Aim: Insulin resistance is a characteristic feature of type 2 diabetes and obesity. The present study examined the effects of TZD300512, a thiazolidinedione, on glucose and lipid metabolism in the fatty Zucker rat (fa/fa), a rat model of insulin resistance.
Methods: TZD300512 was administered (2.0 mg/kg/day) in the diet for 1 week to chronically catheterized Zucker fa/fa rats. We measured triglyceride clearance rate and hepatic triglyceride output. We assessed baseline glucose metabolism, and insulin-mediated glucose uptake. We also determined whether the insulin sensitivity enhancing effects of TZD300512 could be reversed by infusion of Intralipid.
Results: TZD300512 treatment markedly reduced fasting plasma triglyceride by 72% and nonesterified free fatty acids by 46%. Moreover, treatment significantly enhanced plasma triglyceride clearance (AUC; 60.36+/-11.50 v 131.44+/-18.45 mM/min), but hepatic triglyceride output was not altered. Drug treatment significantly reduced fasting plasma glucose by 25%, plasma insulin by 73%, and had no effect on glucagon levels. Glucose infusion rate (GIR) needed to maintain euglycemia during hyperinsulinemic clamp was significantly increased from 34.96+/-3.94 micromol/kg/min to 123.80+/-4.80 micromol/kg/min, while whole body glucose uptake was more than doubled (58.49+/-2.86 control vs. 126.97+/-3.8 treated micromol/kg/min). Insulin-induced suppression of hepatic glucose production was nearly complete with treatment. Intralipid infusion reversed drug-induced improvement in insulin sensitivity.
Conclusions: These results suggest that TZD300512-favourable alterations in lipid metabolism have a significant impact on its effectiveness in enhancing insulin sensitivity in a severely insulin resistant rodent model of type 2 diabetes.