2588‑pub withdrawn...male naturally occurring diabetic cynomolgus monkeys (n=5-10) and their...

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ADA-Supported Research

INTEGRATED PHYSIOLOGY—INSULIN SECRETION IN VIVO

2588‑PUB

INTEGRATED PHYSIOLOGY—INSULIN SECRETION IN VIVO

2589‑PUBAntidiabetic Effect of Tetrapanax Papyrifer Extract on C57BL/KsJ db/db MiceBO HUANG, XIANHUA ZHANG, Jinzhou, China

This study investigated the effects of Tetrapanax papyrifer extract (TPE) in a mouse model of diabetes (C57BL/KsJ db/db). Four treatment groups received diabetic control group (DC), 100 or 200 mg/kg TPE (TPE 100 or PCE 200), or 10 mg/kg pinitol (pinitol 10) daily for 8 weeks. Fasting blood glucose levels were 59% lower in TPE 200 mice and 43% lower in the pinitol 10 group. Insulin levels were 1.3- fold higher in the TPE 200 group, than in the DC. Furthermore, the PCE 100 mice showed 1.5- fold increased C-peptide and adiponectin levels and 23% decreased HbA1c levels. Compared to the DC mice, the PCE-treated mice showed significant prevention of pancreatic β-cell damage and higher insulin content in immunohistochemical analyses. To investigate TPE’s mechanism of action, microarray analyses were per-formed liver and fat tissues.

In summary, our results suggested that TPE exerted antidiabetic effects through protection of pancreatic β-cells, increase of insulin secretion, and reduction of blood glucose level by improving insulin sensitivity in C57BL/KsJ db/db mice.

Supported By: Natural Science Foundation of Liaoning Province, China

2590‑PUBThe Capacity of Controlling Hyperglycemia Depends on the Degree of Glucotoxicity during Long‑Term Insulin Pump Therapy in Type 2 Diabetic PatientsSOO BONG CHOI, EUN SHIL HONG, YUN H. NOH, Seoul, Republic of Korea

We aimed to investigate the effect of glycemic control on beta cell function, insulin sensitivity, and disposition function during long-term CSII therapy (for up to 2 years) in patients with type 2 diabetes (T2D). We discontinued oral anti-diabetics and applied CSII therapy to T2D patients (number, 570 with 54.1% of male; age, 59.5 ± 9.8 years; duration, 11.6 ± 8.1 years; HbA1c 9.0 ± 2.0%; BMI 24.3 ± 3.4 kg/m2). Blood samplings were performed at 6 month and yearly, after overnight fasting and 120 minutes after ingestion of a standard mixed meal (500 kcal). Serum C-peptide, glucose, and HbA1c were measured, and

C-peptidogenic Index (CI), Matsuda Index (MI), and disposition Index (DI) were calculated. Patients were divided into Good (G; n=194, HbA1c ≤ 6.5%), Medium (M; n=271, 6.5% <HbA1c ≤ 7.5%), and Poor (P; n=105, HbA1c >7.5%) glycemic control groups by the mean value of HbA1c during 2 years of CSII therapy: the effects of glycemic control on serum C-peptide were different among these groups (Figure), i.e., the lower the HbA1c, the higher the serum C-peptide.

In conclusion, the capacity of controlling hyperglycemia (serum C-peptide, CI, MI, and DI) in T2D might be affected by the degree of glucotoxicity during CSII therapy.

Figure.

2591‑PUBProtective Biphasic Insulin Secretion with Decreasing Circulating Free Fatty Acid Level in Newly Diagnosis T2DMSHARVAN RAMPERSAD, Shanghai, China

A biphasic insulin secretion during the 5-point Oral Glucose Tolerance Test is not an expected and normal finding. We wanted to know what kind of patients have such finding, and what phenotypes of these patients dif-fer from other controls. We collected data about patients having a biphasic insulin secretion and compared them to both normal healthy subjects and to diabetic patients with absence of the first insulin secretory phase. Only male patients between 30 to 55 years of age, having a similar BMI, were selected for this comparison. The 3 groups were divided into group 1 having only nor-mal controls, group 2 comprising of those with a biphasic insulin secretion and group 3 consisting of type 2 diabetes mellitus (T2DM) patients with a delayed insulin secretion. Most patients in the biphasic group were newly diagnosed type 2 diabetic patients, with a glucometabolic profile in between the other 2 groups. Hence, these were shown to represent the early stage of T2DM pathogenesis. Of interest, they had the lowest free fatty acid (FFA) levels (0.55±0.18 vs. 0.29±0.14 vs. 0.48±0.21, P-values being 0.001 and 0.009 respectively) while the other parameters of the lipid profile were not sig-nificantly different. We believe this decreased in FFA level to be due to a protective mechanism in order to decrease insulin resistance in the skeletal muscle by decreasing competition between glucose and FFA for energy pro-duction. This is most probably due to the diacylglycerol O-acyltransferase 2 (DGAT2) enzyme activity. Hence, found that presence of a biphasic insulin secretion indicates early pathogenesis of T2DM. Moreover, a FFA lowering mechanism, we believe to halt the progress of peripheral insulin resistance, probably by an increase in DGAT2 activity, exists.

2592‑PUBEffects of Anesthesia on Glucose and Insulinotropic Responses to Intravenous Glucose (ivGTT) and Mixed Meal (MMTT) Tolerance Tests in Cynomolgus Monkeys with Naturally Occurring DiabetesGAO SUN, XIAOLI WANG, YONGQIANG LIU, BINGDI WANG, GUOFENG SUN, KEEFE CHNG, YONG FU XIAO, YI XIN (JIM) WANG, Taicang, China, New Iberia, LA

Intravenous glucose (ivGTT) and mixed meal tolerance tests (MMTT) are commonly used to evaluate glucose homeostasis in both human and labo-ratory animals. Spontaneously developed diabetes in non-human primates (NHPs), as a translatable model for assessing antidiabetic therapeutics, have been shown to exhibit abnormal glucose control similar to that in type 2 diabetic (T2D) patients. However, the effects of anesthesia on glucose or hormonal responses during these tests are not known. The aim of this study is to further characterize the metabolic responses of glucose and hormonal changes during ivGTT and MMTT in the presence or absence of anesthesia.

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INTEGRATED PHYSIOLOGY—LIVER

Male naturally occurring diabetic cynomolgus monkeys (n=5-10) and their normoglycemic controls (n=5-10) were subject to i.v. glucose or oral mixed meal challenge either in conscious or under ketamine anesthesia when glu-cose, insulin, entero-gastric hormones, adipokines and inflammatory cyto-kines were measured. Diabetic cynomolgus monkeys developed impaired tolerance to both i.v. glucose and mixed meal challenge during awake or under anesthesia. During ivGTT, anesthesia further differentiated diabetic and control NHPs by enlarging the difference in glucose clearance rate which can be reflected by the enhanced insulin response in controls. Dur-ing MMTT, anesthesia appeared to reduce the baseline glucose response in control NHPs accompanied with reduction in serum levels in GIP, leptin, resistin, visfatin, IL-6 and MCP-1.

MMTT along with ivGTT can serve as an additional tool to accurately examine glucose homeostasis in the development of diabetes in cynomol-gus macaques. Anesthesia can be used to increase the window of glucose responses between diabetic and normoglycemic NHPs in above tests for the evaluation of potential glucose lowering drugs.


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2594‑PUBInfluence of Pegylated Interferon and Ribavirin on Insulin Resis‑tance and Metabolic Factors in Patients with Chronic Hepatitis CZEYNEP ALTIN, SERHAT OZER, BETUL KOYUNCU, Izmir, Turkey, Istanbul, Turkey, Usak, Turkey

Objective: It was aimed in this study to evaluate the effect of pegylated interferon alfa 2a/2b and ribavirin - the agents used in chronic hepatitis c - on insulin resistance and metabolic factors.

Material and Methods: A total of 104 chronic hepatitis c patients applying to Katip Celebi University Ataturk Research and Training Hospital, Depart-ment of Gastroenterology between 01.01.2005 - 01.11.2012 with ages rang-ing between 20 and 75 years having serum insulin (0 and 48 weeks) and HCV-RNA (0, 12, 24, 48 and 72 weeks) levels available were included in the study. These parameters were assessed according to the groups based on response to therapy (sustained virologic response-SVR, relapse and non-responders).

Results: Of the 104 patients, SVR was achieved in 55 but 49 (non-SVR). In univariate analyses, no statistically significant association was obtained in gender, age, body mass index, waist circumference, total cholesterol, triglyceride, LDL-cholesterol, HDL-cholesterol, fasting plasma glucose plus insulin and HOMA score at week 0, platelet, arterial blood pressure, degree of steatosis and the last but not least histological activity index between SVR and non-SVR groups. However; a statistically significant difference

was noted in GGT, insulin level plus HOMA score and existence of insulin resistance at week 48, log HCV-RNA and fibrosis between the aforemen-tioned groups (p<0,05). In multivariate analyses, it was concluded that log HCV-RNA, triglyceride and week 48 insulin resistance had influence on SVR (p<0,05) while age, body mass index and fibrosis did not.

Conclusion: Insulin resistance is accepted to have a negative effect of SVR. Insulin resistance may improve once SVR is achieved. In this context, it can be advocated that the regression of insulin resistance at week 48 detected in week 0 may be a predictive factor for SVR at week 72.

2595‑PUBProteomic and Bioinformatic Analysis of the Effect of Platycodon Grandiflorum in the High‑Fat Diet‑Induced Type 2 Diabetic MiceWOO YOUNG KIM, SUNG HO YUN, SANG YEOP LEE, CHI WON CHOI, GUN HWA KIM, SEUNG I.I. KIM, EDMOND C. PARK, Daejeon, Republic of Korea

Extract of Platycodon grandiflorum root (PGE) is known to have beneficial effects on diabetes. However, its detailed mechanism of antidiabetic effect is poorly understood. In this study, we investigated the antidiabetic role of PGE by proteomic and bioinformatic analysis in the mice liver tissue. Mice were faed with 60% kcal of high fat diet (HFD) with or without 5% of ethanol extract of PG root. Experimental groups were (1) AIN-76A formal diet (ND), (2) HFD, (3) HFD+PGE. After 16 weeks of diet, mice fed with PGE showed dramatic reduced body weight. Weight of liver and fat tissue also decreased in PGE group. Furthermore, mice of PGE group showed lower fasting glucose level and improved glucose and insulin sensitivity. In order to investigate the underlying mechanism of antidiabetic effect of PGE, the livers were isolated and hepatic proteome was examined by LC-MS/MS. We identified 1,119, 1,143, 1,250 proteins in ND, HFD, and HFD+PGE, respectively. Comparison of protein expression profiles revealed that changes of protein expres-sion in HFD mostly reverted to normal state by intaking PGE. The proteins were mainly involved in lipid metabolism, fatty acid β-oxidation, oxidative phosphorylation, energy production, and mitochondrial dysfunction. Inter-estingly, proteins associated with epithelial adherents junction signaling are also regulated by PGE in the rescue process of type 2 diabetes. Further extensive bioinformatics analysis would provide us valuable information for possible antidiabetic function and mechanisms of PGE.

Supported By: Korean Ministry of Science, ICT and Future Planning (2015R1C1A1A01054897)

2596‑PUBFasting Levels of Amino Acids Are Correlated to Hyperglucago‑nemia in Patients with Nonalcoholic Fatty Liver Disease Indepen‑dently of Type 2 DiabetesNICOLAI J. WEWER ALBRECHTSEN, ANDERS E. JUNKER, KATRINE D. GALS-GAARD, JENS JUUL HOLST, FILIP K. KNOP, TINA VILSBØLL, Copenhagen, Denmark, Hellerup, Denmark

Hyperglucagonemia is linked to the pathophysiology of diabetes. Interest-ingly, patients with nonalcoholic fatty liver disease (NAFLD) exhibit fasting hyperglucagonemia independently of their diabetic state. In rodents, it has been demonstrated that amino acids (AA) link glucagon actions on hepatic AA metabolism to the pancreatic alpha cells causing hyperglucagonemia and alpha cell hyperplasia if disconnected. Whether a similar relationship can be observed in humans is unknown. We investigated whether elevated AA can explain the hyperglucagonemia in biopsy-verified NAFLD patients compared to individuals without NAFLD, both with and without type 2 dia-betes (T2D). Fasting plasma levels of AAs and glucagon were measured in obese, middle-aged patients with I) normal glucose tolerance (NGT) and NAFLD, II) T2D and NAFLD, III) T2D without liver disease, and IV) healthy con-trols. Elevated plasma levels of AAs were observed in NAFLD patients with NGT (937±281μM vs. 1310±235μM, p=0.03) as well as with T2D (511±235μM vs. 1356±349μM, p<0.0001). Plasma levels of AAs correlated significantly with plasma levels of glucagon also when adjusting for BMI, HbA1c, and cholesterol (β=0.023±0.007, p=0.01). Thus, elevated plasma levels of AAs associate with hyperglucagonemia in NAFLD patients independently of gly-cemic control, BMI or cholesterol - supporting the potential importance of a ‘liver-alpha cell axis’ in which glucagon regulates AA metabolism. AAs may therefore regulate alpha cell secretion and growth, and disruption (e.g., impaired liver function) may lead to increasing plasma levels of glucagon. Fasting hyperglucagonemia in patients with T2D may therefore represent impaired hepatic glucagon action.

Supported By: Novo Nordisk Foundation; Augustinus Foundation; Aase and Ejnar Danielsens Foundation

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2597‑PUBThe Short‑ and Long‑Term Influence of Lixisenatide in Nonalcoholic Fatty Liver Disease in Patients with Type 2 Diabetes Mellitus Com‑pared with Sitagliptin and PioglitazoneANASTASIOS KOUTSOVASILIS, ALEXIOS SOTIROPOULOS, EVDOXIA BLETSA, VASILIS KORDINAS, SOFIA ELVANIDI, DIMITRIOS PANAGIOTOU, EFSTATHIOS SKLIROS, STAVROS BOUSBOULAS, THEODOROS PEPPAS, Athens, Greece

Aim: Accumulating evidence suggests that nonalcoholic fatty liver dis-ease (NAFLD) is associated with an increased prevalence of cardiovascular disease. The aim of the study was to examine the short- and long-term influ-ence of lixisenatide in NAFLD patients with type 2 diabetes mellitus (T2DM) compared with sitagliptin and pioglitazone.

Methods: 142 T2DM patients with NAFLD were included in the study. 48 patients received lixisenatide, 43 pioglitazone and 51 sitagliptin. All patients also received metformin. The patients’ somatometric and laboratory charac-teristics were recorded, as well as metabolic comorbidities every 3 months during the 12 months of follow-up. The evaluation of liver fibrosis depended on aspartase aminotransferase (AST) to platelet counts ratio (APRI) index. All patients went through an ultrasonography before being included in the study and after the end of the study.

Results: There were no differences between groups in patient age (p=0.337), duration of T2DM (p=0.221), Body Mass Index (BMI) (p=0.433) and HbA1c (p=0.198). There was a greater improvement of APRI index from base-line to 3 and 12 months under treatment for the lixisenatide (1.07 (0.46-1.23) vs. 0.94 (0.041-1.12) vs. 0.75 (0.36-0.91) p<0.001) compared to pioglitazone (1.10 (0.49-1.27) vs. 1.03 (0.49-1.22), vs. 0.87 (0.47-1.06), p=0.012), and sita-gliptin (1.01 (0.39-1.14) vs. 0.99 (0.38-1.15) vs. 0.98 (0.36-1.14) p=0.366). APRI index’s improvement was accompanied by a significant change of fatty liver in ultrasonography. The decrease of body weight in the lixisenatide group was statistically significant (p<0.001) with most patients (38) achieving a >5% decrease.

Conclusion: Administration of lixisenatide led to a significant improve-ment of liver inflammation, alteration of liver fibrosis, and reduction of body weight since the first 3 months while there was an even greater improve-ment 12 months after its initiation.

2598‑PUBHepatic FGF‑21 Secretion Does Not Serve a Protective Role in Limit‑ing Diet‑Induced Insulin Resistance (IR)THOMAS C. BECK, FFOLLIOTT M. FISHER, GARIMA SINGHAL, ELEFTHERIA MARATOS-FLIER, OWEN P. MCGUINNESS, Nashville, TN, Boston, MA

Obesity induces IR and increases plasma fibroblast growth factor-21 (FGF-21). Pharmacological FGF-21 improves while global deletion of FGF-21 ampli-fies IR. Prior report (PMC4238010) suggests hepatic loss of FGF-21 in obese mice impaired glucose uptake after an overnight fast. Overnight-fasting mice induces FGF-21 in the liver, which is a source of circulating FGF-21. We examined if loss of hepatic derived FGF-21 impacts insulin action in a physiological fasting state. FGF-21fl/fl mice were mated with Albumin-Cre mice to generate liver specific knockout mice (LKO). Six-week-old male LKO and WT littermates (n=9/group) were placed on a high fat diet (8 wks). One week after insertion of carotid artery (blood sampling) and jugular vein (infusion) catheters a hyperinsulinemic (4 mU-1∙kg∙min-1) euglycemic clamp was performed in 5 hour- fasted conscious mice. Whole body glucose flux ([33H] glucose) and tissue specific glucose uptake ([14C]-2deoxyglucose) were assessed. Body weight (40±2 vs. 37±2 g; WT vs. LKO) and adiposity (24±4 vs. 30±3%) were similar. Plasma FGF-21 was unaltered (152±25 vs. 141±61 pg/ml) despite absence of hepatic expression of FGF-21. The glucose infusion rate, Insulin suppression of hepatic glucose production and glucose uptake in muscle, white and brown adipose were unaltered. Thus, with a more physiologic 5 h fast hepatic-derived FGF-21 does not modulate insulin action in obesity.

Table. Clamp Parameters.Clamp

glucose (mg/dl)

Clamp insulin (ng/ml)

Glucose infusion rate (mg/kg/min)

Basal hepatic glucose

production (mg/kg/min)

Clamp hepatic glucose

production (mg/kg/min)

Gastrocnemius glucose uptake

(μmol/100g tissue/min)

Brown adipose glucose uptake

(μmol/100g tissue /min

WT 145±4 3.5±0.8 21±3 10.3±0.7 1.1±1.4 10.4±0.8 152±29LKO 140±3 2.7±1.0 24±1 9.4±0.5 1.4±1.0 13.1±1.8 144±16

Supported By: National Institutes of Health (DK043748, DK020593, DK059637, DK007563)

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2600‑PUBIncreased Liver Fat Content in Totally Pancreatectomized PatientsASGER B. LUND, JONATAN I. BAGGER, NICOLAI J.W. ALBRECHTSEN, MIKKEL CHRISTENSEN, MAGNUS GRØNDAHL, CARSTEN P. HANSEN, JAN H. STORK-HOLM, JENS JUUL HOLST, TINA VILSBØLL, FILIP K. KNOP, Hellerup, Denmark, Copenhagen, Denmark

Lack of glucagon signaling has been shown to increase hepatic fat content in animal studies. Furthermore, administration of glucagon receptor antago-nists are associated with increases in hepatic transaminases and fat con-tent in type 2 diabetes patients. Here we evaluated hepatic fat content and aspartate transaminase (AST) and alanine transaminase (ALT) in totally pan-createctomized patients without glucagon-secreting pancreatic alpha cells. Fasting blood samples and transient liver elastography (Fibroscan 501®, EchoSensTM, Paris, France), as a measure for hepatic fibrosis and steatosis, were performed in 10 totally pancreatectomized patients (age [mean ± SD]: 59.8±9.9 years; BMI: 21.5±4.3 kg/m2; HbA1c: 67.3±11.0 mmol/mol; time since operation: 4.6±4.5 years), and 10 age, sex and BMI-matched healthy control subjects (age: 58.4±5.0 years; BMI: 22.9±2.4 kg/m2; HbA1c: 34.6±6.2 mmol/mol). In both groups hepatic elasticity were within normal range (Fibrosis stage 0) with no difference in transmission speed of the ultrasonic waves between the pancreatectomized group and the control group (5.1±0.34 vs. 4.8±0.52 kPa, P=0.52). In the pancreatectomized group, two patients had steatosis grade 3 (67-100% of hepatocytes with fat accumulation), two patients had steatosis grade 2 (33-66% of hepatocytes with fat accumula-tion), one patient had steatosis grade 1 (11-33% of hepatocytes with fat accumulation) and five patients had steatosis grade 0 (<11% of hepatocytes with fat accumulation). In the control group, two subjects had steatosis grade 2, and eight subjects had steatosis grade 0. Fasting concentrations of AST were higher in the pancreatectomy group compared to the control group (54.2±4.5 vs. 35.0±3.0 U/L, P=0.003) while no difference was observed for ALT (33.6±4.5 vs. 25.6±2.2 U/L, P=0.13) Totally pancreatectomized patients are characterized by increased hepatic fat content and higher fasting plasma concentrations of AST, which may relate to surgical removal glucagon-secreting alpha cells.

Supported By: European Foundation for the Study of Diabetes/Merck Sharpe & Dohme; Novo Nordisk Foundation; University of Copenhagen; European Molecular Biology Organization; European Foundation for the Study of Diabetes; A.P. Møller Foundation; Aase and Ejnar Danielsens Foundation; Johan Boserup and Lise Bos-erup’s Foundation

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INTEGRATED PHYSIOLOGY—MACRONUTRIENT METABOLISM AND FOOD INTAKE

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2603‑PUBEffect of Pioglitazone on Insulin Sensitivity and Hepatic Mitochon‑drial Function in a Mouse Model of Nonalcoholic SteatohepatitisSRILAXMI KALAVALAPALLI, KAITLYN ABDO, DHANYA JOSE, PAIGE ANDREWS, KENNETH CUSI, NISHANTH E. SUNNY, Gainesville, FL

We have reported that the PPARγ agonist pioglitazone is effective in improving insulin resistance and liver histology in patients with nonalcoholic steatohepatitis (NASH) (Cusi et al, Ann Intern Med, 2016). Because hepatic mitochondrial dysfunction is a central feature of NASH, we speculated that this was due, at least in part, from effects of pioglitazone on adipose tissue and/or hepatic mitochondrial metabolism. To test this hypothesis, we stud-ied the effect of pioglitazone in a NASH model in which C57/BL6 mice con-sistently develop NASH when fed a high-fructose high trans-fat diet (TFD) for 24 weeks. After 4 weeks on a TFD diet, half of the mice were given piogli-tazone (0.1 mg pioglitazone per gram of TFD) for the next 20 weeks (n= 6-8/group). A mice control group was also studied. Hepatic mitochondrial metab-olism was evaluated by jugular vein infusion of [13C3]propionate and [3,4-13C2] glucose followed by nuclear magnetic resonance based 13C-isotopomer analysis. Tissues were analyzed for gene and protein expression. Fasting

plasma glucose (109±8 vs. 88±4 mg/dL) and postprandial plasma insulin and FFAs (both -40%) were all lower in the pioglitazone group (p≤0.05), indicat-ing an improvement in hepatic and adipose tissue insulin sensitivity. Liver TG content decreased ~20% in the pioglitazone group, as well as plasma ketones (TFD: 133±22 vs. PIO: 85±3, p=0.07). This was associated with a significant reduction in hepatic TCA cycle flux (TFD: 8.4±1.2 vs. PIO: 5.5±0.4, p=0.02), anaplerosis (p=0.08) and pyruvate cycling (p=0.07).

In conclusion, our results suggest that pioglitazone-induced improvement in adipose tissue insulin sensitivity (likely associated with a reduced FFA flux to the liver), play a major role in regulating hepatic mitochondrial oxidative flux and liver insulin sensitivity in mice with steatohepatitis. Additional work is needed to further understand the direct effects of pioglitazone on hepato-cyte mitochondrial function.

INTEGRATED PHYSIOLOGY—MACRONUTRIENT METABOLISM AND FOOD INTAKE

2604‑PUBBeneficial Effects of White and Brown Rice on Weight Gain, Insulin Sensitivity, and Gut Microbiota while on High‑Fat DietHISASHI YOKOMIZO, ATSUSHI ISHIKADO, YASUTAKA MAEDA, KYOUNGMIN PARK, TAKANORI SHINJO, I-HSIEN WU, DAVID M. POBER, DEVKOTA SUZANNE, MOTONOBU MATSUMOTO, GEORGE L. KING, Boston, MA, Los Angeles, CA, Osaka, Japan

Increased consumption of white rice (WR) and the parallel decreased intake of brown rice (BR) have been associated with the dramatic elevation of type 2 diabetes (T2DM) prevalence in Asians and Asian Americans. The ben-eficial actions of BR are attributed to the fibers and antioxidants in the bran and the germ that are removed during the processing to WR. However, diet containing WR (Duke rice diet) has been touted to cause weight loss. To test whether white or brown rice have differential effects that can increase the risks for diabetes, C57BL/6 mice were fed 6 different diets: control diet (CD), high fat diet (HFD) and CD and HFD with either WR or BR for 18 weeks. When WR or BR was added to CD or HFD, they did not change the total calories of the original diets. After 12 or 18 weeks, the median weights of mice on HFD were 37% more than those on CD. Interestingly, the addition of WR or BR to HFD decreased the weight gains equally by 48% even though the amount of daily food intake did not differ amongst the various diets. Intraperitoneal insulin tol-erance (IPITT) and intraperitoneal glucose tolerance tests (IPGTT), performed at 12 and 18 weeks after diet initiation also showed that HFD induced fast-ing hyperglycemia, hyperinsulinemia and area under the curves for IPITT and IPGTT vs. CD, which were normalized partly by either WR or BR, significantly. However, mice on BR+HFD exhibited significantly greater improvements in insulin tolerance tests than mice on WR+HFD. Gut microbiota, analyzed by 16S sequencing and principal component analysis, showed significant differences between CD vs. HFD as well as between HFD containing BR or WR in parallel with changes in weights and insulin tolerances. Thus, white rice and especially BR, may contain substances that can decrease weight gain and improve insulin sensitivity, possibly due to changes in gut microbiota in mice, even if the host is consuming high fat diet. Further studies are needed to identify those sub-stances in rice that appear to lower risks for T2DM.

2605‑PUBHSF1 Induction of Heat Shock Proteins Is Required for mTOR‑Dependent Protein SynthesisJIA YOU, JU HO YOUN, ROMEO GIULIO, JONGSOON LEE, STEVEN E. SHOELSON, Boston, MA

Heat shock factor 1 (HSF1) is the transcription factor that controls the clas-sic heat shock response (HSR), a rapid, intense induction of heat shock pro-teins (HSPs) after exposure to heat or other stresses. Our studies show that mammalian HSF1 also controls previously unknown physiological responses under unstressed conditions. Feeding, especially after fasting, activates HSF1 and HSP expression in mouse tissues including liver and muscle. mTOR is upstream and required for HSF1 and HSP induction by feeding, which may be mimicked by insulin or Tsc1 or 2 deletion and blocked using mTOR inhibi-tors Torin or INK128 or knockdown of Rheb or raptor. RNAseq analyses of wt vs. Hsf1-/- livers (Flox x AlbCre) showed that HSF1 drives a chaperone pro-gram during fast-refeeding required for proper folding of proteins induced by activated mTOR. Secondary effects of HSF1 deletion included suppression of 1) mTOR dependent protein synthesis and 2) the Xbp1s driven unfolded protein response (UPR), both of which were activated by feeding in wt liver. Despite both being driven by HSF1, the feeding and heat shock responses differ both qualitatively and quantitatively: 1) magnitudes of induced mRNAs

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INTEGRATED PHYSIOLOGY—MUSCLE INTEGRATED PHYSIOLOGY—OTHER HORMONES

for HSR>>feeding; 2) only a small subset of induced mRNAs are common to heat and feeding; 3) the HSF1 feeding response is dependent on canonical Tsc1/2-Rheb-mTORC1 signaling, while the HSR is mTOR independent; and 4) it is well known that prior bouts of heat abrogate subsequent HSRs, whereas feeding occurs repetitively without suppression of induced HSPs. We con-clude that HSF1 is required for mTOR-dependent protein synthesis by driving the production of chaperones needed for proper folding of nascent proteins.

Supported By: American Diabetes Association (7-12-MN-77 to S.E.S.)

INTEGRATED PHYSIOLOGY—MUSCLE

2606‑PUBInsulin Restores UCP3 Activity and Decreases Energy Surfeit to Alleviate Lipotoxicity in Skeletal MuscleWENJUAN TANG, SUNYINYAN TANG, HONGDONG WANG, ZHIJUAN GE, DALONG ZHU, YAN BI, Nanjing, China

Early insulin regimen ameliorates glucotoxicity but also lipotoxicity in type 2 diabetes; the underlying mechanism remains elusive. Here we inves-tigated the role of mitochondria in muscular lipid regulation by early insulin therapy. Male C57BL/6 mice with 8-weeks of high-fat diet were treated with insulin for 3 weeks, and L6 myotubes cultured with 24 h-palmitate (PA) were incubated with insulin for 12 h. Results showed that insulin facili-tated glucose disposal and attenuated intramyocellular lipid content in vivo. Recovered AMP-activated protein kinase (AMPK) phosphorylation, inhibited sterol-regulated element binding protein-1c and increased carnitine palmi-toyltransferase-1B expression were observed after insulin administration. Moreover, insulin decreased muscular ATP content and restored uncoupling protein 3 (UCP3) expression, while knockdown of UCP3 abrogated the impact of insulin on the recovery of AMPK phosphorylation in vitro. Importantly, PA-induced UCP3 decrease could be blocked by a proteasome inhibitor MG132, and insulin was identified to reduce UCP3 ubiquitination, thereby prohibiting its degradation. Our data indicated that insulin, via recovering UCP3 activity, alleviated energy surfeit and potentiated AMPK-mediated lipid homeostasis in skeletal muscle. It provided an energetic insight into the promising effect of early insulin initiation on lipotoxicity.

Figure.

Supported By: National Natural Science Foundation of China (81570736, 81600632, 81600637, 81270906)

2607‑PUBCurcumin Alters Iron Regulation in a High‑Iron C2C12 Skeletal Mus‑cle ModelJACOB G. ANDERSON, DANIEL J. TUELLER, CHAD R. HANCOCK, Provo, UT

According to the American Diabetes Association, 29.1 million people in the U.S. have diabetes, 95% of cases being type 2 diabetes. Diabetic patients show increased levels of circulating iron and signs of iron dysregu-lation. Recent studies show a correlation between iron dysregulation and insulin resistance. Unbound iron in cells leads to increased free radicals causing damage, including insulin resistance. Curcumin, a naturally occur-ring compound in the spice, turmeric, has been shown to be effective in improving insulin sensitivity, although the mechanisms by which it does so are not entirely understood. Curcumin has been shown to bind iron and is very likely to have an effect on iron regulation. Using a C2C12 immortalized mouse skeletal muscle cell line with elevated iron, as seen with diabetes, we investigated the effects of curcumin on iron regulation. Differentiated cells were treated with 0-90 μM FeCl3 for 24 hours. There was a dose dependent response to iron treatment with an increase in total iron, decrease in trans-ferrin receptor (TfR), and increase in ferritin light chain (FLC) expression. Fol-

lowing 24 hours of iron treatment using 10 μM FeCl3 cells were treated with 40 μM curcumin for 15 or 24 hours. Effects of curcumin on the iron status of the treated cells were assessed by analyzing the total iron content and protein expression of TfR and FLC. Total iron content was measured using a total iron colorimetric assay. Proteins were measured using Western blots. Curcumin treatment for 24 hours did not alter total iron concentrations in high iron cells (P=0.75, N=4). TfR protein expression decreased by 10% with 15 hours curcumin treatment (P=0.01 N=5). FLC protein expression increased by 26% with 15 hours curcumin treatment (P=0.05, N=6) and increased by 38% with 24 hours treatment (P=0.02, N=4). Thus, in the context of an iron challenge, as would be seen with diabetes, curcumin can change cellular iron regulation and may play a role in improving insulin sensitivity.

INTEGRATED PHYSIOLOGY—OTHER HORMONES

2608‑PUBNutrient and Hormonal Regulation of Angiopoietin‑Like Protein 8 (ANGPTL8) in Hepatocytes and AdipocytesLU ZHANG, MUHAMMAD ABDUL-GHANI, LUKE NORTON, RALPH A. DEFRONZO, San Antonio, TX

ANGPTL8 plays an important role in modulating lipid profiles and is regu-lated acutely in liver and adipose tissue following fasting and refeeding. However, the molecular mechanisms regulating its expression and secre-tion remain largely unknown. In this study, we investigated the regulation of ANPTL8 by insulin and glucose in vitro and in vivo. Insulin increased ANGPTL8 gene expression in rat hepatoma cells and differentiated 3T3-L1 adipocytes in a dose-dependent manner. The effects of insulin arose rap-idly within 60 minutes following insulin treatment in both cell lines. In mice, a 2-hour euglycemic-hyperinsulinemic clamp markedly stimulated a 5-fold increase of ANGPTL8 mRNA levels in liver and 3-fold increase in adipose tissue. To further examine the regulation of ANGPTL8 by insulin, we cloned the 1.5 Kb promoter upstream of ANGPTL8 start codon into pGL4-Luc vec-tor. Consistent with the data above, insulin stimulated the activity of the luciferase reporter acutely, highlighting the primarily transcriptional regula-tion of ANGPTL8 by insulin. In contrast to hyperinsulinemia, hyperglycemia regulated ANGPTL8 mRNA in adipocytes only, and we observed an additive effect of hyperglycemia and hyperinsulinemia on ANGPTL8 expression in adipocytes. These differences in nutrient regulation of ANGPTL8 suggest that distinct pathways are responsible for regulating ANGPTL8 gene expres-sions in these cells. Our current results imply that the stimulation of insulin on ANGPTL8 in hepatocytes is mediated by inhibiting AMPK activity. Insulin downregulated AMPK activity by phosphorylating AMPKα on S485, and the addition of AMPK activator AICAR abolished the activation of ANGPTL8 by insulin. Interestingly the AMPK inhibitor Compound C augmented the effects of insulin on ANGPTL8 mRNA. These data suggest that the cooperation of insulin, glucose and AMPK regulates ANGPTL8 expressions in response to different nutritional status in two important metabolic tissues.

2609‑PUBDensity of Enteroendocrine Cells in Duodenal Biopsies Obtained before and after Treatment with Duodenal‑Jejunal Bypass Sleeve in Obese Patients With and Without Type 2 DiabetesTINA JORSAL, ULRICH ROHDE, PETER VILMANN, EBBE LANGHOLZ, STEFFEN U. FRIIS, CECILIE A. FEDERSPIEL, STEEN S. POULSEN, TINA VILSBØLL, FILIP K. KNOP, Copenhagen, Denmark, Hellerup, Denmark, Herlev, Denmark

The endoscopically deployed duodenal-jejunal bypass sleeve (DJBS) used for the treatment of obesity and type 2 diabetes (T2D) is anchored in bulbus duodeni and extends 60 cm into the small bowel. The device is imperme-able and thereby prevents ingested nutrients from contact with the upper small intestinal mucosa. We investigated whether DJBS impacts the den-sity of enteroendocrine cells in the duodenum with particular focus on the incretin hormone-secreting K and L cells. Ten normal glucose tolerant (NGT) obese individuals and nine age, sex and body weight-matched metformin-treated patients with T2D underwent treatment with DJBS for either 26 or 52 weeks. Mucosal biopsies were sampled from the second part of the duo-denum during DJBS implantation (IMP) and explantation (EXP) procedure and analyzed for chromogranine A (CgA), glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), peptide YY (PYY) and prohormone convertase 2 (PC2) using immunohistochemical staining and cell count. IMP and EXP were compared within groups (using paired t-tests) and between groups (using unpaired t-tests). DJBS treatment increased CgA-positive cell density in both groups, however only significantly in the NGT group (P=0.02). Density of GIP-positive cells declined in the NGT group

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(P=0.02) and showed a tendency to increase in the T2D group. The number of GLP-1-positive cells increased in T2D patients (P=0.04), however not in NGT individuals. The density of PYY and PC2-positive cells did not change in either group. No significant differences were observed between the two groups at IMP and EXP time, respectively. DJBS leads to divergent altera-tions in enteroendocrine cell density in obese subjects with and without T2D, respectively. These changes might affect gut hormone secretion and potentially influence postprandial glucose metabolism.

2610‑PUBVisceral Adiposity Index and Triglycerides/cHDL Ratio as a Marker of Cardiometabolic Risk in Obese Women with Polycystic Ovarian Syndrome (PCOS)TANIA HOBERUK AYALA, ELVIO BUENO, JORGE T. JIMENEZ, ALDO BENITEZ, MAFALDA PALACIOS, Asunción, Paraguay

Women with PCOS exhibit signs of insulin resistance (IR) and frequently beta cell dysfunction. Although most of them are themselves obese, this is not the rule, suggesting that alone is not a sensitive marker of IR. The Visceral Adiposity Index (VAI) and Triglyceride/cHDL ratio (TG/HDL) could be more accurate indicators in this group of patients of the presence of IR.

Objective: Determine the value of VAI and TG/HDL in the evaluation of cardiometabolic risk (CMR) in patients obese with PCOS.

Research Design and Methods: Prospective, case-control, cross-sec-tional, consecutive study of 60 obese patients of fertile age, followed for 1 year. TG/HDL was found in all patients and the VAI was calculated using the sex-specific equation of Amato et al.

Results: PCOS group (PCOSG) were younger and less obese (Age: 26 ± 5 vs. 32±7 years p: 0.0003 and BMI: 37±6 vs. 42±8 kg/m2 p: 0.002). The TG/HDL was more altered in PCOSG (OR: 4.9 p 0.004), the mean was 4.6 ± 3 SD and 2.89 ± 1.8 SD in the control group (CG). The VAI was higher in the PCOSG with a mean of 8.5 ± 2 SD and 5.5 ± 2 SD in the CG (OR: 2.2 p 0.008). The cut-off point where 100% of women with PCOS had the TG/HDL index altered was 7,4. Phenotype with hyperandrogenism had higher these indexes.

Conclusions: Women with PCOS had a significantly higher TG/HDL and VAI, although the latter were older and more obese. These indexes, which are easy to find in daily practice, would help us to establish those patients with PCOS, who may need to emphasize a primary cardiometabolic preven-tion, besides reaffirming the role of the abdominal fat and the presence of this syndrome in IR and CMR, regardless of age and BMI.

2611‑PUBOxyntomodulin and Glucagon in Healthy Humans: Anthropometric, Hormonal, and Metabolic Predictors and Response to Glucose Load and ExerciseJAGRITI UPADHYAY, GRIGORIOS PANAGIOTOU, ATHANASIOS ANASTASILAKIS, CHRISTOS MANTZOROS, Boston, MA, Thessaloniki, Greece

Aim: Oxyntomodulin (OXM) and glucagon affect glucose homeostasis and energy metabolism. We aimed to study physiology of these molecules and response to a mixed meal or glucose ingestion and exercise.

Method: Study A: Cross-sectional study with two interventional arms. Healthy, young individuals of both genders (n=122) were subjected to anthro-pometric and body composition measurements. Sub-groups were given a mixed meal i.e., 250ml boost (n=18) or performed aerobic exercise for 30 min (n=20). Blood samples were collected before and 30 min after interven-tions. Study B: Response of OXM and glucagon to oral glucose tolerance test (OGTT) in a separate group of patients (n=5) who underwent bariatric sur-gery. OGTT was done before and 6 months after the surgery. OXM and glu-cagon were quantified with ELISA kits from Ansh Laboratories, Webster, TX.

Results: Study A: OXM levels did not show a gender difference, but they were correlated with glucagon (r=0.42; p<0.001), irisin (r=-0.25; p=0.01), and insulin (r=0.37; p<0.001). The association between OXM and glucagon became nonsignificant after adjusting for insulin. OXM increased after 250ml boost (204.97 ± 92.48 vs. 317.01 ± 128.80 pg/ml, p<0.001) and decreased after exercise (253.13 ± 112.05 vs. 218.06 ± 89.18 pg/ml; p=0.02). Glucagon levels were higher in males (p=0.01) and showed baseline correlation with OXM and insulin which persisted after correcting for age, gender, BMI and % Body Fat (p<0.05 for all). Glucagon was not affected by mixed meal or exercise. Study B: Both glucagon and OXM showed a robust response after glucose load in patients who underwent bariatric surgery as compared to baseline (mean iAUC OXM-53.4 vs. 2681.76 pg/ml, p<0.045, mean iAUC glu-cagon-59.75 vs. 166.30pg/ml, p <0.029).

Conclusions: OXM levels correlated with insulin and glucagon, increase after caloric intake and decrease after exercise. Both glucagon and OXM increase in response to OGTT after bariatric surgery vs. pre-surgery.

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2613‑PUBAugmented GH Response to GHRH Combined with Pyridostigmine Unrelated to Raised Glomerular Filtration Rate in Type 1 DMJESÚS PÉREZ-LUIS, JUDITH LÓPEZ-FERNÁNDEZ, JAVIER SALVADOR, San Cristóbal de La Laguna, Spain, Pamplona, Spain

Introduction and Hypothesis: In patients with poorly controlled DM-1, the frequently observed alterations of somatotrophic axis seem to be related to abnormalities in the hypothalamic cholinergic tone regulating this axis. The effects of cholinergic stimulation with pyridostigmine (PD) on GH responses to GHRH were evaluated in patients with DM-1 with poor glycemic control as well as the relationship of these responses to metabolic status and kidney function tests.

Subjects and Methods: Microalbuminuria and creatinine clearance (GFR) on 24 h urine samples, and the effects of the administration of 50 mcg GHRH IV plus placebo (Pb) and GHRH plus PD on GH and glucose circulating lev-els were studied in 16 young males: 10 normal controls and 6 patients with poorly controlled DM-1 (HbA1c 9.2%) without retinopathy or nephropathy. In each test, Pb or PD (120 mg) were given orally in random order on different days at 0830. Blood samples were drawn before Pb or PD, and then every 15 min until 1130. Response parameters and AUC of secretion were calculated. Data are expressed as the mean ± SEM.

Results: GH responses to GHRH plus Pb were not different between diabetics and controls. On the contrary, GHRH plus PD raised GH concen-tration within each group, with the highest GH increase in diabetics (AUC of response of GH: 4085.83 ± 1227.86 vs. 1914.46 ± 385.06 ng/ml/120 min, p <0.05). GFR was greater in diabetics, although not significant (134.85 ± 20.62 vs. 110.12 ± 8.13 ml/min). GH was not correlated with glucose in any of the tests. Moreover, in diabetics, HbA1c, microalbuminuria and GFR showed no correlation with GH.

Discussion and Conclusions: In this study, despite the fact that GH responses to GHRH were not shown to be greater in diabetics, the higher GH responses to GHRH plus PD could indicate that there is augmented choliner-gic and reduced somatostatinergic tones in poorly controlled DM-1 patients. Furthermore, these findings are not related with the higher GFR observed in diabetics.

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2614‑PUBFibroblast Growth Factor‑21 (FGF‑21): A Mediator of Inflammatory Responses to Diets?TAYLOR M. DIXON, SHALIGRAM SHARMA, LAURA A. FORNEY, THOMAS W. GETTYS, DESIREE WANDERS, Atlanta, GA, Baton Rouge, LA

Accompanying obesity is a low-grade inflammation that is an underlying factor linking obesity to chronic diseases including type 2 diabetes. Dietary methionine restriction (MR) by 80% decreases peripheral inflammation and increases insulin sensitivity in rodents despite increasing energy intake. MR rapidly and persistently increases tissue and circulating concentrations of fibroblast growth factor-21 (FGF-21). When administered pharmacologically FGF-21 reduces body weight, increases insulin sensitivity, and improves blood lipids in rodents. Emerging evidence suggests that FGF-21 may exhibit anti-inflammatory properties. The ability of MR to increase energy intake and expenditure is abolished in FGF-21-/- mice, indicating the importance of FGF-21 as a signaling molecule mediating responses to this diet. The objec-tive of this study was to identify the role of FGF-21 in mediating the anti-inflammatory effects of MR. Wild type (WT) and FGF-21-/- mice were fed high-fat (HF) diets for 4 weeks. Mice were then randomized to remain on the HF control diet or be switched to the HF MR diet for an additional 11 weeks. mRNA expression of inflammatory markers (Ccl2, Emr1, Itgam, Itgax, Il6, Tnf, Il1b) were measured in adipose tissue and liver. Western blot analyses were conducted to measure phosphorylation of the inflammatory transcrip-tion factor, STAT3. FGF-21-/- mice were more susceptible to HF diet-induced hepatic inflammation, and displayed increased phosphorylation of STAT3 compared to WT mice. MR decreased inflammation to a similar extent in WT and FGF-21-/- mice. Complicating interpretation of these data is that FGF-21-/- mice on the MR diet unexpectedly decreased food intake resulting in decreased body weight. These studies support a role for FGF-21 in mitigating hepatic inflammatory response to a HF diet, and identified STAT3 as a poten-tially novel signaling molecule in mediating the anti-inflammatory effects of FGF-21. FGF-21 may not be required for the anti-inflammatory effects of methionine restriction.

Supported By: American Diabetes Association (7-13-MI-05 to T.W.G.)

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2616‑PUBApoA‑IV Regulates High‑Fat Diet‑Induced Metabolic Inflammation and Insulin Resistance in MiceYUPENG ZHANG, SR., JING HE, JING ZHAO, CHEN ZHANG, ZHENZHEN LI, PATRICK TSO, ZONGFANG LI, XIAOMING LI, Xi’an, China, Cincinnati, OH

Obesity-associated metabolic inflammation characterized by increased proinflammatory cytokines and macrophage infiltration into white adipose tissue (WAT), which promotes insulin resistance, is the pathogenesis of obesity-related metabolic disorders. ApoA-IV produced by enterocytes plays a role in anti-inflammation induced by LPS in mice. However, the effect of ApoA-IV on metabolic inflammation induced by a high fat diet (HFD) remains unclear.

ApoA-IV deficient (A4-KO), ApoA-IV transgenic (A4-TG) and C57BL/6 wild type mice were fed with the HFD for 16 weeks. IPGTT and IPITT were exam-ined. Proinflammatory cytokines from plasma and the isolated WAT were determined by using Real-time PCR and CBA (BD™ Cytometric Bead Array) respectively. Macrophage infiltration was detected by Histology. The per-centages of M1 macrophages in blood and WAT were analyzed by using flow cytometry (FCM).

After 16 weeks HFD, compared with wild type mice, ApoA-IV-KO mice exhibited abnormal glucose tolerance and more insulin resistance, however, ApoA-IV-TG mice displayed improved glucose tolerance and insulin sensitiv-ity. Plasma concentration of proinflammatory cytokines and the mRNA lev-els of inflammatory genes in adipose tissue were elevated significantly, and anti-inflammatory cytokines were reduced in obesity A4-KO mice, but A4-TG mice showed the opposite results. Furthermore, HE and immuohistochemical (IHC) IHC detection in WAT revealed more macrophage infiltration in ApoA-IV-KO mice compared with WT animals, whereas such infiltration was rarely detected in the mice that overexpress ApoA-IV. Finally, by FCM, circulating M1 (CD11b+Ly6Chi) proinflammatory monocytes in peripheral blood and M1 (F4/80+CD11c+) in WAT were significantly higher in A4-KO mice than that in WT mice, however, A4-TG mice was the opposite. Taken together, ApoA-IV may play an important role in protecting from HFD induced insulin resistance through inhibiting adipose tissue and systematic metabolic inflammation.

Supported By: Shaanxi Provincial Key Scientific and Technological Project (2016JZ032); Key Scientific Research Fund (201410 to X.L.)

2617‑PUBLipocalin‑Type Prostaglandin D2 Synthase Alters Fasting Bile Acid Fractions Pre‑ and Post‑Vertical Sleeve Gastrectomy: A Novel Role in Bile Acid MetabolismSUNIL KUMAR, RAYMOND LAU, THOMAS PALAIA, CHRISTOPHER HALL, MAT-THEW STEVENSON, JENNY LEE, COLLIN BRAITHWAITE, LOUIS RAGOLIA, Mineola, NY

The prevalence of obesity has significantly increased over the last few decades. Recently, bariatric surgery has been considered the most suc-cessful method for sustained weight loss congruent with restoration of normal metabolism, possibly through bile acid modulation. Our lab focuses on lipocalin-type prostaglandin D2 synthase (L-PGDS), an enzyme that also functions as a transporter of lipophilic molecules including bile acids. There-fore, we designed the current study to investigate the role of L-PGDS on bile acids using C57BL/6 and L-PGDS knock-out (KO) mice that underwent either sham or vertical sleeve gastrectomy (VSG); n=5/group. Animal proto-cols were approved by the animal care ethical committee. Plasma bile acids were measured using the Biocrates Life Sciences Bile Acids kit pre- and 10 weeks post-sham or VSG. Data were analyzed using unpaired t-test or one-way ANOVA with a p<0.05 deemed significant.

Our results showed significantly elevated fasting cholic acid, deoxycholic acid and α, β, Ω muricholic acids in L-PGDS KO mice prior to surgery when compared to C57BL/6 control mice, which were later reduced significantly post-VSG and more closely paralleled controls. In addition, fasting glyco-cholic acid levels remained almost unchanged post-VSG in L-PGDS KO mice, but were 3.3-fold higher in C57BL/6 mice. Furthermore, taurodeoxycho-lic acid which was unchanged pre- and post-VSG in L-PGDS KO mice but showed a 10-fold increase in C57BL/6 mice. Finally, fasting glycodeoxycholic acid and glycochenodeoxycholic acid levels in both C57BL/6 and L-PGDS KO groups pre- and post-VSG remained unchanged. Collectively, these findings indicate the possible intervention of L-PGDS in the conjugation of bile acids. Therefore, we conclude that L-PGDS plays an important role in both bile acid metabolism and selective conjugation. Further detailed studies are in-prog-ress to determine the actual molecular mechanism involved.

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2618‑PUBPharmaceutical Inhibition of MEK/ERK Cascade Alleviates Tumor‑Induced Metabolic AbnormalitiesWEI SONG, SHANGYU HONG, ALEXANDER BANKS, NORBERT PERRIMON, Boston, MA

Cross-talk between tumors and host tissues plays essential roles in cancer cachexia or tumor-associated systemic metabolic abnormalities, including muscle wasting, lipid loss and hyperglycemia. However, the patho-genic molecular mechanism(s) is still poorly understood. Using a fly cancer cachexia model, we demonstrate that MEK/ERK signaling is aberrantly activated in the fat and muscle tissues of flies bearing gut Yorkie-tumors. Specific genetic activation of MEK/ERK cascade in the wild type muscle and fat body results in muscle wasting and lipid loss, respectively. Strikingly, feeding tumor-bearing flies with low dose of MEK inhibitors moderately sup-presses MEK/ERK signaling in the fat body and muscle and significantly alle-viates cachectic effects, including muscle wasting, lipid loss, hyperglycemia and mortality, without affecting tumor progression. Moreover, when we generated tumors resistant to MEK inhibitors via overexpression of an active ERK and fed flies high dose of MEK inhibitors, a potent suppression of MEK/ERK signaling in fat and muscle tissues was observed and the cachexia phe-notype was suppressed. Conserved beneficial effects were also observed in mammalian models, as MEK inhibitors improves lipid loss in adipocytes and muscle wasting induced by conditioned medium from cachectic cancer cells. Thus, our results demonstrate the essential roles of MEK/ERK in cancer cachexia and indicate that MEK/ERK inhibitors could be used for treatment of tumor-induced metabolic abnormalities.

Supported By: American Diabetes Association (1-16-PDF-108 to W.S.)

2619‑PUBFish Oil Supplementation Prevents Increases of Specific Endocan‑nabinoids in Rhesus Monkeys with Diet‑Induced Metabolic Syn‑drome: Dyslipidemia and Insulin ResistancePETER J. HAVEL, JAMES L. GRAHAM, KIMBER L. STANHOPE, ANDREW A. BREMER, JOHN NEWMAN, Davis, CA, Bethesda, MD

Fish oil supplementation prevents the development of components of the metabolic syndrome including increases of triglycerides, apolipoprotein-C3, and insulin resistance as assessed by intravenous glucose tolerance tests in rhesus monkeys consuming a high sugar (fructose) diet. Blockade of peripheral endocannabinoid (CB1) signaling has been demonstrated to have multiple beneficial metabolic effects. A targeted metabolomic/lipidomics approach was used to assess changes of plasma endocannabinoids in adult male rhesus monkeys (n=10) fed a high sugar diet provided as 500 ml/day of a 15% fructose-sweetened beverage for 6 months. Five animals received fish oil (4 g/day) and 5 received a control (safflower) oil. As expected, fish oil supplementation markedly increased circulating EPA and DHA concen-trations. Plasma levels of two specific endocannabinoids, N-Arachidonoyle-thanolamine (anandamide/AE-A) and N-dihomo-γ-linolenoyl ethanolamide (DGL-EA) were increased by 37 ± 14% (p> 0.025) and 70 ± 10% (p< 0.01) in control monkeys, but not in those supplemented with fish oil. These results implicate increased endocannabinoid signaling in the adverse metabolic effects of dietary fructose and suggest that the effects of omega-3 fatty acids derived from fish oil may be mediated in part by reducing activation of the endocannabinoid system in a nonhuman primate model of metabolic syndrome.

Supported By: National Institutes of Health (AT-003645)

OBESITY—ANIMAL

2620‑PUBRaphani Semen Extract Prevents Diet‑Induced Obesity, Hepatic Steatosis, and Insulin Resistance in MiceSUJIN SUK, WOO JUNG JANG, SANG GWON SEO, JONG HUN KIM, HYE LIM NOH, RANDALL H. FRIEDLINE, KUNIKAZU INASHIMA, DUY A. TRAN, XIAODI HU, KAREN KELLY, JUNG HAN YOON PARK, JASON K. KIM, KI WON LEE, Worcester, MA, Seoul, Republic of Korea

Raphani Semen (RS), a dried seed of radish, has been used as a traditional Asian medicine to treat hypertension and digestive disorders. Sulforaphene is a major bioactive component of RS and was shown to inhibit adipogen-esis in vitro. Here we prepared sulforaphene-enriched RS extract (RSE) and examined the effects in diet-induced obesity. Male C57BL/6J mice were fed a high-fat diet (HFD) supplemented with RSE (HFD+RSE), HFD alone, or standard diet (SD) for 16 weeks (n=9 for each group). RSE suppressed HFD-induced weight gain and reduced epididymal fat mass by ~50% (Fig-

ure 1; #,*P<0.05). This was associated with 3~4 fold increases in mitochon-drial expression of CPT2 and NRF1 in adipose tissue of HFD+RSE-fed mice. Serum free fatty acid levels were significantly reduced in HFD+RSE-fed mice (1.1±0.2 vs. 1.4±0.3 mM in HFD-fed mice). Liver triglyceride levels were increased by ~60% after HFD, but HFD+RSE-fed mice were protected from hepatic steatosis partly due to a 2-fold increase in CPT1A expression (Figure 2 and 3). HFD+RSE-fed mice showed significantly improved glucose toler-ance as compared to HFD-fed mice (Figure 4).

In conclusion, these data indicate that RSE prevents HFD-induced obesity and fatty liver by upregulating mitochondrial lipid oxidation and partially protects against insulin resistance. Thus, our findings identify a potential therapeutic role of RSE to treat obesity and type 2 diabetes.

Figures.

Supported By: National Institutes of Health (2U2C DK093000-06)

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2622‑PUBExternal Senses Modulate Energy Balance: The Role of Olfactory Sensory NeuronsCELINE RIERA, EVA TSAOUSIDOU, JENS BRUENING, ANDREW DILLIN, Los Angeles, CA, Cologne, Germany, Berkeley, CA

Olfactory inputs help coordinate food appreciation and selection, but their role in systemic physiology and energy balance is poorly understood. Here we demonstrate that mice upon conditional ablation of mature olfactory sensory neurons (OSN) are resistant to diet-induced obesity accompanied by increased thermogenesis in brown and inguinal fat depots. Acute loss of smell perception after obesity onset not only abrogated further weight gain, but improved fat mass and insulin resistance. Reduced olfactory input activates sympathetic nerve activity, resulting in activation of β-adrenergic receptors on white and brown adipocytes to promote lipolysis. Conversely, conditional ablation of the IGF1 receptor in OSNs enhances olfactory acuity in mice and leads to increased adiposity and insulin resistance. These find-ings unravel a new function for the olfactory system in controlling energy homeostasis in response to sensory and hormonal signals.

Supported By: American Diabetes Association (1-15-INI-12 to C.R.)

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2625‑PUBDuodenum‑Jejunum Bypass Surgery (DJB) Improved the Glucose and Lipid Metabolism in Zucker Diabetic RatNA LI, LIANGUANG HUO, HAN SU, MEIJIA ZHANG, QINGTAO YAN, ZHIQIN GAO, MEI HUA QU, Weifang, China

This study focused on the effect of duodenal-jejunal bypass (DJB) sur-gery improving the glucose and lipid metabolism in Zucker Diabetic Fatty Rat(ZDF). ZDF rats were randomly divided into DJB group (ZDF-DJB, n=6) and sham surgery group (ZDF-Sham, n=6), Lean Zucker Rats were used as control (n=6). Food intake and body weight gain was measured during the experiment. Fasting glucose, OGTT was performed at one week prior (p.r), 2nd week , 4th week, 6th week post operation (p.o). Fasting plasma cho-lesterol (Chol), triglyceride (TG), spartate transtaminase (AST) and alanine aminotransferase (ALT) was measured simultaneously to comparing the changing of lipid mechnism by DJB and Sham sugery. During the 6 weeks experiment, the food intake and weight gain were no significant differences in the food intake and body weight between DJB and Sham groups (P > 0.05). The fasting glucose siginificantly decreased in ZDF-DJB rats comparing ZDF-Sham rats at 2nd and 4th week post operation at 5.40±0.95 vs. 9.57±2.35 and 5.77±1.00 vs. 16.76±0.25 respectively. The area under curve of OGTT decreased siginificantly in ZDF-DJB rats comparing ZDF-Sham rats at 2nd and 4th week post operation at 40.23±7.18 vs. 54.75±9.82 and 33.25±7.53 vs. 55.72±4.91 respectively. Fasting plasma Chol decreased siginificantly in ZDF-DJB rats comparing to ZDF-Sham rats at the 4th week post operation at 4.3±0.24 vs. 6.28±0.45; fasting plasma TG at 2.72±0.79 vs. 5.57±1.65; fast-ing AST 80.00±24.15 vs. 172.20±52.62, ALT 128.60±75.87 vs. 246.60±74.55 respectively. The results showed that DJB sugery improved the glucose homeostasis and deceased the lipid concentration independent of the weight lose and food intake. The mechanism of DJB in T2D treatment need further investigation.

Supported By: National Natural Science Foundation of China (31671208 to Z.G.); Shandong Province Natural Science Foundation (ZR2015HL128 to M-H.Q.); Health Department of Shandong Province (2014WS0478 to M-H.Q.); Shandong Province Higher Educational Science and Technology Program (J14LK15)

2626‑PUBRegulation of Unfolded Protein Response Modulator XBP1s by Ubiq‑uitinationLIU YANG, JUNLI LIU, Shanghai, China

Obesity contributes to the development of type 2 diabetes, but the under-lying mechanisms are poorly understood. In eukaryotic cells, accumulation of unfolded/misfolded proteins in the ER lumen causes ER stress and initiates the cellular unfolded protein response (UPR). In recent years, growing bod-ies of evidence have shown that increased ER stress in obesity has a vital role in the development of pathologies such as insulin resistance and type 2 diabetes. XBP1s (X-box-binding protein 1), serves as a master regulator of ER folding capacity, plays a crucial role in the reinstatement of ER homeostasis by increasing the transcription of genes related to ER folding, phospholipid synthesis and component of ER-associated degradation. Under obesity and

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diabetic conditions, there is a severe defect in the nuclear localization of XBP1s. In the meanwhile, overexpression of XBP1s in livers of liver-specific IR knockout mice significantly improved glucose tolerance and insulin resistance. Moreover, Although XBP1 transcriptional regulation has been extensively investigated; posttranslational XBP1s regulatory mechanisms are largely unknown. Evidence shows that XBP1s is at least regulated by acetylation, small ubiquitin-like modifier (SUMO) ylation and phosphoryla-tion. XBP1s was shown to be phosphorylated by p38MAPK, an event that significantly enhanced the mRNA stability and nuclear translocation of the XBP1. In this study, we have discovered a previously unknown mechanism in which IKK-beta directly interacts with XBP1s to protect from its degrada-tion. Taken together, it is clear that alleviating ER stress though manipulating the expression and/or activity of XBP1s may offer high-potential treatment options for insulin action and glucose homeostasis. We will investigate the precise mechanism and consequences of this interaction and the possibil-ity of increasing XBP-1s action in obese conditions for treatment of glucose intolerance and type 2 diabetes.

2627‑PUBHigh‑Fat Diet Disrupts an Age‑Dependent Drop in Invasive Mono‑cytes in the Bone MarrowPARASTOO BOROUMAND, KENNY L. CHAN, IVAN TATTOLI, DAVE PRESCOTT, STEPHEN GIRARDIN, AMIRA KLIP, Toronto, ON, Canada

Introduction: Type 2 diabetes and predisposing obesity are chronic low-grade inflammatory disorders characterized by gains in adipose tissue (AT) macrophages (ATM). High fat diet (HFD) induced obesity in mice promotes ATM infiltration and proliferation. Concomitantly, there are more invasive Ly6Chigh monocytes than patrolling Ly6Clow monocytes in the blood. Blood monocytes originate in the bone marrow (BM) and differentiate into macro-phages in tissues. Recently, BM monocyte development was found favored with prolonged HFD. Remarkably, the causal and temporal link between the increases in ATM, circulating monocytes and BM monocyte development remains unknown. We hypothesize that BM monocytes are affected prior to changes in ATM due to changes in the BM environment.

Methods: Three groups of 9-week-old male C57BL/6 mice were fed low fat diet (LFD) or HFD (10% and 60% kcal fat, respectively) for 3, 8 or 18 weeks. Flow cytometry, gene expression and tissue histology analysis were followed.

Results: While there was no rise in AT Ly6Chigh monocyte infiltration or pro-inflammatory ATM until 18 weeks of HFD, BM Ly6Chigh monocytes were already higher at 8 weeks. Notably, in control mice, we discovered a rise in BM patrolling Ly6Clow and a drop in invasive BM Ly6Chigh monocytes pro-gressing from 3 to 18 weeks of LFD. This trend was lost with HFD such that both monocyte populations remained constant. Hence, the HFD-induced increase in Ly6Chigh monocytes is due to loss of their age-dependent normal decrease. Furthermore, in the BM, HFD increased lipid deposition and white vs. brown adipocyte gene expression, which may influence the Ly6Chigh

monocyte developmental pattern.In summary, HFD alters the BM environment where a progressive drop in

invasive monocytes is disrupted and instead becomes stabilized over time. This may explain the comparatively higher circulating Ly6Chigh monocytes and pro-inflammatory ATM.

2628‑PUB

2629‑PUBOral Trypsin Inhibitor Reduces Body Weight and Blood Glucose in ob/ob MiceKAMAL A. ALBARAZANJI, JAMES LANTER, BHANU SINGH, KAI WU, JAMES LENHARD, Spring House, PA

Obesity is a global epidemic and risk factor for developing type 2 dia-betes mellitus. Humans with trypsinogen deficiency fail to grow despite adequate calorie intake. Camostat (CM) is a synthetic trypsin inhibitor used to treat pancreatitis. It was previously shown that CM-treatment of CCK-R1 deficient OLETF rats increased daily fecal energy (protein) excretion, reduced body weight gain and improved glucose tolerance despite increas-ing food intake (1). We further investigated this pathway by giving CM in feed for 7-day to hyperphagic ob/ob mice and measuring body weight, organ weight, food intake, blood glucose and fecal protein excretion. In contrast to OLETF rats, CM given in feed to ob/ob mice at 0.08mg/g, 0.25mg/g and 0.8mg/g caused a dose-dependent reduction in cumulative food intake of 3.2%, 16.1% (p<0.05) and 34.4% (p<0.05), respectively. CM treatment also increased fecal protein excretion, measured on day 4, by 1.4, 1.7, and 2.1 folds (p<0.05, all), respectively. There was a marked reduction in weight gain (-8.3%, p<0.05) at the two higher doses. Five hr fasted blood glucose was significantly reduced at the highest dose (36.9%, p<0.05). In addition, CM treatment reduced liver weight and lipidosis and increased pancreatic weight in a dose dependent manner. In the same study, a pair-fed group showed significantly lower fecal protein excretion and pancreatic weight and higher blood glucose relative to the highest CM dose-treated group, suggesting that CM treatment may improve glycemic control independent of reducing food intake or body weight. Similar results were observed in a separate study using an oral trypsin inhibitor with low systemic exposure. These results indicate that inhibiting intestinal trypsin may improve metabo-lism through both satiety dependent and independent pathways. 1) Metab Clin Exper 2005, 54:619- 627.

2630‑PUBCritical Role for Hypothalamic Endoplasmic Reticulum‑Associ‑ated Degradation in Proopiomelanocortin Maturation and Energy HomeostasisGEUN HYANG KIM, SOOBIN SONG, DIANE SOMLO, LING QI, Ann Arbor, MI, Ithaca, NY, New Haven, CT

Pro-opiomelanocortin (POMC) is a pro-hormone expressed in POMC neu-ron, which is converted to critical metabolic hormones including Adreno-corticotropic hormone (ACTH), melanocortin-stimulating hormones (MSHs). Especially, α-MSH is a key metabolic hormone secreted by the POMC neu-rons, which links leptin to food intake and systemic energy homeostasis. POMC is folded via two disulfide bonds to exit from ER, which is crucial for POMC maturation. Heterozygosity of a POMC mutation C28F, a misfolded mutant, is causally associated with early-onset obesity in mammals; how-ever, the underlying molecular mechanism remains vague. Here we report the identification of a novel mechanism to understand POMC maturation in the endoplasmic reticulum (ER). Sel1L-Hrd1 ER-associated degradation (ERAD) is a highly conserved branch of ERAD from yeast to mammalian. The Sel1L-Hrd1 ERAD targets misfolded POMC for proteasomal degrada-tion, thereby preventing the dominant-negative effect of misfolded POMC towards “bystander” species in the ER. POMC is accumulated in hypotha-lamic arcuate nucleus of POMC-specific Sel1L deficient mice. The accumula-tion of POMC in the absence of Sel1L recapitulates in vitro. Furthermore, ubiquitination assay with Hrd1 demonstrates that POMC is an endogenous substrate of Sel1L-Hrd1 ERAD. The mice with POMC-specific Sel1L deficiency develop adult-onset obesity due to hyperphagia and impaired hypothalamic leptin responsiveness. Hence, Sel1L-Hrd1 ERAD in the POMC neuron modu-lates systemic energy homeostasis, at least in part, by targeting misfolded POMC for degradation. Indeed, human obesity-associated POMC C28F mutant acts as a role of dominant-negative of wild type POMC via disulfide bond formation, which might bypass Sel1L-Hrd1 ERAD. Therefore, we con-clude that Sel1L-Hrd1 ERAD in POMC neurons is a crucial metabolic regulator for POMC pro-hormone processing via misfolded POMC degradation.

Supported By: American Diabetes Association (1-17-PDF-142 to G.H.K.)

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2632‑PUBSexual Dimorphism in Obesity‑Associated Aortic Stiffness and Maladaptive Vascular RemodelingANNAYYA AROOR, GUANGHONG JIA, JAVAD HABIBI, VINCENT DEMARCO, CAMILA MANRIQUE, BRADY BARRON, DONGQING CHEN, SR., ZHE SUN, GER-ALD MEININGER, LUIS MARTINEZ-LEMUS, JAMES R. SOWERS, Columbia, MO

Obesity associated arterial stiffening is an independent predictor of future cardiovascular disease (CVD). Although premenopausal nonobese women are protected against CVD, aortic stiffness in obese women is more pronounced than in men. This disproportionate increase in stiffness in obese females may partly explain their loss of sex-related CVD protection. In this regard, we have recently reported increased aortic stiffness in female mice consuming a diet high in saturated and refined carbohydrates (western diet, WD). In this study, we hypothesized that female mice fed a WD would exhibit increased vascular stiffness compared to male mice. Four week old male and female C57BL6/J mice were fed a WD containing high fat (46%), sucrose (17.5%), and high fructose corn syrup (17.5%) for 16 weeks. Diet-induced aor-tic stiffness, assessed via pulse wave velocity, was significantly increased in female mice fed WD compared to WD-fed male mice. This in vivo finding was associated with a significant increase in endothelial stiffness as determined by atomic force microscopy of aortic explants. Furthermore, augmented aor-tic stiffness in female mice was also accompanied by greater accumulation of 3-nitrotyrosine, increased fibrosis and elastogenesis/breaking of elastic lamella compared to males. Collectively these observations provide cellular mechanisms for sex-differences in diet-induced obesity associated aortic stiffness. These studies also underscore the utility of preclinical studies on sexual dimorphism on vascular remodeling.

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2634‑PUBThe Differences in Visceral Adipose Tissue between Tibet and Han PopulationYUNHONG WU, Chengdu, China

Objective: To examine the differences of visceral adipose tissue in two different ethnicities and the independent factors related to visceral fat.

Methods: This is a mono-centric-cross-section observational study. 148 Hans, 150 Tibetans aged 18-65 years were recruited in this study. The assessments included blood tests, anthropometry and questionnaires. The abdominal adiposity was assessed by Computed Tomography image. Regression was used to estimate ethnic effects in the relationship between visceral adipose tissue and independent variables. An equation was estab-lished to estimate the visceral adipose tissue of Han and Tibetan.

Results: In Han group, after adjustment for risk factors (age, urea, fast-ing insulin, NC, HDL-C), markedly attenuated the association between BMI and VFA (β 95% CI: from 11.64 (9.37,13.91) to 6.65 (4.06,9.25)). In Tibetan, attenuation was observed from 12.51 (10.49, 14.53) to 4.86 (2.65, 7.06). Before adjustment, when WC increased 1cm, the increase of VAT in Han and Tibetan were 4.51 (95% CI: 3.85, 5.17) and 4.86 (95% CI: 4.25, 5.47), respectively. After adjustment of risk factors (age, NC, DBP), the increment of VAF was larger in Han than in Tibetan (coefficient β changed: 4.02 (3.15, 4.89) vs. 2.06 (1.75, 3.44)).

Conclusions: After adjustment of confounding factors, when increased one unit of BMI or WC, the Tibetan’s increment of VFA is less than Han’s.

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2638‑PUBAre GLP‑1 Receptor Agonists Effective and Safe after Bariatric Sur‑gery?ANNA TUMYAN, LAURENTIU M. POP, ILDIKO LINGVAY, JAIME ALMANDOZ, Dallas, TX

Weight loss following bariatric surgery plateaus at 6-24 months, followed by an upward trend in weight. GLP-1 receptor agonists (RAs) can promote weight loss, but their effectiveness in patients with bariatric surgery is unknown, especially after RYGB or sleeve gastrectomy (SG) which result in sharp increases in native postprandial GLP-1 levels. To determine the effi-cacy and safety of GLP-1 RA therapy after bariatric surgery, we conducted a retrospective review of 36 patients treated with a GLP-1 RA after surgery. Primary outcome was change in body weight. Secondary outcomes were changes in HbA1c and other metabolic parameters. Data are median (IQR), or N (%). Patient were 55 (16) years old, 83% female, 58% African American, 36% Caucasian, 56% had diabetes; 12 (33%) had RYGB, 14 (39%) GS, and 10 (28%) Gastric Band at a median of 5.5 (7) years prior to treatment start. Patients were treated with liraglutide 1.8 (1.2) mg daily (N=33), exenatide 10 mcg twice daily (N=2), or dulaglutide 0.75 mg weekly (N=1) and had a median follow-up of 8 months (range 2-38). Main outcomes are in the Table. 31% of patients reported nausea, of which one was severe and led to treat-ment discontinuation. No pancreatitis or hypoglycemia was reported. GLP-1 RAs after bariatric surgery leads to further weight loss and improvements in metabolic parameters. The mechanisms of action prevailing in this setting where native GLP-1 levels are already stimulated should be studied.

2639‑PUBA Qualitative Assessment of Weight Management in Youth with Type 1 DiabetesANNA R. KAHKOSKA, MADISON E. WATTS, KIMBERLY A. DRISCOLL, FRANZISKA K. BISHOP, JOAN THOMAS, JENNIFER R. LAW, NINA JAIN, ELIZABETH MAYER-DAVIS, Chapel Hill, NC, Aurora, CO

Obesity is common in youth with type 1 diabetes (T1D), but no current clini-cal guidelines focus on weight management in T1D youth. The present study aimed to characterize the patient-perceived experience and barriers to weight management as well as the role of the care team in supporting weight man-agement. Participants were youth ages 12-17 with T1D > 1 year and HbA1c < 13% recruited from the University of North Carolina (n=16, 56% female, 60% white, 50% pump users, mean age 14.8, mean HbA1c 8.5%) and the Univer-sity of Colorado (n=18, 50% female, 80% white, 53% pump users, mean age 15.3, mean HbA1c 9.3%). Focus groups were stratified by gender and weight status (BMI cutoff=25). Discussions were guided by a consistent set of ques-tions, audio-taped, transcribed, and analyzed using standard inductive quali-tative methods. Three interrelated themes of antagonism between T1D and weight management were expressed in all groups—appetite dysregulation, hypoglycemia as a barrier, and disruption of glycemia from changing diet or

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exercise patterns (Figure). Variance in emphasis of specific thematic elements was greatest across gender. The data indicated that weight management is challenged by T1D self-management. Youth with T1D report a need to access multiple members of the care team for weight goals and a desire for person-alized and T1D-specific weight recommendations to overcome the inherent antagonism between T1D and weight management.

Figure.

Supported By: University of North Carolina School of Medicine

2640‑PUBEffect of Phentermine on Weight Loss in the Obese in an Active Clinical PracticeRAHIL AHMED, ERLIN MARTE, HUSAM GHANIM, AJAY CHAUDHURI, PARESH DANDONA, Buffalo, NY

In view of the rising tide of obesity and the high cost of the newer anti-obesity drugs, we have carried out a retrospective analysis of the effect of phentermine, the oldest licensed anti-obesity drug in the pharmacopeia. The study compared the magnitude of its effects in patients with and without dia-betes and the occurrence of side effects like palpitation in active clinical prac-tice. Out of 97 obese patients (Body weight=110±25 Kg) who were prescribed phentermine at a dose between 30-37.5 mg daily for about 6±1 months in our practice, 16 patients did not respond (<1Kg change). In the responders (n=81), the overall fall in body weight was 7.2±3.7Kg or 6.4±3.1% (P<0.05) with a fall in systolic blood pressure (SBP) of 3.4±1.6 mmHg (P<0.05) and diastolic blood pressure (DBP) of 1.6±1.3 mmHg (NS). When patients were stratified accord-ing to their diabetes status, the mean weight loss in nondiabetics (n=32) was 10.4±5.4 Kg (P<0.001) while SBP and DBP fell by 6.2±3.3 (p=0.09) and 1.4±1.8 mm (NS) respectively. Among patients with diabetes, weight loss was 4.1±2.4 Kg (p=0.06) in those with HbA1c >6.5% (n=16), 3.2±1.6 Kg (p=0.09) in those with HbA1c between 6.0 to 6.5% (n=12). Blood pressure did not change signifi-cantly in any of the diabetes subgroups. There was a slight and non-significant increase in the heart rate in obese patients without diabetes by <2±1 bpm and in patients with diabetes by 5±4 bpm. Two patients complained of moderate to severe palpitation and had to stop the drug; one of them had a heart rate of 140 (sinus tachycardia). HbA1c levels did not change significantly with the use of phentermine. We conclude that in a real life setting, the use of phentermine is associated with a significant weight loss and a fall in SBP without significant systemic side effects. The magnitude of fall is significantly lower in patients with diabetes. These results are important considering the fear of side effects currently in the minds of physicians, on the one hand, and the expense of the novel anti-obesity drugs on the other.

2641‑PUBCase Report: Association of Bolus Nutrient Delivery to the Upper Intestine with Weight Loss in an Adult with Obesity and Type 2 DiabetesELIZABETH O. BEALE, VIORICA IONUT, RITA CHEN, ADAM LEE, HONGSHENG TONG, PHILONG PHAM, PETER F. CROOKES, Los Angeles, CA

Background: In obese adults with T2D a single nutrient bolus delivered directly to the upper intestine acutely increases satiety and appetite-regu-lating hormones relative to levels following oral ingestion.

Aim: To determine the effect of repeated bolus delivery of nutrient to the upper intestine on body weight in an ambulatory subject over 2 week periods.

Subject: Male; 45 y; T2D for 9 y; on metformin 2g/d, glimepiride 8mg/d and NPH 28Units/d; BMI 47.4kg/m2; A1c 8.4%.

Intervention: An orojejunal feeding tube (FT) was placed under electro-magnetic guidance. The modified access port was secured discreetly intra-orally. The subject was asked to bolus 120cc of mixed meal (120kcal: inter-vention) or low calorie solution (10kcal: control) 4 times/d via FT for 2 weeks. He ate and drank orally ad lib and continued with usual daily activities.

Results: The subject underwent 3 2-week interventions and 1 2-week con-trol over 1 year. He reported marked satiety and decreased appetite after intervention bolus feeds and minimal satiety with control bolus feeds. The FT was well tolerated. Clinically significant weight loss was seen with inter-ventions but not control. (Figure) A1c was 8.1% at 1 year despite stopping insulin.

Conclusion: Repeated bolus nutrient administration to the upper intestine warrants further evaluation as a nutrient-based approach to promoting sati-ety and weight loss.

Figure.

Supported By: University of Southern California Clinical and Translational Science Institute; National Institutes of Health/National Center for Advancing Translational Sciences (UL1TR000130); University of Southern California Coulter Translational Research Partnership Program (USCWCF/GRZYWACZ/2011CORPAK); Medsystems

2642‑PUBThe IGFBP4/Stanniocalcin‑2/PAPP‑A Axis: Associations with Anthropometric and Metabolic Parameters and Effects of Meal Intake, Exercise, and Day‑Night VariationGRIGORIOS PANAGIOTOU, JAGRITI UPADHYAY, ATHANASIOS D. ANASTASILA-KIS, CHRISTOS S. MANTZOROS, Boston, MA, Thessaloniki, Greece

Purpose: To study anthropometric and biochemical predictors of the IGFBP4/Stanniocalcin-2 (STC2)/PAPP-A axis (ISPa), and their regulation in response to meal intake, exercise and day-night variation.

Studies: Observational: One hundred twenty two healthy individuals (50% females- age 20.0 ± 0.1 yr, BMI 23.4 ± 0.2 kg/m2) were studied cross-section-ally. Interventional: A) Participants were given either 125 ml (N= 18) or 250 ml Boost (N= 18). B) Twenty subjects underwent a 30 min aerobic exercise protocol. Blood samples were drawn prior and 30 min after interventions. C) Twenty subjects were sampled every 3 h over a 24 h period. We used novel ELISA kits from Ansh Laboratories.

Results: STC2 was higher in females (p=0.04) and PAPP-A was higher in males (p<0.001). Adjusted models for gender (Model 1- M1), age (Model 2- M2), BMI (Model 3- M3), age and BMI (Model 4- M4) and age and % body fat (Model 5- M5) revealed correlations between total IGFBP4 and PAPP-A (M1: r= 0.28; M2: r= 0.21; M3: r= 0.22; M4: r= 0.21; M5: r= 0.26 p<0.05 for all) and total IGFBP4 and glucose (M1: r= -0.19; M2: r= -0.22; M3: r= -0.2; M4: r= -0.21; M5: r= -0.23; p<0.05 for all). STC2 was associated with total (M1: r= 0.23; M2: r= 0.24; M3: r= 0.24; M4: r= 0.24; M5: r= 0.21; p<0.05 for all) and LDL cholesterol (M1: r= 0.25; M2: r= 0.25; M3: r= 0.25; M4: r= 0.25; M5: r= 0.23; p<0.05 for all). PAPP-A associations with weight (M1: r= 0.03; M2: r= 0.27; M3: r= 0.36; M4: r= 0.34; M5: r= 0.22; p<0.05 for all, except M1) and lean body mass (M1: r= 0.14; M2: r= 0.4; M3: r= 0.43; M4: r= 0.41; M5: r= 0.25; p<0.05 for all, except M1) were only affected by gender. PAPP-A decreased after 125 ml (p= 0.03) and 250 ml (p= 0.001), while total IGF-BP4 was reduced only after 250 ml Boost (p= 0.001). Exercise increased STC2 and PAPP-A lev-els (p<0.001 for both). Only total and intact IGFBP4 displayed a circadian variation (p<0.001 for both).

Conclusions: We report for the first time predictors of the ISPa serum lev-els in healthy humans.

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2644‑PUBEffect of Roux‑en‑Y Gastric Bypass on Thyroid Function in Euthyroid PatientsJUNFENG HAN, FANGYUAN LIU, JIANZHONG DI, HAOYONG YU, RONGHUI DU, YINFANG TU, XU LI, HONGWEI ZHANG, XIAODONG HAN, WEIJIE LIU, PIN ZHANG, YUQIAN BAO, Shanghai, China

Background: Studies regarding changes of thyroid hormone levels after bariatric surgery generated inconsistent results. The study aimed to evalu-ate changes in serum FT4 and TSH after Roux-en-Y gastric bypass (RYGB) and to identify factors that could predict the changes.

Methods: A retrospective cohort study of 81 ethnic Chinese patients was conducted. Participants were evaluated for changes in anthropometic parameters, metabolic indexes, FT4 and TSH at baseline and 6 months after surgery. Multiple linear regression analysis was used to identify factors that could predict changes of FT4 and TSH.

Results: The mean FT4 levels decreased from 16.26 to 14.59 pmol/L (P<0.001), meanwhile TSH levels showed significantly decreased (2.19±0.12 mIU/L vs. 1.97±0.12 mIU/L, P=0.027) sixth months later. Multiple linear regression analysis showed that the waist/hip ratio (WHR; β=-7.406, P=0.031) and duration of diabetes (β=-0.087, P=0.009) were independent factors contribute to the decrease of FT4 levels; Moreover changes in TSH were significantly and positively correlated with two-hour postprandial blood glucose (2hPG) at baseline (β=0.064, P<0.001).

Conclusion: Serum levels of FT4 and TSH were decreased after RYGB in euthyroid Chinese patients. WHR and duration of diabetes are contributing factors in the changes of FT4. And baseline 2hPG was related to the reduc-tion in TSH. So RYGB not only can improve the metabolic abnormalities, but also may affect the feedback regulation of the thyroid system.

2645‑PUBDecreased Circulating ZAG Levels Are Correlated with Central Obesity and Insulin Resistance in Male NAFLD PatientsXIAOYAN QI, XINHUA XIAO, YADI WANG, HAN LI, JING YANG, JIANGHUA LIU, GEBO WEN, Hengyang, China

Zinc alpha2 glycoprotein (ZAG) plays an important role in lipolysis and insu-lin sensitivity. Nonalcoholic fatty liver disease (NAFLD) was one of the main threats to public health in the world. The prevalence of NAFLD is closely associ-ated with obesity and insulin resistance (IR). To investigate the ZAG levels and the correlation among ZAG, obesity and insulin resistance in NAFLD patients, we examined the level of serum ZAG, adipose tissue ZAG expression, anthro-pometric parameters and biochemical indicators in NAFLD patients. We found that circulating ZAG levels and liver tissue ZAG protein in male NAFLD patients were significantly lower than those in control subjects (p <0.05). Moreover, in male NAFLD patients, serum ZAG levels were negatively correlated with ALT,

AST, FPG, FIns, HOMA-IR and several parameters of central obesity, including WC, WHR and WHtR (all p<0.01). In addition, increasing serum ZAG level was associated with deceased risk of NAFLD in male, when concentrations were analyzed by the multiple logistic analysis. Collectively, these data suggest that serum ZAG levels were significantly associated with NAFLD and can be poten-tially used as a biomarker for diagnosis of male NAFLD patients.

Supported By: National Natural Science Foundation of China (81270925)

2646‑PUBAnthropometric Measures and Adiposity Indexes Cannot Explain Excessive Daytime Sleepiness in DM2 Obese SubjectsFERNANDO GOMEZ-PERALTA, CRISTINA ABREU, MARGARITA CRUZ-BRAVO, ELVIRA ALCARRIA-GONZALEZ, NIR Y. KRAKAUER, JESSE C. KRAKAUER, Segovia, Spain, New York, NY, Southfield, MI

Excessive daytime sleepiness (EDS) is associated with DM2. Previous studies showed that the association was independent of obesity, however EDS is reduced with weight reduction.

We studied if other anthropometric indexes of visceral obesity, including “a body shape index” (ABSI) and adiposity deposition indexes, were related to EDS in an obese DM2 population.

This cross-sectional study comprised 199 consecutive DM2 subjects with BMI ≥ 30 kg/m2. Epworth Sleepiness Scale (ESS) measured EDS. Anthropo-metric parameters included ABSI (WC/[BMI2/3 * height1/2]), Visceral Adi-posity Index (VAI) (Male: WC/36.58 + [1.89 × BMI]) × [TG/0.81] × [1.52/HDL)]; female: [WC/39.68 + [1.88 × BMI]] × [TG/1.03] × [1.31/HDL]) and the Lipid Accumulation product (LAP) (Male: [WC-65] × TG); female: [WC-58] × TG). Body composition by bioelectrical impedance. Metabolic parameters: HbA1c, mean blood glucose, fasting plasma glucose, lipid profile and the ratio TG/HDL. Subject characteristics are shown in Table. Pearson and Spearman cor-relations between ESS and anthropometric measures, body composition and metabolic parameters, both for the whole sample and separately for men and women, were calculated and found to be statistically not significant.

These data show that anthropometric measures and adiposity indexes cannot explain EDS in obese DM2 people.

Table. Study Population Characteristics.Characteristics Women (n=100) Men (n=99) p‑valueAge (years) 61.5 ± 12.2 57.0 ± 10.7 0.004Duration of type 2 diabetes (years) 12.9 ± 8.3 11.0 ± 6.9 0.247Epworth Sleepiness Scale (ESS) 5,7± 4,7 6,5 ± 4,6 0,157Height (cm) 154.8 ± 7.0 167.9 ± 7.2 < 0.001Weight (kg) 95.1 ± 19.3 102.7 ± 20.0 0.007BMI (kg/m2) 39.7 ± 6.9 36.4 ± 6.5 < 0.001WC (cm) 117.8 ± 14.9 118.3 ± 17.0 0.791ABSI (m11/6 kg-2/3) 0.0810 ± 0.0072 0.0827 ± 0.0081 0.001Body fat (%) 45.3 ± 5.2 36.7 ± 8.9 < 0.001FM (kg) 44.0 ± 12.7 37.5 ± 15.5 < 0.001FFM (kg) 51.4 ± 7.9 64.5 ± 9.4 < 0.001FMI 18.3 ± 4.8 13.3 ± 5.5 < 0.001FFMI 21.5 ± 2.9 22.8 ± 2.6 < 0.001FM/FFM ratio 0.85 ± 0.16 0.59 ± 0.26 < 0.001

< 0.4, n (%) 0 (0.0) 11 (11.5) < 0.001≥ 0.4 and ≤ 0.8, n (%) 35 (36.5) 76 (79.2)> 0.8, n (%) 61 (63.5) 9 (9.4)

HbA1c (%) 8.3 ± 1.7 8.4 ± 1.3 0.109MBG (mg/dL) 190.5 ± 48.9 194.8 ± 38.5 0.033FPG (mg/dL) 172.1 ± 73.0 182.0 ± 50.2 0.109HDL (mg/dL) 44.8 ± 8.9 38.8 ± 11.7 < 0.001LDL (mg/dL) 112.6 ± 40.6 99.8 ± 30.2 0.060TG (mg/dL) 199.9 ± 182.6 202.7 ± 225.1 0.246TC (mg/dL) 194.7 ± 57.7 176.1 ± 35.0 0.003TG/HDL 4.7 ± 5.1 6.3 ± 9.5 0.440≤ 1.8, n (%) 7 (10.1) 7 (9.5) > 0.999> 1.8, n (%) 62 (89.9) 67 (90.5)

VAI 9.5 ± 10.4 9.0 ± 13.7 0.013LAP 128.7 ± 121.6 124.0 ± 192.5 0.057Data are expressed as mean ± standard deviation, unless otherwise indicated.

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2648‑PUBLaparoscopic Sleeve Gastrectomy Improves Body Composition and Insulin Resistance in Obesity‑Related Acanthosis NigricansZHANG YI, Shanghai, China

Objective: To observe the effect of laparoscopic sleeve gastrectomy (LSG) on body composition and insulin resistance in Chinese obese patients with acanthosis nigricans.

Methods: A total of 37 obese patients who underwent LSG in our hospital were selected for analysis. They were divided into simple obesity (OB n=14) and obesity with acanthosis nigricans (AN n=23) group respectively. Body composition was measured by dual-energy X-ray absorptiometry (DEXA). Anthropometric measurements and glucolipid metabolism before and 3 months post LSG were collected for analysis.

Results: Patients with AN got noticeable improvement in skin condition and their AN score was significantly decreased (3.52±0.79 vs. 1.48±0.73, P<0.001). Alleviated insulin resistance and more trunk fat loss than limbs’ were observed in both groups (P value<0.01). In AN group, preoperative android fat mass (FM) was positively correlated with fasting insulin and natural logarithm of HOMA-IR (LNIR) (r=0.622, 0.608, respectively; all P<0.01). Besides, changes in android FM and visceral adipose tissue (VAT) also showed significantly positive correlation with changes in LNIR (r=0.588, r=0.598, respectively; all P<0.01).

Conclusions: LSG had a positive impact on body composition and skin condition in Chinese obese patients with AN. Loss of android FM and VAT might result in the alleviation of insulin resistance in AN patients. Android fat distribution seems to be a potential indicator of postoperative metabolic benefits for obese patients with AN.

Supported By: Fundamental Research Funds for the Central Universities (1501219107)

2649‑PUBImpact of Type 2 Diabetes on Outcomes in an Intensive Weight Reduction ProgramGERALD C. DEMBROWSKI, KRISTA M. CURRY, MARIA LEE, JESSICA W. BARNES, Boston, MA, Foster City, CA

Recent animal studies report significant and wide ranging benefits of fasting/calorie reduction. As a result, there is heightened interest in the feasibility and effects of a Very Low Calorie Diet (VLCD) in humans particu-larly in a real world setting. Additionally, given the increasing proportion of overweight or obese adults diagnosed with type 2 diabetes (T2D), how this subgroup of adults respond to such treatment is of special concern. Here, we present data collected after IRB review and approval over the past 2 years from the 20Lighter Program (T20LP), a 3-phase (9 wk) intensive weight reduction program. This abstract focuses on data from participants tak-ing vs. not taking prescription medications for T2D over the first 2 phases

(6 wk) between Jan 2015-Dec 2016. 755 participants completed the first 6 wk of T20LP by Dec 31, 2016; 89 reported taking at least one prescrip-tion T2D medication (oral and/or injectable). Baseline age, comorbidities, history and prescription medications were similar between groups, and typical of metabolic syndrome. From initial baseline to 6 wk, each group (T2D and non-T2D) showed statistically significant (p<0.05) and clinically meaningful reductions in body weight (28.1±1.1; 25.0±0.32), Body Mass Index (BMI) (4.2±0.14; 3.9±0.06), body fat (4.9±0.30; 3.9±0.15), visceral fat (4.2±0.18; 3.0±0.09), basal metabolic rate (112.6±11.3; 119.6±4.5), metabolic age (8.7±1.65; 10.3±0.40), and increases in body water (2.4±0.18; 2.0±0.05). When comparing mean changes between T2D and non-T2D groups we found a statistically significant difference in reduction of BMI and in reduc-tion of body fat % (p<0.05) favoring the T2D group, and a trend in reduction of visceral fat (p=0.0500) favoring the T2D group. Data reported as: (T2D; Non-T2D) and shown as mean±SEM. Improvements from baseline were significant for all outcomes in both T2D and non-T2D groups. Interestingly, when comparing the mean changes between groups we found BMI, body fat reductions, and visceral fat favored the T2D group.

2650‑PUBThe Association of Epicardial Adipose Tissue with Serum Level of Cystatin C in Type 2 DiabetesTOMOMI MURAI, NORIKO TAKEBE, YASUSHI ISHIGAKI, Morioka, Japan

Objective: The accumulation of epicardial adipose tissue (EAT) is consid-ered as a cardiovascular risk factor independent from visceral adiposity, obesity, hypertension and diabetes. In this study, we aimed to clarify the effects of EAT accumulation on the clinical conditions, especially humoral factors, in the Asian subjects with type 2 diabetes (T2DM).

Methods: EAT was measured as the sum of the adipose tissue area within the pericardial sac, obtained by plain CT scans among 208 subjects with 2DM (125 males, mean age 58 years) without history of CAD.

Results: EAT correlated positively with age, BMI, VFA, leptin, cystatin C, HOMA-IR, HOMA-β and C-peptide, meanwhile, negatively with adiponec-tin, eGFRcre, eGFRcys and liver to spleen ratio. Multiple linear regression analysis, adjusted for sex, adiponectin and liver to spleen ratio, revealed serum cystatin C (β= 0.175), leptin (β= 0.536) and age (β= 0.269) to be the only parameters showing independent statistically significant associations with EAT. In this analysis, when cystatin C was replaced with eGFRcre, eGFRcre did not show a significant correlation with EAT. In reverse, serum cystatin C was significantly associated with EAT (β= 0.226), sex (β= -0.182) and C-peptide (β= 0.241) after an adjustment for age, maxIMT, hypertension and coronary calcification.

Discussion: Both EAT accumulation and high cystatin C concentration increased risk of cardiovascular event. This study showed a strong asso-ciation between EAT and cystatin C independent of several confounders, including estimated glomerular filtration rate. Cystatin C is recognized as not only a marker of eGFR, but an inhibitor of collagenolytic cysteine proteases linked to an inflammatory state associated with atherosclerosis. In addition, cystain C is highly secreted by adipose tissue. Taken together, combined elevation of EAT and cystatin C is thought to be possible mediators of car-diometabolic risk in T2DM.

2651‑PUBEffectiveness of Intragastric Balloon Associated with Diet on Treatment of Patients with Type 2 Diabetes (T2DM)SILVIA M. REIMÃO, MARIA ELIZABETH R. SILVA, LUIZ HENRIQUE M. MESTIERI, GABRIEL C. NUNES, THIAGO F. SOUZA, MARCO AURÉLIO SANTO, ROSA F. SAN-TOS, EDUARDO G.H. MOURA, São Paulo, Brazil

Introduction: Obesity is a chronic disease that has become one of the biggest health problems on the last decades. Intra-gastric balloon (BIB) is a short term, reversible, minimally invasive method for weight loss. Fur-thermore, it helps changing eating habits and behavior. It promotes gastric distension and delays gastric emptying, enhancing the feeling of satiety and decreasing food intake. The objective of this study was to evaluate the effects of BIB on patients with T2DM which were overweight or have grade I obesity, by analyzing the weight loss, body composition, glucose and lipid metabolism and quality of life.

Methods: This prospective study included forty patients with T2DM, aged 45,1±7,9 years, without glucose control on oral medications and body mass index of 27-35 kg/m2. They were kept with BIB for 6 months and followed-up for another 6 months after withdrawn. A standardized meal test diet was carried out at 0 and 6 months. Glucose, insulin and triglycerides levels were measured at times 0, 30, 60, 120 and 180 minutes post-meal.

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Results: The body weight decreased 15,6 ± 7,23 kg after 6 months of BIB placement, corresponding to a loss of 17.1% of the total weight. After 6 months of follow-up, mean weight loss was maintained at 13.89 kg (15.2%). There was a significant reduction of mean body fat mass of 22%. Areas of glucose, insulin and triglycerides meal curves decreased 24%, 28% and 39%, respectively (p ranged from <0.001 to 0.003). HbA1c decreased from 8.2±1.9% to 6.5 ±1.4% and 6.7±1.6% (p<0.001). Of the 24 patients (60%) with hypertension at baseline, only 3 (7.5%) remained hypertensive after BIB use. The quality of life improved in all domains analyzed: physical functioning, physical function, pain, general health, vitality, social functioning, emotional aspects and mental health (p ranged from <0.001 to 0.051).

Conclusion: BIB is effective for weight loss, control of DM2 and quality of life improvement.

Supported By: São Paulo Research Foundation

2652‑PUBAssociation between BMI, HbA1c Control, and Diabetes‑Related Health‑Care Expenditures among U.S. Patients with Type 2 DiabetesSTEPHEN JOHNSTON, CHIA WEN HSIAO, LAURA GOLDSTEIN, MEHMET DASKI-RAN, ROBIN SCAMUFFA, New Brunswick, NJ, Cincinnati, OH, Toronto, ON, Canada

This study examined the association between body mass index (BMI), poor HbA1c control (≥7%), and diabetes-related healthcare expenditures among U.S. patients with type 2 diabetes and BMI of overweight or greater (i.e., BMI ≥25). Retrospective, observational study using electronic health records linked to insurance claims. Included patients were aged ≥18, had BMI ≥25 during 2014, and had ≥1 medical claim with a diagnosis for type 2 diabetes and ≥1 antihyperglycemic prescription claim within 6 months before or after the last BMI measurement in 2014 (evaluation period). Multi-variable regressions adjusting for patient demographics were used to gener-ate adjusted estimates of: (1) poor HbA1c control prevalence by BMI cate-gory (25-29.9, 30-34.9, 35-39.9, ≥40); (2) evaluation period diabetes-related healthcare expenditures by BMI/HbA1c control categories. Study included 27,117 patients (mean age=64). Adjusted prevalence of poor HbA1c control increased significantly (P<.01) by BMI category: BMI 25-29.9, 62.0%; BMI 30-34.9, 63.6%; BMI 35-39.9, 65.3%; BMI ≥40, 66.9%. Within BMI catego-ries, adjusted diabetes-related healthcare expenditures were higher (P<.01) for patients with poor HbA1c control and were highest (P<.01) for patients with BMI ≥35 (Figure). Strong associations exist between BMI, poor HbA1c control, and diabetes-related healthcare expenditures.

Figure.

Supported By: Johnson & Johnson

2653‑PUBEfficacy of Lorcaserin by Race: A Post‑hoc Analysis of Phase 3 Stud‑ies in Adults with Overweight or Obesity With and Without Type 2 Diabetes Mellitus (T2DM)A.E. CABALLERO, ELENA NIKONOVA, SHARON ZHOU, CARLOS PERDOMO, Boston, MA, Woodcliff Lake, NJ

Racial differences have been reported for weight loss (WL) interventions, w/ non-Hispanic (HSP) white patients (pts) losing more weight than African American (AA) and HSP pts.1 In this post-hoc analysis of lorcaserin (LOR) Phase 3 studies by race, BLOOM/BLOSSOM pts (N=6380) had a body mass

index (BMI) of 27.0-29.9 kg/m2 and ≥1 comorbidity or BMI of 30.0-45.0 kg/m2; BLOOM-DM pts (N=508) had T2DM and BMI of 27.0-45.0 kg/m2. Data are presented for pts randomized to receive LOR 10 mg twice daily or placebo (PBO) plus diet and exercise counseling (D/E) for 52 weeks. Race was self-reported. More pts achieved ≥5% WL w/LOR compared to D/E across all race groups (P<0.05 in pts w/o T2DM). In pts w/o T2DM, PBO-adjusted least-squares (LS) mean WL w/LOR was 3.57 kg, 2.75 kg, and 2.04 kg in non-HSP white (N=2111), AA (N=576), and HSP (N=339) pts, respectively; in pts w/T2DM, non-HSP white, AA, and HSP pts lost 3.40 kg, 3.13 kg, and 1.76 kg, respectively (PBO-adjusted LS means; Table 1). Despite numerically less WL, HSP pts w/T2DM had numerically greater improvements in glycemic param-eters (GPs) w/LOR vs. PBO compared to non-HSP white and AA pts (Table 1). In pts w/o T2DM, this analysis demonstrated efficacy of LOR for WL across racial subgroups compared to D/E; in pts w/T2DM, particular improvements in GPs were seen in the HSP subgroup.

1Ethn Dis. 2015;25:511-514.

2654‑PUBReal‑Life Experience with Liraglutide 3.0mg in Obese Patients or Overweight Patients with ComorbiditiesNAIM SHEHADEH, NEHAMA ZUCKERMAN-LEVIN, WISAM ABO ZAID, MARY MARJIEH, SAGIT ZOLOTOV, Haifa, Israel

Background: Obesity is a chronic condition associated with medical com-plications and co-morbidities. 5-10% weight loss has shown to reduce risk for complications and improve quality of life in overweight patients. How-ever, weight loss of this magnitude isn’t easy to accomplish and maintain solely by changes in lifestyle, and adjuvant pharmaceutical therapy is some-times required to achieve better outcomes. liraglutide 3.0mg (Saxenda), GLP-1 RA was recently approved for weight loss in obese patients with a BMI >30 or BMI >27 with at least one weight-related comorbidity.

Methods: Out of the 153 patients prescribed with liraglutide 3.0mg for weight loss in our obesity clinic at Rambam Medical Care Campus, 51 patients completed 3 months of follow-up and their data was analyzed. Patients treated with liraglutide, also received lifestyle and dietary counsel-ling. The starting dose of liragtlutide was 0.6 mg SC once a day, gradually increased to a maximal dose of 3.0 mg. Adherence to treatment, weight change, and adverse effects were followed by recurrent clinic visits and telephone calls follow-up.

Results: At baseline, mean age (±SD) was 45.04±12.38 years, 76% (39) of the patients were females. Mean pre-treatment weight was 98.21±17.53 kg and mean BMI 34.57±4.72 kg/m2. At week 12, the mean weight loss was 7.73±6 kg (-7.9%), (95% CI 6.046-9.421); p<0.0001. A total of 37 patients (73%) lost at least 5% of their initial body weight, and 13 patients (25%) lost at least 10% of their initial body weight in their first 3 months of follow-up. 17 patients (33.33%) developed adverse side effects, mainly gastrointestinal and 5 of them (10%) stopped treatment due to side effects.

Conclusions: In our clinic, we observed that the combination treatment of liraglutide 3.0mg with lifestyle and dietary changes was associated with a significant weight loss, and minimal adverse effects.

2588‑pub withdrawn...male naturally occurring diabetic cynomolgus monkeys (n=5-10) and their...

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