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Diabetes 51:2090-2098, 2002
© 2002 by the American Diabetes Association, Inc.

Sustained Exposure of L6 Myotubes to High Glucose and Insulin Decreases Insulin-Stimulated GLUT4 Translocation but Upregulates GLUT4 Activity

Carol Huang1,2, Romel Somwar1,3, Nish Patel1,4, Wenyan Niu1, Dóra Török1, and Amira Klip1,3

1 Programme in Cell Biology, Hospital for Sick Children, Toronto, Canada
2 Institute of Medical Science, University of Toronto, Toronto, Canada
3 Department of Biochemistry, University of Toronto, Toronto, Canada
4 Department of Physiology, University of Toronto, Toronto, Canada

Hyperglycemia and hyperinsulinemia are cardinal features of acquired insulin resistance. In adipose cell cultures, high glucose and insulin cause insulin resistance of glucose uptake, but because of altered GLUT4 expression and contribution of GLUT1 to glucose uptake, the basis of insulin resistance could not be ascertained. Here we show that GLUT4 determines glucose uptake in L6 myotubes stably overexpressing myc-tagged GLUT4. Preincubation for 24 h with high glucose and insulin (high Glc/Ins) reduced insulin-stimulated GLUT4 translocation by 50%, without affecting GLUT4 expression. Insulin receptor and insulin receptor substrate-1 tyrosine phosphorylation, phosphatidylinositol 3-kinase activation, and Akt phosphorylation also diminished, as did insulin-mediated glucose uptake. However, basal glucose uptake rose by 40% without any gain in surface GLUT4. High Glc/Ins elevated basal p38 mitogen-activated protein kinase (MAPK) phosphorylation and activity, and a short inhibition of p38 MAPK with SB202190 corrected the rise in basal glucose uptake, suggesting that p38 MAPK activity contributes to this rise. We propose that in a cellular model of skeletal muscle, chronic exposure to high Glc/Ins reduced the acute, insulin-elicited GLUT4 translocation. In addition, basal state GLUT4 activity was augmented to partially compensate for the translocation defect, resulting in a more robust glucose uptake than what would be predicted from the amount of cell surface GLUT4 alone.


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Copyright © 2002 by the American Diabetes Association.