The specific carnitine palmitoyltransferase I (CPT I)-inhibitor POCA - sodium-2(5-(4-chlorphenyl)pentyl-oxirane carboxylate - was used in isolated perfused hearts of acutely diabetic, ketotic (AD, 100 mg streptozotocin/kg body weight), chronically diabetic (CD, 60 mg streptozotocin/kg body weight), and obese ZUCKER rats (fa/fa) to study different forms of insulin resistance. In hearts of AD rats an absolute insulin resistance was observed which could be attenuated by perfusion of the hearts with POCA (10 microM). The insulin sensitivity could be fully restored and was not any longer significantly different from control hearts. In hearts of CD rats, which show a relative insulin resistance, POCA only slightly stimulated glucose oxidation and uptake, but the total rate of uptake and conversion of glucose as well as the responsiveness of these hearts to insulin remained low. In hearts of obese ZUCKER rats, the rate of glucose oxidation was accelerated to control levels by perfusion with POCA, however, the rate of glycolysis and glucose uptake remained reduced as compared to controls. Thus, POCA shifted the glucose metabolism by stimulating oxidation without normalizing the reduced glucose uptake. It follows that in hearts of AD rats the insulin resistance is due to the accelerated lipid metabolism described and is, therefore, fully reversible if the oxidation of fatty acids is inhibited. In hearts of ZUCKER rats a form of insulin resistance mediated by lipid metabolism seems to be responsible for the reduced glucose oxidation and the lowered rate of glycolysis. The insulin resistance can be eliminated and has to be distinguished from a defect in the glucose uptake system not affected by POCA. In hearts of CD rats insulin resistance is not dependent on disturbances in lipid metabolism and is practically not influenced by POCA. Thus, a CPI I-inhibitor might be useful to differentiate various forms of insulin resistance and therapeutically beneficial in forms mediated by lipid metabolic defects.