Insulin Signaling Pathways Regulating Translocation of GLUT4

One of the most important metabolic actions of insulin is to promote glucose transport in skeletal muscle and adipose tissue. Insulin-stimulated glucose transport in these target tissues is mediated by translocation of the insulinresponsive glucose transporter GLUT4 from an intracellular location to the plasma membrane where GLUT4 facilitates entry of glucose into the cell. Over the past decade, tremendous progress has been made in elucidating insulin signaling pathways regulating translocation of GLUT4. One essential signaling pathway in this process is a PI 3-kinase-dependent pathway that controls activation of downstream ser/thr kinases such as PDK-1, Akt, and PKC-ζ leading to an increase in the exocytosis rate for GLUT4. Although activation of PI 3-kinase is necessary for insulin-stimulated translocation of GLUT4, it is not sufficient. Recently, a PI 3-kinase-independent pathway involving activation of TC10 (a GTPase belonging to the rho family) has been identified as another necessary element. Insulin-stimulated phosphorylation of Cbl results in assembly of signaling complexes that activate TC10. This leads to rearrangements of actin structures that facilitate translocation of GLUT4. In this review, we will discuss details of both the PI 3-kinase-dependent and - independent pathways mediating translocation of GLUT4 in response to insulin.