Intracellular organization of insulin signaling and GLUT4 translocation

Glucose is cleared from the bloodstream by a family of facilitative transpo rters (GLUTs), which catalyze the transport of glucose down its concentrati on gradient and into cells of target tissues, primarily striated muscle and adipose. Currently, there are five established functional facilitative glu cose transporter isoforms (GLUT1-4 and GLUTX1), with GLUTS being a fructose transporter. GLUT1 is ubiquitously expressed with particularly high levels in human erythrocytes and in the endothelial cells lining the blood vessel s of the brain. GLUT3 is expressed primarily in neurons and, together, GLUT 1 and GLUT3 allow glucose to cross the blood-brain barrier and enter neuron s. GLUT2 is a low-affinity (high Km) glucose transporter present in liver, intestine, kidney, and pancreatic P cells. This transporter functions as pa rt of the glucose sensor system in P cells and in the basolateral transport of intestinal epithelial cells that absorb glucose from the diet. A new fa cilitative glucose transporter protein, GLUTX1, has been identified and app ears to be important in early blastocyst development. The GLUT4 isoform is the major insulin-responsive transporter that is predominantly restricted t o striated muscle and adipose tissue. In contrast to the other GLUT isoform s, which are primarily localized to the cell surface membrane, GLUT4 transp orter proteins are sequestered into specialized storage vesicles that remai n within the cell's interior under basal conditions. As postprandial glucos e levels rise, the subsequent increase in circulating insulin activates int racellular signaling cascades that ultimately result in the translocation o f the GLUT4 storage compartments to the plasma membrane. Importantly, this process is readily reversible such that when circulating insulin levels dec line, GLUT4 transporters are removed from the plasma membrane by endocytosi s and are recycled back to their intracellular storage compartments. Theref ore, by establishing an internal membrane compartment as the default locali zation for the GLUT4 transporters, insulin-responsive tissues are poised to respond rapidly and efficiently to fluctuations in circulating insulin lev els. Unfortunately, the complexity of these regulatory processes provides n umerous potential targets that may be defective and eventually result in pe ripheral tissue insulin resistance acid possibly diabetes. As such, underst anding the molecular details of GLUT4 expression, GLUT4 vesicle compartment biogenesis, GLUT4 sequestration, vesicle trafficking, and fusion with the plasma membrane has become a major focus for many laboratories. This chapte r will focus on recently elucidated insulin signal transduction pathways an d GLUT4 vesicle trafficking components that are necessary for insulin-stimu lated glucose uptake and GLUT4 translocation in adipoctyes.