Lipid lowering explains the insulin sensitivity enhancing effects of a thiazolidinedione, 5-(4-(2-(2-phenyl-4-oxazolyl)ethoxy)benzyl)-2,4 thiazolidinedione.
OBJECTIVE
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.
Yakubu-Madus
F E
FE
Division of Endocrinology, Eli Lilly and Company, Indianapolis, IN 46285, USA. Yakubu-Madus@Lilly.com
Stephens
T W
TW
Johnson
W T
WT
D000818:Animals; D003924:Diabetes Mellitus, Type 2; D005260:Female; D005947:Glucose / Q000378:metabolism; D015309:Glucose Clamp Technique; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance; D008099:Liver / Q000378:metabolism*; D009765:Obesity / Q000378:metabolism / Q000503:physiopathology*; D051381:Rats; D011924:Rats, Zucker; D013844:Thiazoles / Q000008:administration & dosage / Q000494:pharmacology*; D045162:Thiazolidinediones; D014280:Triglycerides / Q000378:metabolism*
D007328:Insulin; D013844:Thiazoles; D045162:Thiazolidinediones; D014280:Triglycerides; C089946:2,4-thiazolidinedione; D005947:Glucose