| First Author | Duan C | Year | 2004 |
| Journal | Mol Cell Biol | Volume | 24 |
| Issue | 17 | Pages | 7435-43 |
| PubMed ID | 15314154 | Mgi Jnum | J:92794 |
| Mgi Id | MGI:3054513 | Doi | 10.1128/MCB.24.17.7435-7443.2004 |
| Citation | Duan C, et al. (2004) Disruption of the SH2-B gene causes age-dependent insulin resistance and glucose intolerance. Mol Cell Biol 24(17):7435-43 |
| abstractText | 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. |
