Pancreatic angiotensin type 1a receptors and type 2 diabetes

Type 2 diabetics progress from hyperinsulinemia and insulin resistance to gradual declines in pancreatic beta-cell failure, necessitating the administration of insulin to assist in glycemic control. Mechanisms for beta-cell failure in the progression of type 2 diabetes are unknown. Emerging evidence suggests that blockers of the renin-angiotensin system (RAS) prevent new onset diabetes and improve insulin resistance. Pancreatic beta-cells express several components of the RAS, including angiotensin type 1 a receptor (AT1aR). Angiotensin II (AngII), the primary peptide of the RAS, promotes oxidative stress and reduced insulin secretion from pancreatic beta-cells. Mice with diet-induced obesity from consumption of a high fat (HF) diet have marked impairments in glucose tolerance. Our data demonstrate that HF-fed mice have robust increases in plasma concentrations of AngII. Preliminary data demonstrate that AngII totally abolished glucose-stimulated insulin secretion (GSIS) from isolated pancreatic islets of 4 month HF-fed obese mice. Islets from obese mice also exhibited elevated mRNA abundance of AT1aR. The hypothesis of this pilot project is that pancreatic AT1aR deficiency will improve GSIS from pancreatic islets and whole body glucose tolerance in obese mice. We will first determine if pancreatic AT1aR deficiency is capable of (1) ameliorating HF diet-induced glucose intolerance and (2) abolishing in vitro effects of AngII to impair GSIS from isolated pancreatic islets. Since preliminary data demonstrate that AT1R blockade improves glucose tolerance in obese mice, we will determine the role of pancreatic AT1aR in effectiveness of losartan to improve whole body glycemic control in obese mice. Finally, we will investigate AngII/AT1R-stimulated oxidative stress as the mechanism for AngII-induced reductions in insulin secretion from pancreatic islets of obese mice. Aim 1 will determine if pancreatic AT1aR deficiency improves glycemic control and GSIS in obese versus lean mice. Aim 2 will define efficacy of losartan, an AT1R antagonist, on glucose tolerance in obese mice lacking pancreatic AT1aR.