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