Elimination of negative feedback control mechanisms along the insulin signaling pathway improves β-cell function under stress

OBJECTIVE - Cellular stress and proinflammatory cytokines induce phosphorylation of insulin receptor substrate (IRS) proteins at Ser sites that inhibit insulin and IGF-1 signaling. Here, we examined the role of Ser phosphorylation of IRS-2 in mediating the inhibitory effects of proinflammatory cytokines and cellular stress on β-cell function. RESEARCH DESIGN AND METHODS - Five potential inhibitory Ser sites located proximally to the P-Tyr binding domain of IRS-2 were mutated to Ala. These IRS-2 mutants, denoted IRS-2^5A, and their wild-type controls (IRS-2^WT) were introduced into adenoviral constructs that were infected into Min6 cells or into cultured murine islets. RESULTS - When expressed in cultured mouse islets, IRS-2^5A was better than IRS-2^WT in protecting β-cells from apoptosis induced by a combination of IL-1β, IFN-γ, TNF-α, and Fas ligand. Cytokine-treated islets expressing IRS2 ^5A secreted significantly more insulin in response to glucose than did islets expressing IRS-2^WT. This could be attributed to the higher transcription of Pdx1 in cytokine-treated islets that expressed IRS-2 ^5A. Accordingly, transplantation of 200 islets expressing IRS2 ^5A into STZ-induced diabetic mice restored their ability to respond to a glucose load similar to naïve mice. In contrast, mice transplanted with islets expressing IRS2^WT maintained sustained hyperglycemia 3 days after transplantation. CONCLUSIONS - Elimination of a physiological negative feedback control mechanism along the insulin-signaling pathway that involves Ser/Thr phosphorylation of IRS-2 affords protection against the adverse effects of proinflammatory cytokines and improves β-cell function under stress. Genetic approaches that promote IRS25A expression in pancreatic β-cells, therefore, could be considered a rational treatment against β-cell failure after islet transplantation.