Disruption of IRS-2 causes type 2 diabetes in mice.
Withers, Dominic J.; Gutierrez, Julio Sanchez; Towery, Heather; Burks, Deborah J.; Ren, Jian-Ming; Previs, Stephen; Zhang, Yitao; Bernal, Dolores; Pons, Sebastian; Shulman, Gerald I.; Bonner-Weir, Susan; White, Morris F.
[Letter] Nature. 391(6670):900-904, February 26, 1998.

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Human type 2 diabetes is characterized by defects in both insulin action and insulin secretion.It has been difficult to identify a single molecular abnormality underlying these features. Insulin-receptor substrates (IRS proteins) may be involved in type 2 diabetes: they mediate pleiotropic signals initiated by receptors for insulin and other cytokines [1]. Disruption of IRS-1 in mice retards growth, but diabetes does not develop because insulin secretion increases to compensate for the mild resistance to insulin [2,3]. Here we show that disruption of IRS-2 impairs both peripheral insulin signalling and pancreatic beta-cell function. IRS-2-deficient mice show progressive deterioration of glucose homeostasis because of insulin resistance in the liver and skeletal muscle and a lack of beta-cell compensation for this insulin resistance. Our results indicate that dysfunction of IRS-2 may contribute to the pathophysiology of human type 2 diabetes.

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