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ABSTRACT: 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.
Biochemical Medicine 03/1985; 33(1):104-9.
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ABSTRACT: The genetically diabetic mouse (db/db) exhibits hyperphagia, progressive weight gain, hyperglycemia, and hyperinsulinemia during the first few months of life during which time characteristic pathologic changes occur in several organ systems including the kidney. The extent to which long chain fatty acid oxidation (LCFAO) contributes to excessive gluconeogenesis and hyperglycemia in these animals in unknown. Therefore, the synthetic fatty acid analogue 2-tetradeclyglycidate (TDHA), a potent inhibitor of LCFAO, was given orally to db/db mice to evaluate its capacity to control the blood glucose and prevent their diabetic nephropathy. Five groups of diabetic mice (N = 6) were assigned to receive TDGA in a dose of 5, 10, and 25 mg/kg/day, vehicle (tragacanth), or nothing (control). TDGA had no observable effects on food intake or growth patterns. Drug-treated animals had significant lowering of fasting glucose at 0 and 4 h after dosing during the midportion of the study (2-6 wk). In the latter part of the study (wk 8-11), blood glucose 4 h after dosing was lowered in mice given 10 and 25 free fatty acids. Animals receiving TDGA 25 mg/kg/day exhibited significant inhibition of immunopathologic changes in the kidney. Heart weight was significantly increased in mice receiving TDGA 25 mg/kg/day, and the total amount of myocardial carnitine content was increased in all three drug-treated groups. Increased tissue deposition of lipid was not apparent on histologic examination of liver in drug-treated animals. Inhibition of long chain fat oxidation in the db/db mouse results in significant lowering of blood glucose, and decreased the renal immunopathologic features of diabetic nephropathy in this animal model.
Diabetes 02/1982; 31(1):12-8. · 8.29 Impact Factor
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ABSTRACT: Diabetes in the C57BL/KsJ(db/db) mouse is initially expressed as hyperinsulinemia, followed by hyperphagia, progressive obesity, and widespread pathologic abnormalities. This study was designed to evaluate the effects of metabolic control on the natural history of the diabetic nephropathy. Beginning at 1 mo of age and continuing for 12 wk, diabetic mice were subjected to controlled dietary restriction, such that their weight was maintained similar to that of age-matched, nondiabetic heterozygotes. Diet-restricted diabetics were compared with diabetics fed ad libitum and heterozygote nondiabetics. Significant lowering of fasting blood glucose, water intake, and plasma insulin was achieved by diet restriction. The diet-restricted diabetes demonstrated enhanced metabolic efficiency, consuming approximately half as much food as the nondiabetics, while maintaining a similar weight. Diabetics fed ad libitum evidenced well-defined renal lesions that included 3 + to 4 + immunoglobulin deposition in the glomerular mesangium, and generalized mesangial matrix expansion. These lesions were completely prevented in diet-restricted diabetes whose glomeruli were normal light microscopy, and demonstrated trace to 1 + mesangial immunoglobulin deposition, features identical in all respects to the nondiabetics. These results indicate that diabetic control achieved by preventing of obesity in the db/db mouse prevents the development of diabetic nephropathy.
Diabetes 03/1981; 30(2):106-11. · 8.29 Impact Factor
