Upregulation of insulin receptor substrate-2 in pancreatic β cells prevents diabetes

Abstract

The insulin receptor substrate-2 (Irs2) branch of the insulin/IGF signaling system coordinates peripheral insulin action and pancreatic cell function, so mice lacking Irs2 display similarities to humans with type 2 diabetes. Here we show that cell-specific expression of Irs2 at a low or a high level delivered a graded physiologic response that promoted cell growth, survival, and insulin secretion that prevented diabetes in Irs2 -/-mice, obese mice, and streptozotocin-treated mice; and that upon transplantation, the transgenic islets cured diabetes more effectively than WT islets. Thus, pharmacological approaches that promote Irs2 expression in cells, especially specific cAMP agonists, could be rational treatments for cell failure and diabetes.