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 d ileucine motif in its COOH-terminal region. Acute stimulation of sugar uptake by insulin results from GLUT4 redistribution to the plasma mem brane and may reflect disruption of dileucine motif function as well a s enhanced bulk membrane exocytosis. Candidate signaling elements for these postulated actions of insulin are PI 3-kinase and p21(ras), both acutely activated by the hormone. Recent work in our laboratory and o thers demonstrates the localization of PI 3-kinase to intracellular me mbranes via its docking to the insulin receptor substrate-1 (IRS-1). A n important hypothesis for future testing is that 3' phosphoinositides generated in the endosomal tubulovesicular system in response to insu lin cause budding or movements of GLUT4-containing membranes to the ce ll surface.