Hyperglycemia can lead directly to a secondary state of
insulin resistance or can worsen a preexisting
insulin-resistant state.
Troglitazone is an orally active
hypoglycemic agent that has been shown to ameliorate
insulin resistance and
hyperinsulinemia in both diabetic animal models and
NIDDM subjects. To determine whether this
drug could prevent the development of
hyperglycemia-induced
insulin resistance and to investigate the mechanism by which this might occur, we studied
troglitazone's effect on
insulin action in rats made hyperglycemic or infused with
glucosamine. Normal male SD rats were fed regular powdered diet with or without
troglitazone as a food admixture (0.2%). After 2 weeks, rats were made hyperglycemic with
glucose (52 mg x kg(-1) x min[-1]) and
somatostatin (0.8 microg x kg(-1) x min[-1]) infusion or were infused with
glucosamine (6.5 mg x kg(-1) x min[-1]) for 6.5 h. In vivo
insulin action was measured by the hyperinsulinemic-euglycemic clamp technique at a submaximal (24 pmol x kg(-1) x min[-1]) or maximal (240 pmol x kg(-1) x min[-1])
insulin infusion rate. The infusion of
glucose and
somatostatin caused a pronounced rise in the plasma
glucose concentration (19.8 +/- 0.6 mmol/l) compared with saline-infused animals (8.0 +/- 0.2 mmol/l; P < 0.001).
Hyperglycemia resulted in
insulin resistance, as evidenced by a marked reduction in the submaximal
glucose disposal rate (GDR) (78 +/- 7 vs. 135 +/- 6 micromol x kg(-1) x min(-1); P < 0.01) and maximal GDR (141 +/- 9 vs. 237 +/- 6 micromol x kg(-1) x min(-1); P < 0.01) compared with the control group.
Troglitazone treatment largely prevented the
hyperglycemia-induced decline in submaximal (116 +/- 7 micromol x kg(-1) x min[-1]) and maximal GDR (209 +/- 9 micromol x kg(-1) x min(-1); P < 0.05).
Glucosamine infusion also resulted in a marked reduction in the submaximal GDR (85 +/- 3 vs. 135 +/- 6 micromol x kg(-1) x min(-1); P < 0.01) and maximal GDR (137 +/- 14 vs. 237 +/- 6 micromol x kg(-1) x min(-1); P < 0.01) compared with the control group. In contrast to the results in the hyperglycemic animals,
troglitazone treatment had no effect on
glucosamine-induced
insulin resistance. In summary, 1) in normal rats, experimental
hyperglycemia, as well as
glucosamine infusion, led to a marked state of peripheral and hepatic
insulin resistance; 2)
troglitazone treatment prevented the
hyperglycemia-induced, but not the
glucosamine-induced,
insulin resistance; and 3) either
troglitazone acts at one or more sites proximal to the entry of
glucosamine into the
hexosamine pathway, or the increased flux of
glucose-derived products through the
hexosamine pathway is not a major mechanism for the
hyperglycemia-induced defect in
insulin action in these animals.