Abstract 037: Pancreatic-Angiotensin Type 1a Receptor Deficiency Prevents Angiotensin II-Mediated Reductions In Glucose-Stimulated Insulin Secretion From Isolated Islets Of Obese Mice.

Abstract

Objective: Diet-induced obesity promotes type 2 diabetes (T2D). Drugs that inhibit the renin-angiotensin system (RAS) have been demonstrated in clinical trials to decrease the onset of T2D. Pancreatic islets have been reported to possess components of the renin-angiotensin system (RAS), including angiotensin type 1a receptors (AT1aR). Previously, we demonstrated that mice made obese from chronic consumption of a high-fat diet (HF) have marked elevations in systemic concentrations of angiotensin II (AngII). We tested the hypothesis that pancreatic-specific deletion of the AT1aR would improve glucose-stimulated insulin secretion (GSIS) from isolated islets of mice with diet-induced obesity. Methods and Results: In preliminary studies, we demonstrated that GSIS from islets isolated from obese mice was markedly diminished in the presence of AngII compared to vehicle (VEH) (VEH, 0.94 ± 0.22; AngII, 0.017 ± 0.15 fold increase over basal; P<0.05). A mouse model of pancreatic-AT1aR deficiency was created using AT1aR fl/fl mice on a C57BL/6 background bred to transgenic Cre mice expressing the pdx-1 promoter to generate pancreatic AT1aR-deficient mice ( AT1aR pdx ) and littermate controls ( AT1aR fl/fl ). AT1aR mRNA expression was markedly decreased in whole pancreas of AT1aR pdx mice ( AT1aR fl/fl , 2.24 ± 0.79; AT1aR pdx , 0.53 ± 0.24 ΔΔ Ct AT1aR/18S; P < 0.05). Male, 8-week old AT1aR fl/fl and AT1aR pdx mice were fed a HF diet (60% kcal as fat) for 17 weeks. GSIS from isolated islets of HF-fed AT1aR fl/fl mice was significantly reduced in the presence of AngII (10nM) compared to VEH (VEH, 229 ± 43; AngII, 129 ± 43 ng insulin/ng protein; P<0.05). Moreover, incubation of HF-fed islets from AT1aR fl/fl , but not AT1aR pdx mice, with losartan (1μM) prevented AngII-induced reductions in GSIS (AngII + losartan, 244 ± 118 ng insulin/ng protein). However, at 17 weeks of HF feeding there was no significant effect of pancreatic AT1aR deficiency on glucose tolerance. Conclusions: These results demonstrate that AngII markedly reduces glucose-stimulated insulin secretion from pancreatic islets of obese mice through an AT1aR-mediatd mechanism. Further studies are required to determine if pancreatic AT1aR influence the decline of insulin secretion during the progression of T2D.