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MBC in Press, published online ahead of print August 16, 2006
Mol. Biol. Cell 10.1091/mbc.E06-07-0585

A more recent version of this article appeared on October 1, 2006
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Submitted on July 10, 2006
Revised on August 3, 2006
Accepted on August 4, 2006

Insulin Signaling Diverges into Akt Dependent and Independent Signals to Regulate the Recruitment/Docking and the Fusion of GLUT4 Vesicles to the Plasma Membrane

Eva Gonzalez and Timothy E. McGraw

Department of Biochemistry, Weill Medical College of Cornell University, New York, NY 10021

Monitoring Editor: Jean Gruenberg

Insulin modulates glucose disposal in muscle and adipose tissue by regulating the cellular redistribution of the GLUT4 glucose transporter. Protein kinase Akt/PKB is a central mediator of insulin-regulated translocation of GLUT4; however, the GLUT4 trafficking step(s) regulated by Akt is not known. Here we use acute pharmacologic Akt inhibition to show that Akt is required for insulin-stimulated exocytosis of GLUT4 to the plasma membrane. Our data also suggest that the AS160 Rab GAP protein is not the only Akt target required for insulin-stimulated GLUT4 translocation. Using a total internal reflection microscopy assay to show that Akt activity is specifically required for an insulin-mediated pre-fusion step involving the recruitment and/or docking of GLUT4 vesicles to within 250 nm of the plasma membrane. Moreover, the insulin-stimulated fusion of GLUT4 vesicles with the plasma membrane can occur independent of Akt activity, although based on inhibition by wortmannin, it is dependent on PI3-kinase activity. Hence, to achieve full redistribution of GLUT4 into the plasma membrane, insulin signaling bifurcates to independently regulate both fusion and a pre-fusion step(s).

Address correspondence to: Timothy E. McGraw (temcgraw{at}med.cornell.edu)




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