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

The earliest defect in developing type 2 diabetes is insulin resistance(1,2 ), characterized by decreased glucose transport and metabolism in muscle an d adipocytes(3,4). The glucose transporter GLUT4 mediates insulin-stimulate d glucose uptake in adipocytes and muscle by rapidly moving from intracellu lar storage sites to the plasma membrane(4). In insulin-resistant states su ch as obesity and type 2 diabetes, GLUT4 expression is decreased in adipose tissue but preserved in muscle(3,4). Because skeletal muscle is the main s ite of insulin-stimulated glucose uptake, the role of adipose tissue GLUT4 downregulation in the pathogenesis of insulin resistance and diabetes is un clear. To determine the role of adipose GLUT4 in glucose homeostasis, we us ed Cre/loxP DNA recombination to generate mice with adipose-selective reduc tion of GLUT4 (G4A(-/-)). Here we show that these mice have normal growth a nd adipose mass despite markedly impaired insulin-stimulated glucose uptake in adipocytes. Although GLUT4 expression is preserved in muscle, these mic e develop insulin resistance in muscle and liver, manifested by decreased b iological responses and impaired activation of phosphoinositide-3-OH kinase . G4A(-/-) mice develop glucose intolerance and hyperinsulinaemia. Thus, do wnregulation of GLUT4 and glucose transport selectively in adipose tissue c an cause insulin resistance and thereby increase the risk of developing dia betes.