title: Glucose toxicity and the development of diabetes in mice with muscle-specific inactivation of GLUT4.
abstract: Using cre/loxP gene targeting, transgenic mice with muscle-specific inactivation of the GLUT4 gene (muscle GLUT4 KO) were generated and shown to develop a diabetes phenotype. To determine the mechanism, we examined insulin-stimulated glucose uptake and metabolism during hyperinsulinemic-euglycemic clamp in control and muscle GLUT4 KO mice before and after development of diabetes. Insulin-stimulated whole body glucose uptake was decreased by 55% in muscle GLUT4 KO mice, an effect that could be attributed to a 92% decrease in insulin-stimulated muscle glucose uptake. Surprisingly, insulin's ability to stimulate adipose tissue glucose uptake and suppress hepatic glucose production was significantly impaired in muscle GLUT4 KO mice. To address whether these latter changes were caused by glucose toxicity, we treated muscle GLUT4 KO mice with phloridzin to prevent hyperglycemia and found that insulin-stimulated whole body and skeletal muscle glucose uptake were decreased substantially, whereas insulin-stimulated glucose uptake in adipose tissue and suppression of hepatic glucose production were normal after phloridzin treatment. In conclusion, these findings demonstrate that a primary defect in muscle glucose transport can lead to secondary defects in insulin action in adipose tissue and liver due to glucose toxicity. These secondary defects contribute to insulin resistance and to the development of diabetes.
authors: Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut 06536-8012, USA.
authors: J K
authors: JK
authors: Kim
authors: A
authors: A
authors: Zisman
authors: J J
authors: JJ
authors: Fillmore
authors: O D
authors: OD
authors: Peroni
authors: K
authors: K
authors: Kotani
authors: P
authors: P
authors: Perret
authors: H
authors: H
authors: Zong
authors: J
authors: J
authors: Dong
authors: C R
authors: CR
authors: Kahn
authors: B B
authors: BB
authors: Kahn
authors: G I
authors: GI
authors: Shulman
mesh_terms: D000273:Adipose Tissue / Q000187:drug effects / Q000378:metabolism; D017668:Age of Onset; D000818:Animals; D003864:Depression, Chemical; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D004195:Disease Models, Animal; D005947:Glucose / Q000493:pharmacokinetics / Q000633:toxicity*; D051275:Glucose Transporter Type 4; D006943:Hyperglycemia / Q000188:drug therapy / Q000517:prevention & control; D007328:Insulin / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D007332:Insulin Infusion Systems; D007333:Insulin Resistance / Q000235:genetics*; D007684:Kidney Tubules / Q000187:drug effects / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009004:Monosaccharide Transport Proteins / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D009124:Muscle Proteins / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism; D010695:Phlorhizin / Q000494:pharmacology / Q000627:therapeutic use; D011236:Prediabetic State / Q000188:drug therapy / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects
chemical_list: D051275:Glucose Transporter Type 4; D007328:Insulin; D009004:Monosaccharide Transport Proteins; D009124:Muscle Proteins; C495693:Slc2a4 protein, mouse; D010695:Phlorhizin; D005947:Glucose