Table Of Content

INTEGRATED PHYSIOLOCGAYT—EGINOSRUYLIN SECRETION IN VIVO 1719-P INTEGRATED PHYSIOLOGY—INSULIN SECRETION Glucose-Induced Extracellular Matrix Production is Negatively IN VIVO Regulated by Extracellular Signal Regulated Kinase 5 (ERK5) YUEXIU WU, BIAO FENG, SHALI CHEN, SUBRATA CHAKRABARTI, London, ON, Canada Increased extracellular matrix protein production is a characteristic fea- Guided Audio Tour: Genetic and Human Metabolic Predictors of Diabetes ture of diabetic complications. Fibronectin (FN), a key extracellular matrix (Posters 1721-P to 1728-P), see page 17. protein is known to be upregulated in diabetes. ERK5 plays a critical role in cardiovascular development and in maintaining endothelial cell integrity. & The aim of the study is to investigate the regulation of ERK5 signaling on 1721-P glucose-induced FN overproduction.Human microvascular endothelial cells Mexican American Subjects With Impaired Fasting Glucose (IFG) were used. FN mRNA and protein levels were measured using ELISA and are Characterized by Hepatic and Adipocyte Insulin Resistance and real-time PCR respectively. Transforming growth factor beta 1(TGF(cid:96)1) ex- Beta Cell Dysfunction pression and Smad2 proteins were investigated. Constitutively active MEK5 RUTH ARYA, ZANDRA PEREZ-CADENA, ANDREA HANSIS-DIARTE, DEIDRE WIN- (CAMEK5) adenovirus was transducted to upregulate ERK5 signaling. ERK5 NIER, LAUREN CORTEZ, RALPH DEFRONZO, DEVJIT TRIPATHY, CHRISTOPHER siRNA and dominant negative MEK5 (DNMEK5) transfections were used JENKINSON, San Antonio, TX to downregulate ERK5.Glucose caused a dose dependent increase in FN The aim of the current study was to characterize the metabolic defects production. Such increase was associated with upregulation of TGF(cid:96)1 and associated with prediabetic states IFG and impaired glucose tolerance (IGT). Smad2 phosphorylation. ERK5 expression peaked at 24 hrs. Signifi cant de- We compared adipocyte, hepatic and whole body insulin resistance and beta crease of basal and glucose induced increased FN mRNA and protein levels cell function in subjects with normal glucose tolerance NGT n=36 age 46±2 were observed after CAMEK5 transduction. In contrast, ERK5 siRNA and BMI 30±1, IFG n=30 age 47±2 BMI 33±1, IGT n=20 age 49±3 BMI 34±1, IFG/ DNMEK5 treatment led to an increase of FN synthesis. Moreover, West- IGT n=36 age 49±3 BMI 34±1, T2D n=81 age 58±1 BMI 35±1). Indices of in- ern blot analysis showed that phosphorylated Smad2 was suppressed by sulin secretion and insulin sensitivity were derived from plasma glucose, CAMEK5 transduction with or without glucose treatment. On the other hand insulin and FFA concentrations during the OGTT and from hyperinsulinemic siERK5 transfection enhanced TGF(cid:96)1mRNA expression. Furthermore, we in- euglycemic clamp (80/mU/m2/min) with indirect calorimetry and tritiated vestigated neurotrophins, eg. nerve growth factor (NGF) and brain-derived glucose infusion (non-diabetics, n=54) to measure hepatic glucose produc- neurotrophic factor (BNDF). Both are known upstream regulators of ERK5. tion. Adipocyte IR (AR) was the product of fasting FFA and fasting insulin. IFG The alterations of neurotrophins paralleled that of ERK5. Exogenous NGF subjects had similar whole body glucose uptake but higher hepatic insulin re- supplementation resulted in elevated phosphorylated and total ERK5 with or sistance (BGP x Fasting insulin) vs NGT (21.2±4 vs 7.6±1 mg/kg/min, p<0.05). without glucose treatment.Taken together, our experiments demonstrated a Whole body glucose disposal (skeletal muscle) was lower in subjects with novel mechanism of FN regulation under high glucose conditions. Decreased IFG/IGT primarily due to reduced non-oxidative glucose metabolism. Plasma ERK5 signaling contributes to glucose-induced FN overproduction. fasting FFA and AR progressively increased from NGT to IFG to IFG/IGT and Supported by: Canadian Diabetes Association DM. Adipocyte IR correlated with whole body glucose disposal (r=-0.621, p<0.005), hepatic insulin resistance (r=0.766, p<0.005), insulin secretion/ insulin resistance (disposition) index (cid:54)I /(cid:54)G X MI (r=-0.248, p=0.01) 0-120 0-120 1720-P and the non-oxidative glucose disposal during the insulin clamp (r=-0.361, Exenatide Ameliorates Insulin Resistance by Upregulating SIRT1 p=0.03). Compared to NGT subjects the disposition index ((cid:54)I0-120/(cid:54)G0-120 x MI) Expression of Adipose Tissue in db/db Mice was reduced by 18%, 68%, 80% in IFG, IGT, and combined IFG/IGT respectively. In conclusion subjects with IFG are characterized by hepatic insulin ZONGLAN CHEN, HUIMIN GU, FEN XU, JINHUA YAN, HUA LIANG, JIANPING resistance while those with IGT primarily have skeletal muscle insulin resis- WENG, Guangzhou, China Although Exenatide can improve insulin sensitivity of obesity and type 2 tance and are characterized by marked beta cell dysfunction. Therapeutic diabetes, the underlying mechanisms are still poorly understood. Growing interventions to preserve beta cell function should be started early. evidence suggests that SIRT1 has a positive role in the metabolic pathway through its direct or indirect involvement in insulin signaling. In this study, we investigated the regulation of Exenatide on SIRT1 expression in white & adipose tissue of db/db mice. The 7-8 weeks male db/db mice and their 1722-P heterozygous were divided into 3 groups of 10 animals each as follows: NC Insulin Sensitivity, Insulin Secretion and Disposition Index in Per- group (db/m mice, normal control), DM group (db/db mice), EX group (db/ sons With Normal and “Pre-Diabetic” HbA1c Levels: The Pathobiol- db mice treated with Exenatide 24nmol/kg/d for 8 weeks). Intraperitoneal ogy of Prediabetes in A Biracial Cohort (POP-ABC) Study insulin tolerance test (IPITT) indicated Exenatide could improve insulin sen- CHIMAROKE EDEOGA, SOTONTE EBENIBO, SAMUEL DAGOGO-JACK, Memphis, sitivity and lower fasting glucose levels signifi cantly in db/db mice. Western TN blotting analysis demonstrated that DM group had decreased expressions of An A1c range of 5.7-6.4% has been suggested for the diagnosis of predia- SIRT1, IRS1 and increased expression of p-JNK as compared with NC group. betes. In this report, we compared metabolic data in persons with normal All of these changes were attenuated or reversed when the diabetic mice (N=189) or “prediabetic”(N=98) status based on A1c. We studied 287 nondia- were treated with Exenatide. Our data suggested that Exenatide treatment betic adult offspring (147 black, 140 white) of type 2 diabetes (T2DM) par- ameliorated insulin resistance in db/db mice potentially through regulating ents enrolled in POP-ABC, a study of incident dysglycemia among offspring gy/ SIRT1-p-JNK-IRS1 axis. o+aIn nf7s dT.u2 2lA5iDn1 kM cag cl /petmiavo2erne.l ,n(B Mftaos)sl. l weoTlwhianeseei mdr m mebeayea saIsuVnur G(er+eTd mST u Desan)in natdgsg Deein uEwcgXlualAydsc ew4ed4mi t.ai2hcn i +ntch l13ar0o mm.p6poo ,ym na atenhntdsdr ib ocBesfM t,e a7In- 5cwr-oegallll sm Of 3uGe0nnT.ctT2-. d Physiolobesity STERS tion was assessed using acute insulin response (AIR) during IVGTT. The dis- eO O position index (DI) was calculated as the product of AIR and M. Basal homeo- grat P stasis was assessed by calculating HOMA-IR and HOMA-B. Compared to e the normal controls (A1c < 5.7%), subjects with “prediabetic”A1c levels (5.7- nt I 6.4%) were older (47.9 + 9.2 (SD), P=0.0004), and had higher fasting glucose (92.2 + 6.45 vs. 90.2 + 7.25 mg/dl, P=0.011), BMI (31.5 +7.97 vs. 29.2 + 13.2 kg/m2, P=0.03), total body fat (P=0.02) and trunk fat mass (P=0.016). How- ever, there were no signifi cant differences between the two groups with regard to HOMA-IR, HOMA-B, AIR, M value or DI in African Americans or Supported by: Program for Changjiang Scholars and Innovative Research Team Caucasiand (Fig 1). We conclude that an A1c range of 5.7-6.4% is associated with increased adiposity, but does not predict established glucoregulatory impairments that enable distinction from persons with lower A1c values. & ADA-Funded Research Guided Audio Tour poster For author disclosure information, see page 797. A443 INTEGRATED PHYSIOLOCGAYT—EGINOSRUYLIN SECRETION IN VIVO false positive fi ndings. Fortyfi ve SNPs, selected to cover over 90% of common genetic variability, were genotyped in 8 MODY (HNF4A, GCK, HNF1A, PDX1, HNF1B, NEUROD1, KLF11, CEL) and 2 neonatal diabetes (NDM) (KCNJ11, ABCC8) genes. Allelic variants of 4 SNPs (rs1303722 and rs882019 of GCK, rs7310409 of HNF1A and rs5219 of KCNJ11, the latter being a known type 2 diabetes risk variant) exerted independent signifi cant effects on DC of beta- cell function (p=0.007-0.03). Allelic variants of 5 other SNPs (rs2869084 and rs6031544 of HNF4A, rs10774580 of HNF1A, rs1801262 of NEUROD1, and rs7129639 of ABCC8) were found to infl uence signifi cantly PC of beta-cell function (p=0.001-0.04). Only 1 (rs6721191 of KLF11) out of 45 SNPs was associated to insulin sensitivity (p=0.047). In multivariate models, combining GCK, HNF1A and KCNJ11 SNPs accounted for ~2,5% of DC of beta-cell function, whereas combining HNF4A,HNF1A,NEUROD1 and ABCC8 SNPs accounted Supported by: NIH-NIDDK for ~3.6% of PC of beta-cell function. We conclude that common variability of MODY and NDM genes signifi cantly affects beta cell function in patients with type 2 diabetes, thereby potentially playing a role in the pathophysiol- & 1723-P ogy and/or the “metabolic prognosis” of the disease. Short Term Mild Hyperglycemia Improves Oral Glucose Disposal Supported by: European Foundation for the Study of Diabetes/Novartis Grant and (cid:437)-Cell Function in Subjects With Impaired Glucose Tolerance (IGT) & LORENA A. WRIGHT, KRISTINA M. UTZSCHNEIDER, JENNY TONG, SEDA SUVAG, 1725-P STEVEN E. KAHN, Seattle, WA, Cincinatti, OH Mutations in ABCA1 and Enhanced (cid:437)-cell Secretory Capacity in Hu- Mild 24 h hyperglycemia improves insulin sensitivity, (cid:96)-cell function and mans: Preliminary Results glucose disposal in subjects with normal glucose tolerance. To determine MICHAEL R. RICKELS, EUGENE S. GOESER, CARISSA FULLER, CHRISTINE LORD, whether such an intervention has similar benefi ts in subjects with IGT, 6 ANNE M. BOWLER, MARINA CUCHEL, Philadelphia, PA such subjects (4F/2M, 52.4±5.7 y [x±sem], BMI 35.1±6.5 kg/m2) were studied Loss-of-function mutations affecting the cholesterol transporter ABCA1 twice, 4 weeks apart. They received infusions of glucose (10% dextrose; impair cellular cholesterol effl ux and are associated with reduced HDL-C D10) or normal saline (NS) in random order. After 24 h of infusion, a fre- levels that are nearly absent in the homozygous state (Tangier disease). Pub- quently sampled IV glucose tolerance test (FSIGT) was performed, followed lished data suggest that ABCA1 may be important in regulating (cid:96)-cell cho- by an OGTT. Insulin sensitivity index (S), acute insulin response (AIRg), dis- lesterol homeostasis and insulin secretion. To determine whether loss-of- I position index (DI= S x AIRg) and IV glucose tolerance (Kg) were computed function mutations in ABCA1 affect (cid:96)-cell secretory capacity we performed I from the FSIGT. Incremental areas under the curve (iAUC) for glucose and glucose-potentiated arginine tests in 6 subjects with heterozygous loss-of- insulin and iAUC insulin/iAUC glucose as a measure of (cid:96)-cell function were function mutations in ABCA1 and 6 healthy control subjects (HDL-C 28 ± 3 vs. computed from the OGTT.Plasma glucose increased after 24 h of the D10 70 ± 7 mg/dl, p < 0.001; LDL-C 110 ± 4 vs. 100 ± 9 mg/dl, p = NS) pair-matched infusion (5.85±0.35 to 6.87±0.58 mM; p<0.004), but did not change with NS for age, gender, race, BMI and fasting glucose, as well as in one homozygous (5.59±0.40 to 5.59±0.38 mM). S, AIRg nor DI or Kg changed signifi cantly subject (HDL-C 2 mg/dl, LDL-C 62 mg/dl). The acute insulin and C-peptide re- I with D10 (Table). However, with D10 the iAUC glucose decreased and iAUC sponses to 5 g iv arginine were measured fasting (AIR & ACR ) and during arg arg insulin increased, so that iAUC insulin/iAUC glucose increased.In summary, 230 mg/dl (AIR & ACR ) and 340 mg/dl (AIR & ACR ) glucose clamps. pot pot max max mild short term hyperglycemia improved (cid:96)-cell function during the OGTT by AIR was not different between ABCA1 heterozygotes and controls (33 ± arg 240%, while the response to IV glucose (AIRg) increased by only 48%. We 11 vs. 26 ± 7 μU/ml), while under glucose-potentiated conditions both AIR pot conclude that in IGT, the (cid:96)-cell retains its ability to respond to a physiological (209 ± 43 vs. 116 ± 27 μU/ml, p < 0.05) and AIR (226 ± 38 vs. 164 ± 41 μU/ max increase in glucose. The fact that this benefi cial effect of short term hyper- ml, p < 0.05) were greater in ABCA1 heterozygotes than controls. There was glycemia was more apparent during the OGTT suggests that under these a trend toward greater acute C-peptide responses in ABCA1 heterozygotes conditions in IGT, the incretin response is preserved. than controls under all conditions (ACR : 1.8 ± 0.4 vs. 1.3 ± 0.2; ACR : 8.4 arg pot ± 2.2 vs. 6.4 ± 1.3; ACR : 8.3 ± 1.5 vs. 6.0 ± 0.7 ng/ml; p (cid:41) 0.1 for all). There Variable Saline (NS) Glucose (D10) P value was no difference in inmsauxlin sensitivity (M/I). The homozygous subject had ~ Infusion Infusion 4-fold increased acute insulin (AIR : 121; AIR : 794; AIR : 707 μU/ml) and arg pot max SI (x 10-5 min-1/pM) 0.31±0.04 0.41±0.13 0.38 C-peptide (ACRarg: 4.8; ACRpot: 26; ACRmax: 26 ng/ml) responses as compared AIRg (pM.10 min) 2792±1593 4025±2425 0.24 with controls. These data indicate that loss-of-function of ABCA1 may be DI (x102 min-1) 753±331 1062±409 0.23 associated with enhanced (cid:96)-cell secretory capacity that was dramatic in the homozygous subject, and support the importance of cellular cholesterol Kg (%/min) 1.38±0.28 1.92±0.22 0.23 homeostasis in regulating (cid:96)-cell insulin secretion in humans. iAUC glucose (mM.120 min) 344±67 226±58 0.03 Supported by: PHS Grants UL1RR024134 and P30DK19525 iAUC insulin (pM.120 min) 28986±7088 45871±8927 0.009 iAUC insulin/iAUC glucose (pM/mM) 85±19 240±41 0.009 & 1726-P y/ Data are x±SEM; paired t-test g Decreased Activities of Proinsulin Convertase Enzyme (PC)3 Rather o d Physiolbesity STERS Common Variants of Monogenic Diabetes Genes Infl ue&nce B1e7ta2 C4-ePll toHKhAfID aTREnyIN, pPOAeCRK 22II K KDiOnAi aTPSSbaHUenITDtcAeArs,, e KaTIYOtiOScSH HBITIe AStKaUA-Z CUMeKlIU,l sRS AACSCoHHuIIlMHdIA KPO, r eHOdIZRiAOcWHt IAaSn,A T IOnOScNHrUeIHMaIKsAOe, dSK ARADiOsARk-I ateO PO Function in Patients With Newly Diagnosed Type 2 Diabetes MIYOKAWA-GORIN, YOSHIKAZU SUMITANI, TOSHIAKI TANAKA, SUSUMU gr MADDALENA TROMBETTA, SARA BONETTI, LINDA BOSELLI, MARCO DAURIZ, NISHIDA, HITOSHI ISHIDA, Tokyo, Japan Inte GBOIONVOARNAN, IR MICACALERRDBOA C, .E BLOISNAABDETOTNAN TAR, AVeBrEoTnTaI,, ItPaIlEyR FRANCO PIGNATTI, ENZO izeRde alast iav em haynpifeersptraotiinosnu loinf eimmpiaa iinre tdh eb efatas-ticnegll sftuantcet hioans olofntegn b seeeenn c hina rtaycptee r2- We tested the hypothesis that common genetic variability of “beta cell” diabetes (T2D). We investigated whether the altered activities of proinsulin genes responsible for monogenic diabetes may affect beta cell function convertase enzyme (PC)3 and PC2 would participate in the prevalence of in type 2 diabetes (DM2). We studied 590 drug-naive GAD-negative pa- T2DM in subjects with various stages of glucose intolerance. The circulating tients with newly diagnosed DM2 (age: median=60.0 yrs; I.Q. range: 52-66; levels of intact proinsulin (i-PI) were determined using a CLIA and those of BMI:29.3 kg/m2; 26.5-32.9). Beta cell function was assessed by state-of-art intermediate des-31,32-proinsulin (des-31,32-PI) were evaluated from a RIA mathematical modeling of glucose/C-peptide curves during a 240’ frequently for total proinsulin (t-PI) that had also a 95% cross-reactivity to des-31-32- sampled OGTT, to provide the beta cell responses to: i. the rate of increase PI, using identical blood samples taken from subjects of 207 normal glyce- of glucose (derivative control: DC) and ii. glucose concentration itself (pro- mic tolerance (NGT), 287 IFG/IGT and 201 T2D classifi ed according to the portional control, PC). Insulin sensitivity, measured in all patients by the WHO criteria. Based on the above measurements, the PC3 and PC2 activi- insulin clamp technique, was used as an internal control for the number of ties were estimated by the following formulas:des31,32-PI=(t-PI-i-PI)/0.95, & For author disclosure information, see page 797. Guided Audio Tour poster ADA-Funded Research A444 INTEGRATED PHYSIOLOCGAYT—EGINOSRUYLIN SECRETION IN VIVO PC3 activity=des31,32-PI/i-PI, PC2 activity=IRI/des31,32-PI. The levels of clinical deterioration are unclear. In children, an association was previously i-PI/IRI were signifi cantly higher in the T2D group than those in the NGT reported between current and future clinical deterioration and HG (increased group (p<0.01). The levels of des-31,32-PI and PC2 activity were not differ- glucose excursions and especially glucose at 60min during an oral glucose ent among the all groups but PC3 activity was signifi cantly decreased in tolerance test (OGTT)) or HI (reduced insulin excursion during an OGTT).We both of IFG/IGT and T2D groups (p<0.01). Moreover, we examined whether hypothesized that HG or HI during an OGTT could also be associated with PC3 was an independent predictor of the prevalence or development of clinical deterioration in adults.First, westudied, at baseline, 225 adults with T2D as HOMA-(cid:96) or Oral Disposition Index (DIO) was suggested. A lower CF (without known CFRD) who are part of an ongoing observational cohort. PC3((cid:41)1.7), HOMA-(cid:96)((cid:41)30) and DIO(<1.1) were associated with an increased Increased glucose levels at the 60thmin-OGTT were associated with de- risk of T2D (unadjusted odds ratio [OR] 1.94 [95%CI 1.36-2.78], p<0.001, 1.95 creased lung function (spirometry: FEV%; r = -0.241, p <0.01), and decreased [95%CI 1.39-2.71], p<0.001, 11.2 [6.78-18.4], p<0.001 ). In multivariate stud- insulin levels at that time point were associated with decreased BMI (kg/ ies, PC3((cid:41)1.7) was still associated with an increased risk of T2D (2.14 [1.25- m2; r = -0.298, p <0.01). Second, the results of the OGTT were used to clas- 3.64], p<0.05) after adjustment for age, sex, BMI, Cre, HDL-C, TG, HOMA-(cid:96) sify the CF patients as either normal glucose tolerant (NGT), glucose intoler- and DIO. These results strongly suggest that lower PC3 activity rather than ant (IGT), diabetic de novo (CFRD) or as indeterminate HG (INDET; glucose PC2 could be a useful marker of an increased risk of T2D through an impaired <7.8mM at 0min and 120min, (cid:42)11.1mM at 60min). Similarly to IGTs, INDETs proinsulin conversion. had increased glucose area under the curve during the OGTT and a trend towards decreased lung function compared to NGTs. Our results suggest & 1727-P that 1) HG and HI at the 60thmin-OGTT could be good indicators of decreased lung function and weight loss, respectively, and 2) the study of IGT & INDET Baseline Insulin Resistance May Not Contribute Per Se to Progres- patients could allow the identifi cation of early markers of clinical deteriora- sive Loss of (cid:437)-Cell Function: The Insulin Resistance Atherosclero- tion. Prospective analyses are now required to establish predictors of future sis Study (IRAS) clinical deterioration in adults with CF. STEVEN M. HAFFNER, ANTHONY J. HANLEY, LYNNE E. WAGENKNECHT, MAR- Supported by: Cystic Fibrosis, Canada IAN J. REWERS, ANDREW J. KARTER, CARLOS LORENZO, San Antonio, TX, To- ronto, ON, Canada, Winston-Salem, NC, Aurora, CO, Oakland, CA Hyperglycemia may result from an intrinsic (cid:96)-cell defect which results in Guided Audio Tour: Insulin Secretion and Sensitivity—Humans—Type 1 inadequate compensation for insulin resistance. There are few data on the and Type 2 Diabetes (Posters 1729-P to 1735-P), see page 17. impact of insulin sensitivity, adiposity, and plasma glucose levels on future changes in (cid:96)-cell function. Therefore, we examined the association of insulin & 1729-P sensitivity index (S), glucose levels, and body mass index (BMI) with the I 5-year change in acute insulin response (AIR) in 741 non-diabetic subjects. A Comparative Assessment of the Effect of Caloric Load on Meta- S and AIR were measured at the baseline and follow-up visits by the fre- bolic Parameters Evaluated in a Mixed Meal Tolerance Test I quently sampled intravenous glucose tolerance test. In a generalized linear SUDHA S. SHANKAR, LORI MIXSON, DAVID E. KELLEY, Rahway, NJ mixed model analysis, baseline glucose levels were inversely associated The Mixed Meal Tolerance Test (MMTT) offers a physiologically relevant with the 5-year change in AIR (defi ned as follow-up AIR minus baseline AIR), situation to assess effects of disease and of treatment on insulin secretion. whereas baseline S and BMI were not (Model 1). Five-year changes in BMI, Beta cell sensitivity to glucose ((cid:92)) is one of the key parameters of insulin I S, and 2-h glucose were independently associated with the 5-year change secretion that is particularly refl ective of beta-cell impairment and response I in AIR (Model 2 and 3). In conclusion, weight gain and longitudinal declines to therapy. However, there is scant information on the contribution of meal in insulin sensitivity are associated with increases in (cid:96)-cell function. This size and composition upon (cid:92) and other parameters of insulin secretion in supports the concept that (cid:96)-cell function adapts to insulin action. Insulin patients with Type 2 diabetes mellitus (T2DM). We tested the hypothesis resistance may not contribute per se to (cid:96)-cell dysfunction. Elevated plasma that while the metabolic responses to a lower caloric load would differ from glucose levels may have a deleterious effect on the (cid:96)-cell and/or may signal that to a meal with higher caloric load, beta-cell sensitivity to glucose would an intrinsic (cid:96)-cell defect. be an “intrinsic” property that does not vary in relation to meal size. A reto- spective cross-sectional comparative analysis of data was performed, using Table: Multiple mixed regression models with the 5-year change in log AIR MMTT data from trials in T2DM patients with similar baseline character- as the dependent variable istics, who had received either a low calorie meal of 460Kcal (LCM) or a Model 1 Model 2 Model 3 high calorie meal of 680 Kcal (HCM). Both meals had similar macronutrient (cid:96) ± SE (cid:96) ± SE (cid:96) ± SE composition of ~ 66% carbohydrate, ~18% fat, and ~16% protein. MMTT BMI - 0.005 ± 0.024 - 0.035 ± 0.024 - 0.035 ± 0.023 (180 minutes, with 9-point sampling) data from four trials, two with a LCM (N=114) and two with a HCM (N=125) were compared. Data are presented as Log S 0.036 ± 0.042 - 0.099 ± 0.034 † - 0.175 ± 0.034 † I LCM vs HCM, mean ± SEM. Signifi cant differences were observed in incre- Fasting glucose - 0.073 ± 0.026 † - 0.089 ± 0.024 ‡ - 0.082 ± 0.024 ‡ mental AUC glucose (72.9 ± 3.3 vs 89.7 ± 3.8 mg.h/dL, p<0.05), AUC (0-3hr) (0-2hr) 2-h glucose - 0.064 ± 0.024 † - 0.080 ± 0.025 † - 0.117 ± 0.026 ‡ insulin (71.4 ± 9.2 vs 145.3 ± 12.1 μIU.hr/mL, p<0.01) AUC C-peptide (10.1 (0-2hr) 5-year change in BMI — 0.042 ± 0.021 * 0.045 ± 0.020 * ± 0.4 vs 15.2 ± 0.7 ng.hr/mL, p<0.05) and AUC insulin secretion rate (513.3 ± 25.8 vs 609.8 ± 21.0 pmol.h/min, p<0.01). However, the measure of beta cell 5-year change in log S — - 0.147 ± 0.025 ‡ - 0.203 ± 0.026 ‡ I sensitivity to glucose ((cid:92)) was comparable between the two caloric loads 5-year change in fasting glucose — — - 0.043 ± 0.026 (9.6 ± 0.9 vs 8.9 ± 0.8, p=NS). Our fi ndings suggest that acute metabolic 5-year change in 2-h glucose — — - 0.112 ± 0.027 ‡ responses such as glycemic excursion, insulin and C-peptide differ between y/ g MMTTs having different caloric loads, whereas intrinsic parameters of beta o (cid:96)sael s±xSo ,uS ripEnap cceolexurt/pdeeredted hsb nsyini:ec Ndait Hlyfl o,Lt Brch Il1r i(en HSeiLcD -m,4 uf7oan8dmi8te7 ilil,sn yH.c hLr-ies4a7tso8er8y;9 *)o fp d<i0a.b0e5t;e †s ,p a <n0d. 0b1a; s‡e pli n<e0 .A0I0R1 w Aegree, cell function/beta cell responsivity to a mixed meal challenge& do no1t7.30-P d Physiolbesity STERS The Graded Glucose Infusion is a Simple yet Sensitive Tool to Detect eO O Differences in Insulin Secretion due to Metabolic Dysfunction and grat P & Treatment of Disease e 1728-P SUDHA S. SHANKAR, RAVI SHANKAR, LORI MIXSON, DEBORAH L. MILLER, BAR- nt I Association of Hyperglycemia or Hypoinsulinemia During an Oral NALI PRAMANIK, CHAN R. BEALS, HELMUT O. STEINBERG, DAVID E. KELLEY, Glucose Tolerance Test With Worse Clinical Profi le Before the On- Rahway, NJ set of Cystic Fibrosis-Related Diabetes in Adults We have previously shown in healthy volunteers, that the Graded Glu- ADÈLE CORIATI, MARIE-SOLEIL GAUTHIER, SOPHIE ZIAI, LINDA BELSON, YVES cose Infusion (GGI) is comparable to the hyperglycemic clamp to measure BERTHIAUME, RÉMI RABASA-LHORET, Montreal, QC, Canada changes in glucose-dependent insulin secretion (GDIS), while being opera- Approximately 40% of adults with cystic fi brosis (CF) develop CF-related tionally simpler. We tested the hypothesis that the GGI can distinguish dif- diabetes (CFRD), a complication that increases mortality. Two to four years ferences between metabolic states, and in response to treatment in Type 2 before its diagnosis, CFRD is preceded by an accelerated clinical deteriora- DM (T2DM), by comparing GDIS between lean (L, n=8), obese non-diabetic tion (decreases in weight and lung function). CFRD is characterized by hy- (OB, n=12) and T2DM (T2DM, n=12); in T2DM, GDIS was also measured after perglycemia (HG) and hypoinsulinemia (HI), but their respective roles in this a single subcutaneous dose of liraglutide 0.6mg (LIRA). All subjects under- & ADA-Funded Research Guided Audio Tour poster For author disclosure information, see page 797. A445 INTEGRATED PHYSIOLOCGAYT—EGINOSRUYLIN SECRETION IN VIVO went a 160-minute GGI with fi xed stepwise increments in glucose infusion Diabetes Prevention Program at baseline and after placebo (PLC), intensive rates (GIR) from 2 to 12 mg/kg/min. Data are presented as mean ± SEM lifestyle (ILS), metformin (MET), or troglitazone (TROG) treatment. Follow-up (Table 1). At similar GIR, signifi cant differences (p<0.01) were observed be- in all arms was 2 years, except for TROG, which was stopped after 1 year. tween all groups in maximal glycemic excursion (G), insulin secretion (ISR), At baseline, log (NT-proBNP) did not differ across groups (Table, p=0.07). and beta cell sensitivity to glucose (ISR/G). Following LIRA, there were sig- At follow-up, log (NT-proBNP) increased in TROG and ILS groups only (non- nifi cant (p<0.001 over PBO) changes in G (222.3 (12.4) mg/dL), ISR (3.65 (0.44) transformed change in NT-proBNP is shown below). Changes in BMI and in- ng/min), and ISR/G (0.023 (0.004)) in T2DM, achieving treatment effects sulin sensitivity (as log-transformed 1/HOMA-IR) are shown below. Change similar to PBO-treated OB (p=NS for comparison). These data indicate that in NT-proBNP was correlated with the change in insulin sensitivity (partial compared to L, OB show compensatory increases in insulin secretion, while correlation coeffi cient = 0.12, p<0.0001, after adjustment for change in BMI, T2DM have impaired beta-cell function; the effect of liraglutide reveals a age, sex, race, and baseline values of NT-proBNP, BMI, and log [1/HOMA-IR]) latent functional reserve in T2DM, responsive to incretin stimulation.These in all groups, and only with the change in BMI in the placebo group(-0.10, fi ndings demonstrate for the fi rst time in a systematic comparison, that the p=0.007). Within the DPP, percentage of TROG participants with heart fail- GGI is sensitive enough to detect differences in GDIS due to metabolic dys- ure (0%) or edema (4.6%) did not differ from PLC.TROG, ILS, and MET data function, as well as treatment. suggest that changes in insulin sensitivity have a greater infl uence on NT- proBNP than changes in BMI. Table 1. GGI data in lean, obese and diabetic (mean ± SEM) Parameter Lean Obese T2DM PLC ILS MET TROG (PBO) (PBO) (PBO) Baseline NT-proBNP (pg/mL) Maximal glycemic excursion during the GGI, 153.3 (13.0) 185.2 (12.8) 277.6 (9.2) Median [IQR] 33.42 [17.12-62.28] 30.90 [13.99-59.89] 29.68 [14.04-54.17] 29.11 [15.66-52.93] as a change from baseline (G), mg/dL N 762 916 959 583 Time-weighted average (TWA) of the insulin secretion 2.85 (0.40) 3.93 (0.47) 1.59 (0.37) (cid:2539) Nt-proBNP (pg/mL) rates (ISR) at the highest glucose infusion rate, as a Median [IQR] +1.32 [-12.4-19.81] +3.20 [-8.81-19.99] +1.45 [-10.5-15.66] +6.28 [-5.39-6.84] change from baseline, in ng/min N 692 832 887 285 p-value 0.19 0.008 0.82 0.0003 Slope of the insulin secretion rate vs ambient glucose 0.015 (0.006) 0.021 (0.004) 0.006 (0.001) over the duration of the GGI (ISR/G) (cid:2539) BMI (kg/m2) Mean±SEM +0.03±0.08 -1.96±0.09 -0.75± 0.07 +0.37± 0.13 N 689 837 887 279 p-value 0.69 0.0001 0.0001 0.005 & 1731-P (cid:2539) Log [1/HOMA-IR] Effects of Acylated and Unacylated Ghrelin on Insulin Secretion and Mean±SEM -0.02± 0.02 +0.22±0.02 +0.11±0.02 +0.31±0.03 Glucose Tolerance in Healthy Humans N 673 818 860 281 p-value 0.35 0.0001 0.0001 0.0001 JENNY TONG, RON L. PRIGEON, MARTIN BIDLINGMAIER, ELIZABETH STAM- BROOK, MATTHIAS TSCHOEP, DAVID D’ALESSIO, Cincinnati, OH, Baltimore, MD, (cid:54)-change Munich, Germany Supported by: NIDDK (U01-DK048489) Unacylated ghrelin (UAG) is the predominant ghrelin isoform in the circulation, and despite an identical peptide sequence with acyl-ghrelin (AG) does & 1733-P not activate the classical ghrelin receptor (growth hormone secretagogue receptor, GHSR 1a). AG inhibits insulin secretion in humans, but preclinical 50-Year Medalist Study: Pattern of Insulin Positive Cells and its Cor- studies suggest that UAG may promote (cid:96)-cell function. We hypothesized relation With C-peptide Levels and Age at Onset that UAG would have the opposite effect of AG on insulin secretion and SUSAN BONNER-WEIR, HILLARY A. KEENAN, BROOKE MORRIS, STEPHANIE glucose tolerance. AG (1 μg/kg/h), UAG (4 μg/kg/h), combined AG and UAG, HASTINGS, SARA TUREK, JENNIFER K. SUN, GEORGE L. KING, Boston, MA or saline were infused to 9 healthy subjects (5M/4F; age 27 ± 2 y; BMI 25 ± The Medalist Study provides a unique opportunity to compare physiologi- 1 kg/m2, fasting plasma glucose 92 ± 2 mg/dl, mean ± SEM) on 4 separate cal factors and post-mortem pancreatic morphology of T1DM patients with occasions in randomized order. AG and UAG were infused for 30 min to >50 years duration. We studied 21 Medalist pancreases and all were found achieve steady-state levels and continued through a 3-h frequently sam- to have insulin positive beta cells. The distribution and quantity of insulin pled IV glucose tolerance test (FSIGT). Acute insulin response to IV glucose positive cells were categorized as: C1) few scattered singlet or clusters (AIRg), insulin sensitivity index (S), disposition index (DI = Sx AIRg) and IV (n=6), C2) similarly scattered with additional occasional insulin positive cells glucose tolerance (Kg) were compuIted from the FSIGT. AG andI the combined within islets (n=11) and C3) at least 30% of the islets having signifi cant num- AG+UAG infusion increased serum GH 20-fold from baseline, while UAG and ber of insulin positive cells (n=4). Most islets in Medalists were atrophic saline had no effect on GH levels. Only AG infusion increased fasting glucose comprised mainly of glucagon positive cells; some scattered glucagon cells levels (p <0.05); none of the treatments had any effect on fasting plasma were in or near ducts. Clinical data was analyzed across categories, only age insulin. Both AG and AG+UAG decreased AIRg (saline 451 ± 93, AG 328 ± of onset and c-peptide levels were signifi cantly different (p (cid:41) 0.01). Those 80, AG+UAG 299 ± 80 pM/l, p = 0.005). UAG also showed a trend towards in C1 were the youngest at onset (3.8±2.0 y) and had the lowest c-peptide a lower AIRg (364 ± 79 pM/l, p =0.08) as compared to saline. Swas not af- (0.07±0.07 ng/dl) while those in C2 had a mean age at onset of 9.3±7.1 y and fected by any of the ghrelin treatments. The AG+UAG treatmenIt decreased a c-peptide of 0.21±0.01 ng/dl, and C3 had a later onset at 25.3±6.3 y and a DI and Kg (p < 0.05 for both). In summary, AG suppresses insulin secretion higher c-peptide level, 2.2±2.2 ng/dl. All but 2 (in C2) had high risk DR3 and/ gy/ and impairs glucose clearance as previously reported. UAG has effects that or DR4 alleles. Antibody positivity (IA2 or GAD65) spanned categories with ed PhysioloObesity OSTERS aescuopffgsSpeegurco epmtapssceto o hrtstna eitm bdh(cid:96)o io-bllcasiyseer: milN tlo i.IeffHu s An (kocG2ft3 iatoDhnnKed.8 It0tnw0h 8ceo1o ,cin sRotorm0af3obsDritnmK ta8os9t i0otoh9fn e0 g o)phfrr eeAlcGilni+n iUincA atGlh es mt uraedygi euhslaa, vttieho enas doedf digtailvtuea- 2lwpOe oniiantsesh e Ct od i1hnf ,oa st4fluhf a lietinthns l eCeep 2pawo saasatnni ts3cdi vr0 Ie1Ae% a 2icns +ie nw.ClAsl3siunt .lh aaiCn lnfy3 edps wh oistas h sdioetc fit av hrtteeeht se cemtre eMoolldsfse titadn hdnaseidulv i lespmintra sa cnpenoco ymhrs eowiotariristvpt eh(hhn ocaa=elmv6olil5gnysl9yg oa:) i ni2dbsd lyhde naectosvpa ioitncsesoglgeim toatss--t. at P ries defi ned by mean c-peptide level of C1, C2 and C3 showed a similarly gr & signifi cant increase in age at onset (p=0.04). Insulin positive cells persist in e 1732-P nt very long-term diabetes even in the absence of measurable c-peptide and a I Preventive Therapies for Type 2 Diabetes that Improve Insulin Sen- greater number of insulin positive cells correlates with higher c-peptide and sitivity Raise NT-proBNP later onset of disease. Beta cells persisted as scattered singlets more com- GEOFFREY A. WALFORD, YONG MA, RONALD B. GOLDBERG, PETR JAROLIM, ED- monly than islets in T1DM patients of extreme duration. WARD S. HORTON, KIEREN J. MATHER, ELIZABETH BARRETT-CONNOR, JACLYN DAVIS, JOSE C. FLOREZ, THOMAS WANG, DPP RESEARCH GROUP, Boston, MA, Rockville, MD, Miami, FL, Indianapolis, IN, San Diego, CA Individuals with obesity and insulin resistance have reduced circulating levels of natriuretic peptides (NPs), which may contribute to increased sus- ceptibility to hypertension and cardiac disease. The effect of interventions that reduce metabolic risk on NP concentrations is unclear.We analyzed N-terminal B-type natriuretic peptide (NT-proBNP) concentrations in the & For author disclosure information, see page 797. Guided Audio Tour poster ADA-Funded Research A446 INTEGRATED PHYSIOLOCGAYT—EGINOSRUYLIN SECRETION IN VIVO & Guided Audio Tour: Insulin Secretion and Action in Animal Models (Posters 1734-P 1738-P to 1742-P), see page 13. BMI is the Major Driver of Beta Cell Loss in RecentOnset Type 1 Diabetes: a Multicentre, Longitudinal Study 1736-P ADAM BARKER, ANGELO LAURIA, NANETTE SCHLOOT, NORA HOSSZUFALUSI, Triglyceride-Rich Lipoprotein Metabolism in the Central Nervous PAL PANCZEL, JOHNNY LUDVIGSSON, CHANTAL MATHIEU, DIDAC MAURICIO, System Regulates Brain Lipid Sensing and Plays an Essential Role in Body Weight RegulatioWn ITHDRAWN ESTER RUBINAT, MARIA NORDWALL, BART VAN DER SCHUEREN, THOMAS MA- HONG WANG, CHARLES W. REHRER III, MATTHEW D. TAUSSIG, AMBER A. DRUP-POULSEN, WERNER SCHERBAUM, NICK WAREHAM, ILSE WEETS, FRANS PALUMBO, KALYANI G. BHARADWAJ, IRA J. GOLDBERG, ROBERT H. ECKEL, Au- GORUS, DAVID LESLIE, PAOLO POZZILLI, Cambridge, United Kingdom, Rome, Italy, rora, CO, New Yorks, NY Lipoprotein lipase (LPL) is rate-limiting in the hydrolysis of triglycerides Düsseldorf, Germany, Budapest, Hungary, Linköping, Sweden, Leuven, Belgium, (TG) and uptake of fatty acids from circulating dietary lipids. We have recent- Lleida, Spain, Copenhagen, Denmark, Brussel, Belgium, London, United Kingdom ly created mice with neuron-specifi c LPL defi ciency (NEXLPL-/-) that have C-peptide is a valuable indicator of residual (cid:96)-cell function in type1 diabe- reduced uptake of TG-rich lipoprotein-derived fatty acids and decreased tes (T1D) patients. Although there is great heterogeneity in C-peptide levels levels of n-3 long chain polyunsaturated fatty acids (n-3 PUFAs) in the hypo- thalamus. Of great interest these mice become obese on chow by 16 wk (Cell at clinical onset, factors infl uencing the subsequent decline of C-peptide Metabolism, 2011). We have now conducted experiments in 10 wk old mice to are not well understood.The aim of this study was to investigate the natu- test if dietary supplementation of n-3 PUFAs prevents obesity. After 40 wk ral course of residual beta cell function in 4411 T1D patients diagnosed in on a synthetic high carbohydrate diet (HC, 70% CHO, 10% fat, n-6:n-3 ratio European centers with longitudinal data available up to 10 years following of 7:1) w/o n-3 PUFA supplement (n-6:n-3 ratio 1:3), NEXLPL-/- mice have an average of 35% fat mass vs. 27% in WT mice on both diets. After 24 wk on diagnosis. The patients were grouped according to age at diagnosis (0-4, synthetic high fat diets (HF, 45% fat) w/o n-3 PUFA supplement, both NEX- 5-9, 10-18 and >18years). Linear regression models with change in fasting LPL-/- and WT mice gain less body weight (38.0 g vs. 39.1 g on HF/n-3 PUFA; C-peptide as an outcome were used to identify variables measured at diag- 50.1 g vs. 47.6 g on HF diet; respectively). This reduction in body weight for both groups on the HF/n-3 PUFA diet is likely an effect of larger amounts of nosis including body mass index (BMI) [expressed as z-scores vs. a matched n-3 PUFA on palatability. Noticeably, HF feeding enhanced the body weight control population], HbA1c and insulin dose that were signifi cant predictors and fat mass gain in NEXLPL-/- mice much less than in WT mice, rendering of fasting C-peptide decline over the following years.There were no signifi - similar body compositions at the end of the HF feeding (42.6% vs. 42.0% cant predictors of fasting C-peptide decline in those with an age of onset fat mass, respectively). Taken together, these data suggest that when LPL is defi cient in neurons, n-3 PUFA supplementation in the diet cannot pre- between 0-4 years or 5-9 years. In individuals diagnosed between 10-18 vent obesity; moreover, NEXLPL-/- mice become insensitive to the amount years of age, the rate of C-peptide decline increased by 0.047 nM per year of fat in the diet and fatty acid composition. Overall, results from the feeding for each standard deviation increase in baseline BMI. In individuals diag- studies further support our hypothesis that LPL regulates TG-rich lipoprotein metabolism, providing important signaling molecule(s) such as n-3 PUFAs nosed at >18 years of age the most consistent predictor of fasting C-peptide that are involved in lipid sensing in the CNS, and plays an essential role in changewas gender with all models showing that in women the decline over regulation of energy balance and body weight. 1-year was greater by approximately 0.13 nM.A higher baseline BMI isas- Supported by: NIH K-12 BIRCWH award, NIH-NIDDK R01 sociated with a greater rate of fasting C-peptide decline in adolescent T1D. This fi nding implies that in patients diagnosed between 10 and 18 years of age,decreased insulin sensitivity can play a key role in disease progression 1737-P and suggests thattherapies that target reduction in BMI might be helpful in preserving beta cell function. WITHDRAWN & 1735-P Healthy Pre-Monopausal Women With Type 1 Diabetes Have In- creased Peripheral Insulin Resistance Compared to Non Diabetic Women TALIA L. BROWN, RACHEL M. SIPPL, JANET K. SNELL-BERGEON, Aurora, CO Increased insulin resistance (IR) exists in adults and adolescents with type 1 diabetes (T1D) and appears to be independent of metabolic syndrome Guided Audio Tour: Insulin Secretion and Action in Animal Models (Posters factors, but has not been investigated in healthy premenopausal women 1738-P to 1742-P), see page 13. with T1D. The objective was to determine relative IR in premenopausal women with and without diabetes, using the gold standard hyperinsulinemic & euglycemic clamp technique.Women with T1D (n=7, age 33±8 yr, diabetes 1738-P duration 17±7 yr) and women without diabetes (Non-DM) (n=11, age 29±5 yr) Genetic Evidence that Hyperinsulinemia Causes Diet-Induced Obe- from the Women, Sex Hormones and Insulin study were recruited into the sity in Mammals by Preventing “Browning” of White Adipose Tis- IR sub-study. Inclusion criteria were 18-45 years of age with regular men- sue strual cycles, euthyroid, and A1c <9.5% for participants with T1D. Three- ARYA E. MEHRAN, NICOLE M. TEMPLEMAN, KWAN-YI CHU, XIAOKE HU, SU- stage (4, 8, and 40 mu/m2) euglycemic clamps were performed. Adipose and SANNE M. CLEE, JAMES D. JOHNSON, Vancouver, BC, Canada peripheral IR were measured as %free fatty acid suppression (FFA) at the We are taught that obesity, with its elevated lipids and low-grade infl am- end of the second stage and glucose infusion rate (GIR) during the fi nal 30 mation, fi rst leads to insulin resistance, then subsequently to compensatory minutes of the third stage, respectively.Women with T1D had both impaired insulin hypersecretion, followed by diabetes when the (cid:96)-cells fail. However, FFA (41%±36 vs 86%±16 for Non-DM) and decreased GIR (4.9±3 (mg/kg/ there has long been clinical evidence that fasting hyperinsulinemia can pre- y/ min) vs 12.4±5 (mg/kg/min) in Non-DM). Using multivariable linear regres- cede obesity, and clinical trials with some drugs that reduce insulin secretion og sFlHeiFDovAneL ( lmsTc ahaobondlldeee )slfi.s tnM,e adroloi adiln,be saelusnt ledwins es ssyretesar tautoudmlisjcu c wsbotlaneoscdo e adfnon ptr ri rdaneitdsaieosbpuneerste,ne .bdsHo,e esdnatytal tpmghreyae- sdpssiprc eietnmocdireefi oncxfo ,b tbplrooaigouthldsy acGglel IuwRric doaoemnssde-, stm(cid:96)hh-iacocteew l il nasws,s u ewilidighnehi alitet ll s onIenselssfg .2m a Ttmooiv dRdeuNa lcatAeot e,n asttnhr oodelb rsepe, rshwoiatteyes i finbno e uimesn ndae mnxIopnm rsde1ais lrsises.ec Udtr e sgsmientnorgier ceIttn iecswd 1d i-dte/o-em lapyon an(dnts hctIrynraemsta2iuto-is/nc-, d Physiolbesity STERS eO O en with T1D are more likely to have adipose and peripheral insulin resistance brain). By selectively reducing the gene dosage of Ins1, we generated mice at P than Non-DM women, independent of metabolic syndrome parameters. that did not exhibit fasting hyperinsulinemia in response to a prolonged high- gr Models for GIR and FFA. Beta coeffi cient and p-value represent diabetes sta- ftoa th digieht .f Rate dfeuecdiningg I,n sc1o ngfie rnmei ndgo saang ee spsreenvteianlt erdo lies lfeotr hayupteorcprliansei/ap ianr arecrsipnoen isne- Inte tus variable. sulin signaling in this process. Compared to Ins1+/+:Ins2-/- littermate con- Model Beta Coeffi cient P-Value trols, Ins1+/-:Ins2-/- mice were completely protected from obesity, insulin Glucose Infusion Rate resistance and hepatic steatosis caused by high fat feeding, in the absence of sustained changes in glycemia. Genetic prevention of hyperinsulinemia Diabetes Status 7.702 0.0022 increased energy expenditure and uncoupling protein expression in white Diabetes Status + Full Model 10.42 0.0007 adipose tissue (but not brown adipose tissue or muscle), while reducing adi- % Free Fatty Acid Suppression pose infl ammation and fatty acid spillover. Together, our data demonstrate Diabetes Status 41.99 0.0036 that the increase in fasting circulating insulin is required for diet-induced obesity in mammals. Diabetes Status + Full Model 53.33 0.0034 & ADA-Funded Research Guided Audio Tour poster For author disclosure information, see page 797. A447 INTEGRATED PHYSIOLOCGAYT—EGINOSRUYLIN SECRETION IN VIVO & standard diet (SD). After one week glucose levels in CORT-HFD rats were 1739-P elevated (>11 mM) and animals were 15-fold more insulin resistant than con- Differential Development of Insulin Resistance and Beta Cell Adap- trols indicated by HOMA-IR levels (15.1±1.64 vs 1.0±0.12), whereas HOMA-(cid:96) tation in Multiple Diet Induced Obesity Models indicated lower (cid:96) cell function compared to CORT-SD animals (3.72±0.64 BILAL OMAR, GIOVANNI PACINI, BO AHRÉN, Lund, Sweden, Padova, Italy vs 1.64±0.22). Moreover, (cid:96) and (cid:95) cell mass were 1.5- and 0.6-fold higher, The C57BL/6 mouse becomes insulin resistant and glucose intolerant af- respectively, in CORT-HFD treated animals compared to controls. Surpris- ter feeding with a high fat diet (>40% kcal) and is a widely used model for ingly, CORT-HFD isolated islets were found to be highly glucose responsive studying type 2 diabetes (T2D). Many different high fat diets exist and dif- as they released 10-fold more insulin compared to controls. Voluntary wheel ferences in the composition of macronutrients in the diets could induce dif- running showed that CORT-HFD animals had less visceral adiposity (16.2±3.5 ferent metabolic phenotypes. In order to determine which model produces vs 22.4±1.7mg/g) than controls. Blood glucose levels in sedentary CORT-HFD a phenotype most like that of human T2D, the diet models need to be evalu- rats were elevated (12.8±0.15mM) compared to running CORT-HFD animals ated in head-to-head comparisons. We evaluated the two most widely used (9.1±0.55mM). Exercised animals had improved glucose tolerance compared high fat diets in mice, the standard 60% high fat diet (HFD) and the high to sedentary CORT-HFD animals (600.1±121.5 vs 988.4±137.9 following oral fat-high sucrose Surwit diet (HFHS), using intravenous glucose tolerance glucose load, p<0.05). Moreover, insulin sensitivity was improved in running tests (IVGTT) and the euglycemic-hyperinsulinemic clamp, to determine ef- CORT-HFD animals compared to sedentary CORT-HFD animals (53.1±12.0 vs fects on insulin resistance and beta cell adaptation. Mice fed a HFD gained 92.3±26.4mmol/L). We conclude that ROD animals exhibit severe insulin re- more weight than HFHS fed mice (9.5 g v 6.7g, p<0.05) despite near identical sistance that overwhelms (cid:96) cell function. However, exercise intervention energy intake. Both high fat diet models show impaired glucose tolerance introduced in this model greatly improved glucose and insulin tolerance re- after 8 weeks but show marked differences in insulin secretion. Mice fed sulting in better glucose control and body fat composition. the HFD had elevated basal plasma insulin(+111nM, p<0.01), which was not seen in the HFHS fed group. The acute insulin response (AIR) was unchanged & 1742-P in the HFD group, but slightly increased in the HFHS diet group. The HFHS Partial Deletion of the Novel Antioxidant SEPS1 in (cid:437)-Cells Leads to diet group had a 3 fold greater insulin secretion in response to the glucose Impairment in Insulin Secretion load during the IVGTT compared to the HS control diet group (iAUC 15nM CHIA-HENG WENG, TANYA SAMARASEKERA, NICOLE STUPKA, KEN WALDER, v 3nM, p<0.001), while no differences were seen in the HFD group. Insulin JOSEPH PROIETTO, SOF ANDRIKOPOULOS, NICOLE WONG, Heidelberg, Australia, sensitivity, as determined by euglycemic-hyperinsulinemic clamp, was de- Geelong, Australia creased 4-fold in the HFD group (M/I 0.24 μmol/g/nM ND v 0.06 μmol/g/nM Selenoprotein S (SEPS1) is an antioxidant enzyme that has been shown HFD, p<0.01) but not in the HFHS diet group after 8 weeks. After 16 weeks, to protect against oxidative stress (HO) induced cell death in a pancreatic glucose tolerance was not signifi cantly impaired in either the HFD or HFHS 2 2 (cid:96)-cell line. We have preliminary data that showed that (cid:96)-cell specifi c over- diet groups. Basal insulin was signifi cantly elevated in both HFD and HFHS expression of SEPS1 protected against alloxan- and streptozotocin-induced groups but to a greater extent in the HFD group. We conclude that the HFD diabetes. Based on these fi ndings, we hypothesised that the deletion of and HFHS diet models show differential effects on the development of insu- SEPS1 will predispose mice to oxidative stress induced diabetes. The aim of lin resistance and beta cell adaptation. this study was to generate and characterise global and (cid:96)-cell specifi c SEPS1 & deleted mice. Global and (cid:96)-cell specifi c SEPS1 deleted mice were generated 1740-P by PGK-Cre and RIP-Cre respectively and fed a standard chow diet. At eight The SIRT1 Activator Resveratrol Prevents Fat-Induced (cid:437)-Cell Dys- weeks of age, plasma glucose and insulin responses were examined follow- function In Vivo ing an intravenous glucose tolerance test (IVGTT) and an oral glucose toler- TEJAS DESAI, ALEX IVOVIC, BERNARD HAU, KHAJAG KOULAJIAN, DANNA ance test (OGTT) in deleted mice and negative littermates. Global deletion BREEN, ADRIA GIACCA, Toronto, ON, Canada of SEPS1 did not alter plasma glucose and insulin levels during the IVGTT Over the last decade, sirtuins and SIRT1 in particular, have been identifi ed when compared with the negative littermates. Homozygous (cid:96)-cell-specifi c as key regulators of nutrients and metabolism. Within the (cid:96)-cell, there is evi- deletion of SEPS1 led to embryonic lethality. Mice with a partial deletion dence that SIRT1 plays a benefi cial role on insulin secretion. It has also been of SEPS1 in the (cid:96)-cell (+/-) had impaired glucose tolerance (1796.8±159.2 established that excess circulating fat as seen in obesity can be detrimental vs 1349.4±78.3 mmol/Lx120min, p < 0.05, n=5-10) associated with reduced to (cid:96)-cell function (“(cid:96)-cell lipotoxicity”), an effect that may involve decreased insulin levels (87.3±33.7 vs 168.2±21.6 ng/mLx120min, p<0.05, n=6-8). The SIRT1 activity. Consequently, it would seem logical that SIRT1 activation IVGTT confi rmed the reduced glucose mediated insulin secretory response may have a benefi cial role on (cid:96)-cell function in conditions of nutrient excess. in(cid:96)-cell specifi c SEPS1 (+/-) mice (36.2± 5.2 vs 80.0±7.2 ng/mLx30min, p< Here we attempted to mitigate lipotoxicity induced (cid:96)-cell dysfunction using 0.005, n= 12-19). In conclusion, mice with a partial deletion of SEPS1 in the a pharmacological model of SIRT1 activation. Female Wistar rats (n= 4-8 (cid:96)-cell displayed impaired insulin secretion and glucose intolerance, further per group) were infused intravenously for 48h with 1) Saline (SAL, control), emphasising the important role of SEPS1 in glucose homeostasis. 2) Oleate (OLE) at 1.4μmol/min to elevate plasma FFA by 50%, 3) Oleate + the SIRT1 activator Resveratrol (RSV, 0.025mg/kg.min) and 4) RSV alone 1743-P (0.025mg/kg.min). The infusion period was followed by assessment of (cid:96)-cell Micro-RNA 122 Regulates Insulin Secretion in Diet-Induced Obese function by hyperglycemic clamp. OLE infusion resulted in decreased plasma Mice insulin and c-peptide levels in response to the rise in glucose that were RANDALL H. FRIEDLINE, GREGORY WU, HWI JIN KO, YONGJIN LEE, XIAODI HU, signifi cantly decreased (>50%) compared to SAL control infusion (p<0.05). HSUN-FAN WANG, YOSHIHIRO AZUMA, SARAH R. NATHAN, YUN HEE NOH, d Physiology/besity STERS Iicitnnnioo dfnnutuht scrceioeoa ldung i srnadoefleuduocp snbr ieeocy.a on 4Tsi.n8 heNfhe uio snOs e seLi idnrEge s niwsuniufilfi ilutcnthass ai noOinntn Lddd,E iiacc+fna-fRpe tSeeereVf pftn,teh icccadeotte mtw RhwpSaalaVstes tmsp esera eeepyevnr ebne bn evcete Sostn wImttRihepoTeean1 nr (cid:96) meo -Sdfce A edtthlLoila e datt eynhosddelef. uRaSntSAecVL-- KSgardeLoAoMipwuUoilc,tSs hrR eoP,e -aEptRCniusNHdbs lHAufiuceOs n,o L acfDl ritKve,i ooe JinrrUne,, t aNaae nngXddrIa E alp,lr yaGe n UihncAivrgNeohalGlvysPe .e IdNHx piGenr r eGemsA aswOene,dy J ifeAnaxS cmaOemetNsti na Koeb.fd o Kc liItecMhl loe, dr Wgrifoaoflneercsr ee oisnnft ctemilrau, itdMciiornoAng-,, eO O & RNA-122 (miR-122) on glucose homeostasis by generating mice with adeno- egrat P Rapid-Onset Diabetes Induced by High Corticosterone Ex1p7o4s1u-rPe awsistho cAiaAtVed-m viiRra-1l2 k2n oorc ksdcorawmnb olefd m vieRc-1to2r2 .( SMcra),l ea nCd5 7sBtaLr/t6e dm oicne a w heigreh -tfraet adtieedt nt and High-Fat Feeding Impairs In Vivo Islet Function in Rats (HFD) 4 wks later. miR-122 treatment did not affect body weight or insulin I JACQUELINE L. BEAUDRY, ANNA D’SOUZA, YANIV SHPILBERG, TREVOR TEICH, sensitivity in chow-fed mice. During 16 wks of HFD, miR-122 and Scr mice ROBERT TSUSHIMA, MICHAEL RIDDELL, Toronto, ON, Canada became obese with similar whole body fat mass. Basal plasma insulin lev- We have recently established a new rapid-onset-diabetic (ROD) rodent els tended to be lower in miR-122 mice compared to Scr mice after HFD. A model, induced by elevations in the stress hormone, corticosterone (CORT) 2-hr hyperglycemic clamp was performed in awake mice to assess glucose- and a high-fat diet (HFD). Together these treatments induce severe insulin induced insulin secretion in vivo (n=5/group). Plasma glucose levels were resistance however, rarely in concert have they been investigated on (cid:96) cell quickly raised and maintained at ~350 mg/dl in both groups of mice. Plasma function. Regular exercise alleviates insulin resistance and preserve (cid:96) cell insulin levels were similarly elevated during clamps in chow-fed mice (Fig. mass. We examined the short-term effect of these stressors and voluntary 1). In contrast, HFD-fed miR-122 mice showed lower plasma insulin levels exercise on (cid:96) cell dynamics in male Sprague-Dawley rats (~6 weeks) given during clamps compared to HFD-fed Scr mice (Fig. 2). This resulted in ~20% CORT pellets (400 mg/rat) or wax pellets (control) and placed on a HFD or reduction in area-under-curve of insulin levels in miR-122 mice, suggesting & For author disclosure information, see page 797. Guided Audio Tour poster ADA-Funded Research A448 INTEGRATED PHYSIOLOCGAYT—EGINOSRUYLIN SECRETION IN VIVO blunted insulin secretion in these mice (Fig. 3). This was further confi rmed mg/kg/min, NHP showed robust glycemic and C-peptide responses through- by measuring total serum C-peptide levels which were 2-3 fold lower in out the 160-minute GGI (Fig.1). Data are represented as mean ± S.E. At the HFD-fed miR-122 mice following glucose injection (Fig. 4; *P<0.05). Overall, highest GIR, signifi cant (P<0.001) glycemic (124.2 mg/dL) and C-peptide (9.70 our fi ndings indicate that miR-122 knockdown impairs insulin secretion in ng/mL) responses expressed as a change from baseline, were observed. diet-induced obese mice and further identify a novel role of miR-122 in the In a similar experiment, HV had robust glycemic and C-peptide responses regulation of pancreatic function in obesity. (Fig.1). Comparison of data was done between NHP and HV (Fig.1). While at the highest GIR, NHP and HV had similar [geometric mean ratio (90%CI)] maximal glycemic [0.85 (0.63, 1.16), p=0.18], and C-peptide [1.62 (1.04, 2.53), p=0.04] responses, overall quantitative responses to a GC in NHP appear more robust than in humans. Together, these fi ndings demonstrate for the fi rst time in a systematic evaluation, that in adult healthy NHP, the GGI is able to detect metabolic responses to a glycemic challenge, and the response patterns are highly similar to those in healthy human volunteers. Supported by: NIH (R01-DK080756) 1744-P GRP78 Over-Expression in Pancreatic (cid:437)-Cells Protects from High Fat Diet-Induced Diabetes in Mice TRACY TEODORO, IRMGARD SCHUIKI, LILING ZHANG, ALLEN VOLCHUK, Toronto, ON, Canada Endoplasmic reticulum (ER) stress is a mechanism involved in type 2 diabetes pathology and has been shown to contribute to both insulin resistance in liver and adipose tissue and pancreatic (cid:96)-cell dysfunction. To examine whether ER stress in pancreatic (cid:96)-cells contributes to the development of type 2 diabetes we generated a mouse model that over-expresses the resident ER chaperone and Unfolded Protein Response regulator GRP78 in pancreatic (cid:96)-cells. Under the control of a rat insulin promoter GRP78 was overexpressed by approximately 8-fold in pancreatic (cid:96)-cells and the mice had normal weight gain and metabolic physiology on a regular chow diet. We hypothesized that increased chaperone capacity would protect (cid:96)-cells from dysfunction resulting from obesity and improve glucose homeostasis in mice on a chronic high fat diet (HFD). As expected, control transgene negative mice on a 20-week HFD developed obesity, glucose intolerance and insulin resistance. Remarkably, GRP78 transgenic mice tended to be leaner than their transgene negative littermates and were protected from glucose intolerance, hyperinsulinemia and insulin resistance. Islets from transgenic mice were also protected from the hypertrophy characteristic of obesity-induced insulin resistance. Compared to transgene negative animals on a HFD, islet 1746-P area (mass) was reduced and was comparable to islet mass in regular chow Quantifi cation of Glucose-Stimulated Insulin Secretion Rate in fed mice. HFD feeding caused mild ER stress in islets and islets from GRP78 Normal, Pre-Diabetic, and Diabetic Cynomolgus Monkeys (Macaca transgenic mice were protected from ER stress. In summary, increased Fascicularis) Using a Graded Glucose Infusion chaperone capacity in pancreatic (cid:96)-cells protects from the pathogenesis YI-XIN (JIM) WANG, PAUL B. HIGGINS, CHEN WANG, JIAN WANG, YUPENG y/ g of obesity-induced type 2 diabetes by improving pancreatic (cid:96)-cell function, FANG, FENGLAI DU, BINGDI WANG, XIAOLI WANG, FRANCINE M. GREGOIRE, o whSiuchp puolrttiemda btye:l yC IiHmRp (rMovOePs- 1w14h9o9l2e) body glucose homeostasis. 1745-P BccreAelGRlt irfBoauAndnR ecrAatdi t oCegn. l ( uHIiSncAodRNse) eSpu eEsiNninnfd,gu eT stanihiotcelnay G n o(gGGf, GIiC npIhs)r iuopnlvarioni, d cKseeaesdnn niusnarisetpiisogv lhiihtstya, .ivN nQetCu o,b atTenhaetemin fitp cruaaas,j teFeiLdoc ntto oor ifee isvn asolufu l(cid:96)aint cese e(cid:96)l-l ed PhysiolObesity OSTERS Mlenegtaeb ionl Lice aRne sHpeoanltshey P Naotnte-rHnusm toa na PPraimreantteesr aRle Hseympebrlgel ythcoesmei icn C Lheaaln- dthyes feufnfcetcitosn o ifn t hdeiarbaepteeust idc eavgeelonptsm oenn t(cid:96) a cnedll cfaunn cbtieo nu.s IeSdR two adsir deecttleyr mevinaeluda btey egrat P Healthy Human Volunteers deconvolution of serum C-peptide concentrations measured in a 5 stage GGI nt (glucose infusion rates of 2, 4, 8, 16, and 32mg/kg/min for 40mins each) in 6 I EFFIE TOZZO, LORI MIXSON, STACEY L. CONARELLO, BARBARA C. HANSEN, normal (6.0±0.2yrs, 7.6±0.7kg, fasting glucose: 60±4mg/dL), 14 prediabetic CHAN R. BEALS, DAVID E. KELLEY, SUDHA S. SHANKAR, Rahway, NJ, Tampa, FL We have previously shown that the Graded Glucose Infusion (GGI) method (15.0±0.8yrs, 9.0±0.9kg, fasting glucose: 80±4mg/dL), and 4 untreated newly can successfully detect glucose-dependent insulin secretion (GDIS) re- diabetic (16.0±1.2yrs, 9.0±1.8kg, fasting glucose: 169±22mg/dL) cynomolgus sponses to a parenteral stepwise glycemic challenge (GC) in healthy human macaques. After correction for circulating glucose concentrations, group volunteers (HV). We tested the hypothesis that the GGI can detect GDIS in mean ISRs were compared by one-way ANOVA with Tukey’s post hoc com- healthy adult NHP, with response patterns resembling those in HV, by comparisons. A signifi cant mean difference in ISR was found between the groups paring GDIS between NHP (N=6, weight: 10.7±1.0 kg, FPG: 62.4±5.6 mg/dL, (F=6.18, p=0.001). ISR was signifi cantly less in the diabetic group compared mean ± SD) and HV (N=8, BMI: 23.3±2.1 kg/m2, FPG: 86.9±7.3 mg/dL). After to the normal (p<0.01) and prediabetic groups (p<0.05). No signifi cant differ- an overnight fast, in response to glucose infusion rates (GIR) from 2 to 16 ences in ISR were noted between the normal and prediabetic groups (Figure & ADA-Funded Research Guided Audio Tour poster For author disclosure information, see page 797. A449 INTEGRATED PHYSIOLOCGAYT—EGINOSRUYLIN SECRETION IN VIVO 1). Observations are consistent with those in rhesus macaques and humans. 1748-P We conclude that the GGI with ISR calculation produced predictable mea- Signifi cant Early Changes During Time Course Assessment of Lipid sures of (cid:96) cell responsiveness in normal, prediabetic, and diabetic cyno- and Metabolic Profi le Following Bariatric Surgery molgus macaques and could be of utility in assessing the effi cacy of agents ROBERT V. CONSIDINE, LORI A. MIXSON, AIZZA HASSAN, ROSEMARIE JONES, targeting improvements in (cid:96) cell function. SAMER G. MATTAR, MANU CHAKRAVARTHY, CHAN R. BEALS, DAVID E. KELLEY, SUDHA S. SHANKAR, Indianapolis, IN, Rahway, NJ Studies of the acute metabolic improvements in Type 2 diabetes after Roux-en-Y gastric bypass surgery (RYGB) have largely focused on single time-points, with changes attributed primarily to altered gut hormone release. Scant data exist on the time course of metabolic changes, especially lipid parameters, in the intermediate period between recovery from RYGB, but before signifi cant weight loss. We tested the hypothesis that the pattern of change in fasting and prandial glucose homeostasis and lipid parameters between 1-4 weeks post RYGB (POST) refl ect the interaction of multiple prevailing metabolic processes. Fasting parameters were measured at 1, 2 and 4 wks POST, and enteroinsular response to a meal (~350 kcal; 25.9g carbohydrate, 8.4g fat, 44g protein) at 2 and 4 wks POST, in 18 women with Type 2 diabetes (BMI 52.7±14.2 kg/m2, 44.0±10.1 yr; mean±SD). Compared to presurgery (PRE), at 1 wk there were signifi cant (p<0.01) decreases in fasting glucose (20%), insulin (47%), and C-peptide (32%), which were maintained at 2 and 4 wks. During meal test at 2 and 4 wks, a return to pre-meal values of glucose, insulin and C-peptide was observed at 120-minutes, in contrast to PRE excursions which remained well above pre-meal values at 120-minutes. Robust increases in circulating prandial PYY AUC (p<0.005) occurred at 2 (253%) and 4 wks (136%). Decreases (p<0.01) in triglycerides (11%), and HDL- C (23%) at 1 wk were maintained at 4 wks, with LDL-C signifi cantly reduced (14%) at 4 wks. The pattern of changes in fasting and prandial glucose homeostasis at 2 and 4 wks POST are consistent with improved enteroinsular axis function. Changes in PYY may be associated with earlier satiety, while 1747-P lipid profi le changes at 1 and 4 wks POST are consistent with caloric restric- Differences between Japanese and Caucasians in Insulin Sensitiv- tion, both of which may also lead to improved glucose homeostasis. Taken ity and Beta-Cell Function: Contribution of BMI together, our fi ndings suggest that multiple interactive processes may con- MITSURU OHSUGI, HARUHIKO TANAKA, MARIA PEDERSEN, JONAS B. MØLLER, tribute to the weight loss independent metabolic improvement after RYGB. RUNE V. OVERGAARD, JAN LYNGE, KATRINE ALMIND, NINA-MARIA VASCON- CELOS, PERNILLE POULSEN, CHARLOTTE KELLER, KOHJIRO UEKI, STEEN H. IN- 1749-P GWERSEN, BENTE K. PEDERSEN, TAKASHI KADOWAKI, Tokyo, Japan, Copenha- Pancreatic Fat Does Not Impair Beta-Cell Function in a Non-Dia- gen, Denmark, Bagsvaerd, Denmark betic Cohort The pathophysiology of type 2 diabetes (T2D) is perceived to be differ- BETTINA NOWOTNY, ROSHAN LIVINGSTONE, SABINE LINK, BIRGIT KLÜPPEL- ent in Japanese compared to Caucasians. Japanese have been reported HOLZ, PETER J. NOWOTNY, JONG-HEE HWANG, GIOVANNI PACINI, GUIDO GI- to have higher insulin sensitivity but less ability to compensate for insulin ANI, MICHAEL RODEN, Düsseldorf, Germany, Padova, Italy resistance by increased beta-cell function, although the supportive scien- Beta cell dysfunction contributes to the development of type 2 diabetes tifi c data are limited.We undertook a cross-sectional study in 120 Japanese on the basis of insulin resistance. Ectopic lipid storage has been shown to living in Japan and 150 Caucasians living in Denmark, with the objective be associated with insulin resistance of liver and muscle. Whether elevated to compare insulin sensitivity and beta-cell function, and to investigate the pancreatic fat contents are related to impaired beta cell function in humans role of demographic, genetic, biochemical and life-style related factors. remains unclear. Thus, this study analyses the association of pancreatic fat Participants were grouped according to their glucose tolerance: normal or content and beta cell function in a non-diabetic cohort. 75non-diabetic sub- impaired glucose tolerance (NGT, IGT) or T2D, with comparable distributions jects (43f/32m; mean age 58±11 years; body mass index (BMI) 26.0±3.8kg/m2) of high/low BMI according to regional obesity defi nitions. Insulin sensitiv- underwent a 75g oral glucose tolerance test (OGTT). Blood glucose, insulin ity and beta-cell function were estimated from oral glucose tolerance test and C-peptide levels were determined at various time points, and pancreatic data.Mean glucose profi les were similar in Japanese and Caucasian NGT, fat (median 6.5%, range 0.3-41.9%) content was measured using 1H MRS IGT and T2D participants respectively, whereas the insulin and C-peptide using a 3TPhilips scanner with stimulated echo acquisition mode (STEAM) responses were lower in Japanese. The Japanese participants were less sequence. Indices of beta cell function [Insulinogenic index (IGI, pmol / INS insulin resistant as determined by HOMA-IR and Matsuda index, and had mmol ), adaptation (AI) and disposition (DI) index (common units)] and in- GLUC lower beta-cell function as determined by HOMA-B, insulinogenic index and sulin sensitivity (OGIS, ml/min/m2) were calculated. Pancreatic fat contents insulin secretion ratio than Caucasians. Disposition indices, expressing be- ranged from 0.25 to 41.89 % (mean 9.31±9.26%), and means±SEM of beta y/ ta-cell function relative to insulin resistance, were similar in Japanese and cell function were 215±36 for IGI, 0.45±0.01 for AI and 2.60±0.12 for DI, while g o Caucasians.BMI and other measures of body size such as weight and waist, insulin sensitivity (OGIS) was 444±8. Pancreatic fat correlated signifi cantly ed PhysiolObesity OSTERS wAastnceadcrt oeiCsr atmdiuicancajgaol lsrys i,ida gfennostilefil owrcwmaeniirnnet ga is nnuB tbNMss GfIto-aTarn dabtjinouadtslhl tyI mG irnTees nduptula,ic nrtet hsidece i ipndnsai fainftleitl vsrgi.etrInnoy cuaceponssnd bac belnuetdswt iawoe-nece,ern eol l Ju nfarou p rnleaocsnntuiegolsetnesr. wecoonri rctCrhee- p lw(aer=tepii0otgi.ndh3set0 w,(l re=pev0=ree.0l3 s.f50 ot,0h up5rno=)d,u 0 wgw.0hhi0otih2cu h)t,f atBwhsMetai snIO g(Gsr =toTr0roT ..2n3 Nhg7 ,eo wrp ih=nino0d l.eef0ex 0b mo0lofa3 obl)e deas tn gatdl huc awcenolal s iifesnut na mccnitardicl oeuinnsm s.w ufNelairons- at P confi rm that Japanese generally have higher insulin sensitivity and lower associated with pancreatic fat content, nor we observed a clear correlation egr beta-cell function than do Caucasians. The major part of these differences with OGIS (r=-0.18; p=0.08). Linear regression analyses with adjustment for nt can be explained by differences in body size (BMI). sex, age and BMI did not improve the associations. In conclusion, pancreatic I Supported by: Japan Sci. & Techn. and Danish Sci. Techn. Innov. Agencies; Novo fat content is associated with increased body weight and body fat mass, but Nordisk A/S cannot serve as a surrogate of impaired beta cell function in a non-diabetic population. & For author disclosure information, see page 797. Guided Audio Tour poster ADA-Funded Research A450 INTEGRATED PHYSIOLOCGAYT—EGINOSRUYLIN SECRETION IN VIVO 1750-P 1752-P Vietnamese Americans Demonstrate Markedly Impaired Insulin Se- Beta Cell-Specifi c Overexpression of the Intracellular Protein p8 cretion Across Glycemic Status Preserved Glucose Tolerance during High Fat Diet- or Insulitis-In- LAN CHI T. LUU, TIMOTHY ALLERTON, GABRIEL UWAIFO, ROBERT DUBIN, WIL- duced Beta Cell Damage In Vivo LIAM T. CEFALU, New Orleans, LA AMIR E. MEHANA, INGO H. PILZ, BIANCA DUFNER, CHRISTINA JÄGER, SAN- Vietnamese Americans (VNA) represent one of the fastest growing minor- DRA SOJKA, JOHANNES BAUMANN, MARCUS ALT, JOCHEN SEUFERT, GÜNTER ity populations in the United States with a 38% population growth since PÄTH, Freiburg, Germany 2000. Previous studies have shown that Asian Americans, as a group, are OBJECTIVE: p8 was initially described to protect exocrine acinar tissue at greater risk to develop Type 2 Diabetes (T2DM) than Caucasians. How- from infl ammatory damage. To evalute the protective potential in the en- ever, there is currently a dearth of research investigating the unique meta- docrine pancreas, we generated transgenic (tg) mice with beta cell-specifi c bolic risk factors that contribute to the development of T2DM in VNA. We p8 overexpression. Previously, we introduced the tg phenotype and demon- sought to evaluate insulin secretion (IS), insulin sensitivity (Si) and metabolic strated that upon 10 weeks high fat diet (HFD) tg and wild type (wt) mice fl exibility [(MF), the switch in substrate oxidation, i.e., utilization of fat to gain weight, develop insulin resistance and became glucose intolerant. carbohydrate] across glucose classifi cations of VNA [normal glucose toler- Importantly, tg mice preserved a signifi cantly enhanced 1st phase insulin ance (NGT), impaired glucose tolerance (IGT), and T2DM}. In vivo physiologic secretion. Here, we analysed beta cell mass in HFD-mice and investigated measures were conducted in 30 VNA subjects of mixed gender (15 NGT, 8 the effects insulitits and STZ-induced beta cell damage combined with HFD. IGT, and 7 T2DM), ages 18 - 69, and BMI of 18-40 kg/m2. Subjects completed RESULTS: After 10 weeks of HFD (60%) mice demonstrate signifi cant loss of a mixed meal tolerance at which time indirect calorimetry was performed beta cell mass. This loss was signifi cantly reduced in HFD-tg mice. We next pre and post meal to assess MF by measuring resting quotient (RQ). During analysed effects of 5 x 40 mg/kg STZ-induced insulitis. Unfasted blood glu- a separate visit, subjects underwent a frequently sampled intravenous glucose levels do not signifi cantly change. In contrast, glucose tolerance mea- cose tolerance test to calculate IS and Si. First phase IS was 43.0+18.0mu/L sured by fasted ipGTT dramatically decreases in wt mice (1st and 2nd phase) in NGT, 17.1+ 9.9mu/L in IGT, and 11.8+9.2 in T2DM (P < 0.0001 across while tg mice demonstrate levels similar to untreated tg controls. Next, we groups). Beta cell function was reduced(P<.03) across NGT 120+45.6 mU/ fed mice with normal diet or HFD and inject a single dose of 150 mg/kg STZ mM, IGT 73.2+26.6 mU/mM, and T2DM 73.6+46.7mU/mM. The disposition after 4 weeks resulting in acute diabetes (unfasted blood sugar above 400 index (DI) was positively correlated with 2-hour plasma glucose (r2=0.74, mg/dl). Within the next 4 weeks normal and HFD fed wt do not change their P<0.0001). At glucose values indicative of IGT (2hr value of 140 mg/dl), DI diabetic state while tg recover. Interestingly, recovering in normal-fed tg values were markedly impaired by 80%. Insulin resistance increased from mice was less pronounced (n.s.) than in HFD-fed tg mice, which signifi cantly 0.75+0.3 in NGT, 0.88+0.32 in IGT, to 2.0+2.1 in T2DM. After RQ was adjusted ameliorate their diabetic blood sugar levels down to values below 300 mg/ for Si the (cid:54)RQ values for NGT, IGT, and T2D were (0.075, 0.010, and 0.00) dl in weeks 3 and 4.CONCLUSION: p8 protects beta cell mass from damage respectively.In conclusions, Vietnamese Americans have markedly impaired by HFD-induced lipotoxicity and insulitis. p8 appears to be also regenerative. insulin secretion when already diagnosed as IGT with further progression To further evaluate its anti-infl ammatory and regenerative potential we are to T2DM. Vietnamese Americans have severe impairment in metabolic fl ex- currently investigating insulitis-induced lymphocyte infi ltration into islets ibility as they progress from NGT to T2DM. and beta cell proliferation after STZ-damage. Supported by: LSUHSC School of Medicine Supported by: Deutsche Forschungsgemeinschaft (DFG) Grant PA1663-2-1 (G.P.) 1751-P 1753-P Decreased Insulin Responses to IV Glucose and Tolbutamide in Sub- GIP Elicits Additive But Not Synergistic Effects of Glucose Lower- jects With Impaired Fasting Glucose: Clues to Cellular Mechanisms ing Over Sub-Optimal Doses of GLP-1 for (cid:437)-Cell Failure? ANNE M. CHRISTIANSEN, SARAH WILL, OVER CABRERA, DAVID TESS, XIANG- SEDA SUVAG, KRISTINA UTZSCHNEIDER, LORENA A. WRIGHT, BRIAN FISH, STE- PING LI, SNEHA NARAYANAN, SHENA PATEL, BHAVNA PARATALA, I-CHEN YU, VEN KAHN, Seattle, WA JESSIE DOW, MYLENE PERREAULT, MARGARET JACKSON, JULI JONES, Cam- In subjects with impaired fasting glucose (IFG), the 1st phase insulin re- bridge, MA, Groton, CT sponse to IV glucose is impaired. Whether the 2nd phase insulin response to Glucose-dependent insulinotropic peptide (GIP) and glucagon-like pep- glucose and the response to the K-ATP channel blocker tolbutamide are simi- tide-1 (GLP-1) are both insulin secretagogues and metabolic modulators but larly impaired, is not known. To address this, 233 subjects with normal fast- have differing biological effects. The purpose of the current studies were ing glucose (NFG) (n=156, 53M/103F, age 52±0.8 y, BMI 26±0.3 kg/m2, fast- to examine if GIP can elicit an additive or synergistic effect over a GLP-1 ing glucose 92.8±0.4 mg/dl) or IFG (n=77, 45M/32F, age 53±1.1 y, BMI 28±0.5 agonist (Exendin-4 (EX4)) for glucose lowering in vivo in mice and ex vivo in kg/m2, fasting glucose 106.3±0.6 mg/dl, x±sem) underwent an IV glucose human islet cultures. In all of these studies we choose doses based on PK/ tolerance test with tolbutamide given at 20 min. First phase insulin response PD modeling in order to address combination agonism. To look at the effects was calculated as the incremental area under the curve (iAUC) insulin from of GIP and GLP-1 in vivo, lean, fasted C57/B6 mice were injected with varying 0-10 min; 2nd phase response as iAUC insulin/iAUC glucose from 10-19 min doses of GIP (sc) or EX4 (ip) prior to an ip glucose tolerance test. Based on the and tolbutamide response as iAUC insulin/iAUC glucose from 19-30 min. modeled dose effect relationship, the ED50 and ED75 of EX4 and the ED90 Insulin sensitivity (S), determined by the minimal model, was lower in IFG of GIP were chosen for combination studies. We found that when EX4 was I subjects (median [IQR]: 2.5 [2.1] vs 3.8 [3.0] x 10-4 min-1/(μU/mL), p<0.001). As administered at the ED50, the addition of ED90 GIP could demonstrate an ad- S determines the magnitude of insulin responses, analyses were adjusted ditive effect on glucose lowering. However, a combination of ED75 EX4 and foIr S. Subjects with IFG had lower 1st phase (33.7 [31.9] vs 52.6 [39.5] μU/ ED90 of GIP could not provide greater than maximal GLP-1 glucose lowering. y/ I g mL; p<0.001), 2nd phase (0.17 [0.17] vs 0.22 [0.20] μU/ml per mg/dl, p<0.001) To further understand the human biology of GIP and GLP-1, we performed ex o (adlraln2,t= dep0 d=t. o50inl6.b 0;au 0pltl4a< s)m0.u .Tib0dhj0eee1 c i)1nt. sssIt n u(pr lc2ih=noa 0nrs.ete5rs a7ap;sn otpd,n< stt0heo.es0lb 02(u01nt.d)a6 apm9nh id[ad0 sei.ne6 r 5Nein]s FsvpGuso l in(0nrs.2 7=er5e0s s .[w60p9.oe6;nr 9pes]< e sμ 0tdU.ri0o/dm0n n1gl)o l pyate nccrdoo m rrIrrFgeeG/-- vrfEoeiXvrc4o o3 evw-e7xirp tedehda r iyamfsnr.oed mnI swt lseni ttoihnsr omhwuuateml rahea u nmtm riaesaxlaneitm tes caduul b aljctecuocurntetcses el.ay nIn stwdrlea ictttsuhio l wtnau eromrefeda G ixsiiInomP l CaaaMtlt e cAdvoa RfnrrLcyo eibmnnag tps reacao ntmincorceneed aonias-f ed PhysiolObesity OSTERS late with either 1st phase or tolbutamide responses in any group. Thus, the (cid:96)- trations of glucose and insulin secretion was measured. Similar to the in at P cell defect in IFG affects both glucose- and tolbutamide-induced responses. vivo studies, a combination of GIP and EX4 did not demonstrate synergistic egr The strong relationship between the 1st phase and tolbutamide responses effects. Taken together, these data help elucidate the complex combinatory nt I suggests that these share a common mechanism through the K-ATP channel, effects of GIP and GLP-1 on metabolism and suggest that these effects may while the lack of a relationship between these and the 2nd phase suggests be similar in both in vivo mouse and ex vivo human model systems. that an alternative or additional mechanism underlies this latter response. & ADA-Funded Research Guided Audio Tour poster For author disclosure information, see page 797. A451 INTEGRATEDC APTHEYGSOIORLYOGY—LIVER 1754-P INTEGRATED PHYSIOLOGY—LIVER Prolyl Endopeptidase (Prep) Regulates Insulin Secretion and Glu- cose Metabolism in Mice JUNG DAE KIM, GIUSEPPE D’AGOSTINO, JIN KWON JEONG, RICHARD KIBBEY, Guided Audio Tour: Physiological Studies of Hepatic and Lipid Metabolism OWEN CHAN, SABRINA DIANO, New Haven, CT (Posters 1756-P to 1763-P), see page 15. Prolyl endopeptidase (Prep)is a highly conserved serine protease impli- & cated in regulation of neuronal functions, including hypothalamic processes. 1756-P However, Prep is still the subject of studies attempting to elucidate its Liver Glycogen Loading Amplifi es Counterregulatory Hormone Re- physiological role. Here we report that Prep expression in the hypothala- lease and the Hepatic Response to Hypoglycemia mus is predominantly presented in the ventromedial nucleus (VMN) which JASON J. WINNICK, GUILLAUME KRAFT, BEN FARMER, MARGARET LAUTZ, is involved in the regulation of energy and glucose metabolism. Thus, we ERIC ALLEN, ALAN D. CHERRINGTON, Nashville, TN analyzed glucose metabolism in Prep null (Prepgt/gt) mice compared to wild The purpose of this study was to determine whether the hepatic glycogen type controls (WT). Although Prepgt/gt mice fed on a standard chow diet level infl uences the response to hypoglycemia. During the fi rst 4h of each showed no signifi cant difference in body weights, body composition and study animals received somatostatin and basal intraportal infusions of both food intake compared to wild types, glucose tolerance test (GTT) showed insulin and glucagon. Plasma glucose was doubled by glucose infusion into that Prepgt/gt mice had a marked increase of blood glucose level after 1g/kg a peripheral vein and liver glycogen loading was either enhanced (L+; n=5; intraperitoneal glucose challenge and circulation insulin measurement dur- estimated liver glycogen content of ~82±7 mg/g) due to glucokinase translo- ing GTT showed signifi cant lower insulin levels in Prepgt/gt mice compared to cation brought about by intraportal fructose infusion, or not (saline infusion; WT, indication that Prepgt/gt mice have a decreased insulin secretion by the L-; n=5; ~54±4 mg/g). The 4h glycogen loading period was followed by a 2h pancreas. Consistent with decreased glucose-induced insulin secretion in control period during which basal replacement of hormones was continued Prepgt/gt mice, Prepgt/gt mice have shown less phosphorylation level of insulin but fructose infusion was stopped. In the fi nal 2h, the somatostatin and receptor by glucose challenge in VMN compared to WT. In agreement with glucagon infusions were stopped and plasma insulin levels were increased these fi ndings, the hyperinsulinemic-euglycemic clamp study has also shown 16-fold in both groups. During the ensuing 2h hypoglycemic period the ar- that the Prepgt/gt mice have an impaired insulin secretory response to a hy- terial plasma glucose was clamped at 47±1 and 47±2 mg/dL in L+ and L-, perglycemic challenge. Moreover, the Prepgt/gt mice require less glucose to respectively. The hepatic sinusoidal insulin levels were 427±18 and 402±34 maintain the hyperglycemic plateau which is consistent with the lower insu- μU/mL in L+ and L-, respectively. However, the amount of glucose required lin response. However, when in vitro pancreatic insulin release was studied, to maintain the hypoglycemic clamp was signifi cantly less in L+ compared no differences were found between WT and Prepgt/gt mice. Finally, Prepgt/gt to L- (1.8±0.2 and 4.7±0.2 mg/kg/min, respectively; p<0.001), as a result of mice showed increased sensitivity to insulin compared to WT controls by greater net hepatic glucose output in L+ than L- (5.1±0.6 and 1.5±0.2 mg/kg/ ITT, indicating that insulin-mediated glucose uptake is not impaired rather is min, respectively; p<0.001). Plasma levels of both glucagon and epinephrine enhanced in the absence of PREP. Altogether these data reveal a previously were basal and not different between L+ and L- prior to the hypoglycemic unsuspected role of PREP in hypothalamic control of glucose metabolism. challenge. However, the average hepatic sinusoidal plasma glucagon level during the hypoglycemic period was higher in L+ compared to L- (113±30 vs 1755-P 63±81 pg/mL, respectively; p=0.07) as was the average arterial plasma epi- Poor Compensatory Insulin Secretion against Insulin Resistance nephrine level (1736±43 and 942±274 pg/mL, respectively; p=0.08). These during Oral Glucose Tolerance Tests in Korean Subjects With Im- data suggest that the increase in hepatic glucose output was secondary paired Glucose Tolerance or Type 2 Diabetes Mellitus to augmented epinephrine and glucagon secretion and that the brain can TAE JUNG OH, KYONG SOO PARK, SEONG YEON KIM, HONG KYU LEE, EUN KY detect the hepatic glycogen content. KIM, MIN KYEONG KIM, YOUNG MIN CHO, Seoul, Republic of Korea & It has been known that the amount of insulin secretion during oral glu- 1757-P cose tolerance tests (OGTTs) is much lower in Asian subjects with impaired PEPCK-C is Required for Normal Mitochondrial Substrate Shuttling glucose tolerance (IGT) or type 2 diabetes than in Caucasian counterparts. JOAO DUARTE, JOHN G. JONES, SHAWN C. BURGESS, Dallas, TX, Coimbra, Por- Oral disposition index (DI), which is the product of 1/fasting plasma insulin tugal and insulinogenic index during the standard 75 g OGTTs, refl ects the pan- Cytosolic phosphoenolpyruvate carboxykinase (PEPCK-C) catalyzes the creatic beta cell function corrected for insulin sensitivity. In this study, we conversion of oxaloacetate (OAA) to phosphenolpyruvate and has long been addressed the beta cell function in Korean subjects with normal glucose associated with the transcriptional regulation of gluconeogenesis. We’ve tolerance (NGT), IGT, or type 2 diabetes in terms of oral DI. A total of 269 demonstrated that this pathway is also critical for the regulation of he- subjects (93 men and 176 women) aged 30-80 years were recruited by local patic energy metabolism and the tricarboxylic (TCA) cycle. The importance advertisement. Standard 75g oral glucose tolerance tests were performed. of PEPCK in non-gluconeogenic pathways is underscored in PEPCK-C liver Plasma glucose and insulin levels during OGTTs were measured. Oral DI, in- knockout (LKO) mice which have a severely impaired hepatic TCA cycle, sulinogenic index, and Matsuda index were calculated. We analyzed three fasting hepatic steatosis and markedly higher concentrations of some TCA groups according to degrees of glucose tolerance (183 NGT, 57 IGT, and 29 cycle intermediates, including a 10-fold elevation in liver malate. To further type 2 diabetes subjects). The oral DI was remarkably reduced in type 2 investigate the role of PEPCK-C in the regulation of lipid metabolism we diabetic patients (0.6±3.5 in type 2 diabetes vs. 1.5±1.3 in IGT vs. 2.9±3.1 in examined lipogenic fl ux in mice with varying levels of PEPCK-C expression NGT, P < 0.001). Interestingly, the regression curves for IGT and type 2 dia- and found that PEPCK-C has a robust and positive effect on lipid synthesis. gy/ betes (Fig 1) were fl at rather than hyperbolic, indicating poor compensatory We hypothesized that this occurs through a metabolic mechanism involving d Physiolobesity STERS icKpnorosemrudelpoainemn n sissneuaacbtrnojetert cypio taisnnt hswtouoilp tiohnhv ysIesGericToco lrooemgrt eiyto yinonp fste otu y2 loip ndve ei ra2erb csdoeiismtatebaesen ,p tcwerees.h viTinachh itle ihnmriegsa wpiyn oasbpsueu l viltnaihr tetriueo uasnnil.sliytq auanbec seae nnindt PsPahnEEuPPatlCCytKKlze--esCCd. aLTbKosy O ain1 Havreen NgismutMilagaRlatso t mear notehdft i acsmba poittoaloospcmslheiiborcion liatdtinryci,a a flll liyu vasxein rstds.h rwPcoEyeutPrgoCehs K eom-xlCicci ti oLscKecohOdmo fpmnraodirmcrtieam c lh eosannudttbsr os hwtla radaen rtdaee eO O substantial accumulation of aspartate, malate, glutamate and glutamine in at P gr the cytosol suggesting a blunted malate-aspartate shuttle. Gene expression e analysis revealed reduced expression of the tricarboxylic acid transporter Int but otherwise normal expression of enzymes of the shuttle system. We suggest that PEPCK-C loss of function suppresses lipid synthesis by impairing the mitochondrial substrate shuttle system, including anaplerotic infl ux via the malate-aspartate shuttle and cataplerotic export of citrate, a required pathway for lipogenesis. Supported by: NIH (RO1DK078184) & For author disclosure information, see page 797. Guided Audio Tour poster ADA-Funded Research A452

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Both are known upstream regulators of ERK5. to therapy. resident ER chaperone and Unfolded Protein Response regulator GRP78 in.

2012 ADA Posters 1181-2156.indd PDF

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Both are known upstream regulators of ERK5. to therapy. resident ER chaperone and Unfolded Protein Response regulator GRP78 in.

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