| First Author | Gurevitch D | Year | 2010 |
| Journal | Diabetes | Volume | 59 |
| Issue | 9 | Pages | 2188-97 |
| PubMed ID | 20547979 | Mgi Jnum | J:169348 |
| Mgi Id | MGI:4940464 | Doi | 10.2337/db09-0890 |
| Citation | Gurevitch D, et al. (2010) Elimination of negative feedback control mechanisms along the insulin signaling pathway improves beta-cell function under stress. Diabetes 59(9):2188-97 |
| abstractText | 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 beta-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 beta-cells from apoptosis induced by a combination of IL-1beta, IFN-gamma, TNF-alpha, 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 naive 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 beta-cell function under stress. Genetic approaches that promote IRS2(5A) expression in pancreatic beta-cells, therefore, could be considered a rational treatment against beta-cell failure after islet transplantation. |
