Hexosamines have been shown to mediate effects of
hyperglycemia and so-called "
glucose toxicity" in
insulin-sensitive tissues. To determine the effects of
hexosamines on
insulin synthesis and secretion, transgenic mice were created to overexpress the rate-limiting
enzyme for
hexosamine synthesis,
glutamine:fructose-6-phosphate amidotransferase (GFA), specifically in beta-cells. GFA activity in islets of heterozygous transgenic mice was elevated 76% compared with littermate controls. The increased GFA activity led to 1.4- and 2.1-fold increased pancreatic
insulin content in 2- and 10-month-old transgenic mice, respectively (P < 0.005). Fasting
insulin levels were 1.6-fold higher than in littermate controls (P < 0.05).
Hyperinsulinemia was evident despite a 28% reduction in
insulin mRNA levels. The fasting
glucose levels in the transgenic mice equaled that of controls aged 2-4 months but exceeded that of the controls aged 6-10 months (means +/- SE 6.9 +/- 0.2 vs. 5.9 +/- 0.2 mmol/l, P < 0.001). By 8 months, the males were
overweight and mildly diabetic (fasting
glucose 8.8 +/- 0.5 mmol/l) despite persistent
hyperinsulinemia.
Insulin resistance was confirmed in both males and females using the euglycemic-hyperinsulinemic clamp technique;
glucose disposal rates decreased by 48% in transgenic mice (P < 0.01).
Triglyceride levels did not differ, and
free fatty acid levels were lower in the transgenic animals.
ATP levels were unchanged in the transgenic islets. We conclude that
hexosamine biosynthesis is involved in the regulation of
insulin content in beta-cells by
glucose. Increased
hexosamine flux in the beta-cell results in
hyperinsulinemia,
insulin resistance, and (in males) mild
type 2 diabetes.