Different types of postinsulin receptor defects contribute to insulin resistance in hearts of obese Zucker rats.
The influence of obesity on myocardial function and metabolism was studied in obese (fa/fa) and thin (Fa/Fa) Zucker rats using the isolated perfused heart as model. Cardiac performance of obese Zucker rats was not impaired. Instead, left ventricular pressure and contractility were increased as compared to controls. In agreement with these findings, creatine phosphate and the ratios of ATP/ADP and creatine phosphate creatine were elevated. The uptake and the conversion of glucose by hearts of obese Zucker rats were impaired. Insulin stimulated the uptake and oxidation of glucose. However, the responsiveness of these processes to insulin was diminished. Lipolysis of endogenous lipids was accelerated severalfold in obesity. Inhibition of fatty acid oxidation by a specific carnitine palmitoyl-transferase inhibitor, phenylalkyloxirane carboxylic acid (POCA), led to a slow rate of lipolysis, and to an acceleration of glucose oxidation and of the basal, noninsulin-dependent uptake of glucose. In the presence of POCA, insulin had, however, no additional stimulatory effect on the glucose uptake by hearts of obese rats. In contrast to hearts of ketotic, acutely diabetic rats where POCA fully restored myocardial responsiveness of glucose uptake and conversion to insulin, in hearts of obese rats only a shift in the glucose pathway from glycolytic formation of lactate and pyruvate to oxidation to CO2 was observed. Thus, POCA can be used as a tool to distinguish different forms of insulin resistance in obesity: 1) a lipid metabolism-dependent defect--presumably an inhibition of phosphofructokinase and pyruvate dehydrogenase by metabolites of fatty acid oxidation, influenced by inhibition of carnitine palmitoyltransferasei, and 2) a lipid metabolism-independent defect in the activation of uptake of glucose and glycogen synthesis by insulin not affected by POCA.
D000227:Adenine Nucleotides / Q000378:metabolism; D000818:Animals; D004734:Energy Metabolism; D004852:Epoxy Compounds / Q000494:pharmacology; D005947:Glucose / Q000378:metabolism; D007333:Insulin Resistance; D007773:Lactates / Q000378:metabolism; D019344:Lactic Acid; D008066:Lipolysis; D008297:Male; D009206:Myocardium / Q000378:metabolism*; D009765:Obesity / Q000503:physiopathology*; D010084:Oxidation-Reduction; D010477:Perfusion; D011773:Pyruvates / Q000378:metabolism; D019289:Pyruvic Acid; D051381:Rats; D011924:Rats, Zucker; D011972:Receptor, Insulin / Q000502:physiology*
D000227:Adenine Nucleotides; D004852:Epoxy Compounds; D007773:Lactates; D011773:Pyruvates; D019344:Lactic Acid; D019289:Pyruvic Acid; C033891:ethyl 2-(5-(4-chlorophenyl)pentyl)oxiran-2-carboxylate; D011972:Receptor, Insulin; D005947:Glucose