UC San Diego

Insulin resistance (IR) and Diabetes are well known risk factors for many cardiovascular diseases. IR is a result of dysregulated signaling downstream of the insulin receptor (InsR). Binding of insulin to its receptor triggers the activation of IRS1, which in turn activates the PI3K-Akt pathway and trimeric G protein, Gi, both prerequisites for the translocation of glucose transporters, GLUT4, to the plasma membrane (PM) and glucose uptake. In IR, circulating fatty acids activate PKC[theta], which phosphorylates and antagonizes IRS1- mediated responses. Efforts at reinstating sensitivity in IR simply by targeting the known players within the insulin signaling pathway have failed, and thus, the search for new targets continues. GIV (a.k.a. Girdin) has recently been identified as a multimodular signal transducer and a guanine nucleotide exchange factor (GEF) for Galphai, which enhances the PI3K-Akt pathway downstream of the InsR. Here we show that activation of Gi and PI3K-Akt signals via GIV's GEF function is critical for enhancing IRS1 activation and GLUT4 translocation to the PM. Phosphoinhibition of GIV's GEF function by PKC[theta] antagonized GIV-dependent IRS1 and Akt activation and translocation of GLUT4 to the PM. We conclude that GIV is one of the key mediators of insulin response that activates PI3K-Akt and Gi to maintain insulin sensitivity, and that its phosphoinhibition by the fatty-acid-PKC[theta] pathway contributes significantly to the development of IR. Future work unraveling how GIV-GEF mediates insulin response, and how its inhibition can trigger IR will offer a new target to combat IR and reverse/halt the progression of cardiovascular diseases