Methyl 2-Tetradecylglycidate, An Orally Effective Hypoglycemic Agent that Inhibits Long Chain Fatty Acid Oxidation Selectively

Abstract

The oral hypoglycemic agents methyl 2-tetradecylglycidate (McN-3716) and 2-tetradecylglycidic acid (McN-3802), synthesized in an effort to design a specific inhibitor of long-chain free fatty acid (FFA) oxidation, were tested for their effects on rat hemidiaphragm oxidation of various substrates to CO2. When added in vitro, both compounds were more potent (100-1000 times) in inhibiting long-chain FFA oxidation than either a-bromopalmitic or 4-pentenoic acid. When fasting normal or diabetic rats were pretreated with McN-3716, the ability of the diaphragms to oxidize palmitate-1-l4C to 14CO2 incubated in vitro was also diminished. Closely related nonhypoglycemic analogs of McN-3716 failed to inhibit oxidation. The failure of McN-3716 to inhibit the oxidation by diaphragm of short-chain fatty acids, palmitoyl camitine, glucose, glycolytic intermediates, β-hydroxybutyrate, succinate, or citrate when added in vitro or after treatment of rats suggests that glycolysis, the tricarboxylic acid cycle, and the intramitochondrial β-oxidation of fatty acids were not inhibited. While depressing FFA oxidation, McN-3716 increased the ability of hemidiaphragms from normal and diabetic rats to oxidize glucose-14C to 14CO2. This supports an intimate relationship between FFA oxidation and glucose utilization in hemidiaphragm. The locus of this stimulation appears to be the glycolytic pathway. The earliest onset for the impairment of diaphragm muscle FFA oxidation and the rise of plasma FFA after treatment of fasting rats with McN-3716 preceded the stimulation of hemidiaphragm glucose oxidation and the lowering of plasma glucose and tissue glycogen stores. These results suggest that the carbohydrate changes are secondary to the inhibition of FFA oxidation.