The GLUT4 Code

Despite being one of the first recognized targets of insulin action, the acceleration of glucose transport into muscle and fat tissue remains one of the most enigmatic processes in the insulin action cascade. Glucose transport is accomplished by a shift in the distribution of the insulin-responsive glucose transporter GLUT4 from intracellular compartments to the plasma membrane in the presence of insulin. The complexity in deciphering the molecular blueprint of insulin regulation of glucose transport arises because it represents a convergence of two convoluted biological systems-vesicular transport and signal transduction. Whereas more than 60 molecular players have been implicated in this orchestral performance, it has been difficult to distinguish between mainly passive participants vs. those that are clearly driving the process. The maze-like nature of the endosomal system makes it almost impossible to dissect the anatomical nature of what appears to be a medley of many overlapping and rapidly changing transitions. A major limitation is technology. It is clear that further progress in teasing apart the GLUT4 code will require the development and application of novel and advanced technologies that can discriminate one molecule from another in the living cell and to superimpose this upon a system in which the molecular environment can be carefully manipulated. Many are now taking on this challenge.