Prolonged Elimination of Negative Feedback Control Mechanisms Along the Insulin Signalling Pathway Impairs β Cell Function In Vivo

Cellular stress and proinflammatory cytokines induce phosphorylation of insulin receptor substrate (IRS) proteins at Ser sites that inhibit insulin and IGF-I signaling. We therefore examined the effects of mutation of five "inhibitory" Ser phosphorylation sites on IRS2 function in transgenic mice that overexpress, selectively in pancreatic beta-cells, either wild-type (WT) or a mutated IRS2 protein (IRS25A). Islets size, number, and mRNA levels of catalase and superoxide dismutase were increased, whereas those of nitric oxide synthase were decreased, in 7-to 10-week-old IRS25A-beta mice compared with IRS2(WT)-beta mice. However, glucose homeostasis and insulin secretion in IRS25A-beta mice were impaired when compared with IRS2(WT)-beta mice or to nontransgenic mice. This was associated with reduced mRNA levels of Glut2 and islet beta-cell transcription factors such as Nkx6.1 and MafA. Similarly, components mediating the unfolded protein response were decreased in islets of IRS25A-beta mice in accordance with their decreased insulin secretion. The beneficial effects of IRS25A on beta-cell proliferation and beta-cell transcription factors were evident only in 5- to 8-day-old mice. These findings suggest that elimination of inhibitory Ser phosphorylation sites of IRS2 exerts short-term beneficial effects in vivo; however, their sustained elimination leads to impaired beta-cell function.