The oral
hypoglycemic agent,
methyl 2-tetradecylglycidate (Me-TDGA), which inhibits in vitro mitochondrial
carnitine palmitoyl
transferase A (
CPT-A) was used to study the relationship of
CPT inhibition to changes in
ketonemia and glycemia in normal and diabetic rats. After
oral administration of Me-TDGA, the
CPT activity of isolated rat liver mitochondria was substantially reduced with only the presumed outer
enzyme fraction
CPT-A released by
digitonin treatment showing reduced activity. Mitochondrial
fatty acyl-CoA synthetase was not inhibited. Oral doses of 0.1-2.5 mg/kg Me-TDGA produced both a dose-dependent lowering of plasma
ketones and an inhibition of liver
CPT. With single doses in excess of 2.5 mg/kg, po, heart and skeletal muscle
CPT were also consistently inhibited. The effect on the liver
enzyme persisted for at least 48 hr following 1 mg/kg, po, while the effect on
ketones disappeared by 36 hr. The degree of inhibition of liver
CPT produced by Me-TDGA was not altered by diabetes or the dietary state. At low doses (0.05-0.25 mg/kg, po), the most sensitive parameter was inhibition of hepatic
CPT. Both plasma
ketones and
CPT were lowered with doses 10-fold less (0.1 mg/kg) than were required for
blood glucose lowering, thus making Me-TDGA the most potent hypoketonemic compound known. In conclusion, inhibition of liver beta-oxidation at the stage of
CPT-A by Me-TDGA can explain the potent hypoketonemic effects of this compound in fasted normal and diabetic rats. Higher acute doses are needed for both inhibition of muscle
CPT and lowering of
blood glucose.