The Role of Endogenous Lipid in Gluconeogenesis and Ketogenesis of Perfused Rat Liver

1 The oral antidiabetic glycodiazine (2‐benzene sulfonamido‐5‐β‐methoxyethoxy pyrimidine), an inhibitor of hepatic lipolysis, was used to investigate the metabolic role of liver lipid in gluco‐genesis in the perfused livers of fasted (24–30 h) rats. In a concentration of 10 mM, glycodiazine inhibited almost completely endogenous ketone body formation. 2 Perfusion with pyruvate as substrate, in the presence of glycodiazine, resulted in a higher rate of pyruvate oxidation and suppressed the rate of glucose synthesis in comparison to livers perfused with pyruvate alone. Thus, maximal rates of gluconeogenesis from pyruvate would seem to require an adequate supply and oxidation of fatty acids. 3 Oleate, even in the presence of glycodiazine, stimulates glucose synthesis from pyruvate. Uptake of and ketone body formation from oleate were also not affected by glycodiazine. These results allow the conclusion that glycodiazine specifically inhibits liver lipolysis. 4 Glucagon (57 nM), although having no significant effect on gluconeogenesis from pyruvate at this concentration, overcame the inhibitory effects of glycodiazine on glucose formation and suppressed the elevated pyruvate oxidation which results from the inhibition of endogenous lipid mobilization. 5 Glucagon, in the absence of added substrates, stimulated gluconeogenesis, urea production and ketogenesis. The increase in gluconeogenesis due to glucagon was not impaired by glycodiazine. This indicates that intermediates arising from fatty acid oxidation do not limit the rate of gluconeogenesis under these conditions.