Tissue-specific actions of antidiabetic thiazolidinediones on the reduced fatty acid oxidation in skeletal muscle and liver of Zucker diabetic fatty rats

Fatty acid overload has been proposed as a cause of decreased responsivenes s in the major insulin target tissues of the body such as muscle and liver tissue. We therefore investigated fatty acid oxidation in soleus muscle and liver isolated from Zucker diabetic fatty (ZDF) rats treated with thiazoli dinediones, a new class of antidiabetic agents. (CO2)-C-14 production from [C-14]palmitic (C16:0) acid was lower in the soleus muscle and liver of ZDF rats versus lean rats (P <.05). When administered orally to ZDF rats for 2 weeks, the thiazolidinediones troglitazone (300 mg/kg) and KRP-297 (10 mg/ kg) increased palmitic acid oxidation in the soleus muscle of ZDF rats (P < .05). KRP-297, but not troglitazone, increased palmitic acid oxidation in t he liver of ZDF rats (P <.05), and both troglitazone and KRP-297 inhibited triglyceride accumulation in the skeletal muscle of ZDF rats. Hepatic trigl yceride accumulation in ZDF rats was inhibited by KRP-297, but not by trogl itazone. A reduction of fatty acid oxidation in the liver of ZDF rats and a n increase in response to KRP-297 were observed only when C16:0 and C18:0 f atty acids, not C8:0, were used as substrates. Thus, there were defects in fatty acid catabolic activity and triglyceride accumulation in the soleus m uscle and liver of ZDF rats. These results indicate that KRP-297 has advant ages over troglitazone in the amelioration of these lipid metabolic abnorma lities in insulin resistance associated with obesity. Copyright (C) 2000 by W.B. Saunders Company.