GLUT4 activation: thoughts on possible mechanisms.

A family of facilitative glucose transporters or GLUTs mediates glucose uptake by cells and tissues. The glucose transporter isoform GLUT4, which is the predominant isoform expressed in mature muscle and fat tissues, is primarily responsible for the increase in glucose uptake in response to insulin stimulation. Recent work in our laboratory suggests that there are two divergent responses initiated by insulin stimulation. The first response involves the recruitment of GLUT4 transporters from intracellular reserves and their subsequent insertion into the plasma membrane. The second pathway results in an increase in the intrinsic activity of the transporters. This review will discuss evidence supporting the divergence of the two pathways regulating glucose uptake and, in particular, evidence for the increased intrinsic activity of GLUT4 in response to insulin stimulation. Inhibitors of p38 mitogen-activated protein kinase (MAPK) affected only the arm leading to the insulin-stimulated activation of GLUT4. This implicates p38 MAPK involvement in the regulation of this pathway. There is further evidence that p38 MAPK is itself recruited to the plasma membrane. The role of the phosphorylation state of the glucose transporter in response to insulin stimulation has been studied and indicates that, contrary to what might be predicted, there is actually a decrease in its phosphorylation at the plasma membrane in response to insulin. The relationship of this change to glucose uptake remains to be established. Other possible mechanisms regulating GLUT4 activity include binding of (+) or (-) modulators of its function.