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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, characterized by decreased glucose transport and metabolism in muscle and adipocytes. The glucose transporter GLUT4 mediates insulin-stimulated glucose uptake in adipocytes and muscle by rapidly moving from intracellular storage sites to the plasma membrane. In insulin-resistant states such as obesity and type 2 diabetes, GLUT4 expression is decreased in adipose tissue but preserved in muscle. 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.

Pubmed ID: 11217863


  • Abel ED
  • Peroni O
  • Kim JK
  • Kim YB
  • Boss O
  • Hadro E
  • Minnemann T
  • Shulman GI
  • Kahn BB



Publication Data

February 8, 2001

Associated Grants

  • Agency: NIDDK NIH HHS, Id: R01 DK040936

Mesh Terms

  • Adipocytes
  • Animals
  • Animals, Genetically Modified
  • Biological Transport
  • Crosses, Genetic
  • Diabetes Mellitus
  • Down-Regulation
  • Female
  • Gene Targeting
  • Glucose
  • Glucose Transporter Type 4
  • Insulin
  • Insulin Resistance
  • Liver
  • Male
  • Mice
  • Monosaccharide Transport Proteins
  • Muscle Proteins
  • Muscle, Skeletal