Fellowship for Shoemaker: The Role of the Pancreatic Renin-Angiotensin System in the Development of Type 2 Diabetes

Clinical trials have demonstrated that in patients with symptoms of cardiac disease, blockade of the renin-angiotensin system (RAS) can reduce the risk of developing new onset diabetes. Evidence from animal studies suggests that the RAS may modulate glucose homeostasis either through inhibition of insulin secretion or by promoting insulin resistance. Results from our laboratory demonstrated that male C57BL/6 mice with diet-induced obesity have elevated concentrations of plasma AngII that contribute to the development of obesity-related hypertension. In addition, high fat (HF)-fed male mice exhibit pronounced glucose intolerance. Our results demonstrated that administration of the angiotensin type 1 receptor (AT1R) antagonist, losartan, to obese hypertensive mice normalized blood pressure. Studies from other laboratories demonstrated that chronic administration of AT1R antagonists to mice with diet-induced obesity improved glucose and insulin tolerance. Mechanisms contributing to effects of AT1R antagonism to improve glucose homeostasis in obese mice included improved insulin secretion from pancreatic islets and reduced macrophage infiltration into adipose tissue. In addition, treatment of isolated mouse pancreatic islets with an AT1R antagonist reduced fatty acid-induced increases in reactive oxygen species, suggesting that AT1R antagonism reduces oxidative stress in pancreatic islets. Preliminary data demonstrate that deficiency of angiotensin type 1a receptors (AT1aR) specifically in adipocytes has no effect on HF diet-induced impairment of glucose and insulin tolerance. These data suggest that improved insulin sensitivity in adipose tissue does not contribute to previously observed effects of AT1R antagonists to improve glucose homeostasis in obese mice. We hypothesize that elevated plasma concentrations of AngII in obese mice act directly at AT1aR on pancreatic islets to promote oxidative stress and reduce glucose-induced insulin secretion. An important aspect of the proposed studies is to unravel the direct versus indirect (e.g., hypertension end-organ damage at the pancreas) effects of AT1R antagonism on glucose homeostasis.