Effect of phenformin on gluconeogenesis in perfused rat liver. II. Dependence on the ATP-ADP ratio

Abstract

The effect of phenformin (phenethylbiguanide) on gluconeogenesis from lactate. pyruvate, oxalacetate, glycerol, dihydroxyacetone, fructose and mannose in perfused rat liver was studied. 1 mM phenformin inhibited gluconeogenesis from all these substrates. The time-course of the inhibition of gluconeogenesis from lactate showed a good correlation between lactate removal and glucose production, indicating that the effect of phenformin on gluconeogenesis was independent on the activity of the mixed function oxidation system, in perfused rat liver.

Our findings suggest an indirect inhibition of phenformin on gluconeogenesis likely related with its effect on oxidative phosphorylation. The fall in ATP/ADP ratio and the increase in total ketone bodies in liver following perfusion with phenformin seem to support this suggestion. The well-known effect of ethionine in decreasing hepatic ATP levels and gluconeogenesis in vivo prompted us to investigate its influence in perfused rat liver. The inhibition of the rate of glucose production in these conditions after ethionine administration was very similar to that found perfusing with phenformin.