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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 β-cells, either wild-type (WT) or a mutated IRS2 protein (IRS2^5A). 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 IRS2^5A-β mice compared with IRS2^WT-β mice. However, glucose homeostasis and insulin secretion in IRS2^5A-β mice were impaired when compared with IRS2^WT-β mice or to nontransgenic mice. This was associated with reduced mRNA levels of Glut2 and islet β-cell transcription factors such as Nkx6.1 and MafA. Similarly, components mediating the …