Prevention of the metabolic effects of 2-tetradecylglycidate by octanoic acid in the genetically diabetic mouse (db/db).
2-Tetradecylglycidate is a specific inhibitor of the enzyme carnitine palmitoyl transferase, the rate-limiting step in long chain fatty acid oxidation. We previously showed that chronic administration of TDGA to genetically diabetic mice caused a dose-dependent decrease in blood glucose, retarded the development of renal immunopathologic lesions, and resulted in significant cardiomegaly. The present study was designed to evaluate whether all the observed consequences of chronic TDGA administration resulted from inhibition of long chain fatty acid oxidation or whether the drug exerted other nonspecific effects. To circumvent the effects of LCFAO inhibition, diabetic mice were dosed with TDGA and given a diet containing 9% octanoic acid. Octanoic acid is a medium chain fatty acid, whose oxidation is not dependent on the carnitine transferase system and is not inhibited by TDGA. Administration of the octanoate diet to diabetics receiving TDGA abrogated all the drug effects, including lowering of blood glucose and prevention of renal immunopathology. Cardiomegaly, a consequence of increased protein accretion associated with TDGA dosing, did not occur in the octanoate-fed animals. These results indicate that all the actions of TDGA are mediated via its inhibitory effects on long chain fatty acid oxidation. The cardiac changes resulting from chronic TDGA administration suggest that long chain fatty acid oxidation and its relationship with myocardial energetics may exert a regulatory role on protein synthesis in the myocardium.
D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D002210:Caprylates / Q000627:therapeutic use*; D003920:Diabetes Mellitus / Q000235:genetics; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy*; D004347:Drug Interactions; D004852:Epoxy Compounds / Q000627:therapeutic use*; D004988:Ethers, Cyclic / Q000627:therapeutic use*; D005227:Fatty Acids / Q000627:therapeutic use*; D006321:Heart / Q000187:drug effects; D007004:Hypoglycemic Agents; D007668:Kidney / Q000187:drug effects / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D009929:Organ Size / Q000187:drug effects
D001786:Blood Glucose; D002210:Caprylates; D004852:Epoxy Compounds; D004988:Ethers, Cyclic; D005227:Fatty Acids; D007004:Hypoglycemic Agents; C031492:octanoic acid; C021756:2-tetradecylglycidic acid