Exendin-4 Uses Irs2 Signaling to Mediate Pancreatic β Cell Growth and Function

Abstract The insulin receptor substrate 2 (Irs2) branch of the insulin/insulin-like growth factor-signaling cascade prevents diabetes in mice because it promotes β cell replication, function, and survival, especially during metabolic stress. Because exendin-4 (Ex4), a long acting glucagon-like peptide 1 receptor agonist, has similar effects upon β cells in rodents and humans, we investigated whether Irs2 signaling was required for Ex4 action in isolated β cells and in Irs2-/- mice. Ex4 increased cAMP levels in human islets and Min6 cells, which promoted Irs2 expression and stimulated Akt phosphorylation. In wild type mice Ex4 administered continuously for 28 days increased β cell mass 2-fold. By contrast, Ex4 failed to arrest the progressive β cell loss in Irs2-/- mice, which culminated in fatal diabetes; however, Ex4 delayed the progression of diabetes by 3 weeks by promoting insulin secretion from the remaining islets. We conclude that some short term therapeutic effects of glucagon-like peptide 1 receptor agonists can be independent of Irs2, but its long term effects upon β cell growth and survival are mediated by the Irs2 branch of the insulin/insulin-like growth factor signaling cascade.