INTEGRATED PHYSIOLOGY—INSULINCATEGORY SECRETION IN VIVO diet rich in carbohydrate (CHO), b) diet rich in monounsaturated fat (MUFA) INTEGRATED PHYSIOLOGY—INSULIN SECRETION and c) diet high in saturated fat (SAT). Total cholesterol, LDL-C and ApoB IN VIVO levels were increase after SAT diets as compared with MUFA and CHO diets. PAT from 9 subjects was collected and Microarrays RT–qPCR was used for transcriptomic analysis of 86 GEN-FAT. The table shows relationship 2585-PO between diet induced changes in GEN-FAT expression and lipid profi le. In Age as a Modifi er of β-Cell Response to Insulin Resistance among summary, specifi c gene-expression on GEN-FAT in peripheral adipose tissue Normo glycemic African American and Caucasian Offspring of Parents are related with the specifi c plasma lipid profi le diet-induced by different with or without Diabetes macronutrient composition. EBENEZER NYENWE, CHIMAROKE EDEOGA, EMMANUEL CHAPP-JUMBO, JIM WAN, SAMUEL DAGOGO-JACK, Memphis, TN Table 1. Correlationship between changes on GEN of Fatty Acid Metabolism We studied the interaction of ethnicity, age, insulin action and secretion and Lipid profi le after the three dietary. among normoglycemic African-Americans (AA) and Caucasians who were Correlationship, ( n=9) GEN-FAT MUFA SAT CHO offspring of parents with or without type 2 diabetes (T2D). Given the genetic basis of T2D, we postulated that normoglycemic offspring of T2D Free Fatty acids FADS1 -0.43; p=0.24 -0.25; p=0.52 -0.88; p=0.002 ACSL6 0.85; p=0.001 0.85; p=0.004 -0.23; p=0.54 parents would exhibit discernable glucoregulatory defects. The subjects and controls (N=62 each) were matched for age, sex, race and BMI. Subjects Cholesterol Total ACOT12 0.03; p=0.93 0.90; p=0.001 -0.62; p=0.07 underwent 75 g OGTT after an overnight fast, with blood sampling at 0, BDH2 -0.80; p=0.01 -0.90; p=0.001 0.16; p=0.66 30 and 120 minutes. Glucose and insulin levels were measured and insulin LDL-C BDH2 -0.88; p=0.002 -0.70; p=0,03 -0.08; p=0.83 resistance was assessed by HOMA-IR and QUICKI, while insulin secretion PRKAG1 -0.32; p=0,41 -0.87; p=0.002 0.20; p=0.61 was evaluated by HOMA-B and insulinogenic index. Data were analyzed FABP4 0.03; p=0,93 -0.87; p=0.002 0.15; p=0.70 using paired t-test, Chi square and multivariate analyses. We found (Table LDL-C PRKAG1 -0.89; p=0.001 -0.56; 0.12 0.05; 0.89 1) that parental history of T2D was associated with 50% increase in insulin Triacylglycerols ACADS 0.52; p=0.15 -0.10; p=0.80 -0.90; p=0.001 resistance and compensatory increase (38%) in secretion. These changes CRAT 0.89; p=0.001 -0.33; p=0.38 -0.16; p=0.67 were similar in AA and C offspring, but β-cell compensation decreased by ApoA1 ACOT2 0.02; p=0.97 0.90; p=0.001 -0.14; p=0,71 29.2% in subjects ≥ 35 y of age compared with those < 35 y. Obesity and FABP4 -0.42; p=0.26 -0.68; p=0.04 0.92; p=0.000 parental T2D were independent predictors of HOMA-IR, HOMA-B and FPG. ApoB GK2 -0.07; p=0.86 -0.12; 0.76 0.98; p=0.000 We here document increased insulin resistance coupled with compensatory hyperinsulinemia in normoglycemic offspring of T2D parents, and show that Data are Spearman’s rank correlation coeffi cient and p-value. the pattern is similar in AA and C and modifi ed by advancing age. Supported by: Spanish Ministry of Health (ISCIII, FIS PI070239/07) Parameter NO Parental T2D Parental T2D P-Value Age (years) 37.6 ± 1.5 38.0 ± 1.3 0.64 2584-PO Gender (M/F) 36/26 36/26 NS The Role of Placental p38-MAPKα Nitration and Antioxidant Supple- Ethnicity (Caucasian/AA) 26/36 26/36 NS mentation in the Pathogenesis of Type 1 Diabetic Pre-Eclampsia in a Sub-Cohort of the Diabetes and Pre-Eclampsia Intervention Trial BMI (Kg/m2) 28.6 ± 0.8 26.7 ± 0.7 0.91 (DAPIT) FPG (mg/dL) 88.7 ± 0.9 91.0 ± 0.6 0.01 PHILIP C. JOHNSTON, DAVID R. MCCANCE, KATHY POGUE, CYRIL MCMASTER, Fasting insulin (µiu/ml) 4.6 ± 0.5 6.8 ± 0.5 0.001 SARAH GILCHRIST, VALERIE A. HOLMES, LESLEY POWELL, IAN S. YOUNG, ANN HOMA-IR 1.02 ± 0.1 1.5 ± 0.1 0.001 MCGINTY, Belfast, United Kingdom Oxidative stress is involved in the pathogenesis of diabetes and pre- HOMA-B 63.4 ± 5.8 87.5 ± 6.4 0.005 eclampsia. p38-mitogen-activated protein kinase α (p38-MAPK) is centrally QUICKI 5.5 ± 0.05 5.2 ± 0.04 < 0.0001 involved in placental development. Tyrosine nitration of p38-MAPKα Insulinogenic index 1.07 ± 0.1 1.63 ± 0.3 0.07 by the free radical peroxynitrite results in loss of its catalytic activity. Supported by: NIDDK ADA-Funded Research Increased levels of nitrated, and decreased levels of catalytically active, p38-MAPKα, have been reported in pre-eclamptic placentae. We examined the role of placental p38-MAPKα nitration in the pathogenesis of diabetic 2586-PO pre-eclampsia, and the putative modulation of this by vitamin C and E Effect of Aging on Insulin Secretion supplementation in DAPIT sub-cohort placentae. JOSE DE JESUS GARDUNO-GARCIA, R. LERTWATTANARAK, YOLANDA CIPRI- DAPIT placentae: placebo-treated normotensive (n=17), pre-eclamptic ANI, RALPH DEFRONZO, AMALIA GASTALDELLI, EUGENIO CERSOSIMO, NICOLAS (n=6): vitamin-treated, normotensive (n=20), pre-eclamptic (n=3) were MUSI, San Antonio, TX analysed. Protein tyrosine nitration was assessed immunohistochemistry A g i n g i s a s s o c i a t e d w i t h a h i g h r i s k o f d e v e l o p i n g i m p air e d g lu c o s e t o l e r a n c e in paraffi n-embedded tissue and quantifi ed by a modifi ed histoscore. The and type 2 diabetes (T2D). The incretin hormones glucagon-like peptide (GLP) catalytic activity of placental phospho p38-MAPKα was measured by 1 and glucose-dependent insulinotropic peptide (GIP) are secreted by the gut enzyme-linked immunosorbent assay (ELISA). in response to nutrients (glucose), and they stimulate insulin secretion by the Nitrotyrosine immunostaining was present in placebo-supplemented beta cells. In T2D there is decreased incretin release, and this could play a role normotensive and pre-eclamptic placentae, with no signifi cant difference in the insulin secretory that occurs in these subjects. We hypothesized that observed between the groups. Vitamin supplementation did not change aging per se will also lead to defective GLP1 and GIP secretion in response to nitrotyrosine formation in normotensive or pre-eclamptic placentae. There glucose ingestion. Methods: 40 younger (25.2±3.4 y) and 53 older (73.8±7.3 was a non-signifi cant trend towards decreased p38-MAPKα activity in y), lean (BMI≤25 kg/m2), healthy, nondiabetic, community-dwelling subjects pre-eclamptic vs normotensive placentae, but this was not augmented underwent a 75-gm, 2-h, oral glucose tolerance test (OGTT). Plasma glucose, by vitamin-supplementation in either group. No correlation was observed Obesity C-peptide, insulin, GLP1, and GIP concentrations were measured during the between nitrotyrosine expression and p38-MAPKα activity in placebo or OGTT. The insulin secretory rate (ISR) was quantitated by deconvolution of vitamin-supplemented normotensive or pre-eclamptic placentae. the plasma C-peptide concentration curve. The fi nding of nitrotyrosine immunopositivity in normotensive diabetic PUBLISHED ONLY Integrated Physiology/ Based on the results of the OGTT, subjects were divided in 3 groups: placentae indicates some degree of tyrosine nitration in uncomplicated younger normal glucose tolerant (YNGT, n=40), Older NGT (n=33), and Older diabetic pregnancy, most probably due to inherent oxidative stress and IGT (n=20). peroxynitrite production. Our results, however, suggest that p38-MAPKα Results: First phase ISR (at 15 min) was signifi cantly reduced in Older IGT nitration is not directly involved in the pathogenesis of type 1 diabetic pre- (662±130 pmol/min) vs. Younger NGT (987±89 pmol/min) (P<0.05) and vs. eclampsia and is not modulated by vitamin-supplementation. Older NGT subjects (965±99 pmol/min) (P<0.05). Both older groups displayed Supported by: R&D fund a delayed plasma insulin peak (45 min in Younger NGT, 60 min in Older NGT, and 105 min in Older IGT). Against our hypothesis, GLP1 secretion was signifi cantly higher in both older groups: the GLP1 area under the curve was 2.7±0.9 in Younger NGT, 3.6±2.5 in Older NGT, and 3.7±1.7 nmol/l×120min in Older IGT (P<0.05). GIP secretion was not signifi cantly different between For author disclosure information, see page 785. ADA-Funded Research A680 INTEGRATED PHYSIOLOGY—INSULINCATEGORY SECRETION IN VIVO groups. Conclusions: Aging alone (Older NGT group) is associated with of a 7-day very low calorie diet (VLCD: 400 kcal/day) on insulin secretion and impaired insulin secretion, and this impairment is greater in IGT individuals. sensitivity, in 14 type 2 diabetic patients with severe obesity (BMI> 40 kg/m2) This reduction in insulin secretion is not caused by defective incretin release.