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.
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This work was supported by NIH Grants (to E.D.A., G.I.S. and B.B.K.) and an American Diabetes Association award to B.B.K. E.D.A. was the recipient of awards from the Robert Wood Johnson Foundation and the Eleanor and Miles Shore Scholars in Medicine Fellowship (Harvard Medical School). O.P. was supported by grants from the ALFEDIAM Society and Nestlé, France; and O.B. by the Human Frontier Sciences Program. We thank H. Chen for performing the TaqMan assays; P. She and M.A. Magnusen for breeding aP2–Cre mice with Rosa26–lacZ floxed mice; G. Hotamisligil for helpful advice; and C. Oberste-Berghaus and M. Pham for expert assistance.
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