Putting Rac1 on the Path to Glucose Uptake

Abstract

In spite of numerous and key advances in our understanding of insulin signaling, the molecular basis for impaired insulin-stimulated glucose uptake underlying insulin resistance remains unclear. Because skeletal muscle accounts for the majority of glucose utilization in the postprandial insulin-regulated state, defects in insulin action in muscle can determine whole-body glucose utilization. In muscle and fat cells, overall similarities exist in the signals emanating from the insulin receptor that mobilize glucose transporter GLUT4 to the membrane. Importantly, defects in the signaling network connecting the activated insulin receptor to GLUT4 vesicles are of particular consequence to insulin resistance in muscle, where, unlike the case of fat cells, GLUT4 expression is not significantly reduced. The complex structural organization of muscle tissue and its associated cells have limited the molecular scrutiny of glucose uptake regulation. Instead, cell culture systems have been instrumental in revealing intricacies in the signals and traffic machinery mobilizing GLUT4 to the membrane. This signaling relay is initiated by insulin receptor substrate (IRS)-1 (and not IRS-2)–associated activation of class I phosphatidylinositol-3-kinase (PI3K). At this point, a signal bifurcation takes place, one arm leading to Akt2 activation, inhibition of its substrate AS160 (a GTPase-activating protein for Rabs) and consequent activation of its target Rab GTPases, which in skeletal muscle cells are Rab8A and Rab13 (1). The other arm leads to Rac1, a Rho-family GTPase (2,3) that enacts a dynamic cycle of cortical actin filament remodeling through the Arp2/3 complex and cofilin (4). Joint activation of these distinct signaling arms is required …