INTEGRATED PHYSIOLOGY—INSULINCATEGORY SECRETION IN VIVO tigate this, we built upon our zinc data to explore activation of IRAP, via An- giotensin IV, in our rodent model of T2DM. The present data show that zinc is Measure (Mean ± SE) South Asian Caucasian P a neuromodulator, regulating hippocampal memory processes, and suggest Clamp M (mg/kg·min) 4.48±0.24 7.46±0.34 < 0.0001 that zinc supplementation and administration of zinc-dependent peptides Clamp Si (mg/kg·min per μU/ml) 0.088±0.009 0.151±0.009 < 0.0001 may be useful therapeutic agents for cognitive impairment in T2DM. Matsuda Index 7.60±0.99 13.60±1.79 0.0036 Supported by: NIH and the Alzheimer’s Association HOMA-IR (μU/ml·mmol/l) 1.56±0.19 0.77±0.07 0.0013 2762-PO OGTT Mean Insulin (μU/ml) 49.1±6.2 26.5±4.1 0.0064 Tumor Necrosis Factor-ƴ-Induced NF-ƽB Signaling in Human Pan- OGTT Mean Glucose (mg/dl) 115±6 107±5 NS creatic Islets and Human Ƶ-Cells JAI PARKASH, Miami, FL 2+ TNF-_ induces dysregulation of intracellular calcium, [Ca ]i, in `-cells by 2+ 2764-PO decreasing the levels of a cytoplasmic Ca binding protein calbindin-D28k. In the present study we wanted to test the hypothesis that “In human islets Fatty Acids Stimulate Glucose-Induced Insulin Secretion In Vivo in and human islets cells including human pancreatic `-cells, TNF-_ activates Mice NF-gB signaling pathway resulting in nuclear translocation of NF-gB and PAYAL R. PATEL, HWI JIN KO, DAE YOUNG JUNG, XIAODI HU, ISAAC SHIELDS, transcriptional activation by NF-gB”. To test this hypothesis, we treated hu- SARAH E. KINICKI, ASHWINI D. JAVLEKAR, ANNIE H. HUYLER, JUN HO LEE, YUN man islets and human islets cells including human pancreatic `-cells with HEE NOH, JASON K. KIM, Worcester, MA, Seoul, Republic of Korea increasing concentrations of TNF-_. Upon treatment of human islets and Chronic hyperinsulinemia is a compensatory event when insulin resis- human islets cells including human pancreatic `-cells with 2, 5, 10, 20, and tance develops in obesity. Increasing evidence suggests that hyperplasia 30 ng/ml TNF-_, the relative increases in the transcriptional activities by and hypertrophy of pancreatic islets and associated hyper-secretion of in- NF-gB, determined by utilizing the DNA binding activity of NF-gB in an ELI- sulin are precipitating events to islet decompensation, `-cell apoptosis, and SA-based kit, were 1.69±0.32, 1.42± 0.07, 1.77± 0.43, 2.02± 0.02, and 1.96± type 2 diabetes. Thus, it is important to understand the molecular mecha- 0.2 folds respectively (n=3, P< 0.05). The nuclear translocation of NF-gB nism by which obesity leads to chronic hyperinsulinemia. Here we exam- measured by immunofl uorescence confocal microscopy showed the nuclear ined the effects of fatty acids on islet function in vivo. Male C57BL/6 mice translocation of NF-gB both in human islets and in human islet cells includ- received an intravenous infusion of lipid emulsion at 2 different doses (2.5 ing human pancreatic `-cells. These observations suggest that in human or 5 ml/hr/kg; n=7-8/group) or glycerol (controls; n=8) for 5 hrs. Lipid infusion islets and in human islet cells including human pancreatic `-cells, the TNF-_ increased circulating fatty acids (FA) levels to 3~4 mM in a dose-dependent indeed activates NF-gB signaling pathway resulting in nuclear transloca- manner, whereas a glycerol infusion maintained FAs near basal levels (~1 tion of NF-gB and transcriptional activation by NF-gB. Although the exact mM) (Fig. 1; *p<0.05 vs. glycerol). After the 5 hr lipid infusion, a 2-hr hyper- mechanism of NF-gB activation by Ca2+ is still not known, what is known is glycemic clamp was conducted to assess glucose-induced insulin secretion that Ca2+ signaling in cells is generally presented as changes in Ca2+ concen- in awake mice. Plasma glucose levels were quickly raised and maintained at tration as brief spikes which are often organized as regenerative Ca2+ waves. ~20 mM. Hyperglycemia caused a rapid and sustained increase in plasma The intracellular Ca2+ waves can induce changes in the gene expression and insulin levels (Fig. 2). Lipid infusion at 2.5 and 5 ml/hr/kg induced further thus regulate several signal-transduction pathways. dose-dependent increases in plasma insulin levels (Fig. 2). Area-under-curve Supported by: NIH/NIGMS Grant to J.P., SC3GM084751 of plasma insulin levels was signifi cantly increased by 20~40% compared to glycerol (Fig. 3). Overall, these results indicate that elevated circulating FAs dose-dependently increase insulin secretion in mice. Our fi ndings further suggest that fatty acids potently regulate insulin secretion and contribute to chronic hyperinsulinemia in obesity. INTEGRATED PHYSIOLOGY—INSULIN SECRETION IN VIVO 2763-PO Comparison of Measures of Insulin Sensitivity in South Asians SUBBULAXMI TRIKUDANATHAN, ANNASWAMY RAJI, BINDU CHAMARTHI, EL- LEN W. SEELY, DONALD C. SIMONSON, Boston, MA South Asians have increased visceral adiposity, insulin resistance, and diabetes compared with Caucasians of European origin. Quantifying insu- lin sensitivity in this population is vital for large clinical and epidemiologi- cal studies. Surrogate measures of insulin sensitivity have been validated against hyperinsulinemic euglycemic clamps in Caucasian populations, but ethnicity and variations in body composition may affect these surrogate in- dices. We compared insulin sensitivity determined by the euglycemic clamp (1 mU/kg·min), the Matsuda index (75 gm OGTT) and HOMA-IR in 23 non- diabetic South Asians and 18 Caucasians who had similar age (mean ± SE = 34 ± 2 vs. 36 ± 3 yrs), BMI (25.2 ± 1.1 vs. 24.6 ± 0.9 kg/m²), waist-hip ratio (0.81 ± 0.02 vs. 0.77 ± 0.02), and BP (131 ± 4 / 69 ± 3 vs. 123 ± 4 / 65 ± 3). Fasting metabolic measures showed similar FPG (91 ± 2 vs. 89 ± 2 mg/dl) and Supported by: NIH (R01-DK080756) Obesity LDL-C (107 ± 6 vs. 104 ± 7 mg/dl), but South Asians had lower HDL-C (49 ± 2 vs. 60 ± 4 mg/dl; P = 0.0095), higher triglycerides (112 ± 16 vs. 82 ± 10 mg/ 2765-PO dl), and higher fasting insulin (6.9 ± 0.8 vs. 3.6 ± 0.3 μU/ml; P = 0.0016). All Delayed Insulin Secretory Responses Are Seen in Patients With PUBLISHED ONLY Integrated Physiology/ measures of insulin sensitivity were signifi cantly impaired in South Asians Gout (Table). The Matsuda index was correlated with the clamp M value in South SHENGLI YAN, CUICUI LIANG, YANGANG WANG, Qingdao, China Asians (r = 0.50, p = 0.014), Caucasians (r = 0.47, p = 0.046), and in both groups From our previous data of epidemiological investigation of gout and hy- combined (r = 0.62, p < 0.0001). HOMA-IR also was highly correlated with peruricemia in Shandong coastal area we found that the prevalence of dia- the clamp M in South Asians (r = 0.56; p = 0.005), but not in Caucasians (r = betes in patients with gout and/or hyperuricemia was signifi cantly higher 0.34; p = 0.17). Thus, the Matsuda index and HOMA-IR provide simple and than that of normal population. To explore the change of islet `-cell function valid surrogate measures of insulin sensitivity in South Asians, which may in patients with gout, blood samples of 76 patients with gout(37 gout with be useful in performing larger clinical studies in this population. IGT and /or IFG,39 gout with NGT)and 30 healthy subjects were drawn at 0,2,4 and 6 min for determination of the fi rst phase insulin secretion with intravenous arginine stimulation. In the very next day, the second phase insulin secretion at 0, 60, 120 min was determined with OGTT. Statistical For author disclosure information, see page 797. ADA-Funded Research A688 INTEGRATED PHYSIOLOGY—INSULINCATEGORY SECRETION IN VIVO analysis was performed using the unpaired T test for comparisons between 2768-PO each group. Correlations between the clinical parameters were evaluated by GLP-1 and Exendin-4 Inhibit Insulinotropic Effects of Glucagon and using multiple step regression analysis. The time of peak distributed differ- Oxyntomodulin in Cattle ently between the gouty group and the healthy group (L-arginine stimulation SINT THANTHAN, HONGQIONG ZHAO, SWE YANNAING, HIDETO KUWAYAMA, 2 min:100% vs 27.6%, P<0.05;OGTT 30-60 min:100% vs 32.9%, P<0.05). The Obihiro, Japan peak value of insulin stimulated by L-arginine and OGTT of gouty group was GLP-1, glucagon and oxyntomodulin (OXM) play an important role in glu- higher than that in the healthy group(P<0.05;P<0.01). The incremental plasma cose homeostasis. GLP-1 and GLP-1 analogs, such as exenatide (a synthetic insulin area under the curves (AUCs) after stimulation of L-arginine and OGTT form of exendin-4 (1-39) amide) and liraglutide, are used for treatment of was higher in gouty group than the healthy group (P<0.01;P<0.01). The time type 2 diabetes in humans. This study was aimed to investigate the rela- of peak signifi cantly delayed after the stimulation of OGTT in the gout with tionships among these 4 peptides in the insulinotropic action in cattle. Four IGT and /or IFG subgroup (P<0.05). Multiple step regression analysis showed mo-old Holstein steers (111 ± 2 kg, n = 8) were assigned randomly in an in- that islet secretion was positively correlated with BMI, waist circumference complete Latin square design (8 steers x 9 treatments x 9 experiment days).