The search for the underlying mechanism through which insulin regulates glucose uptake into peripheral tissues has unveiled a highly intricate network of molecules that function in concert to elicit the redistribution or 'translocation' of the glucose transporter isoform GLUT4 from intracellular membranes to the cell surface. Following recent technological advances within this field, this review aims to bring together the key molecular players that are thought to be involved in GLUT4 translocation and will attempt to address the spatial relationship between the signalling and trafficking components of this event. We will also explore the degree to which components of the insulin signalling and GLUT4 trafficking machinery may serve as potential targets for the development of orally available insulin mimics for the treatment of diabetes mellitus.

The activation of protein kinase B (or Akt) plays a central role in the stimulation of glucose uptake by insulin. Currently, however, numerous questions remain unanswered regarding the role of this kinase in bringing about this effect. For example, we do not know precisely where in the GLUT4 trafficking pathway this kinase acts. Nor do we know which protein substrates are responsible for mediating the effects of protein kinase B, although two recently identified proteins (AS160 and PIKfyve) may play a role. This paper addresses these important questions by reviewing recent progress in the field.

The translocation of GLUT4 to the plasma membrane underlies the ability of insulin to stimulate glucose uptake, an event that involves the activation of protein kinase B, several members of the Rab family of GTP-binding proteins and the phosphorylation of the Rab GTPase-activating protein AS160. Here, we explored the regulation by insulin of the class I Rab11-interacting proteins Rip11, RCP and FIP2. We show that Rip11, but not RCP or FIP2, translocates to the plasma membrane of 3T3-L1 adipocytes in response to insulin. This unique response of Rip11 prompted us to explore the role of this protein in more detail. We found that Rip11 partially colocalises with GLUT4 in intracellular compartments. siRNA-mediated knockdown of Rip11 inhibits insulin-stimulated uptake of 2-deoxyglucose, and overexpression of Rip11 blocks insulin-stimulated insertion of translocated GLUT4 vesicles into the plasma membrane. We additionally show that Rip11 forms a complex with AS160 in a Rab11-independent manner and that insulin induces dissociation of AS160 from Rip11. We propose that Rip11 is an AS160- and Rab-binding protein that coordinates the protein kinase signalling and trafficking machinery required to stimulate glucose uptake in response to insulin.

Background: Insulin stimulates glucose uptake by adipocytes through increasing translocation of the glucose transporter GLUT4 from an intracellular compartment to the plasma membrane. Fusion of GLUT4-containing vesicles at the cell surface is thought to involve phospholipase D activity, generating the signalling lipid phosphatidic acid, although the mechanism of action is not yet clear.