinnati, OH mg/dL; p=0.005) The patients on Ward B showed no signifi cant differences: Ghrelin (AG) is the only known orexigenic peptide in human and rodents. It intervention (N= 62;162 to 190 mg/dL), standard diet (N=57; 144 to 171 is converted from its precursor, unacylated ghrelin (UAG), to the biologically mg/dL; p=ns). active peptide, acylghrelin. Two independent groups (Yang et al., 2008; Guti- This pilot study demonstrates that a moderate reduction in breakfast CHO errez 2009) using different approaches identifi ed the same protein, named content can signifi cantly improve subsequent BG values in a subgroup of GOAT (Ghrelin O-Acyl Transferase), as the long sought enzyme which is diabetic inpatients. Differences between the two wards may result from responsible to for the bioactivation of ghrelin peptide. Results from GOAT differences in patient population (e.g., diagnosis, overall disability, or medica- gene knockout mice confi rmed that GOAT is the principal enzyme which is tions). Further study is necessary to determine which subgroups of diabetic responsible for the acylation of ghrelin. inpatients will benefi t most from reasonable alterations in dietary CHO. We have developed a GOAT enzymatic assay. Using this assay, we have demonstrated the detailed molecular mechanism of the GOAT enzymatic reac- tion. In addition, we used genetic and pharmacologic data to build a model INTEGRATED PHYSIOLOGY—MUSCLE for GOAT/ghrelin processing in mouse. We also used plasma acylghrelin and desacylghrelin profi les from human volunteers, following three doses of acyl- 2883-PO ghelin infusion, to enrich this model and improve understanding of the dynam- Cholinesterase Inhibition Improves Gastric Antrum Smooth Muscle ics of ghrelin processing in humans. We will present the ghrelin processing Function in OB/OB Mice models for human and mouse, as well as how we use these models to answer BHUPAL B. BHETWAL, CHANGLONG AN, KRISTIN L. LYON, SALAH A. BAKER, key questions regardingon the ghrelin metabolism and regulation. Our data BRIAN A. PERRINO, Reno, NV suggest that plasma unacylated ghrelin is secreted from the stomach, and Diabetic gastroparesis is a common complication of diabetes, adversely not generated through deacylation in the plasma. affecting quality of life with nutritional insuffi ciency and symptoms of abdom- inal discomfort, nausea, and vomiting. The pathogenesis of this motility dis- 2881-PO order involves abnormalities in neurons, interstitial cells of Cajal, and smooth A Whole-Body Modeling Approach to Glycaemia and Diabetes muscle cells. The ob/ob mouse model of obesity and diabetes develops delayed DAVID GURARIE, SHARI BOLEN, NEAL DAWSON, FARAMARZ E. ISMAIL-BEIGI, gastric emptying, suggesting that this model is useful for investigating the Cleveland, OH pathophysiology of diabetic gastroparesis. We hypothesized that reduced Many mathematical models of glycemia and diabetes exist for analysis and phosphorylation of the myosin light chain phosphatase (MLCP) inhibitory prediction of symptoms, diagnostics, and drug therapies. Minimal models are proteins MYPT1 and CPI-17 in ob/ob gastric antrum smooth muscles could limited in scope and the complex physiologic models are proprietary and contribute to antrum smooth muscle dysfunction in diabetic gastroparesis. require large computing resources. Spontaneous, carbachol- and high K+-evoked contractions of gastric antrum We developed an intermediate level whole-body system based on the smooth muscles from 7 and 12 week old male ob/ob mice were reduced com- Sorensen approach. It contains major body components and processes. This pared to strain- and age- matched controls, as recorded with myobath tension system has a modular structure with different sub-models corresponding to measurements. There were no differences in spontaneous and agonist-evoked “agents” (metabolites, hormones) or metabolic pathways. Each agent is trans- intracellular Ca2+ transients as measured with fura-2. Western blotting ported throughout the body system, and undergoes metabolic changes con- showed that Rho kinase 2 (ROCK2) expression was decreased at both ages. trolled by other components. The basic system consists of 22 coupled dif- Basal and agonist-evoked MYPT1 and myosin light chain 20 (LC20) phospho- ferential equations. We implemented the architecture and design on a rylation, but not CPI-17 phosphorylation, was reduced compared to age- Wolfram Mathematica platform and its Modeler tools. matched controls, as quantitated by western blotting and densitometry. ob/ Our results include: (i) analysis of fasting steady-states for different meta- ob antrum smooth muscle contractions and MYPT1, CPI-17, and LC20 phos- bolic conditions (normal through DM2); (ii) dynamic simulations of GTT and phorylation were increased to control levels or greater by the cholinesterase diet; (iii) insulin and beta-cell function and sensitivity; and (iv) extended inhibitor neostigmine. These fi ndings suggest that reduced MLCP inhibition Sorensen physiology with glycogen to study the long term effect of diet and due to decreased ROCK2 phosphorylation of MYPT1 in gastric antrum smooth physical activity. We simulated large ensembles and groups of subjects over muscles may contribute to the antral dysmotility of diabetic gastroparesis, a wide range of physiological conditions and interventions. Results of glucose and that increasing acetylcholine availability by cholinesterase inhibition can and insulin dynamics following an intravenous bolus injection of glucose are compensate for the reduced ROCK2 expression and improve contractile shown below. responses by enhancing ROCK2 activation and MLCP inhibition. This open access methodology can be applied to epidemiology of diabetes for different population groups: risk analysis, prediction and glycemic control. 2884-PO Supported by: NCRR (KL2RR024990); NCATS (KL2TR000440) WITHDRAWN 2882-PO A Balanced Breakfast Improves Blood Glucose in Hospitalized Patients With Diabetes Obesity KATHRYN EVANS, LILLIAN LIEN, JAMES LANE, JENNIFER SNOW, EDMUND CHAN, MARK N. FEINGLOS, Durham, NC PUBLISHED ONLY A standard hospital meal often contains a high percentage of carbohydrates Integrated Physiology/ (CHO), which may not be ideal for patients with diabetes. This concern is particularly pertinent to the breakfast meal, which often contains mainly CHO. Clinical observations suggested that such diets elevate pre-lunch blood glu- cose (BG) values. We compared standard hospital “no concentrated sweets (NCS)” breakfast meals with more balanced meals. We hypothesized that a balanced breakfast would improve pre-lunch BG values. This 8-week pilot study was conducted at Duke Hospital on two non-ICU cardiology wards. Ward A consisted mainly of patients with a primary diag- nosis of coronary artery disease (CAD). Ward B consisted mainly of patients with a primary diagnosis of congestive heart failure (CHF). The intervention

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A731 INTEGRATED PHYSIOLOGY—MUSCLE

2885-PO 2887-PO Irisin and Renal Function A Case of Frozen Hip: A Diagnosis We Should Consider More Often? THOMAS EBERT, JUDIT RICHTER, ANETTE BACHMANN, ULRIKE LOSSNER, SUSAN ELEANA NTATSAKI, THWIN AYE, MARK SYKES, IMRAN RIAZ, PETER MERRY, KRALISCH, JURGEN KRATZSCH, JOACHIM BEIGE, INGOLF BAST, MATTHIAS KETAN K. DHATARIYA, Norwich, United Kingdom ANDERS, MATTHIAS BLUHER, MICHAEL STUMVOLL, MATHIAS FASSHAUER, There are only a few isolated case reports of adhesive capsulitis affecting Leipzig, Germany joints other than the shoulder. We report a case of bilateral frozen hips Irisin has recently been introduced as a novel myokine which reverses A 42-year-old woman with an 18 year history of poorly controlled T1DM visceral obesity and improves glucose metabolism in mice. However, regula- presented with a 9 month history of bilateral hip pain & restriction of move- tion of irisin in humans in relation to renal and metabolic disease has not been ment. Her HbA1c had been consistently >119mmol/mol (13%) for more than 6 determined. years prior to presentation. She had already received 3 steroid injections for Serum irisin levels were quantifi ed by enzyme linked immunosorbent assay presumed trochanteric bursitis. Initial imaging of her hips was normal. On and correlated to anthropometric and biochemical parameters of renal func- examination she was unable to weight bear on the left hip & it was extremely tion, glucose and lipid metabolism, as well as infl ammation, in 532 patients irritable, with severe capsular restriction of movement with stages 1 to 5 of chronic kidney disease (CKD). Blood tests showed an HbA1c of 143mmol/mol (15.2%), ESR 36mm/hr, CRP Median serum irisin levels adjusted for age, gender, and body mass index 5mg/L, with normal biochemistry & hematology. Extensive rheumatologic were signifi cantly lower in CKD stages 3 to 5 as compared to stage 1. Fur- investigations were negative. Repeat MRI scan of the left hip, pelvis and thermore, irisin concentrations were positively associated with facets of the spine looking for underlying psoas muscle pathology or referred spinal pain metabolic syndrome including systolic blood pressure, waist-to-height ratio, showed insignifi cant degenerative changes only fasting glucose, and low density lipoprotein (LDL) cholesterol besides renal Initial joint injection into the left hip with bupivacaine and depomedrone function in univariate analyses. Moreover, LDL cholesterol remained indepen- resulted in a transient improvement in pain but not mobility for 3 weeks. Her dently associated with circulating irisin levels in multivariate analysis. symptoms recurred within a few weeks We show for the fi rst time that irisin serum concentrations decrease with After 18 months she developed a similar pattern of symptoms affecting increasing CKD stage and are independently and positively predicted by LDL the right hip. Repeat MRI of the both hips showed non-specifi c minor edema cholesterol. The physiological relevance of these fi ndings, as well as the in the right tensor fascia lata. She was diagnosed with bilateral frozen hips. factors contributing to irisin regulation in humans, need to be established in Due to failure of treatment she was referred to the orthopedic surgeons for future experiments. manipulation & arthroscopic pressure dilatation under GA Supported by: DFG; BMBF Germany; Deutsche Hochdruckliga e.V.; Medical Fac- Adhesive capsulitis of the hip is rare & poorly recognised, with a paucity ulty Leipzig of literature. There is a common association between adhesive capsulitis of the shoulder & diabetes, with a prevalence of 10.3% in T1DM and 22.4% in 2886-PO T2DM. Frozen hip shares similar clinical characteristics & associations with the shoulder & it may respond to similar therapeutic interventions. However, WITHDRAWN as with the shoulder, treatment can be unrewarding

2888-PO Identifi cation of Protein Phosphatase 1 Regulatory Subunit 12A in Human Skeletal Muscle Biopsies MONIQUE LEWIS, DANJUN MA, XIANGMIN ZHANG, MICHAEL CARUSO, RODNEY BERRY, ZHENGPING YI, Detroit, MI Protein Phosphatase 1 Regulatory Subunit 12A (PPP1R12A), also known as myosin phosphatase target subunit 1 (MYPT1 or MBS), regulates the specifi c- ity and activity of the δ isoform of Protein Phosphatase 1 catalytic subunit (PP1cδ). Recent evidence supports its role in insulin signaling possibly through dephosphorylation of insulin signaling proteins. It is possible that PPP1R12A protein abundance in skeletal muscle is altered in obesity and type 2 diabetes. PPP1R12A is found in all major subcellular localizations, and is widely expressed in many cell types. Recently, PPP1R12A protein was detected in mouse EDL and soleus muscles by Western blot analysis. However, whether PPP1R12A protein is expressed in human skeletal muscle is currently unknown. Detection of PPP1R12A protein in human skeletal muscle may provide an opportunity to study it’s abundance in different disease states. Muscle biop- sies from three lean healthy participants were homogenized and lysate pro- teins were immunoblotted with antibodies against PPP1R12A. Several bands showed up close to the predicted molecular weight of PPP1R12A (115kD). Therefore, we optioned to use a proteomics approach to verify the western blot results. Lysate proteins were resolved on a 1D-SDS-PAGE, the gel portion that may contain PPP1R12A and beta-actin were sliced and subjected to trypsin digestion and HPLC-ESI-MS/MS analysis. When a non-targeted approach was used, beta-actin was detected due to its high abundance in muslce, while PPP1R12A was not detected. However, when several potential tryptic peptides unique to PPP1R12A were targeted during the HPLC-ESI-MS/MS analysis,

Obesity PPP1R12A was detected with 99% confi dence based on Scaffold anaylsis. This targeted proteomic approach offers an alternative means to detect proteins with low abundance in human tissue and to investigate their roles in health and PUBLISHED ONLY

Integrated Physiology/ disease conditions, such as insulin resistance and type 2 diabetes. Supported by: NIH (R01DK081750)

For author disclosure information, see page 829. ADA-Funded Research

A732 INTEGRATED PHYSIOLOGY—OTHER HORMONES

INTEGRATED PHYSIOLOGY—OTHER HORMONES disease (CD) and ulcerative colitis (UC). Subjects included 13 patients with IBD (7 patients with CD and 6 patients with UC both without history of oper- 2889-PO ation), and 7 healthy controls. Plasma glucose (PG), insulin (IRI), glucagon, as well as active GLP-1 (aGLP-1) and GIP levels measured with specifi c immuno- Effect of the GLP-1 Receptor Agonist, Liraglutide as an Adjunct to assay, in response to 75g oral glucose load were determined. Insulin resistance Insulin Treatment in a Rodent Model of Type 1 Diabetes and insulin secretion were also determined using the homeostasis model THOMAS H. MEEK, MONICA KUMAR, MILES E. MATSEN, JONATHAN D. FISCHER, assessment (HOMA) and the insulinogenic index (IGI, calculated by the fol- GERALD J. TABORSKY, JR., MICHAEL W. SCHWARTZ, GREGORY J. MORTON, lowing formula: (PG[30min.]-FPG)/(IRI[30min.]-Fasting IRI). There was no sig- Seattle, WA, Mobile, AL nifi cant difference in PG response, insulin sensitivity and insulin secretion Although insulin remains the cornerstone of therapy for patients with type among the groups. Although the peak stimulated aGLP-1 values were not 1 diabetes (T1D), achieving and maintaining tight glycemic control is often signifi cantly different, aGLP-1 values at 60 minutes were signifi cantly higher diffi cult and is associated with increased risk of hypoglycemia and weight in the patients with CD and UC than controls (4.53±2.17, 3.86±1.14, and gain. Thus, there is strong interest in identifying adjuncts to insulin that 2.73±0.65 pM/L, respectively. p<0.05). GIP values at fasting and 60 minutes enhance its safety and effi cacy. Based on the benefi cial effects of glucagon- were signifi cantly higher in patients with CD (49.2±22.1 and 274.1±90.7 pg/ like-peptide-1 (GLP-1) analogues in the treatment of T2D, which include ml) than controls (27.4±7.6 and 178.7±58.7 pg/ml, p<0.05) while there was no increased insulin secretion, reduced glucagon secretion and weight loss, we difference in the patients with UC. There was no difference in glucagon hypothesized that the GLP-1 receptor agonist, liraglutide (Novo Nordisk) would response among the groups. In conclusion, although there were no differences be a useful adjunct to insulin in the treatment of T1D. To test this hypothesis, in PG response, insulin sensitivity and insulin secretion in IBD, patients with streptozotocin-diabetic (STZ-DM) rats and their non-diabetic controls were CD showed an increased response to oral glucose load of both GLP-1 and GIP, implanted subcutaneously (sc) with either an insulin pellet (2U/day) or placebo and patients with UC showed an increased response of GLP-1 only. and then received daily sc injections of liraglutide or its vehicle. As expected, plasma insulin and pancreatic pre-pro insulin mRNA levels were severely reduced (>95%) in all STZ-placebo-treated animals, irrespective of whether 2892-PO they received vehicle or liraglutide. Unlike in T2D, liraglutide does not appear A Neural Relay may Mediate the Effects of Xenin-25 (Xen) on Islet to restore pancreatic beta cells or increase insulin secretion in STZ-DM. Function in Humans Moreover, the effect of insulin treatment to lower blood glucose levels in SARA CHOWDHURY, SONGYAN WANG, BURTON M. WICE, St. Louis, MO STZ-DM rats (relative to vehicle) was not signifi cantly increased by liraglutide Xen is a neurotensin-related peptide produced with glucose-dependent (p=ns), despite the fact that the dose markedly enhanced the modest inhibition insulinotropic polypeptide (GIP) by a subset of enteroendocrine cells. We of hyperphagic feeding induced by insulin (mean FI: 26.8±2.4 vs. 35.1±2.1 g/ previously published that 1) Xen, with GIP but not alone, increases insulin day; p<0.05). As expected, this effect was accompanied by a signifi cant release in mice via a cholinergic relay in the periphery independent of the attenuation of body weight gain (15.3±4.1 vs. 46.7±6.1 g; p<0.05) and body CNS and 2) during intravenous graded glucose infusions (GGIs), Xen increases adiposity (26.5±2.6 vs. 32.8±2.0 g; p<0.05) relative to STZ-insulin-treated effects of GIP on insulin secretion in humans with normal (NGT) or impaired controls. Taken together, these data indicate that although liraglutide may glucose tolerance (IGT), but not type 2 diabetes mellitus (T2DM). Thus, it is limit weight gain associated with insulin treatment of insulin-defi cient diabe- important to determine how Xen increases insulin release in humans and why tes, it does not increase insulin’s glucose-lowering effect. this effect is lost in T2DM. Supported by: Novo Nordisk, Inc. The pancreatic polypeptide response (PPR) is an indirect measure of cho- linergic input to islets. Xen similarly increased the PPR during GGIs or after 2890-PO liquid meal ingestion in humans with NGT, IGT, and T2DM. The PPR to Xen was further amplifi ed by GIP during the GGIs. Thus, a cholinergic relay to islets Glucose-Stimulated Insulin Secretion Suppresses Circulating Ghre- may also mediate the effects of Xen in humans and the beta cell response to lin Concentration: A Hyperglycemic Clamp Study acetylcholine (ACh) may be lost in T2DM. Unlike mice, human islets are poorly CHII-MIN HWU, YEN-JUI CHANG, PAULUS S. WANG, Taipei, Taiwan innervated and ACh may be released from alpha cells rather than neurons. Recent evidence highlights an important role of ghrelin in glucose homeo- Since Xen binds to and activates Neurotensin Receptor 1 (NTSR1), studies stasis. It has been demonstrated that endogenous ghrelin might suppress were conducted to defi ne the pattern of NTSR1 expression in the adult human insulin secretion. However, the inhibitory effect of endogenous insulin on pancreas. Tissue sections were stained with antibodies to NTSR1 plus: 1) ghrelin secretion was not clear. The purpose of this study was to test the PGP9.5 to label neurons and beta cells; 2) tyrosine hydroxylase to label sym- hypothesis that glucose-stimulated insulin secretion suppresses circulating pathetic neurons; 3) glucagon, 4) smooth muscle actin (SMA) to label blood ghrelin in healthy subjects. Thirty-four healthy volunteers (11 men and 23 vessels; or 5) platelet endothelial cell adhesion molecule to label endothelial women) were recruited for a 3-h hyperglycemic clamp. Plasma glucose, insu- cells. NTSR1 was not detected on islet endocrine cells or sympathetic neurons lin and ghrelin were determined. Hyperglycemia increased circulating insulin but was present on PGP9.5 positive axons in the exocrine tissue. Neurotensin concentrations,and decreased ghrelin concentrations by 15 % (Figure). The regulates bicarbonate secretion and NTSR1 was expressed on ductal epithe- levels of circulating ghrelin returned to near-basal values 40 minutes after lial cells. NSTR1 was not detected on endothelial cells but was present in the clamp halted. Our data demonstrated that hyperglycemia-induced endog- close proximity to SMA-labeled structures. Thus, a non-sympathetic neural enous insulin secretion suppressed plasma ghrelin levels. We propose that relay may mediate the effects of Xen on islet function in humans. there exists inhibitory feedback between ghrelin and insulin. Supported by: Blum Kovler Foundation (5RC1DK086163); 1R01DK088126

2893-PO WITHDRAWN Obesity PUBLISHED ONLY Supported by: NSC (94-2314-B-010-031) Integrated Physiology/

2891-PO Enhanced Responses of Incretin Hormones to Oral Glucose Tolerance Test in Patients With Infl ammatory Bowel Diseases YOSHIYUKI HAMAMOTO, SACHIKO HONJO, YUKIKO KAWASAKI, KANTA FUJIM- OTO, HISATO TATSUOKA, KANAKO MORI, HIROKI IKEDA, YOSHIHARU WADA, HIROYUKI KOSHIYAMA, Osaka, Japan, Hyogo, Japan It is not known how the incretin hormones, namely, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are affected in patients with chronic infl ammatory bowel diseases (IBD) such as Crohn’s

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A733 INTEGRATED PHYSIOLOGY—OTHER HORMONES

2896-PO Enhanced Nicotine Self-Administration and Suppressed Dopamine Systems in a Rat Model of Diabetes LAURA E. O’DELL, LUIS A. NATIVIDAD, JOSEPH A. PIPKIN, JESUS JURADO, IVAN TORRES, THEODORE FRIEDMAN, JOHN TENAYUCA, ARBI NAZARIAN, El Paso, TX, Compton, CA, Pomona, CA It is unclear whether subjects with metabolic disorders are especially vul- nerable to tobacco use. To address this issue, the present study examined 2894-PO the reinforcing effects of nicotine in a rodent model of diabetes involving Postprandial Gallbladder Emptying in Patients With Type 2 Diabe- administration of streptozotocin (STZ), a drug that is toxic to pancreatic tes: Potential Implications for Thyroid Function and Glucose insulin-producing cells. The fi rst study compared STZ- and vehicle-treated rats Homeostasis that had 23-hour access to intravenous self-administration (IVSA) of nicotine DAVID P. SONNE, TINA VILSBØLL, FILIP K. KNOP, Hellerup, Denmark or saline and concomitant access to food and water delivery. The rewarding Bile acids are increasingly being recognized as metabolic regulators of effects of nicotine are largely modulated via dopamine transmission in the postprandial glucose homeostasis and energy expenditure. Preclinical studies nucleus accumbens (NAc). In order to examine the contribution of dopamine suggest that bile acids activate the enzyme type 2 iodothyronine deiodinase systems to nicotine, food and water intake, dopamine transporter (DAT), D1 (D2), which deiodinates thyroxine (T4) to the biologically active triiodothyro- and D2 receptor levels were compared in the NAc following 10 days of nico- nine (T3). We aimed to describe whether the degree of postprandial gallblad- tine or saline IVSA. A second study compared dopamine levels in the NAc of der emptying affects postprandial levels of T3/T4 and thyrotropic hormone STZ- and vehicle-treated rats following administration of nicotine and then (TSH) in patients with type 2 diabetes (T2D) and in healthy control subjects. amphetamine. STZ-treated rats displayed enhanced nicotine intake as well Fifteen patients with T2D (mean duration of T2D: 7.5 years (range: 6-20); as a robust increase in food and water intake relative to controls. Protein 2 age: 59.4±9.6 years (mean±SD); body mass index (BMI): 28.0±2.2 kg/m ; HbA1c: analysis revealed an increase in DAT and a decrease in D1 receptor levels in 7.5±1.4%) and 15 healthy age, gender and BMI-matched control subjects (age: the NAc of STZ- versus vehicle-treated rats regardless of IVSA condition. 2 59.7±10.0 years; BMI: 27.9±2.0 kg/m ; HbA1c: 5.2±0.2%) were studied on 4 STZ-treated rats also displayed suppressed NAc dopamine levels during base- separate days. 75g-OGTT and three isocaloric (500 kcal) and isovolemic (350 line and in response to nicotine and amphetamine administration. Our fi ndings ml) meals (I: 2.5 g fat, 107 g carbohydrate and 13 g protein; II: 10 g fat, 93 g suggest that STZ suppressed dopamine systems, which may have lead to carbohydrate, 11 g protein; III: 40 g fat, 32 g carbohydrate and 3 g protein). compensatory increases in nicotine intake. Our studies also suggest that Gallbladder emptying was determined by ultrasonography. strong reinforcing effects of nicotine may contribute to enhanced tobacco Gallbladder emptying increased with increasing meal fat content, but no use in patients with diabetes. intergroup differences were demonstrated. Levels of T3/T4 were similar in Supported by: 7-12-BS-135 the two groups and did not change after meal ingestion. Fasting TSH levels were signifi cantly lower in patients with T2D. In both groups plasma TSH 2897-PO decreased (equally) postprandially (P<0.05). As expected, postprandial glucose Combination Therapy With Liraglutide and Growth Hormone Delays excursions were exaggerated (P<0.008) and insulin and C-peptide levels were Type 2 Diabetes Onset and Preserves Islet Morphology in UCD-T2DM reduced (P<0.01) in patients with T2D vs. controls. Rats In conclusion, patients with T2D exhibited normal gallbladder emptying to BETHANY P. CUMMINGS, JAMES L. GRAHAM, LOTTE B. KNUDSEN, KIMBER L. meals with a wide range of fat content. Basal and postprandial TSH levels STANHOPE, KIRSTEN RAUN, PETER J. HAVEL, Davis, CA, Måløv, Denmark were within normal range, but lower in patients with T2D vs. controls. Of Due to the increasing prevalence of type 2 diabetes (T2DM), there is a need interest, both groups displayed signifi cant postprandial TSH suppression to identify strategies for T2DM prevention. We have previously shown that independently of the degree of gallbladder emptying. chronic administration of the glucagon like peptide-1 (GLP-1) analog, lira- glutide, delays the onset of T2DM in UCD-T2DM rats. We hypothesized that 2895-PO administration of liraglutide in combination with growth hormone would WITHDRAWN enhance liraglutide’s benefi cial effects by further protecting β-cell mass. At 2 months of age male UCD-T2DM rats were divided into fi ve groups: control (CON), restricted (RES), rat growth hormone (GH), liraglutide (LIR) and lira- glutide + growth hormone (LIR + GH) (n=16). CON, RES and LIR rats received liraglutide (0.2 mg/kg) or vehicle injections BID and GH and LIR + GH rats received growth hormone (0.3 mg/kg) injections once daily and vehicle or liralgutide BID for 4 months. RES rats were food restricted to match body weights to LIR + GH rats. Non-fasting blood glucose was measured weekly to determine diabetes onset (<200 mg/dl). Energy intake and body weight at 6 months were highest in GH and were signifi cantly lower in LIR and LIR + GH compared with CON (BW: CON= 633 ± 11, RES= 566 ± 10, GH= 660 ± 11, LIR=

Obesity 550 ± 12, LIR + GH= 578 ± 12 g; P<0.05). Energy expenditure was elevated by ~5% in LIR and LIR + GH compared with CON (P<0.01). By 6 months of age none of the LIR or LIR + GH and 5 CON, 5 GH and 1 RES rat had developed PUBLISHED ONLY Integrated Physiology/ diabetes. Thenumber of diabetes free days was signifi cantly greater in LIR and LIR + GH compared with CON and GH (P<0.05). During an OGTT, RES, LIR and LIR + GH exhibited lower glucose excursions compared with CON and GH (Glucose AUC: CON= 8842 ± 707, RES= 3832 ± 426, GH= 7770 ± 656, LIR= 100 ± 262, LIR + GH= 4741 ± 241 mg/dl × 120 min; P<0.01). LIR and LIR + GH exhibited an improvement of islet morphology as assessed by immunohis- tochemistry and an increase of pancreatic insulin content compared with CON (P<0.05). LIR and LIR + GH appear to delay diabetes onset by improving glucose tolerance and protecting β-cells. Supported by: Novo Nordisk A/S

For author disclosure information, see page 829. ADA-Funded Research

A734 INTEGRATED PHYSIOLOGY—OTHER HORMONES

2898-PO 2900-PO Diets Supplemented With Pisum Sativum Seed Coats Enhance Glu- WITHDRAWN cose Homeostasis Potentially by Modulating Glucose Handling in the Gut ZOHRE HASHEMI, CATHERINE B. CHAN, Edmonton, AB, Canada Consumption of whole pulses has been associated with enhanced long-term glycemic control in both animal and human subjects; however, results regard- ing the underlying mechanisms remain rather vague. Pisum sativum (pea plant) seed coats are rich sources of fi bre, which are discarded as a by-product during production of some foods. We hypothesized that supplementing rat diets with pea seed coats could improve glucose homeostasis mainly by modifying gut responses to glucose. We also assessed the effect of prepara- tion method of pea seed coat diets on glucose homeostasis. Twenty four male Sprague Dawley rats were fed a high fat diet (HFD, 20% w/w) for 6 weeks to induce insulin resistance, while n=8 were on normal rat chow (LFD). The HFD-fed rats were then randomly assigned to the following diets: HFD, raw-pea seed coat (RP) and cooked-pea seed coat (CP). Oral glucose tolerance test (OGTT), intraperitoneal glucose tolerance test (IPGTT) and insulin tolerance tests (ITT) were done, and plasma GLP-1 levels were mea- sured. The expression of hexose transporters in the jejunum was measured by quantitative real-time PCR. OGTT results showed that HFD induced glucose intolerance; CP improved the glycemic response compared to the HFD group at t=10 (p <0.001), t=20 (p <0.01) and t=30 (p <0.05). Although none of the pea seed groups had different IPGTT from the HFD group, LFD had improved response at t=20, 30 (p <0.01). Compared with HFD, plasma GLP-1 was higher in CP group (p <0.05); jejunal Glut-2 mRNA was increased in both RP and CP rats (p <0.01 & p <0.001 respectively). CP group also showed higher expression of Glut-5 and SGLT-1 (p <0.001 & p <0.01). Pisum sativum seed coats have benefi cial effects on glucose tolerance in diabetic rats only when they are cooked, and glucose is delivered orally. Increased plasma GLP-1 in the CP rats could play a role in this; however, further investigation is needed to have a more detailed picture of the gut mechanisms responding to pea seed coat.

2899-PO 2901-PO Lactate Is an Early Indicator of Insulin Resistance Serum Lactate Is Elevated in Children With High Fasting Blood Glu- FEVEN BERHANE, ALEMU FITE, NOUR DABOUL, ANTEER WISSAM, MICHAEL cose, HbA1c and HOMA-IR CARUSO, MONIQUE LEWIS, ZHENGPING YI, MICHAEL DIAMOND, ABDUL B. ABOU- ALEMU FITE, KIMBERLY CAMPBELL-VOYTAL, JOANNA MIRAGAYA, ABDUL B. SAMRA, BERHANE SEYOUM, Detroit, MI ABOU-SAMRA, BERHANE SEYOUM, Detroit, MI Insulin resistance (IR), which plays a central role in the pathogenesis of Insulin resistance plays a central role in the pathogenesis of Type 2 diabe- type 2 diabetes (T2D) is an early indicator that heralds the occurrence of T2D. tes (T2D) and its complications. Lactate has been shown to be elevated in It is imperative to have a simple way to diagnose IR in order to prevent or obese subjects and in patients with T2D and may predict the occurrence of reduce the occurrence of T2D. The objective of this study was to determine diabetes. The purpose of this study was to determine fasting serum lactate the pattern of circulating lactate levels during oral glucose tolerance test concentration among obese children and correlate it with markers of insulin (OGTT) and hyperinsulinemic euglycemic clamp (HIEC) and verify if could pre- resistance. dict insulin resistance. A total of 45 children (25 boys, 25 girls) 10 to 15 years of age, body weights Lactate and glycerol were determined every 30 minutes during OGTT and above 95th percentile were included in the study. Fasting serum lactate (FSL) HIEC for 22 participants. Of these 16 were males and 6 were females. The levels were determined using a commercially available colorimetric enzymatic mean age was 41+12.4 years and the average BMI was 27.8 + 4.8 kg/m2. All assay. The intra-assay and inter-assay variations were 6% and 15%, respec- participants were non-diabetic healthy subjects. tively. There was no change in circulating lactate levels from base line during the FSL concentration was found to correlate with fasting blood glucose (FBG), OGTT. However, those with HIEC M-values ≤4 had signifi cantly higher lactate serum insulin, HbA1c, and HOMA-IR. FBG levels were positively correlated levels during OGTT compared to those with M-values>4 (5.2+ 2.5mM vs 4.2+ with FSL (r =0.299, P=0.004). Children in the 4th quartile FBG had FSL levels 1.9mM, P<0.01). In addition, those with impaired glucose tolerance test (IGT) of 22.3±1.9 mM (mean ± SEM) that was signifi cantly (P < 0.001) higher than had signifi cantly higher mean lactate levels compared to those with normal those with lower FBG (14.4±0.7 mM lactate). The mean lactate levels for all glucose tolerance (NGT) (5.7+ 2.0mM vs 3.7+ 1.7mM, P<0.001). Lactate sig- children having lower than the mean HbA1c (mean = 5.3) was signifi cantly nifi cantly increased with time during the HIEC study (P<0.001) but there was lower than those above the mean HbA1c (14.2±0.7 mM versus 18.1±1.4 mM no correlation with M-values. Participants with BMI<30 had signifi cantly lactate; P=0.016). Comparing children with the lowest and the highest quartile higher mean M-values compared to those with BMI≥30 (9.7+ 4.3 vs 5.6+ 3.5, HOMA-IR (HOMA-IR < 2.5 and > 4.5), one-way analysis of variance showed

P<0.05). signifi cantly different FSL (P=0.021). Boys in the interquartile range had sig- Obesity In conclusion, we found that lactate increases during HIEC study, which is nifi cantly higher lactate levels than their female counter parts (mean±SEM; a state of hyperinsulinemia similar to the metabolic milieu seen during the 19.1±1.0 versus 13.4±1.2 mM, P=0.001). HOMA-IR correlated positively with PUBLISHED ONLY

early stages in the development of T2D. Lactate was also signifi cantly high lactate, HbA1c and triglycerids and negatively with HDL. Integrated Physiology/ among subjects with IGT compared to those with NGT suggesting that the In this study we have demonstrated that elevated lactate is associated increase in lactate is indicative of IR. This pilot data could indicate that lactate with HOMA-IR, which is an indirect measure of insulin resistance, HbA1c, FBG can be used to predict IR early on before the occurrence of T2D. and insulin. This suggests that serum lactate is a potential marker of insulin resistance in children.

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A735 INTEGRATED PHYSIOLOGY—OTHER HORMONES

2902-PO Hypothalamic Knockdown of Nesfatin-1/NUCB2 in Rat Augments Hepatic Gluconeogenesis Through Inhibition of mTOR-STAT3- SOCS3 Signal Pathway LING LI, ZHONGMIN A. MA, GANGYI YANG, Chongqing, China, Ann Arbor, MI Nesfatin-1 is a hypothalamic neuropeptide derived from nucleobindin2 (NUCB2) and characterized as a potent metabolic regulator. However, the signaling mechanisms directly associated with the action of nesfatin-1 have not been well characterized. To determine the role of hypothalamic nesfatin-1/ NUCB2 in regulating glucose homeostasis in vivo, we established a loss-of- function model of the hypothalamic nesfatin-1/NUCB2 signaling in rats by intracerebroventricular injection of Ad-shNUCB2, an adenovirus-mediated 2905-PO RNAi. Using this model, we showed that specifi c inhibition of hypothalamic Suppression of Pancreatitis Without Infl uence on Ductal Cell Prolif- nesfatin-1/NUCB2 expression signifi cantly increased hepatic glucose fl uxes eration in Spontaneously Diabetic Goto-Kakizaki Rats Treated With and decreased glucose uptake in peripheral tissues in both normal chow Dipeptidyl Peptidase-IV Inhibitor Vildagliptin diet- and high fat diet-fed rats. The change of hepatic glucose fl uxes in the KOHSUKE KAMATA, HIROKI MIZUKAMI, WATARU INABA, KENTARO TSUBOI, hypothalamic nesfatin-1/NUCB2 defi ciency rats was accompanied by signifi - SOROKU YAGIHASHI, Hirosaki, Aomori, Japan cantly increasing in the hepatic expression of glucose-6-phosphatase and The risk of side effects of dipeptidyl peptidase (DPP)-IV inhibitors on the phosphoenolpyruvate carboxykinase (PEPCK) and decreasing in the phospho- exocrine pancreas, particularly the high risk of pancreatitis, is controversial. rylation of Insulin receptor, IRS-1, and AKT in the liver. Furthermore, specifi c In this study, we examined the exocrine pancreatic function and structure in knockdown of hypothalamic nesfatin-1/NUCB2 in rats resulted in the reduced spontaneously diabetic Goto-Kakizaki (GK) rats treated with vildagliptin (VG). phosphorylation of mammalian target of rapamycin (mTOR), signal transducer Male GK rats (GK) and normal Wistar rats (W) 4 weeks of age were treated and activator of transcription 3 (STAT3), and subsequently diminished expres- with VG (15 mg/kg/day, twice a day) for 18 weeks. At end, serum amylase and sion of suppressor of cytokine signaling 3 (SOCS3) in the liver. Taken together, lipase were examined in addition to serum insulin, GLP-1 (activated form), and our results demonstrated that hypothalamic nesfatin-1/NUCB2 plays a central blood glucose evaluations. Subsequently, exocrine pancreatic pathology and integratory role in regulating hepatic glucose homeostasis through mTOR- function in treated animals were compared to those in untreated animals. STAT3-SOCS3 signal pathway. The presence of apoptosis and promoting effect of cell proliferation in treated animals were evaluated by TUNEL and Ki67 staining, respectively. While 2903-PO serum GLP-1 concentrations were reduced in GK, VG-treatment normalized WITHDRAWN the level. There was a signifi cant elevation of serum amylase and lipase in untreated GK. This was associated with increased frequencies of infl amma- tory foci around ducts, around vessels, and in acinar areas with acinar-ductal metaplasia. Apoptotic acinar cells were also more frequent in GK compared to W. VG-treatment suppressed elevated serum concentrations of amylase and lipase, reduced the number of infl ammatory foci and apoptotic acinar cells. Ki67 rate in ductal gland cells was 10% lower in GK compared to W, while its rate in the main duct, peripheral duct and acini was not different between GK and W. VG-treatment had no effect on the proliferation rate in these cells. No signifi cant infl uence was detected in VG-treated control W. Perturbation of exocrine pancreatic function and structure in GK was amelio- rated by long-term VG-treatment. There appears to be no signifi cant risk on the induction of abnormal proliferation of ductal cells or infl ammatory lesions in VG-treated animals. Supported by: Japan Pancreas Society Foundation

2906-PO Pectin Corrects the Diabetes in Zucker Diabetic Fatty Rats Without Increasing Postprandial GLP-1 YAPING J. LIU, JUDI MCNULTY, ANDREW A. YOUNG, LIHONG CHEN, Research Triangle Park, NC, Durham, NC Pectin, a dietary fi ber, has shown antidiabetic effi cacy in patients with type 2 diabetes mellitus and multiple potential mechanisms have been proposed. It was reported that pectin released GLP-1 and PYY in a perfused rat colon model. We therefore investigated the antidiabetic effi cacy of pectin in Zucker diabetic fatty (ZDF) rats and the role of GLP-1 as a potential mechanism. Eight-week old male ZDF rats were fed with regular chow (control) or regular chow mixed with 1%, 3%, or 6% (w/w) pectin. Blood glucose, insulin, lipids and HbA1c were monitored once a week for three weeks. At the end of the fourth week, a food challenge test was performed in overnight fasted animals. Blood glucose, insulin and GLP-1 were monitored for four hours post challenge.

Obesity In a separate study, effects of pectin, oligofructose and resistant starch were 2904-PO compared in ZDF rats using a similar study design. Compared to the control WITHDRAWN group, pectin dose dependently decreased blood glucose and HbA1c in ZDF PUBLISHED ONLY Integrated Physiology/ rats and attenuated the reduction of plasma insulin. In the food challenge test, pectin signifi cantly decreased the postprandial glucose excursion, and enhanced the insulin response. Pectin also reduced postprandial plasma GLP- 1, compared to the control group. While oligofructose and resistant starch increased postprandial plasma GLP-1 and PYY, neither decreased blood glu- cose and HbA1c. The antidiabetic effect of pectin in ZDF rats was associated with a signifi cant decrease in postprandial glucose excursion, but no increase in postprandial GLP-1. This contrasts with the effects of oligofructose and resistant starch.

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A736 OBESITY—ANIMAL

OBESITY—ANIMAL 2909-PO WITHDRAWN 2907-PO The Effect of All-Trans Retinoic Acid on the Progression of Type 2 Diabetes in db/db Mice SANA HASAN, FREDERICK G. HAMEL, RONDA SIMPSON, CYRUS V. DESOUZA, ROBERT G. BENNETT, Omaha, NE Retinoic acid is a vitamin A metabolite, whose effects are primarily medi- ated via its acid derivatives including all-trans Retinoic acid (ATRA) and 9-cis Retinoic acid (9cRA). Recent studies suggest a role for vitamin A in the treat- ment of obesity; however, its potential for the treatment of type 2 diabetes (T2DM) has not been assessed. We investigated the effect of ATRA on a progressive model of obesity-related T2DM, the leptin receptor mutant db/ db mouse. Three month old female db/db mice (10 per group) were treated with vehicle (corn oil) or ATRA at 600 ug/mouse, 5 days/week for 12 weeks by voluntary oral feeding. Body weight and random glucose levels were deter- mined weekly, and oral glucose tolerance test was performed at 6 and 12 weeks. Both groups had similar starting values for random blood glucose (264±18mg/dl control vs 246±20mg/dl ATRA) and body weight (46.5±0.5g control vs 46.1±1.5g ATRA). After 12 weeks of treatment, random glucose levels increased in control mice, but signifi cantly decreased with ATRA treat- ment (343±16mg/dL control vs 150±33mg/dL ATRA, p<.0001). Control mice gained 3.9±1.6g body weight, while ATRA-treated mice lost 10.0±1.9g, with a signifi cant difference at the end of the study (50.3±1.7g control vs 36.6±2.8g, p<.0005). While both values decreased steadily in the ATRA group throughout the study, random glucose levels were signifi cantly lower almost immediately (1 week of treatment), while body weight only reached statistical difference at 6 weeks. ATRA treatment caused signifi cantly lower fasting glucose levels at both week 6 (359±25mg/dL control vs 185±43mg/dL ATRA, p <.005) and at week 12 (342±36mg/dL control vs 127±29mg/dL ATRA, p <.0005). ATRA treat- ment also improved glucose tolerance as determined by OGTT at 6 weeks (AUC 43.4±3.9 control vs 28.7±5.8 ATRA, p=0.056), and a signifi cant improve- ment was reached at 12 weeks (43.4±3.9 control vs 18.4±4.6 ATRA, p<.001). Our results demonstrate the potential for ATRA in the treatment of T2DM and 2910-PO obesity. PPAR-Delta Attenuates Angiotensin II-Induced Adipocytes Dysfunc- tion in Obese Hypertensive Rats by a Novel Heme Oxygenase-1 Dependent Mechanism 2908-PO ZEID KHITAN, TARIQ REHMAN, LARRY DIAL, JOSEPH SHAPIRO, Huntington, WV Proteomic Analysis of Circulating Microparticles from db/db Diabetic Angiotensin II induces adipocytes dysfunction and hypertrophy by increas- Mice ing oxidative stress. This can lead to a number of metabolic derangements XIANG XIAO, SHUZHEN CHEN, WILLIAM C. GRUNWALD, JR., CHENG ZHANG, including obesity and metabolic syndrome. Recently, PPARδ agonist was found JINJU WANG, DAVID R. COOL, YANFANG CHEN, JI CHEN, Dayton, OH to attenuate Angiotensin II induced oxidative stress. This study will explore Type-2 diabetes is a well known risk factor for vascular diseases. Our pre- a mechanistic link between PPARδ and the heme oxygenase system. In this vious study showed that preincubation with circulating microparticles (MPs) study the Goldblatt 2K1C rats was used and divided into four groups, Sham from db/db diabetic mice induces dysfunction to endothelial progenitor cells operated animal, 2K1C Rats, 2K1C Rats treated with GW(501516), a PPARδ and cerebrovascular endothelial cells and endothelial progenitor cells. This agonist in the absence and presence of the HO1 activity inhibitor SnMP. Infl am- study was designed to investigate the underlying mechanism by analyzing matory cytokines, circulatory levels or expression of AII, Renin, gp9, Wnt10b, the protein profi le of MPs from the circulation of db/db mice. Adult (9-12 weeks) β-Catenin, Wnt5b and levels of Mest and C/EBPα were studied in each group. male db/db and their age-matched control (db/+) mice were used for the study. To establish effect of PPARδ on HO1 gene, we assessed luciferase activity Circulating MPs were isolated from the plasma of db/db and db/+ mice by after transfection of COS-7 cells with a luciferase-HO1 promoter construct. centrifuge method. The proteins were extracted from MPs with lysis buffer We found that the 2K1C animal had increased visceral adiposity, adipocte (Roche Diagnostic) with protease inhibitor. The resulted proteins were ana- hypertrophy compared with Sham operated Rats. Infl ammatory cytokines lyzed by Mass spectrum (Bruker Autofl ex III MALDI TOF/TOF). Results showed including IL-6, MCP-1 along with circulatory and adipose tissue levels of AII (Figure 1): 1) Over spectral 360-820 m/z, MPs from db/+ mice contained two and Renin and expression of gp91 phox were increased when compared to unique protein peaks at 390.4 and 810.9, while MPs from db/db diabetic mice Sham operated animals. Treatment with GW(501516) resulted in increased had specifi c peaks at 786.8, 791.8 and 818.8; 2) Database search found that adipose tissue Adiponectin levels and enhanced expression of Wnt10b and claudin 8, Anthrax toxin receptor-1, Dentin matrix marker 8, hemopexin pro- β-Catenin. On the other hand, treatment with GW(501516) resulted in teins were indentifi ed in the circulating MPs from db/db mice, but not detected decreased expression of Wnt5b and levels of Mest and C/EBPα along with in circulating MPs from db/+ mice. In conclusion, different protein profi le in increased number of small adipocytes (P<0.05). These effects were reversed the circulating MPs of diabetic mice could have an implication in the different in the the 2K1C animal exposed to SnMP (P<0.05). Finally, we demonstrated functions of MPs in diabetes. increased luciferase activity in COS-7 cells transfected with luciferase HO1 Obesity promoter construct. Our study demonstrated that PPARδ attenuates the del- eterious effects of AII on adipocytes via upregulation of the HO1 system PUBLISHED ONLY gene. Integrated Physiology/

Supported by: NIH (HL-098637); AHA (13POST14780018)

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A737 OBESITY—ANIMAL

2911-PO differences in NPY mRNA expression between the groups, and no c-fos acti- vation in the ARC. These data show that a combination of nutrients in the WITHDRAWN brain alters peripheral glucose metabolism differently than the separate nutrients and these effects are mediated outside the ARC. Supported by: ZonMW

2913-PO Fasting Gut Hormone Levels after Roux-en-Y Gastric Bypass in a Diet- Induced Rodent Model of Obesity RAYMOND G. LAU, COLLIN E. BRATHWAITE, DREW RIDEOUT, LOUIS RAGOLIA, Mineola, NY, Atlanta, GA Remission of type 2 diabetes has been observed in nearly 80% of those who undergo gastric bypass surgery. Several mechanisms have been proposed to mediate this metabolic improvement including weight loss, increased insu- lin sensitivity, and altered gut hormone levels such as glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). Increased fasting GLP-1 levels have been reported and may contribute to the improve- ment of glucose control in obese rodents. Seven obese Sprague Dawley rodents on a high fat diet underwent the Roux-en-Y Gastric Bypass (RYGB) surgery and four diet-induced obese rodents underwent sham surgery. Fast- ing glucose, insulin, GLP-1, and GIP were measured prior to surgery, and 4 weeks, and 10 weeks post-surgery. Additional tissue biopsies of liver, adipose, and skeletal muscle were obtained at the time of surgery and at 10 weeks post-surgery. RYGB rodents lost as much as 12% of their pre-operative body weight after surgery, while sham rodents gained an additional 8%. Fasting insulin levels decreased from 2.09 +/- 0.33 ng/dL pre-operatively to 1.26 +/- 0.40 ng/dL post-operatively. Similarly fasting glucose levels decreased nearly 50 mg/dL as compared to pre-operatively. HOMA-IR (Homeostasis Model Assessment of Insulin Resistance) also decreased after RYGB. Fasting total GLP-1 levels increased from 15.3 +/- 2.9 pM prior to surgery, to 4 weeks 49.0 +/- 0.42 pM, and 10 weeks 118.3+/- 17.2 pM. Fasting total GIP levels similarly increased from 171.2 +/- 17.2 pM prior to surgery, to 4 weeks 177 +/- 36.1 pM, and 10 weeks 257.2 +/- 68pM. We conclude that the potential improvement of glucose metabolism following RYGB in rodents is partially attributed to increased fasting gut hormones.

2914-PO Alteration of Sweet Taste in Dietary Obese Rats Following 4 Weeks Treatment of Exendin-4 (Exenatide) XIAO JUAN ZHANG, YU QING WANG, YANG LONG, LEI WANG, YUN LI, FA BAO GAO, HAO MING TIAN, Chengdu, China Exendin-4 (Exenatide) is effective on inducing weight loss, the exact mechanisms are not fully understood. Reduced appetite and food intake may play a role. Since sweet taste contributes to food palatability, which promotes intake, we are wondering whether this specifi c taste will change after treat- ment of exenatide. Twenty four male Wistar rats (180-200g) were randomly divided into high caloric diet (HC, n=16) and normal chow (NC, n=8) fed groups. 2912-PO Four months later, 8 HC rats were treated with exenatide (EX, 3ug/kg, bid) Concomitant Intracarotid Infusion of a Soybean Oil Emulsion and while the other 8 received no intervention (HC-N). Body weight and food intake Glucose towards the Brain Alters Glucose Metabolism Without were measured every week. After 4 weeks, all rats were investigated about Changes in Neuropeptide Y Expression their brain responses to 0.5M sucrose stimulation by fMRI. Two bottle prefer- MEREL RIJNSBURGER, CELINE CRUCIANI-GUGLIELMACCI, JULIEN CASTEL, ence test of sweet taste was conducted before and after the intervention. CHRISTOPHE MAGNAN, ERIC FLIERS, ANDRIES KALSBEEK, MIREILLE J. SERLIE, The results demonstrated that preference for sweet taste was increased in SERGE LUQUET, SUSANNE E. LA FLEUR, Amsterdam, Netherlands, Paris, France HC rats. After 4 weeks treatment of exenatide, EX rats experienced smaller Different nutrients are known to specifi cally alter glucose metabolism. body weight gain and lesser food intake when compared with HC-N rats. When saturated fat and a sugar solution are consumed in addition to chow, Besides, the preference for sweet taste was decreased. fMRI study showed rats become hyperphagic and insulin resistant. This is accompanied by an stronger brain activity of HC-N rats to sweet taste in insular, primary soma- increase in Neuropeptide Y (NPY) in the arcuate nucleus (ARC) of the hypo- tosensory cortex and caudate putamen (striatum) when compared with NC thalamus, a nucleus important for regulating glucose metabolism. In addition rats. However, these stronger activities were not observed in EX rats. In Obesity it has been shown that intracerebroventricular (icv) infusion of oleic acid summary, our study suggests that exenatide may have effects on sweet taste reduces hepatic glucose production, and a bolus of oleic acid injected icv preference and central taste processing, which may benefi t obesity.

PUBLISHED ONLY decreases NPY mRNA. We hypothesized that fat and sugar alone, or a com- Integrated Physiology/ bination of both would differentially affect glucose metabolism through a direct action onto hypothalamic ARC neurons. We used an intracarotid cath- eter directed towards the brain to mimick the physiological route by which nutrients enter the brain. Male rats were fasted overnight and infused either with either a soybean emulsion (Intralipid 20% (IL)), glucose (G, 1%), IL+G or saline (5 µl/min) for 2 hours. Blood glucose was measured throughout the experiment and animals were decapitated 30 minutes after the end of the infusion. All infusions were associated with a decrease in plasma glucose after 1hr except the combination of IL+G that selectively prevented the decrease in glycemia (IL+G vs IL (P < 0.01)). In situ hybridization showed no

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A738 OBESITY—ANIMAL

2917-PO Pulmonary Irradiation Induces Weight Gain and Obesity in C57BL/6 Mice STEVEN B. ZHANG, SHANMIN YANG, ZHENHUAN ZHANG, DAVID MAGUIRE, AMY ZHANG, MEI ZHANG, WENLONG LV, LUQIANG HUANG, LIANGJIE YIN, STEVE SWARTS, SADASIVAN VIDYASAGAR, LURONG ZHANG, PAUL OKUNIEFF, Gaines- ville, FL According to the WHO, “worldwide obesity has more than doubled since Supported by: 2011SCU11055 1980.” Although animal models have been developed to combat this escalat- ing problem, they have met with modest success; indeed, the exact mechanism and specifi c infl uences of weight gain and obesity remain unclear. Recently, 2915-PO we found that pulmonary irradiation (PIR) resulted in region-, dose-, and time- dependent weight gains and obesity in C57BL/6 female mice. Our studies in The Kinetics of Insulin Resistance and β-Cell Mass Expansion in mice exposed to PIR showed that: (1) body weight (BW) increased signifi cantly Response to Diet-Induced Obesity at 6 and 12 months after irradiation; however, no signifi cant change in BW ROCKANN E. MOSSER, MATTHEW F. MAULIS, JENNIFER C. DUNN, MAUREEN was observed after total body or sub-total body irradiation; (2) not all irradiated A. GANNON, Nashville, TN mice exhibited weight gain, thus indicating that the increase in BW was Diabetes is a disease of the pancreatic cell, whereby insuffi cient cell β β dependent upon each individual’s physiological response to radiation; (3) as mass leads to inadequate amounts of insulin resulting in elevated blood compared to the control group, the PIR group experienced a signifi cant increase glucose levels. Treatments vary among the different types of diabetes; in BW with an increase in age (e.g., at 12 months, 80.1%, 62.4%, and 44.2% however, increasing cell mass would benefi t all types of the disease. β β of irradiated mice experienced a >30%, 40%, and 50% increase in BW, respec- cell mass expands in response to insulin resistant states such as obesity tively, as compared to control mice); (4) abdominal visceral fat storage and pregnancy. Expansion of cell mass occurs through proliferation, neo- β increased signifi cantly (similar to obesity induced by a high-fat diet); no sig- genisis, and hypertrophy; though proliferation is the primary mechanism for nifi cant difference was found in other organs; (5) mitochondrial DNA copy expansion in the adult. Expansion of cell mass in response to diet-induced β number was signifi cantly decreased in hepatic and cardiac tissues, whereas obesity occurs in rodents and humans; however, this cell mass expansion β deletions of the mitochondrial DNA 3,860 sequence were signifi cantly has only been studied after long-term exposure to high fat diet. Our goal is increased in hepatic and cardiac tissues; (6) the gene message level of CPT1, to better defi ne the kinetics of insulin resistance, cell dysfunction, and β β which plays a key role in fatty acid metabolism, was signifi cantly decreased cell mass expansion in response to high fat diet (HFD) feeding. To address in the liver; and (7) insulin receptor substrate 2, which contributes to lipid this, we placed 8-week old male C57Bl/6J mice on HFD for 1, 3, 5, 7, 9, and metabolism and ERK signaling, was signifi cantly decreased at the mRNA and 11 weeks and determined their glucose tolerance, insulin secretion in protein levels in the liver. Collectively, these results suggest that PIR-induced response to glucose, insulin tolerance, cell mass, and cell proliferation β β weight gains in mice are dependent upon individual physiological responses at each time point. HFD-fed mice showed impaired glucose tolerance one and independent of other models such as a high-fat diet. These fi ndings pro- week after starting the diet. Interestingly, HFD-fed mice showed improved vide a novel model to study factors that result in obesity. insulin sensitivity in the 1st through 5th weeks. However, this improvement in insulin sensitivity diminished after week 5 and HFD-fed mice became markedly insulin insensitive after week 9. Our results suggest impaired β 2918-PO cell function early in the absence of insulin resistance, providing an interest- Down-Regulation of miR-223 in the Bone Marrow during Obesity- ing insight into the progression of type 2 diabetes. Induced Type II Diabetes Disrupts Bone Marrow Niche Supported by: U.S. Dept. of Veterans Affairs VIHITABEN S. PATEL, MEILIN CHAN, CLINTON RUBIN, Stony Brook, NY Obesity-induced type II diabetes (T2D) has been shown to degrade bone 2916-PO health [1]. However, the mechanism for this process is unknown. In addition, T2D is associated with increased chronic infl ammation of adipose tissue WITHDRAWN through infi ltration of immune cells [2] and overexpression of microRNA miR-223 in the adipose tissue [3]. Hence, we hypothesize that the changes in microRNA miR-223 in the bone marrow, which is a source of immune cells, can potentially disrupt the bone marrow niche and eventually the bone quality. Twenty, 5 weeks old, male C57BL/6 mice were separated in 2 groups, regular diet (RD, n=9) and high fat diet (HF, n=7). While RD mice were fed

on normal diet (10kcal% fat), HF mice were fed on high fat diet (45kcal% Obesity fat) for 8 weeks. At the end of the experiment, while the glucose intolerance, a typical characteristic of T2D, of HF increased by +15% (p=0.009) compared PUBLISHED ONLY to RD, the expression of miR-223 in the bone marrow of HF decreased by Integrated Physiology/ -29.5% (p=0.008) in comparison to RD (Fig 1). Since miR-223 has been shown to reduce formation of pro-infl ammatory macrophages [3], we conclude that the down-regulation of miR-223 in the bone marrow disrupts the bone mar- row niche. Further studies may help reveal the role of miRNA in bone deg- radation. 1.Chan, M E, et al., The FASEB Journal, 2012, 26: 1-9. 2.Surmi, B., and Hasty, A., Future Lipidol, 2008, 3: 545-556. 3.Zhuang, G., et al., Circulation, 2012, 125(23): 2892-2903.

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A739 OBESITY—ANIMAL

2921-PO Toll-Like Receptor 4 Is Not in Integral to Stimulate Cathepsin L by Palmitate in Adipocytes JEONG SEON YOO, SUN OK SONG, JI SUN NAM, TAE-WOONG NOH, SHINAE KANG, JOO YOUNG NAM, JONG SUK PARK, CHUL SIK KIM, CHUL WOO AHN, YOUNG DUK SONG, KYUNG RAE KIM, Goyang, Republic of Korea, Seoul, Republic of Korea, Anyang-si, Republic of Korea It has been reported that elevated concentration of palmitate leads to activa- tion of toll-like receptor 4 and stimulates cathepsin L not in adipocytes but in Supported by: EB14351, AR49438 macrophages. Therefore we tested that palmitate can stimulate cathepsin L in adipocytes without any infl uence of macrophages via toll-like receptor 4. Six-week-old C3H/HeJ mice which have missense mutation of toll-like 2919-PO receptor 4 were fed on high fat diet for 12 weeks and sacrifi ced to obtain (-)-Epigallocatechin-3-Gallate Attenuates Adipose Tissue Infl amma- epididymal fat. 3T3-L1 cells were fully differentiated to mature adipocytes tion Possibly Through TLR4 Signaling Pathway in High-Fat-Diet for 8 days and harvested after treatment with palmitate and bacterial lipopoly- Rats saccharide which is the ligand of toll-like receptor 4. Real-time PCR revealed YANLI CAO, SUQING BAO, ZHONGYAN SHAN, WEIPING TENG, Shenyang, China that cathepsin L mRNA expression increased in epididymal fat of mice who Background: Infl ammation plays a signifi cant role in metabolic regulation and fed with high fat diet, compared with chow diet. Bacterial lipopolysaccharide mounting evidence highlight the contribution of adipose tissue to systemic and palmitate stimulated cathepsin L mRNA transcription in 3T3-L1 by dose- infl ammatory state. The major green tea polyphenol, (-)-Epigallocatechin-3- and time-dependent manner, and RAW264.7 macrophages didn’t infl uenced gallate (EGCG) has been found to exert systemic anti-infl ammatory actions, cathepsin L mRNA expression level in 3T3-L1. however the anti-infl ammatory actions of EGCG on adipose tissue remain to be These result showed that palmitate stimulates cathepsin L transcription determined. In the present study, we investigated whether EGCG has anti- in adipocytes without macrophages but toll-like receptor 4 is not integral in infl ammatory effects on adipose tissue in high-fat-diet rats. Methods: Sprague- this pathway. Dawley rats were fed with high-fat-diet (HFD , n=20, 40% energy as fat) or standard rat diet (SD, n=10, 10% energy as fat) for 16 weeks. Then HFD group divided into two groups, supplementation with dietary EGCG treatment (n=10, 2922-PO EGCG 3.2 g/kg diet) and HFD group (n=10) for 16 weeks. Metabolic parameters Background Data on Fatty Zucker Diabetic (ZDF) Rat Model for Struc- in serum were evaluated, and western blot analysis in adipose tissue were ture Function Studies completed. Results: Following treatment with EGCG for 16 weeks, a decrease ANNICK PREFONTAINE, CHRISTINE COPEMAN, FLORENCE POITOUT, LUC HUARD, in body weight gain in obese rats (P < 0.01) were observed compared to controls. Senneville, QC, Canada EGCG treatment decreased FFA content (P < 0.01) compared to high-fat-fed The Food and Drug Administration have requested conduct of additional struc- control. In adipose tissue, EGCG attenuated Toll-like receptor 4 (TLR4) protein ture function studies in insulin-resistant rodent model of Type II diabetes for some expression (P < 0.05). EGCG also reduced IKK- β, NF-kappaB (P < 0.05) regulated compounds aimed to treat this disease. The male Zucker Diabetic Fatty (ZDF) rat adipose tissue infl ammation transcriptional activity. Adipose tissue infl amma- has proven to be an appropriate model for these studies as when provided with tion cytokines, including TNF-α and IL-6, also decreased with EGCG treatment. a standard rodent diet, this strain of male rats typically starts to develop hyper- Conclusion: EGCG may improve adipose tissue infl ammation possibly through glycemia and hyperlipidemia by 8 weeks (wks) of age and Type II diabetes by TLR4 signaling pathway in HFD rats. These fi ndings could be of relevance in the 12wks of age. Background data, specifi c husbandry/handling procedures and dietary management of obesity and obesity related diseases. assessment for this strain plays an important role in the overall interpretation of Supported by: NSFC (81000327) these studies. Consequently, compilation of background data of control animals (body weight, food consumption (FC), clinical chemistry parameters along with the details of the specifi c handling and veterinary care procedures) were compiled. From 7 to 15wks of age, ZDF rats gain weight rapidly and have increased FC. By 2920-PO 15wks of age, ZDF rats maintain their weight and food consumption. Glucose, WITHDRAWN glycated hemoglobin (HbA1c) and insulin levels are elevated by 12wks and glucose and HbA1c continue to increase as compared to insulin levels that are maintained up to 21wks. Specifi c husbandry/veterinary care was performed for alleviating the increased incidence of discharge, swelling and redness of the prepuce which can lead to infections/complications. Restraint procedures were adapted for blood collection procedure given their different physical proportions (short limbs and increase fat deposit). Specifi c histopathology and immunohistopahtology assessments of the pancreas are also performed to assess pancreatic structural effects. Based on this background data and modifi ed handling/veterinary care, the male ZDF rat is considered a suitable candidate with reliable background data for the conduct of regulatory compliant studies with minimal experimental procedure-related interference to assess the potential pancreatic structure/ function impact of diabetic compounds.

2923-PO Synergistic Effect of Curcumin and Alpha-Lipoic Acid on Energy Expenditure and Glucose Tolerance in High-Fat Diet-Fed Mice

Obesity EVGENIY PANZHINSKIY, SIDNEY REN, DEBASIS BAGCHI, XIHUI XU, JUN REN, SREEJAYAN NAIR, Laramie, WY, Houston, TX The natural compounds curcumin (CUR) and alpha-lipoic acid (ALA) have been PUBLISHED ONLY Integrated Physiology/ credited with anti-diabetic properties although the possibility of simultaneous use of two agents has not been explored. The purpose of this study was to evaluate the synergistic effects of CUR and ALA on metabolic parameters, ambu- latory activity and glucose tolerance in mice fed a high-fat diet (HFD). C57BL/6J mice were administered a high fat diet (HFD) or normal diet (ND) containing 10% fat for 7 weeks following which they were randomly assigned to diet containing CUR, ALA or ALA+CUR® for 10 weeks. Metabolic parameters, ambulatory activ- ity and glucose tolerance, were evaluated using indirect open-circuit calorimetry, infrared measurements and intraperitoneal glucose tolerance test (IPGTT) respectively. Mice that received HFD showed lower oxygen consumption (VO2, mL/kg/h) compared to those that received a ND (3475±95 vs 4069±119 mL/kg/h),

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A740 OBESITY—HUMAN which was reconciled by ALA+CUR (4781±212 mL/kg/h). In contrast the lower 2925-PO respiratory exchange ratio (RER= V /V ) in the HFD-fed mice compared to the CO2 02 WITHDRAWN ND-fed mice (0.736±0.017 vs 0.954±0.031) was unaltered by ALA, CUR or ALA+CUR (0.725±0.008, 0.763±0.028 and 0.778±0.005 respectively). High-fat feeding resulted in decreased energy expenditure (EE= [[3.815+1.232 x RER]VO2]/ kg) (16.4±0.4 vs 20.1±0.6 in ND group), which was reversed by ALA+CUR (22.8±1.0). Neither diet nor the test agents had any effect on the ambulatory activity of the mice, either under dark or light conditions. Furthermore, IPGTT revealed signifi cant glucose intolerance in the mice receiving HFD, which was reversed by ALA+CUR. In contrast, ALA or CUR alone had marginal effects on HFD-induced glucose intolerance. Collectively, our data indicate that ALA and CUR act via distinct mechanisms to exhibit synergism in augmenting energy expenditure and improv- ing glucose disposal under obese conditions. Supported by: NIH (P20-RR-016474)

OBESITY—HUMAN 2924-PO WITHDRAWN

2926-PO Medication Adherence among Adults With Type 2 Diabetes Mellitus who Lost vs. Gained Weight SUSAN GRANDY, KATHLEEN M. FOX, ELISE HARDY, SHIELD STUDY GROUP, Wilm- ington, DE, Monkton, MD Certain diabetes medications lead to weight gain, whereas others are weight neutral or lead to weight loss. This study investigated whether adults with type 2 diabetes mellitus (T2DM) who lost weight had better medication adherence than those who gained weight, and examined the infl uence of medication regimen on this association. Weight change over 1 year (2007 to 2008) was assessed among respondents in the US Study to Help Improve Early evaluation and management of risk factors Leading to Diabetes (SHIELD). Weight loss of >1.0%, ≥3%, and ≥5% of body weight was compared with weight gain of ≥1.0%. Medication adherence was assessed using the Morisky 4-item questionnaire that evaluates medica- tion-taking behavior, with lower scores representing better adherence. There were 746 T2DM respondents who lost >1.0%, 483 who lost ≥3%, 310 who lost ≥5%, and 670 who gained ≥1.0% of body weight. Each weight-loss group had signifi cantly lower Morisky scores (better adherence) than the weight-gain group -- mean scores of 0.389 vs. 0.473 (p = 0.050) for >1.0% weight-loss group, 0.365 vs. 0.473 (p = 0.026) for ≥3% weight-loss group, and 0.334 vs. 0.473 (p = 0.014) for ≥5% weight-loss group. Signifi cantly fewer respondents who lost weight had received insulin, SU, or TZD therapy (72%) compared with respondents who gained weight (81%, p < 0.01). Other factors did not explain the association between weight loss and better medication adherence, as the T2DM weight-loss respondents were similar to the weight-

gain group in age, gender, race, Hispanic ethnicity, education, household Obesity composition, exercise habits, and dieting. T2DM respondents with weight loss had signifi cantly better medication adherence and were less likely to be PUBLISHED ONLY

on treatment regimens that increase weight than T2DM respondents with Integrated Physiology/ weight gain. These fi ndings suggest that strategies that include antihyperg- lycemic medicines which also result in weight loss may be associated with better medication adherence.

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A741 OBESITY—HUMAN

2927-PO 2929-PO WITHDRAWN Translating the Diabetes Prevention Program into Worksites for Native Hawaiians and Pacifi c Peoples: The PILI@Work Project JOSEPH K. KAHOLOKULA, REBECCA WILSON, CLAIRE M. TOWNSEND, KATHRYN BRAUN, MARJORIE L. MAU, GUANGXIANG ZHANG, DONNA-MARIE PALAKIKO, DIANE PALOMA, ROBIN MIYAMOTO, IRIS KAUKA, DESIREE PUHI, MOMI AKANA, JAMEE MILLER, PILI@WORK PROJECT, Honolulu, HI, Kaunakakai, HI, Kailua, HI The overweight/obesity (BMI ≥ 25) prevalence for Native Hawaiians and Pacifi c Peoples (NHPP; e.g., Samoans, Filipinos) exceeds 75%, rendering them at greater risk for diabetes than other ethnic groups. Effective obesity inter- ventions are needed for NHPP, and worksites offer a promising venue. The Diabetes Prevention Program’s Lifestyle Intervention (DPP-LI) was adapted for NHPP. It was further adapted to a 3-month intervention to initiate weight loss delivered in the worksite setting as part of a 12-month weight loss main- tenance intervention called, the PILI@Work Program. We examined the adapted DPP-LI’s effects on weight (kg) loss, blood pressure, physical function- ing (6 min. walk test), fat intake, and exercise and the socio-demographic (ethnicity, age, sex, education, marital status), clinical, and behavioral cor- relates of initial weight loss in NHPP. Employees (n=149; 65% NHPP) from 9 Native Hawaiian-serving organizations participated. The adapted DPP-LI was delivered in groups of 8-12 people by a peer educator at the worksite. At baseline, mean BMI=32.9 7.1, mean weight = 86.5kg 21.4, and mean age = 44.4 12.1, and majority were female (84%), college graduates (62%), and mar- ried (58%). From baseline to 3-month follow-up, weight [t(149) = 5.3, p < .01; -1.2kg 2.7], systolic blood [t(148) = 2.6, p = .01; -2.5mmHg 11.7] and diastolic [t(148) = 3.2, p = .01; -2.1mmHg 7.7] blood pressure, 6 min walk test [t(142) = -4.8, p < .01; 59.9ft 154.2], exercise intensity [t(148) = 6.4, p < .01], and fat in daily diet [t(148) = 7.3, p < .01] signifi cantly improved. Only the 6-min. walk test was correlated with weight loss (r = .18, p < .05). No weight loss difference between NHPP and non-NHPP (i.e., Asians and whites). The worksite adapted DPP-LI shows promise in reducing the burden of obesity in NHPP and other native and Pacifi c populations in the U.S. In addition to weight loss, it led to improvements in blood pressure, physical functioning, and diet and exercise habits. Supported by: NIH; National Cancer Institute (1U54CA153459)

2930-PO A Comparison of the Miffl in-St Jeor and Cunningham Equations for Estimating Resting Metabolic Rates in Overweight and Obese Patients TRAVIS COMBEST, MICHELLE MARDOCK, ROBERT GOLDBERG, ASHA JAIN, JAME- SON TADE, LAURA NEWMAN, ANNE ANDREWS, Bethesda, MD Two methods for estimating resting metabolic rate (RMR) were compared in a clinic setting. Resting Metabolic Rate (RMR) is an estimate of how many calories the body burns at rest and has been used to determine energy intake requirements for weight loss in weight management programs. The Miffl in-St Jeor (MSJ) equation is frequently used as the standard for calculating RMR due to its 2928-PO documented accuracy. Recently, body composition equipment has been devel- The Effect of Body Mass Index on the Incidence of Acute Heart Failure oped that estimates RMR using lean body mass as a component of the Cun- in Japanese Type 2 Diabetes Patients With Chronic Heart Failure ningham (CU) equation. To our knowledge this is the fi rst study comparing MAYU TOCHIYA, HISASHI MAKINO, OHATA YOKO, TAMIKO TAMANAHA, AYA Direct Segmental Eight Point Bioelectrical Impedance (DSM-BIA) with the CU TANAKA, RYO KOEZUKA, ICHIRO KISHIMOTO, Suita, Japan equation to MSJ. Epidemiological studies suggest that even mild obesity is associated with Twenty one subjects aged 52.8 ± 7.8 years old with a BMI of 33.3 ± 5.1 and an increased risk of heart failure (HF), whereas, in patients with chronic HF, Body Fat% of 39.1% ± 7.6 were enrolled in a weight loss study at Walter Reed increased body mass index (BMI) is paradoxically associated with a survival National Military Medical Center in Bethesda, MD. MSJ and the CU equation benefi t. Yet, little is known about the impact of BMI on the HF event in patients derived RMR were compared in this population. with diabetes. In the present study, we have examined the association There was good agreement between the methods (ICC=0.92, p<0.001).The between baseline BMI and a risk of hospitalization for HF in asymptomatic estimated MSJ RMR was higher than CU RMR in 19% (n=4) of subjects with type 2 diabetes patients with high B-type natriuretic peptide levels a range of 10.72-12.72%. The error between MSJ and the CU equation was

Obesity (< 18.4pg/ml) or low LV systolic function (ejection function < 60%) at a mean >10% when the bodyfat was >50%. follow-up of 5.6 years. Among all eligible 858 subjects (mean age, 67.2 years; The MSJ and DSM-BIA with CU equations were well correlated and may 67.8% men; HbA1c 8.6%; mean BMI, 25.1), 138 patients were hospitalized for be useful in the clinical setting for weight loss management. The practical PUBLISHED ONLY

Integrated Physiology/ acute decompensated HF during follow-up. When the study population was advantage of using DSM-BIA with CU over MSJ is that lean muscle mass is categorized to three groups according to baseline BMI with the clinical cutoff considered the most important body compartment for determining RMR. points (i.e. 22 and 25), Kaplan-Meier estimation indicates that the patients in Disclaimer: The views expressed in this presentation are those of the author the lowest BMI group (less than 22) displays a signifi cantly increased risk of and do not refl ect the offi cial policy of the Department of Defense or U.S. future HF hospitalization compared to the middle (from 22 to 25) or the high- Government. est (equal to or higher than 25) group (p=0.0068; log-rank test). Multivariable Cox regression analysis shows that BMI less than 22 is a risk factor for future HF hospitalization after adjustments for age, gender, hypertension, smoking, and cardiac function parameters at baseline (p=0.05). It is, therefore, sug- gested that, in type 2 diabetes with chronic HF, BMI less than 22 is an inde- pendent risk marker for acute HF.

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A742 OBESITY—HUMAN

2931-PO 2 diabetes (T2DM) after Roux-en-Y gastric bypass (RYGB). We investigated The Resolution of Diabetes after Bariatric Surgery among Predomi- whether OC and ucOC affected HOMA-DI in obese persons before and nantly African American Patients 6-months after RYGB. The homeostasis model of assessment (HOMA) was MEREB ARAIA, MICHAEL H. WOOD, ABDUL B. ABOU-SAMRA, BERHANE SEYOUM, used to estimate insulin resistance (HOMA-IR), insulin sensitivity (HOMA-%S), Detroit, MI and β-cell function (HOMA-%β) with HOMA-DI calculated as β-cell function The purpose of this study is to assess the relative effi cacy in diabetes x insulin sensitivity/100. Subjects (n=32, 91% women, 25% T2DM) were aged remission among patients who have undergone the three different types of 38±11 (mean±SD) yrs with BMI 50±10 kg/m2 at baseline. After weight loss, bariatric surgical procedures. The surgical procedures that were performed OC, ucOC, and HOMA-DI (64±25 vs.109±28) increased while BMI and HOMA- included, laparoscopic sleeve gastrectomy, roux-en-y gastric bypass, and IR decreased (all p<0.001). Delta HOMA-DI with weight loss was similar for adjustable gastric banding. those with or without a history of T2DM (44±33 vs.45±29, p=0.93); however, A total of 597 obese patients underwent one of the three bariatric surgical the increase in OC and ucOC was greater (p<0.05) for those with a history. procedures at Harper University Hospital, Detroit, Michigan from 2008 to Correlations are shown in Table 1. In linear regression with delta HOMA-DI 2011. The type of surgery was determined by patient’s choice. Of the three as the dependent variable and delta BMI, OC or ucOC as independent variables, bariatric surgical procedures 203 (34%) patients had laparoscopic sleeve only reduction in BMI (p<0.01) was associated with improved glucose dispo- gastrectomy, 264 (44.2%) patients had laparoscopic gastric bypass and 130 sition (R2=0.31, p<0.01). Contrary to animal models, OC and ucOC appear to (21.8%) had laparoscopic adjustable gastric banding. The prevalence of dia- have a minimal effect on glucose disposition in obese humans, particularly betes prior to surgery was 20.7%, 17.4% and 24% respectively. There was no after RYGB. statistical difference in the prevalence of diabetes among the different Table 1. Correlation of change in HOMA-DI with BMI, OC, and ucOC groups. Delta BMI (kg/m2) Delta OC (ng/mL) Delta ucOC (ng/mL) Of the 119 patients with diabetes, 46 patients (38.7%) were males and 73 (n=29) (n=29) (n=26) (61.3%) patients were females. The majority of patients were African-Amer- ican. The average age of the patients by surgical procedure was 42.2 ± 8.3 Delta HOMA-DI r= -0.55 r= -0.06 r= -0.04 years for sleeve gastrectomy, 44.8 ± 7.9 years for gastric banding, and 41.5 ± p-value p= 0.002 p= 0.77 p= 0.84 7.7 years for gastric bypass. Of all the study patients with a pre-operative Supported by: American Society for Metabolic & Bariatric Surgery diagnosis of type 2 diabetes, 86 patients (72.3%) had resolution of diabetes at their one-year mark. This resolution of diabetes was seen in 89.1%, 66.7% and 54.8 % among patients who underwent laparoscopic gastric bypass, 2934-PO sleeve gastrectomy and gastric banding procedures respectively. WITHDRAWN The results of this study are consistent with results that have been reported by others. Patients, who underwent laparoscopic gastric bypass, appeared to benefi t the most in terms of achieving better remission of diabetes.

2932-PO WITHDRAWN

2935-PO Reduction of Carotid Intima-Media Thickness Associated With Weight Loss in Diabetic Patients Undergoing Bariatric Surgery ANDREA Z. PEREIRA, JULIO SERGIO MARCHINI, GLAUCIA CARNEIRO, LUCIANA MELLA UMEDA, MARIA TERESA ZANELLA, São Paulo, Brazil Obesity Introduction: The increase in the carotid intima-media thickness (IMT) cor- relates to the increased cardiovascular risk that associated with diabetes PUBLISHED ONLY mellitus, increases the risk of stroke, myocardial infarction and death. Weight Integrated Physiology/ loss reduces these risks by reducing co-morbidities. Bariatric surgery is asso- ciated with weight loss and maintenance of loss in severely obese patients. 2933-PO The aim of this study was to evaluate and correlate weight loss reduction of Osteocalcin and HOMA Measures of Glucose in Obese Persons After IMT in diabetic and non-diabetic patients undergoing bariatric surgery (Gas- Gastric Bypass: Any Association? tric Bypass Roux-en-Y). RAELENE E. MASER, M. JAMES LENHARD, Newark, DE Material and Methods: We followed 18 patients, 9 diabetic and 9 nondia- Animal and some human studies suggest that osteocalcin (OC) is associated betic patients undergoing bariatric surgery at UNIFESP-Brazil, in 2009-2011. with cross-talk between bone and energy metabolism. Undercarboxylated There were four males and 14 females, mean age of 45 ± 13 years (range from OC (ucOC) may act as a regulator of glucose metabolism. Glucose disposition 19 to 59 years). The patients’ right and left carotid intima-media thicknesswere (HOMA-DI), a measure of residual β-cell function, predicts reversibility of type measured before the operation and 180 days postoperatively by ultrasound.

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A743 OBESITY—HUMAN

Results: There was a signifi cant reduction in the IMT in both groups, diabet- ics and non-diabetics. The IMT left of diabetics was higher than non-diabet- Anthropometric data during OPOD treatment ics (p <0.01). Both, right and left thickness, showed greater reduction in diabet- T0 T1 T2 T3 ics compared to non-diabetic patients in the postoperative period (p <0.05). weight (Kg) 148±29 138±25 41±5 138±25 In all patients a reduction of IMT was signifi cantly associated with reduced BMI (kg/m2) 52±8 49±8 49±8 49±7 body weight (p <0.01). Conclusion: Bariatric surgery reduces cardiovascular risk by reducing the Waist (cm) 140±16 125±20 125±18 125±16 IMT in diabetic and non-diabetic. Diabetic patients seem to have a greater Neck (cm) 43±4 41±5 41±4 41±3 reduction of this risk factor.

2936-PO 2938-PO WITHDRAWN Sfrp5 and Metabolic Function in Non-Obese and Morbidly Obese Men MARGRIET OUWENS, MAREN CARSTENSEN, CLAUDIA WIZA, MARLIES BEKAERT, KARIN ROEHRIG, MICHAEL RODEN, JOHANNES RUIGE, CHRISTIAN HERDER, Düs- seldorf, Germany, Ghent, Belgium Secreted frizzled related-protein 5 (Sfrp5) acts as anti-infl ammatory and insulin-sensitizing adipokine in mice. Yet, its function in humans is unclear. This study assessed whether (i) Sfrp5 levels are changed in obesity and after weight loss, and (ii) whether Sfrp5 associates with markers of metabolic (dys) function. Serum Sfrp5 was determined by ELISA in 36 morbidly obese men (age 49±13 yrs, BMI 44±7 kg/m2, 23 of whom had type 2 diabetes) prior to gastric bypass surgery (GBP), and 19 non-obese men (age 53±13 yrs, BMI 24±3 kg/m2). In 14 men, Sfrp5 levels were also examined two years after GBP. Spearman analy- sis was used to assess whether Sfrp5 associated with determinants of metabolic function, and circulating levels of other adipokines. Sfrp5 levels were similar in obese and non-obese men, and not affected by weight loss after GBP. In contrast, adiponectin was lower in morbidly obese men, and increased after GBP. Age-adjusted regression analysis of the entire cohort identifi ed associations between Sfrp5 and both adiponec- tin (ρ=0.33; P=0.02) and HMW-adiponectin (ρ=0.36; P=0.01). In contrast to adiponectin, Sfrp5 did not associate with markers of metabolic function (HOMA-IR, glucose, insulin, BMI, triglycerides, HDL-cholesterol). Subgroup analysis identifi ed associations between Sfrp5 and HOMA-IR (ρ=0.49; P=0.048), serum IL6 (ρ=0.57; P=0.03), and MCP1 (ρ=0.61; P=0.02) in non- obese, but not in morbidly obese men. In non-obese men, Sfrp5 associates with insulin resistance and pro-infl am- matory cytokines. However, Sfrp5 levels are not affected by morbid obesity or weight loss after GBP, and unrelated to metabolic and pro-infl ammatory factors in morbidly obese men. Supported by: German Diabetes Association; German Center for Diabetes Re- search

2937-PO 2939-PO Very Low Carbohydrate Ketogenic Diet (VLCKD) in Obese Patients WITHDRAWN Candidate to Laparoscopic Bariatric Surgery: Prospective Evaluation of an Original Sequential Diet FRIDA LEONETTI, DANILA CAPOCCIA, FEDERICA COCCIA, LAURA ALESSANDRONI, MARINELLA DEL GIUDICE, SARA CAPONIGRO, GIANFRANCO SILECCHIA, Rome, Italy Bariatric patients co-morbidities should be assessed before surgery to improve postoperative results. Preoperative weight loss reduces operative risk.We evaluate the effect of an original diet (ObesePre-OperativeDiet-OPOD) in morbidly obese diabetic (DM2) and nondiabetic (noDM2) patients candidate 2 to bariatric surgery.32 patients (BMI 52.5±8.6 kg/m ) 11 with type 2 diabetes (DM2), were recruited. OPOD implies 10 days of VLCKD, 10 of Very Low Calo- rie Diet (VLCD) and 10 of Low Calorie Diet (LCD). Patients were evaluated at recruitment (T0), after 10 (T1), 20 (T2) and 30 days (T3). 5 patients underwent ultrasound (US) liver evaluation at T0 and after diet. At T1, T2, T3 the reduction

Obesity in body weight, BMI, waist (WC) and neck circumference (NC) was signifi cant in all patients but two, who discontinued OPOD after 4-7 days. In DM2 patients, fasting plasma glucose (FPG) signifi cantly decreased (from 195±89 to 150±70 PUBLISHED ONLY Integrated Physiology/ mgdl) allowing either reduction or discontinuation of diabetic medications. Plasma and urine ketones increased signifi cantly at T1 with values always<1 mmol/L and hunger degree markedly decreased during the entire treatment. Steatosis pattern was improved and liver volume reduced by 30%. No relevant side effects were recorded. OPOD was safe and effective as preoperative treatment in morbid obese DM2 and noDM2, patients, allowing weight loss and neck circumference reduction.

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A744 OBESITY—HUMAN

2940-PO WITHDRAWN 2942-PO A Multi-Disciplinary Program Based on the USA-Derived Diabetes Prevention Program Can Achieve Equivalent Results in the UK ELLIS KALMUS, ANDREW J. HARTLAND, JO PARKINSON, ANA ELSHAW, JANINE PEMBERTON, ROSIE BAMFORD, BARBARA WATT, SUSAN GILL, VICKIE HART- LAND, JANE DEVILLE-ALMOND, Walsall, United Kingdom, Wolverhampton, United Kingdom In July 2012, in response to the growing health burden of type 2 diabetes, the UK National Institute for Health and Clinical Excellence (NICE) published guidelines for the prevention of type 2 diabetes. It recommends that those identifi ed at high risk be offered intensive lifestyle change programs. From the specifi cations for these programs it is clear that these are based on the USA-derived Diabetes Prevention Program (DPP). Weight loss has been iden- tifi ed as the major factor determining diabetes prevention in this pro- gramme. In 2009, we established a multi-disciplinary medical weight management clinic in Walsall, UK based on the Diabetes Prevention Program, which sub- sequently fulfi lls the specifi cations for a NICE intensive lifestyle change program. We audited 12 months (April 2011 - April 2012) of this service and compared with the results of the Diabetes Prevention Program. 95 patients completed the program. Initial referral criteria: BMI > 35 kg/ m2 with type 2 diabetes or >40 kg/m2 with type 2 diabetes, hypertension, dyslipidaemia and/or obstructive sleep apnoea. Mean weight loss for 24 -week program = 6.4% of initial weight compared with 6.0% (DPP) . This was not statistically signifi cant, but demonstrates non-inferiority with the DPP. 58% of patients lost >5% of initial weight and 27.4%> 10%. For the Type 2 diabetes sub-group (n = 43), mean weight loss = 7.2% (not statistically different from mean weight loss of all completers). Our data is comparable with results from the Diabetes Prevention Program, in a population with a range of co-morbidities. It suggests that, if eligibility criteria for this service were aligned to UK NICE guidelines for the prevention of type 2 diabetes, this would deliver the expected reduction in incidence of type 2 diabetes.

2943-PO Oncostatin M Is Produced in Non-Adipocyte Cells Present in Adipose Tissue of Obese/T2DM Mice and Humans and Acts on Adjacent Adi- pocytes to Promote an Infl ammatory Condition DAVID SANCHEZ-INFANTED, RON F. MORRISON, ERIC RAVUSSIN, JACQUELINE M. STEPHENS, Baton Rouge, LA, Greensboro, NC Adipose tissue Adipocytes and adipose tissue have critical paracrine and endocrine functions that modulate adipose tissue function and establish a 2941-PO hormonal network linking adipose tissue with other tissues. In our studies, WITHDRAWN we have observed the cytokine oncostatin-M (OSM) is produced in adipose tissue and regulated in several rodent of T2DM and in humans. Of note, OSM is not produced in adipocytes, but the cellular origin of OSM in WAT is the stromovascular portion of adipose tissue in ob/ob mice, HFD fed mice, and obese humans. Our results suggest that the non-adipocyte derived OSM acts in a paracrine manner on adjacent adipocytes in adipose tissue under obese and insulin resistant conditions in mice and man. Our data show that both mouse and human adipocytes contain the OSM receptor and are highly sensi- tive to its actions that include promoting selective expression of several pro- infl ammatory genes in adipocytes. Our novel data show for the fi rst time that OSM is highly induced in adipose tissue of obese subjects prior to gastric bypass surgery. In addition, we demonstrate that OSM induces the regulation of target genes implicated in metabolic diseases like PAI-1 and IL-6. In conclu-

sion, all these novel fi ndings suggest a very important role of OSM in the Obesity development of insulin resistance and other metabolic disorders. Supported by: NIH (DK052968) PUBLISHED ONLY Integrated Physiology/ 2944-PO Quality of Life Improvement in Patients With Diabetes: Helping Evaluate Reduction in Obesity (HERO) Study JOHN OLSOFKA, PIETRO FORESTIERI, ELISABETTA VILLAMAINA, DAISY NG-MAK, JIN JIN, JOHN DIXON, Louisville, KY, Naples, Italy, Irvine, CA, Bridgewater, NJ, Mel- bourne, Australia Few have reported the impact of weight loss (WL) using adjustable gastric banding (LAGB) on health-related quality of life (QOL) of diabetic patients. We examine the effect of weight loss on glycemic control and QOL in type 2 diabe- tes (T2D) patients 1 yr after LAGB surgery using the LAP-BAND® AP System.

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A745 OBESITY—HUMAN

HERO is a 5 yr registry of 1,106 obese patients from 29 centers in North 2946-PO America, Europe, and Australia who underwent LAGB. 295 (27%) subjects Body Composition Measures as Predictors of Insulin Resistance and had T2D at baseline (BL). Our analysis includes 638 subjects who to date have Total Daily Insulin Dose in Veterans With Type 2 Diabetes provided complete BL and 1 yr HRQOL data based on the Short-Form 12 (SF-12) GERALD A. CHARLTON, CHRISTOPHER S. WENDEL, GREGORY G. FOTIEO, ELENA and Impact on Weight on Quality of Life-Lite (IWQOL-Lite) questionnaires. V. PLUMMER, JAYENDRA H. SHAH, ALLISON E. MURATA, HEATHER C. BRISLEN, At BL those with diabetes were older (mean 49 v 41 years) and more likely MARC T. MONTANARO, GLEN H. MURATA, Albuquerque, NM, Tucson, AZ, Phoenix, to be male (28% v 18%), but weight was comparable (128 v 125 kg). T2D AZ patients had less % weight loss at 1yr (Table). At 1 year those with and This study sought to determine which measures of body composition (BC) without T2DM had similar and signifi cant improvement in every domains of are the best predictors of insulin resistance (IR) and total daily insulin dose the HRQOL measures (Table). At BL and 1 yr those with T2DM had lower (TDI) in veterans with type 2 diabetes. Percent body fat (PBF) was measured Physical (PCS) but not Mental component scores (MCS) of the SF-12 than non using bioelectrical impedence in 137 pts in the VA Southwest Health Care T2DM patients. Network. IR was estimated using the HOMA method for pts on oral hypogly- cemic agents (OHA) only, and TDI was recorded for pts on insulin. The subjects’ %WL SF-12 PCS SF-12 MCS IWQOL-Lite mean age (SD) was 64.1 (7.5) yrs, duration of diabetes 8.7 (5.8) yrs, 96% male, T2DM - BL — 35.5±10.2 44.9±11.6 43.3±19.5 45% of an ethnic minority, 54% on OHAs alone, and 46% on insulin with or 1yr 15.5% 45.8±9.9 48.2±10.0 69.8±20.1 without OHAs. The mean wt was 101 (18.8) kgs, BMI 32.9 (5.5) kg/m2, waist hip ratio (WHR) 1.0 (0.1) and PBF 33.0 (7.2) percent. Linear regression showed Non-T2DM -BL — 39.8±10.1 43.9±11.0 47.0±19.6 that both PBF and BMI were signifi cantly correlated with IR in pts on OHAs 1yr 17.4% 50.2±8.8 49.8±9.9 77.0±18.4 only, while WHR was not (Table). Stepwise regression including all three T2D patients with HbA1c ≤6.5% (49%) at 1 yr had greater %WL (17.4% v measures of BC suggested that BMI was the best predictor of IR (R2=0.3105, 10.9%, p<0.001) and better SF-12 MCS and overall IWQOL scores than those p<0.00001). Linear regression failed to demonstrate a signifi cant correlation with HbA1c >6.5%.LAGB was associated with signifi cant WL, and improve- between the measures of BC and TDI for pts on insulin. Wt appeared to be ment in glycemic control and QOL by 1 yr. Controlled T2D was also associated the best predictor of TDI (R2=0.084, p=0.02) for pts on insulin. Although some with greater WL and better QOL. Further analysis will examine the sustain- relationships were statistically signifi cant, no measure of BC explained most ability of these effects. of the variance in IR or TDI. Our study suggests that it is hazardous to base Supported by: Allergan, Inc. treatment decisions on such measurements and that a better strategy consists of dose titration and careful assessment of response.

2945-PO Predictors of IR Coeff SE R2 p-value Weight Management Focused Structured Educational Group Improves Glycemic and Weight Loss Outcomes in Patients With Extreme Obe- Percent Body Fat 0.099 0.027 0.220 0.0006 sity and Type 2 Diabetes BMI 0.170 0.037 0.310 <0.00001 ADRIAN BROWN, AMY GOULDSTONE, ALICE WRIGHT, RHIAN DAVIES, GILLIAN Waist-Hip Ratio 4.05 3.11 0.035 0.20 ABERNETHY, WEN BUN LEONG, TERESA ARORA, ALISON JAGIELSKI, JAYADAVE Predictors of TDI SHAKHER, SHAHRAD TAHERI, Birmingham, United Kingdom Diabetes structured lifestyle programmes have been shown to improve Percent Body Fat 1.58 1.0 0.039 0.12 glycemic control and quality of life, but are often very intensive. Specialist BMI 2.27 1.25 0.051 0.07 Lifestyle Management (SLiM) is a medically supported structured patient Waist-Hip Ratio 218.3 111.1 0.061 0.054 education and self-management group focusing on weight management. Each session is run monthly over a 6-month period providing a less intensive long- Supported by: Roche Diagnostics Corporation term approach. The groups are patient-centered, incorporating educational, motivational and behavioural elements. The aim was to assess if a less inten- 2947-PO sive group focusing on weight loss can improve glycemic control with patients WITHDRAWN with extreme obesity (EO) and type 2 diabetes (T2D). A retrospective service evaluation of 142 patients with T2D with extreme obesity (EO) (mean age 52.5±11years, females [64.8%], mean BMI 49.6±9.4kg/ m2, mean weight 136.8±28kg, insulin treated 19.7% and mean HbA1c 64±18.2mmol/mol) who attended SLiM between 08/2009 to 12/2012 was conducted. There was a statistically signifi cant reduction in mean HbA1c levels from baseline to end of SLiM, mean HbA1c was 64±18.2mmol/mol and 60.1±15.5mmol/mol respectively, with a mean reduction of 3.96±14.8mmol/ mol (t=2.38,p<0.05) achieved. Patients lost a statistically signifi cant mean body weight from baseline to end of SLiM ranging from a 29.8kg loss to a gain of 8.8kg, with a mean loss of 5.71±6.89 kg (t=9.88,p<0.001). 86% of patients lost weight with a 30% achieving ≥5% and 11% ≥10% weight loss with a mean weight loss of 4±4.57% (t=10.4,p<0.0001). Attending the SLiM groups produced a statistically and clinically signifi cant weight loss and improvement of glycemic control in patients with EO and T2D. The use of medically supported less intensive group treatment produces similar results to other more intensive diabetes lifestyle programs and is more

Obesity cost and time effective. Further randomised studies are required to assess SLiM further and analyse factors affecting glycemic and weight loss out- comes. PUBLISHED ONLY Integrated Physiology/ Supported by: NIHR-CLAHRC (UK)

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A746 OBESITY—HUMAN

2948-PO 2950-PO Psychological Co-Morbidities of an Extreme Obese Population Obstructive Sleep Apnea Does Not Potentiate Alterations in Insuli- Attending a Specialist Community Weight Management Service nogenic Index or Insulin Resistance in Metabolically Healthy Obese (CWMS): The Impact of Type 2 Diabetes (T2D) Patients With Body Mass Index Higher than 35 ALISON C. JAGIELSKI, IRAIDA NEIRA, MARZIEH HOSSEINI-ARAGHI, ADRIAN JAVIER SALVADOR, PATRICIA ANDRADA, ANA CHACON, EIDER PASCUAL, CAMILO BROWN, SUZANNE HIGGS, G. NEIL THOMAS, SHAHRAD TAHERI, Birmingham, SILVA, JORGE IRIARTE, MARIA J. GIL, PEDRO PUJANTE, CRISTINA ABREU, JAVIER United Kingdom ESCALADA, GEMA FRÜHBECK, Pamplona, Spain Extreme obesity (EO) and associated co-morbidities are one of the greatest Obstructive sleep apnea (OSA) exerts deleterious effects on glucose challenges to affect individuals and healthcare services. Much research has metabolism in obese patients. There is no information on OSA effects in focussed on the physical co-morbidities of EO, whilst the impact on quality metabolically healthy obese (MHO) patients. In order to compare the infl uence of life and mental health are less understood. The psychological co-morbid- of OSA on insulin sensitivity (IS) and insulinogenic index (II) in MHO patients ities of a sample of 270 obese individuals with and without T2D entering a with BMI>35 with those having features of metabolic syndrome, a cross- CWMS were investigated. Patients were aged 18-80y (mean 43.5 S.D=12.4). sectional analysis of 424 subjects (39,3% men) with BMI >35 kg/m2 was Mean baseline weight was 131.9kg (S.D=24.5) and mean BMI 47.0kg/m2 performed. The study comprised full polysomnographic study and OGTT with (SD=7.8). The sample included a substantial proportion of women (75%) and glucose and insulin measurements. Diverse insulin sensitivity indexes were individuals with T2D (26.3%). Patients completed questionnaires assessing calculated. A metabolic score including hypertension, diabetes, dyslipidemia quality of life, mental health and sleep (EQ5D, IWQOL-Lite, HADS, PSQI, ESS). and hyperuricemia was determined. Individuals with T2D had a greater mean BMI (48.8kg/m2Vs46.3kg/m2 p<0.05) Patients were classifi ed according to metabolic score into 2 groups: MHO and signifi cantly lower score on the IWQOL-Lite physical function subscale (score 0: n=47. 11.1%) and metabolically unhealthy obese (MUHO) (score >0: (35.6Vs45.5 p<0.05), indicating they felt that weight had a greater impact on n=377. 88.9%) and divided in OSA (MHO n=16 and MUHO n=245) and non-OSA physical function. Those with T2D had signifi cantly greater self-esteem than subgroups according to an apnea-hypopnea index cut-off point of 10. OSA those without the condition (31.9Vs23.9 p<0.05) and signifi cantly less anxiety patients showed lower oxygen desaturation index, and minimum oxygen (9.4Vs10.9 p<0.05), however means for both groups fell within the clinical saturation (all p<0,001) in both MHO and MUHO subjects. Whereas MUHO case range for anxiety and depression. No signifi cant difference was found patients with OSA exhibited higher fasting and postOGTT insulin levels (21.2 in relation to depression, general quality of life (EQ5D) and sleep quality vs 17.5 and 87.4 vs 71.2 p<0.01 respectively), HOMA-R values (5.9 vs 4.6.p<0.01) between groups. In this sample with EO, the presence of T2D did not have a and lower IS indexes like QUICKI and Matsuda (2.2 vs 3. p<0,005) than their signifi cant effect on mood, quality of life, or sleep, above and beyond the non-OSA counterparts, no differences in these parameters were seen in OSA impact of obesity itself. Greater self-esteem and reduced anxiety could refl ect vs. non-OSA MHO patients (fasting insulin: 12.3 vs 14.8, Matsuda index: 3.3 greater psychological resilience in those with T2D who are more familiar with vs 4.1. p ns). Presence of OSA was not associated with differences in II in healthcare services and chronic disease. In the whole population, the preva- MUHO or MHO patients. lence of anxiety and depression were high whilst perceived quality of life was These data indicate that 11% of patients with BMI>35 can be classifi ed as low, indicating a need for specialist psychological support in addressing these MHO, 34% of them having OSA, but suggests that, in contrast with MUHO issues in conjunction with weight management. individuals, OSA does not affect IS parameters in MHO subjects. We found Supported by: NIHR-CLAHRC (UK) no evidences of association between OSA and impairment of II in patients with BMI>35. 2949-PO The Impact of a Medical Weight Management Program on Health- 2951-PO Related Quality-of-Life WITHDRAWN AMY E. ROTHBERG, LAURA N. MCEWEN, ANDREW T. KRAFTSON, CHRISTINE E. FOWLER, GINA M. NESHEWAT, CHARLES F. BURANT, WILLIAM H. HERMAN, Ann Arbor, MI A major benefi t of weight loss is its impact on health-related quality-of-life (HRQL) and the degree of improvement in HRQL is a major determinant of the cost-effectiveness of weight loss interventions. In this study, we assessed the impact of a medical weight management program on HRQL and described the factors associated with improvement in HRQL. We studied 188 patients with body mass index (BMI) ≥ 35 kg/m2 or ≥32 kg/m2 with one or more comorbidities who participated in a medical weight management program for at least 6 months and who had baseline and follow- up assessments of BMI and HRQL using the EuroQoL (EQ5D) and its visual analog scale (VAS). At baseline, age was 50 ± 8 years (mean ± SD), 52% were women, and 87% were white. Baseline BMI was 40.0 ± 5.0 kg/m2. Comorbidities were common: 51% had hypertension, 45% dyslipidemia, 27% type 2 diabetes, 26% osteoar- thritis, and 18% depression. Baseline EQ5D was 0.85 ± 0.13 and baseline VAS was 67 ± 18. At 6 months, after 12-16 weeks of very low calorie diet and intensive behavioral intervention, weight loss was 20.5 ± 10.1 kg (range -50.6 to +0.7 kg). Reduction in BMI was 7.0 ± 3.2 kg/m2. Improvement in EQ5D was 0.06 ± 0.13 and improvement in VAS was 14 ± 16. In multivariate analyses, factors associated with improvement in EQ5D and VAS included lower base-

line BMI, fewer baseline comorbidities, lower baseline HRQL, and greater Obesity reduction in BMI at follow-up. The models explained 48 to 60% of the variance in improvement in HRQL. For any given BMI, EQ5D tended to be higher at PUBLISHED ONLY

follow-up than at baseline and for any given BMI, VAS was signifi cantly higher Integrated Physiology/ at follow-up than at baseline.Improvements in HRQL after a 6 month medical weight management program were substantial and clinically meaningful. Measured improvements in HRQL between baseline and follow-up were greater than predicted by the reduction in BMI at follow-up. Patients may minimize the negative impact of obesity on HRQL. If investigators fail to rec- ognize this, they will underestimate the benefi ts of weight loss. Supported by: P30DK089503; MNORC; MCDTR; P30DK092926

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A747 OBESITY—HUMAN

2952-PO 2954-PO Increasing Prevalences of Obesity and Metabolic Syndrome in Chi- Plasma Cortisol Trend in Obese and Superobese Subjects With and nese Subjects over 55 Years Old in an Urbanized Village Without Type 2 Diabetes SHUO LIN, LI HU, CHUNPING ZENG, XIAOFENG LI, YANMING CHEN, SHENGQING DANILA CAPOCCIA, MARINELLA DEL GIUDICE, FEDERICA COCCIA, VALENTINA HE, ZHUOZHUO REN, PANWEI MU, LONGYI ZENG, Guangzhou, China PAGLIA, STEFANIA MARCHIONE, BEATRICE FERRETTI, FRIDA LEONETTI, Rome, To determine the trend of prevalences of obesity and metabolic syndrome Italy (MS) in Chinese subjects in an urbanized village (Shipai community, Guang- In literature, not recent studies showed increased cortisol plasma levels zhou, China), we conducted two surveys in subjects over 55 years old in 2002 (CPL) in obese diabetic and non diabetic patients. Aim of this study was to and 2010-2011. All subjects were invited to participate the survey. A total of examine the trend of CPL and ACTH related to anthropometric parameters in 726 subjects (77.0%) and 1151 subjects (77.6%) were investigated in 2002 and a large population from normal-weight to superobese patients (BMI 20.3-75.9 2010-2011, respectively. Obesity was defi ned as BMI≥25kg/m2, and diagnosis Kg/m2), with and without diabetes. 573 patients (430 women; 15-80 years) of MS was based on the IDF 2005 criteria. The prevalences of obesity and were divided in diabetic (n=129, diagnosed according to ADA guidelines) and MS were standardized based on the composition of national population in non-diabetic subjects and then divided in 7 groups according to BMI (GroupA 2000. The demographic structure of participants were similar to that of the BMI 20-24.9; GroupB 25-29.9; GroupC 30-34.9; GroupD 35-39.9; GroupE whole population in two surveys, which indicated the samples were represen- 40-49.9; GroupF 50-50.9; GroupG ≥60). All the patients were evaluated for tive. After excluding subjects with missing data, data of 639 and 1134 subjects anthopometric parameters (BMI, percentage of fat mass [%fat], waist cir- in 2002 and 2010-2011 were analysed, respectively. In 2002, the prevalences cumference) and fasting plasma levels of cortisol, ACTH and HbA1c. CPL in of obesity and MS in this population were 37.9% (standardized rate 32.7%) non-diabetic patients resulted signifi cantly lower (p= 0.0034) in obese (GroupC and 40.4% (standardized rate 35.2%), respectively. In contrast, the preva- 12.1±5.3 µg/dl; GroupD 11.4±4.0; GroupE 12.1±5.3; GroupF 12.2±4.4; GroupG lences of obesity and MS in 2010-2011 were 39.4% (standardized rate 38.0%) 12.8±5.3) than in normal-weight (15.6±7.3 µg/dl) and overweight subjects and 44.5% (standardized rate 41.2%), respectively. Table 1 shows the preva- (14.8±5.7 µg/dl); no correlation was found with waist circumference. ACTH lences of obesity and MS in this population in 2010-2011. The prevalences of levels, specularly, rised proportionally to BMI (r=0.2, p=0.0015). Differently, obesity and MS in women were higher than that in men. Our study demon- in diabetics, CPL and ACTH levels were not signifi cantly related to BMI (p=ns), strated an increasing trend in the prevalences of obesity and MS in subjects resulting meanly higher than in the corresponding BMI group of non-diabetics. over 55 years old in this urbanized village. In diabetic patients, CPL trend showed a positive correlation (r=0.18) to HbA1c levels (p=0.01). ACTH levels, instead, were not related to HbA1c (p=ns). These unexpected results of decreased CPL in obesity could be explained by the hypothesis of adipose tissue is an active endocrine organ, responsible of the increased peripheral clearance of cortisol followed by the consequent increase of the plasmatic ACTH levels. The lack of CPL reduction in diabetic obese patients could be related to metabolic stress, as confi rmed by the positive relation between CPL and HbA1c levels.

2955-PO WITHDRAWN 2953-PO WITHDRAWN Obesity PUBLISHED ONLY Integrated Physiology/ 2956-PO Weight Loss Improves Arterial Stiffness Parameters in Young and Middle Aged Obese Subjects VIVIANA I. ELIAN, CRISTIAN SERAFINCEANU, DAN CHETA, LIVIU DRAGOMIRESCU, Bucharest, Romania The cardiovascular disease is the main cause of mortality and morbidity in obese patients. While many studies have focused on obese patients who have already developed cardiovascular pathology, few tried to address the prevention of atherosclerosis in healthy young adults. The aim of this study was assessing the effect of a weight loss lifestyle intervention on arterial stiffness.

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A748 OBESITY—HUMAN

We have enrolled 159 obese (BMI=30-45kg/m2) patients (120 females) with 2959-PO no cardiovascular pathology that were assigned, for 6 months, to either weight WITHDRAWN loss program or a weight maintenance recommendation. In the intensive care group subjects participated to weekly visits consisting of counseling on hypocaloric diet, and physical exercise programs. We have measured anthro- pometric parameters, body composition, cell adhesion molecules (CAMs) and adipokines levels and markers of arterial stiffness (Cardio-Ankle Vascular Index (CAVI), systolic and diastolic blood pressure and Ankle Brachial Index). At the study endpoint, we found a clinically and statistically signifi cant (p<0.001) difference between the CAMs levels and the adipokine profi les. In univariate analysis, weight loss correlates with: CAVI decrease r=0.71, VCAM-1 decrease r=0.63, ICAM-1 decrease r=0.61, adiponectin variation r=-0.59, leptin decrease r=0.6 and also with abdominal circumference decrease. The adipose tissue loss correlated with CAVI decrease(r =0.71) and diastolic blood pressure decrease(r= 0,4). In multivariate analysis VCAM-1 and fat loss were the predictors of arterial stiffness. The weight loss (using a moderate hypocaloric diet and physical exercise) increased vascular compliance and improved CAMs and adipokines levels in young obese patients without cardiovascular pathology. This suggest that an early weight loss intervention can prevent future cardiovascular complications and should be advised to obese subjects before the co-morbidities develop- ment. Supported by: POSDRU (6/1.5/S/17)

2957-PO WITHDRAWN

2960-PO Ten Year Changes in Prevalence of Overweight, Obese and Centrally Obese Chinese Adults in Urban Shanghai XUHONG HOU, YU LIU, HUIJUAN LU, XIAOJING MA, WEIPING JIA, Shanghai, China In the last decade there has been no comprehensive report on secular trends 2958-PO in the prevalence of obesity among Chinese adults in urban Shanghai, the Genetic Variation in the Nocturnin Gene Modulates Body Mass Index largest city and one of the most economically developed areas of southern and Related Metabolic Traits in Taiwanese Population China. Here, we aimed to report the prevalence of overweight, obese, and YI-CHENG CHANG, YEN-FENG CHIU, LEE-MING CHUANG, Taipei, Taiwan, Miaoli, centrally obese Chinese adults in urban Shanghai in 2007-2008 and to compare Taiwan the fi gures with previous data from 1998-2008. The molecular circadian clock genes are critical regulators of energy homeo- We analyzed datasets from two cross-sectional surveys: the Shanghai stasis and metabolism. However, whether variation in the circadian genes is Diabetes Study (SHDS) of 1998-2000 and SHDS II from 2007-2008. The par- associated with metabolic phenotypes in humans remains uncertain. In this ticipants were aged 20-74 years and lived in urban communities; 4,894 from

study, we systemically genotyped 20 tag single nucleotide polymorphism the SHDS and 4,395 from SHDS II for whom complete data on waist circum- Obesity (SNP) in 8 candidate genes involved in circadian clock, including CLOCK, BMAL1, ference (WC) and body mass index (BMI) were available were selected for PER1, Per2, Cry1, Cry2, Casein Kinase 1, and Nocturnin in 1,250 Taiwanese sub- analysis. Overweight was defi ned as 24 kg/m2 ≤ BMI < 28 kg/m2 or 25 kg/m2 2 2 2 PUBLISHED ONLY jects. We found that genetic variation in the Nocturnin gene, rs17050679, was ≤ BMI < 30kg/m and obesity as BMI ≥ 28 kg/m or BMI ≥ 30 kg/m , accord- Integrated Physiology/ associated with body mass index (BMI) (P=0.0028), diastolic blood pressure ing to the Working Group on Obesity in China (WGOC) and the World Health (DBP) (P=0.045), and fasting triglycerides (P=0.014). The association with BMI Organization (WHO) standards, respectively. Central obesity was defi ned as remained signifi cant after Bonferroni’s correction. Another variant, rs11113181, WC ≥ 90 cm in men and ≥ 85 cm in women. in the Cry1 gene was nominally associated with BMI (P=0.017), DBP (P=0.017), In 2007-2008 vs 1998-2001, according to the WGOC and WHO standards, and fasting glucose (P=0.023). Signifi cant cumulative effects on BMI, DBP, the standardized prevalence of overweight and obesity combined was, respec- fasting glucose, and triglycerides were observed by combining all associated tively, 43.4% vs 39.0% (adjusted odds ratio (AOR)=1.08, P=0.083) and 32.3% risk variants (P for trend < 0.0001, respectively). We further found that Noc- vs 29.4% (AOR=1.02, P = 0.648) overall, 51.6% vs 42.9% (AOR=1.37, P<0.001) turnin gene expression in human white adipose tissue was associated with and 39.1% vs 31.5% (AOR=1.32, P<0.001) in men, and 34.7% vs 34.9% BMI, DBP, and fasting serum triglycerides.These data indicate an important (AOR=0.91, P=0.106) and 25.0% vs 27.3% (AOR=0.85, P<0.01) in women. The role of Nocturnin in modulating adiposity and related metabolic traits. standardized prevalence of central obesity was 22.4% vs 17.3% (AOR=1.32,

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A749 OBESITY—HUMAN

P<0.001) overall, 27.3% vs 19.5% (AOR=1.32, P<0.001) in men, and 17.1% vs 2963-PO 15.0% (AOR=1.32, P<0.001) in women. Effects of Glycemic Control by Administration of Sitagliptin in Type Over the 10 year period, though the prevalence of overweight and obesity 2 Diabetic Patients With Insuffi cient Control combined, and of central obesity increased signifi cantly in men, no signifi cant TAKEHIKO WAGO, SHUNICHI TANAKA, Yokohama, Japan increases were observed among women. Sitagliptin, a DPP-IV inhibitor (Sit) can effect then of action that is different from hypoglycemic agents until now, has excellent effi cacy and safety has 2961-PO been recognized abroad, it was fi rst approved in Japan in 2009. We studied WITHDRAWN whether Sit affects glycemic control in poorly controlled (HbA1cə6.5% or FPGə130mg/dl) type 2 diabetic patients (from Jan/2011 to Dec/2012). Selec- tion criteria of patients were unquestioned gender outpatient (ə20 years old) adults. In diabetic patients (63.6±2.4 year-old, 11 male, 9 female) were enrolled. Pulse wave velocity (PWV), ankle/brachial index (ABI) and intima- media thickness (IMT) were evaluated before and after 6 months Sit treatment (50mg/day). Blood samples were obtained for measurements of biochemical markers. After treatment, Sit signifi cantly (p<0.05) decreased PG, HbA1c, LDL- C, ABI, PWV and IMT (Table 1). In conclusion, this study shows that treatment with Sit in poor controlled diabetic patients improved PG, HbA1c and lipid metabolism with tendency toward improvement of arterial stiffness.

Table 1. Baseline characteristics of the patients and effect of treatment with sitagliptin. Variables Before treatment After treatment P-value Age(years) Sex(male or female) PG(mg/dl) HbA1c(JDS%) 2962-PO LDL-C(mg/dl) WITHDRAWN PWV R/L(cm/s) IMT R/L(mm)

2964-PO A BMI of 27.5 Can Improve the Detection of Obesity in a Venezuelan Population RAMFIS E. NIETO, YENDRI PEREZ, MARIA DE LOS ANGELES SUAREZ, EUNICE UGEL, Barquisimeto, Venezuela A BMI of 27.5 Can Improve the Detection of Obesity in a Venezuelan Popu- lation Body mass index (BMI) is the most widely used measure to diagnose obe- sity. However, the accuracy of BMI is limited and can misses people with excess fat. Ethnic differences in body composition are important. Thus, the objective of this study was to assess the diagnostic performance of BMI to detect obesity in a sample of a Venezuelan population. Subjects attending the Cardiometabolic Unit (Barquisimeto, Venezuela) aged 18 o more (n= 1375, 71.1% women, 54% obese) were included. For each subject, anthropometric data and body fat by leg by leg bioimpedance (Tanita ®) were obtained. The defi nition of obesity BF (Body fat) >25% in men and >35% in women proposed by the WHO was used to determine the diagnostic performance of BMI ≥30 kg/m2 to detect obesity. Data on sensitivity, specifi city and the construction of receiver operating characteristic (ROC) curves were used to select the best cutoff for the BMI to detect BF%-defi ned obesity. BMI-defi ned obesity was present in 53.9% of subjects (66.2% men and 48.9% women), while BF%- defi ned obesity was present in 74.6% (82.1% men and 71.6% women). Thus, BMI-defi ned obesity underestimated 21% of obesity. A BMI≥30 had a high specifi city (total = 95.1%, 95% CI, 92-97; men = 97,2%, 95% CI, 89–100; women = 94.6%, 95% CI, 91-97) but lower sensitivity (total = 70.6%, 95% CI, 68-73; men = 80.4%, 95% CI, 75–84; women = 66.1%, 95% CI, 62-70) to detect BF%-defi ned obesity. The area under the curve in the ROC curve was 0,941, Obesity 95% CI, 0,927–0,954). The best cut point of BMI to discriminate obesity in this population (maximum sum of sensitivity and specifi city when each value was over 50% favoring sensitivity) was 27,5 with a sensitivity of 89.3%, 95% PUBLISHED ONLY Integrated Physiology/ CI, 87-91 and a specifi city of 85.4%, 95% CI, 81-89. In conclusion, a BMI cutoff of ≥30 kg/m2 has good specifi city but misses 21% of people with excess fat. A BMI of 27,5 can improve the power to detect subjects with obesity in a Venezuelan population.

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A750