Action of the oral hypoglycemic agent 2-tetradecylglycidic acid on hepatic fatty acid oxidation and gluconeogenesis.

Using isolated hepatocytes from fasted rats, the oral hypoglycemic agents, Z-tetradecylglycidic acid (McN3802) and its methyl ester (McN-3716) inhibited (concentrations down to 5 x lo-’ M) the oxidation of palmitate to CO2 and ketones but not the oxidation of octauoate or palmitoylcarnitine. The antiketogenic effect which occurs at concentrations as low as lo-’ M was accompanied by a lowered P-hydroxybutyrate/acetoacetate ratio and a significant drop in long chain acylcarnitine levels with unchanged levels of total or free acid-soluble carnitine. The fall of long chain acylcarnitines taken together with an observed increase of long chain fatty acyl coenzyme A derivatives suggests that the carnitine acyl transferase I is the site of action of McN-3802 (or its metabolites). Furthermore, it is unlikely that long chain fatty acyl-CoA synthetase is the site of action since McN-3802 inhibited the microsomal synthetase only at high concentrations and since at these concentrations nonhypoglycemic analogs of McN-3802 were also inhibitory. McN-3802 and McN3716 were found to be converted to acyl-CoA thioesters by this enzyme. McN-3802 produced in hepatocytes from normal and diabetic rats a concentration-dependent inhibition of gluconeogenesis from pyruvate and a lowered lactate/ pyruvate ratio which paralleled its inhibitory effect on ketogenesis. Closely related nonhypoglycemic analogs failed to produce these effects even though these analogs were converted to CoA esters by acyl-CoA synthetase. The inhibition of gluconeogenesis when pyruvate was added to liver cells could not be reversed by addition of CoA + carnitine, or by elevating the lactate/ pyruvate and &hydroxybutyrate/acetoacetate oxidation-reduction couples by addition, respectively, of ethanol and fi-hydroxybutyrate. That the inhibition of gluconeogenesis was secondary to inhibition of long chain fatty acid oxidation seems certain since this effect was almost completely reversed upon addition of 1 to 2 mu octanoate. The potential sites where McN-3802 may be inhibiting gluconeogenesis are discussed. McN3802 produced much less of an effect on total production of glucose using hepatocytes from fed rats.