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

Hexosamines have been hypothesized to mediate aspects of glucose sensing an d toxic effects of hyperglycemia. For example, insulin resistance results w hen the rate-limiting enzyme for hexosamine synthesis, glutamine:fructose-6 -phosphate amidotransferase (GFA), is overexpressed in muscle and adipose t issue of transgenic mice. The glucose infusion rates required to maintain e uglycemia at insulin infusion rates of 0.5, 2, 15, and 20 mU/kg.min were 39 -90% lower in such transgenic mice, compared with their control littermates (P less than or equal to 0.01). No differences were observed in hepatic gl ucose output, serum insulin levels, or muscle ATP levels. Uptake of 2-deoxy glucose, measured under conditions of hyperinsulinemia, was significantly l ower in transgenic hindlimb muscle, compared with controls (85.9 +/- 17.8 v s. 166.8 +/- 15.1 pmol deoxyglucose/g.min). The decrease in glucose uptake by transgenic muscle was associated with a disruption in the translocation of the insulin-stimulated glucose transporter GLUT4. Fractionation of muscl e membranes on a discontinuous sucrose gradient revealed that insulin stimu lation of control muscle led to a 28.8% increase in GLUT4 content in the 25 % fraction and a 61.2% decrease in the 35% fraction. In transgenic muscle, the insulin-stimulated shifts in GLUT4 distribution were inhibited by over 70%. Treatment of the transgenic animals with the thiazolidinedione troglit azone completely reversed the defect in glucose disposal without changing G FA activity or the levels of uridine 5'-diphosphate-N-acetylglucosamine. Ov erexpression of GFA in skeletal muscle thus leads to defects in glucose tra nsport similar to those seen in type 2 diabetes. These data support the hyp othesis that excess glucose metabolism through the hexosamine pathway may b e responsible for the diminished insulin sensitivity and defective glucose uptake that are seen with hyperglycemia.