Mechanism of Hexosamine-Induced Insulin Resistance in Transgenic Mice Overexpressing Glutamine:Fructose-6-Phosphate Amidotransferase: Decreased Glucose Transporter GLUT4 Translocation and Reversal by Treatment with Thiazolidinedione

摘要: Hexosamines have been hypothesized to mediate aspects of glucose sensing and toxic effects hyperglycemia. For example, insulin resistance results when the rate-limiting enzyme for hexosamine synthesis, glutamine:fructose-6-phosphate amidotransferase (GFA), is overexpressed in muscle adipose tissue transgenic mice. The infusion rates required maintain euglycemia at 0.5, 2, 15, 20 mU/kg x min were 39-90% lower such mice, compared with their control littermates (P < or = 0.01). No differences observed hepatic output, serum levels, ATP levels. Uptake 2-deoxyglucose, measured under conditions hyperinsulinemia, was significantly hindlimb muscle, controls (85.9 +/- 17.8 vs. 166.8 15.1 pmol deoxyglucose/g min). decrease uptake by associated a disruption translocation insulin-stimulated transporter GLUT4. Fractionation membranes on discontinuous sucrose gradient revealed that stimulation led 28.8% increase GLUT4 content 25% fraction 61.2% 35% fraction. In shifts distribution inhibited over 70%. Treatment animals thiazolidinedione troglitazone completely reversed defect disposal without changing GFA activity levels uridine 5'-diphosphate-N-acetylglucosamine. Overexpression skeletal thus leads defects transport similar those seen type 2 diabetes. These data support hypothesis excess metabolism through pathway may be responsible diminished sensitivity defective are