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Lipid lowering explains the insulin sensitivity enhancing effects of a thiazolidinedione, 5‐(4‐(2‐(2‐phenyl‐4‐oxazolyl)ethoxy)benzyl)‐2,4 thiazolidinedione*
Author(s) -
YakubuMadus F. E.,
Stephens T. W.,
Johnson W. T.
Publication year - 2000
Publication title -
diabetes, obesity and metabolism
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.445
H-Index - 128
eISSN - 1463-1326
pISSN - 1462-8902
DOI - 10.1046/j.1463-1326.2000.00075.x
Subject(s) - medicine , endocrinology , triglyceride , insulin , insulin resistance , glucose clamp technique , chemistry , glucagon , thiazolidinedione , carbohydrate metabolism , metabolism , type 2 diabetes , lipid metabolism , glucose uptake , diabetes mellitus , pancreatic hormone , cholesterol
Summary 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 non‐esterified free fatty acids by 46%. Moreover, treatment significantly enhanced plasma triglyceride clearance (AUC; 60.36 ± 11.50 v 131.44 ± 18.45 m m /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 μmol/kg/min to 123.80 ± 4.80 μmol/kg/min, while whole body glucose uptake was more than doubled (58.49 ± 2.86 control vs. 126.97 ± 3.8 treated μmol/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.