Role of CAP in In Vivo Insulin Action

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DESCRIPTION (provided by applicant): Type 2 diabetes and the metabolic syndrome are epidemic in the US, and a hallmark of both is insulin resistance. Understanding the mechanisms of insulin action is essential in the treatment of these disorders. Recently, a signaling pathway has been identified that links insulin stimulation of its receptor to glucose transport independent of PI3K. This pathway involves the activation Cbl and its adaptor protein CAP and is known to stimulate glucose uptake in cultured adipocytes. In addition to a role in stimulating glucose uptake, the Cbl/CAP complex is involved in the proliferation and motility of macrophages. As macrophage activation and chronic inflammation have been associated with insulin resistance, this dual role of Cbl/CAP may have important consequences. The general purpose of this proposal is to examine the role of CAP in regulating in vivo insulin action. The specific aims are 1) to determine if whole body gene knockout of CAP results in alterations in insulin action, 2) to determine if CAP knockout results in an upregulation of the alternate PI3K-dependent signaling pathway, and 3) to determine if macrophage infiltration, activation and cytokine production is altered in CAP knockout mice and is related to the putative changes in insulin action.