Details

Autor(en) / Beteiligte

• Gurevitch, Diana
• Boura-Halfon, Sigalit
• Isaac, Roi
• Shahaf, Galit
• Alberstein, Moti
• Ronen, Denise
• Lewis, Eli C
• Zick, Yehiel

Titel

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

Ist Teil von

• Diabetes (New York, N.Y.), 2010-09, Vol.59 (9), p.2188

Ort / Verlag

New York: American Diabetes Association

Erscheinungsjahr

2010

Link zum Volltext

Quelle

EZB Electronic Journals Library

Beschreibungen/Notizen

• 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 Set 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.sup.5A], and their wild-type controls ([IRS-2.sup.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.sup.5A] was better than [IRS-2.sup.WT] in protecting [beta]-cells from apoptosis induced by a combination of IL-I[beta], IFN-[gamma] TNF-[alpha], and Fas ligand. Cytokine-treated islets expressing [IRS2.sup.5A] secreted significantly more insulin in response to glucose than did islets expressing [IRS-2.sup.WT]. This could be attributed to the higher transcription of Pdx1 in cytokine-treated islets that expressed [IRS-2.sup.5A]. Accordingly, transplantation of 200 islets expressing [IRS2.sup.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.sup.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.sup.5A] expression in pancreatic [beta]-cells, therefore, could be considered a rational treatment against [beta]-cell failure after islet transplantation. Diabetes 59:2188-2197, 2010