1. Howard Hughes Medical Institute, Joslin Diabetes Center, Department of Medicine, Harvard Medical School, Boston, Massachusetts 02215, USA
2. Howard Hughes Medical Institute, Department of Medicine, Yale University School of Medicine, New Haven, Connecticut 06520, USA
3. These authors contributed equally to this work.

Correspondence to: Morris F. White¹ Correspondence and requests for materials should be addressed to M.F.W. (e-mail: Email: Whitemor@joslab.harvard.edu).

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 cytokines¹. Disruption of IRS-1 in mice retards growth, but diabetes does not develop because insulin secretion increases to compensate for the mild resistance to insulin²,³. Here we show that disruption of IRS-2 impairs both peripheral insulin signalling and pancreatic -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 -cell compensation for this insulin resistance. Our results indicate that dysfunction of IRS-2 may contribute to the pathophysiology of human type 2 diabetes.