The Effects of Metformin Compared to the Effects of Phenformin on the Lactate Production and the Metabolism of Isolated Parenchymal Rat Liver Cell

Abstract

The metabolic effects of metformin were comapred to the effects of phenformin [drugs used in the treatment of diabetes mellitus] on isolated parenchymal liver cells from fed and fasted rats with ethanol or glycerol as the only substrate. Both biquanides caused a fall in the hepatic O2-consumption, in the cellular ATP-content and in the ATP/ADP-ratio. The lactate production and the concentration-ratios of lactate/pyruvate and of .beta.-hydroxybutyrate/acetoacetate rose. The production rate of ketone bodies remained unchanged. This response was the same whether the hepatocyte were from fed or fasted rats and whether glycerol or ethanol was substrate. Only quantitative differences in the response on the biguanides were detected. The effects of the biguanides were dose-dependent. Phenformin was 10 times more potent than metformin. The same holds for their therapeutic potency. Inhibition of the oxidative phosphorylation by both biguanides, resulting in reduction of the cytoplasmic and the mitochondrial redox potentials causing enhanced lactate production is indicated. Metformin evidently excerts the same effects as phenformin on the hepatic metabolism when the concentration ratio is about 10 to 1. Both biguanides give rise to elevated lactate production. This effect is highly increased when ethanol is present. [Lactic acidosis, a severe side-effect of both biguanides, has most often been associated with phenformin treatment.].