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Submitted on October 14, 2004
Accepted on January 3, 2005
Garvan Institute of Medical Research, St. Vincent's Hospital, 384 Victoria St. Darlinghurst, 2010, NSW, Australia
* To whom correspondence should be addressed. E-mail: D.James{at}garvan.org.au.
Insulin stimulates the translocation of glucose transporter GLUT4 from intracellular vesicles to the plasma membrane (PM). This involves multiple steps as well as multiple intracellular compartments. The Ser/Thr Kinase Akt has been implicated in this process but its precise role is ill defined. To begin to dissect the role of Akt in these different steps we employed a low temperature block. Upon incubation of 3T3-L1 adipocytes at 19 C, GLUT4 accumulated in small peripheral vesicles with a slight increase in PM labeling concomitant with reduced TGN labeling. Although insulin-dependent translocation of GLUT4 to the PM was impaired at 19 C, we still observed movement of vesicles toward the surface. Strikingly, insulin-stimulated Akt activity, but not PI-3K activity, was blocked at 19 C. Consistent with a multi-step process in GLUT4 trafficking, insulin-stimulated GLUT4 translocation could be primed by treating cells with insulin at 19 C whereas this was not the case for Akt activation. These data implicate two insulin-regulated steps in GLUT4 translocation: (1) redistribution of GLUT4 vesicles toward the cell cortex - this process is Akt-independent and is not blocked at 19 C; (2) docking and/or fusion of GLUT4 vesicles with the PM - this process may be the major Akt-dependent step in the insulin regulation of glucose transport.
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