The effect of the oral hypoglycemic agent methylpalmoxirate (methyl-2-tetradecylglycidate), a selective inhibitor of long-chain fatty acid oxidation, on the exercise capacity of diabetic rats was evaluated. Rats were made diabetic by injection of streptozocin (75 mg/kg i.p.). which was confirmed by 4+ glucosuria. Daily oral administration of 2.5 mg/kg for 5 days, or a single dose of 10 mg/kg, of methylpalmoxirate produced a slight, nonsignificant decrease in the ability of diabetic rats to perform strenuous exercise of an intensity that caused exhaustion in less than 30 min. The ability of diabetic rats to perform prolonged, moderately strenuous exercise of an intensity that could be maintained for more than 60 min was not affected by methylpalmoxirate treatment. Methylpalmoxirate normalized plasma glucose concentrations, with resting glucose levels reduced 71% compared with nontreated controls, and did not cause hypoglycemic during prolonged exercise to exhaustion. Hepatic glycogen content was significantly reduced in methylpalmoxirate-treated rats in the fed, resting state, and during exercise, suggesting that liver was forced to oxidize carbohydrate at the expense of carbohydrate storage. Blood ketone levels of methylpalmoxirate-treated rats were reduced by 82% at rest, and exercise-induced ketosis was prevented by drug treatment. Muscle glycogen concentration and the rate of muscle glycogen depletion during exercise were not altered by methylpalmoxirate. It appears that the liver is the major site of action of methylpalmoxirate in diabetic rats when given in low doses.

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