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Molecular and Cellular Biology, September 2004, p. 7435-7443, Vol. 24, No. 17
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.17.7435-7443.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Disruption of the SH2-B Gene Causes Age-Dependent Insulin Resistance and Glucose Intolerance

Chaojun Duan,1 Hongyan Yang,1 Morris F. White,2 and Liangyou Rui1*

Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, Michigan,1 Department of Medicine, Division of Endocrinology, Howard Hughes Medical Institute, Children's Hospital Boston, Harvard Medical School, Boston, Massachusetts2

Received 28 March 2004/ Returned for modification 5 May 2004/ Accepted 3 June 2004

Insulin regulates glucose homeostasis by binding and activating the insulin receptor, and defects in insulin responses (insulin resistance) induce type 2 diabetes. SH2-B, an Src homology 2 (SH2) and pleckstrin homology domain-containing adaptor protein, binds via its SH2 domain to insulin receptor in response to insulin; however, its physiological role remains unclear. Here we show that SH2-B was expressed in the liver, skeletal muscle, and fat. Systemic deletion of SH2-B impaired insulin receptor activation and signaling in the liver, skeletal muscle, and fat, including tyrosine phosphorylation of insulin receptor substrate 1 (IRS1) and IRS2 and activation of the phosphatidylinositol 3-kinase/Akt and the Erk1/2 pathways. Consequently, SH2-B–/– knockout mice developed age-dependent hyperinsulinemia, hyperglycemia, and glucose intolerance. Moreover, SH2-B directly enhanced autophosphorylation of insulin receptor and tyrosine phosphorylation of IRS1 and IRS2 in an SH2 domain-dependent manner in cultured cells. Our data suggest that SH2-B is a physiological enhancer of insulin receptor activation and is required for maintaining normal insulin sensitivity and glucose homeostasis during aging.

* Corresponding author. Mailing address: Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI 48109-0622. Phone: (734) 615-7544. Fax: (734) 647-9523. E-mail: ruily{at}umich.edu.

Molecular and Cellular Biology, September 2004, p. 7435-7443, Vol. 24, No. 17
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.17.7435-7443.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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