DISRUPTION OF IRS-2 CAUSES TYPE-2 DIABETES IN MICE

Human type 2 diabetes is characterized by defects in both insulin acti on and insulin secretion, It has been difficult to identify a single m olecular abnormality underlying these features, Insulin-receptor subst rates (IRS proteins) may be involved in type 2 diabetes: they mediate pleiotropic signals initiated by receptors for insulin and other cytok ines(1). Disruption of IRS-1 hl 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 gluco se homeostasis because of insulin resistance in the liver and skeletal muscle and a lack of beta-cell compensation for this insulin resistan ce, Our results indicate that dysfunction of IRS-2 may contribute to t he pathophysiology of human type 2 diabetes.