Effects of troglitazone on hepatic and peripheral insulin resistance induced by growth hormone excess in rats

It is well known that short-term growth hormone (GH) administration in humans and animals induces insulin resistance and glucose intolerance. The purpose of the present study was to clarify whether troglitazone, a new insulin-sensitizing drug of the thiazolidinedione class, counteracts the insulin antagonistic effects of recombinant human (rh) GH on glucose metabolism in rats. Male Wistar rats weighing 184 to 226 g were treated either with rhGH (n = 8) or rhGH plus troglitazone (n = 8). rhGH (20 IU/kg body weight/d) was given by subcutaneous injection twice daily for 2 days. Troglitazone was given at 100 mg/kg/d orally for 5 days before and 2 days during rhGH. Saline was injected to the control rats (n = 7). Euglycemic clamp studies with an insulin infusion rate of 8 mU/kg/min were performed in these rats after an overnight fast. Hepatic glucose output (HGO), glucose infusion rate (GIR), and glucose disappearance rate (GDR) were measured. Fasting levels of plasma glucose (6.6 +/- 0.1, 6.1 +/- 0.3, 6.5 +/- 0.2 mmol/L), insulin (187.5 +/- 24.1, 206.4 +/- 24.1, 182.3 +/- 31.0 pmol/L), and serum free fatty acid (FFA) (1.58 +/- 0.18, 1.43 +/- 0.16, 1.61 +/- 0.25 mEq/L) were comparable among rats treated with rhGH, rhGH plus troglitazone, and controls, respectively. Basal HGO was also comparable among the three treatment groups. HGO was suppressed significantly during the hyperinsulinemic glucose clamp in control rats, but not in rhGH rats. When troglitazone was coadministered with rhGH, suppressibility of HGO during the glucose clamp was comparable to that of controls. GIR (13.5 +/- 4.5 v 24.1 +/- 4.1 mg/kg/min) and GDR (18.1 +/- 5.8 v 30.3 +/- 5.2 mg/kg/min) were decreased by rhGH treatment compared with control values. They returned to normal levels in rats treated with both rhGH and troglitazone (GIR, 22.4 +/- 5.9; GDR, 24.7 +/- 7.1). From these results, it is evident that rhGH treatment impaired insulin's ability to suppress HGO and stimulate peripheral glucose utilization. Troglitazone could block the insulin antagonistic effects of GH on hepatic glucose output and peripheral glucose utilization.