Disruption of IRS-2 causes type 2 diabetes in mice

Dominic J. Withers, Julio Sanchez Gutierrez, Heather Towery, Deborah J. Burks, Jian-Ming Ren, Stephen Previs, Yitao Zhang, Dolores Bernal, Sebastian Pons, Gerald I. Shulman, Susan Bonner-Weir and Morris F. White ()
Additional contact information
Dominic J. Withers: Howard Hughes Medical Institute, Joslin Diabetes Center, Harvard Medical School
Julio Sanchez Gutierrez: Howard Hughes Medical Institute, Joslin Diabetes Center, Harvard Medical School
Heather Towery: Howard Hughes Medical Institute, Joslin Diabetes Center, Harvard Medical School
Deborah J. Burks: Howard Hughes Medical Institute, Joslin Diabetes Center, Harvard Medical School
Jian-Ming Ren: Howard Hughes Medical Institute, Yale University School of Medicine
Stephen Previs: Howard Hughes Medical Institute, Yale University School of Medicine
Yitao Zhang: Howard Hughes Medical Institute, Joslin Diabetes Center, Harvard Medical School
Dolores Bernal: Howard Hughes Medical Institute, Joslin Diabetes Center, Harvard Medical School
Sebastian Pons: Howard Hughes Medical Institute, Joslin Diabetes Center, Harvard Medical School
Gerald I. Shulman: Howard Hughes Medical Institute, Yale University School of Medicine
Susan Bonner-Weir: Howard Hughes Medical Institute, Joslin Diabetes Center, Harvard Medical School
Morris F. White: Howard Hughes Medical Institute, Joslin Diabetes Center, Harvard Medical School

Nature, 1998, vol. 391, issue 6670, 900-904

Abstract: Abstract 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 β-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 β-cell compensation for this insulin resistance. Our results indicate that dysfunction of IRS-2 may contribute to the pathophysiology of human type 2 diabetes.

Date: 1998
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DOI: 10.1038/36116

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