Adipose-selective targeting of the GLUT4 gene impairs insulin action in muscle and liver

E. Dale Abel, Odile Peroni, Jason K. Kim, Young-Bum Kim, Olivier Boss, Ed Hadro, Timo Minnemann, Gerald I. Shulman and Barbara B. Kahn ()
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E. Dale Abel: Diabetes Unit, Beth Israel Deaconess Medical Center and Harvard Medical School
Odile Peroni: Diabetes Unit, Beth Israel Deaconess Medical Center and Harvard Medical School
Jason K. Kim: Yale University School of Medicine
Young-Bum Kim: Diabetes Unit, Beth Israel Deaconess Medical Center and Harvard Medical School
Olivier Boss: Diabetes Unit, Beth Israel Deaconess Medical Center and Harvard Medical School
Ed Hadro: Diabetes Unit, Beth Israel Deaconess Medical Center and Harvard Medical School
Timo Minnemann: Diabetes Unit, Beth Israel Deaconess Medical Center and Harvard Medical School
Gerald I. Shulman: Yale University School of Medicine
Barbara B. Kahn: Diabetes Unit, Beth Israel Deaconess Medical Center and Harvard Medical School

Nature, 2001, vol. 409, issue 6821, 729-733

Abstract: Abstract The earliest defect in developing type 2 diabetes is insulin resistance1,2, characterized by decreased glucose transport and metabolism in muscle and adipocytes3,4. The glucose transporter GLUT4 mediates insulin-stimulated glucose uptake in adipocytes and muscle by rapidly moving from intracellular storage sites to the plasma membrane4. In insulin-resistant states such as obesity and type 2 diabetes, GLUT4 expression is decreased in adipose tissue but preserved in muscle3,4. Because skeletal muscle is the main site of insulin-stimulated glucose uptake, the role of adipose tissue GLUT4 downregulation in the pathogenesis of insulin resistance and diabetes is unclear. To determine the role of adipose GLUT4 in glucose homeostasis, we used Cre/loxP DNA recombination to generate mice with adipose-selective reduction of GLUT4 (G4A-/-). Here we show that these mice have normal growth and adipose mass despite markedly impaired insulin-stimulated glucose uptake in adipocytes. Although GLUT4 expression is preserved in muscle, these mice develop insulin resistance in muscle and liver, manifested by decreased biological responses and impaired activation of phosphoinositide-3-OH kinase. G4A-/- mice develop glucose intolerance and hyperinsulinaemia. Thus, downregulation of GLUT4 and glucose transport selectively in adipose tissue can cause insulin resistance and thereby increase the risk of developing diabetes.

Date: 2001
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DOI: 10.1038/35055575

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