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Molecular and Cellular Biology, July 2004, p. 6456-6466, Vol. 24, No. 14
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.14.6456-6466.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Insulin Increases Cell Surface GLUT4 Levels by Dose Dependently Discharging GLUT4 into a Cell Surface Recycling Pathway{dagger}

Roland Govers,1* Adelle C. F. Coster,2 and David E. James1*

Diabetes and Obesity Research Program, Garvan Institute of Medical Research, Darlinghurst, Sydney, New South Wales 2010,1 School of Mathematics, University of New South Wales, Sydney, New South Wales 2052, Australia2

Received 3 March 2004/ Returned for modification 8 April 2004/ Accepted 27 April 2004

The insulin-responsive glucose transporter GLUT4 plays an essential role in glucose homeostasis. A novel assay was used to study GLUT4 trafficking in 3T3-L1 fibroblasts/preadipocytes and adipocytes. Whereas insulin stimulated GLUT4 translocation to the plasma membrane in both cell types, in nonstimulated fibroblasts GLUT4 readily cycled between endosomes and the plasma membrane, while this was not the case in adipocytes. This efficient retention in basal adipocytes was mediated in part by a C-terminal targeting motif in GLUT4. Insulin caused a sevenfold increase in the amount of GLUT4 molecules present in a trafficking cycle that included the plasma membrane. Strikingly, the magnitude of this increase correlated with the insulin dose, indicating that the insulin-induced appearance of GLUT4 at the plasma membrane cannot be explained solely by a kinetic change in the recycling of a fixed intracellular GLUT4 pool. These data are consistent with a model in which GLUT4 is present in a storage compartment, from where it is released in a graded or quantal manner upon insulin stimulation and in which released GLUT4 continuously cycles between intracellular compartments and the cell surface independently of the nonreleased pool.

* Corresponding author. Present address for Roland Govers: Department of Functional Genomics, Center for Neurogenomics and Cognitive Research, Free University and Free University Medical Center, WN Building, Rm. A445, De Boelelaan 1087, 1081 HV Amsterdam, The Netherlands. Phone: 31-20-4446929. Fax: 31-20-4446926. E-mail: roland{at}cncr.vu.nl. Mailing address for David E. James: Diabetes and Obesity Research Program, Garvan Institute of Medical Research, 304 Victoria St., Darlinghurst, Sydney, New South Wales 2010, Australia. Phone: 61-2-9295810. Fax: 61-2-92958201. E-mail: d.james{at}garva.org.au.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

Molecular and Cellular Biology, July 2004, p. 6456-6466, Vol. 24, No. 14
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.14.6456-6466.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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