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pubmed:abstractText |
Insulin receptor substrate-2 (IRS-2) plays a critical role in the survival and function of pancreatic ?-cells. Gene disruption of IRS-2 results in failure of the ?-cell compensatory mechanism and diabetes. Nonetheless, the regulation of IRS-2 protein expression in ?-cells remains largely unknown. Inducible nitric-oxide synthase (iNOS), a major mediator of inflammation, has been implicated in ?-cell damage in type 1 and type 2 diabetes. The effects of iNOS on IRS-2 expression have not yet been investigated in ?-cells. Here, we show that iNOS and NO donor decreased IRS-2 protein expression in INS-1/832 insulinoma cells and mouse islets, whereas IRS-2 mRNA levels were not altered. Interleukin-1? (IL-1?), alone or in combination with interferon-? (IFN-?), reduced IRS-2 protein expression in an iNOS-dependent manner without altering IRS-2 mRNA levels. Proteasome inhibitors, MG132 and lactacystin, blocked the NO donor-induced reduction in IRS-2 protein expression. Treatment with NO donor led to activation of glycogen synthase kinase-3? (GSK-3?) and c-Jun N-terminal kinase (JNK/SAPK) in ?-cells. Inhibition of GSK-3? by pharmacological inhibitors or siRNA-mediated knockdown significantly prevented NO donor-induced reduction in IRS-2 expression in ?-cells. In contrast, a JNK inhibitor, SP600125, did not effectively block reduced IRS-2 expression in NO donor-treated ?-cells. These data indicate that iNOS-derived NO reduces IRS-2 expression by promoting protein degradation, at least in part, through a GSK-3?-dependent mechanism. Our findings suggest that iNOS-mediated decreased IRS-2 expression may contribute to the progression and/or exacerbation of ?-cell failure in diabetes.
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pubmed:affiliation |
Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, USA.
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