Molecular actions of insulin on glucose transport.

Low basal glucose uptake by insulin-sensitive muscle and adipose cells reflects rapid endocytic retrieval of GLUT4 glucose transporters from the cell surface and their retention in intracellular membranes. Both GLUT4 endocytosis and its intracellular retention are governed by a dileucine motif in its COOH-terminal region. Acute stimulation of sugar uptake by insulin results from GLUT4 redistribution to the plasma membrane and may reflect disruption of dileucine motif function as well as enhanced bulk membrane exocytosis. Candidate signaling elements for these postulated actions of insulin are PI 3-kinase and p21ras, both acutely activated by the hormone. Recent work in our laboratory and others demonstrates the localization of PI 3-kinase to intracellular membranes via its docking to the insulin receptor substrate-1 (IRS-1). An important hypothesis for future testing is that 3' phosphoinositides generated in the endosomal tubulovesicular system in response to insulin cause budding or movements of GLUT4-containing membranes to the cell surface.