Control of Gluconeogenesis in Liver

Abstract

Glucagon, epinephrine, norepinephrine, and cyclic AMP stimulated gluconeogenesis from lactate in perfused livers from fasted and fed rats. The stimulation was most marked when these agents were added to livers from fasted rats in which gluconeogenesis had become partially inactive during a preliminary perfusion without substrate. It is suggested that inactivation is consequent to the degradation of endogenous glucagon and catecholamines. Inactivation could be prevented by high levels of lactate. On a molar basis, glucagon was about 100-fold more effective in stimulating gluconeogenesis than the catecholamines, and 100,000 times more effective than exogenous cyclic AMP. Gluconeogenesis was as sensitive as glycogenolysis to stimulation by any of the agents and was as rapidly activated. It is proposed that cyclic AMP mediates the action of glucagon and catecholamines on gluconeogenesis. Glucagon stimulated gluconeogenesis from lactate and pyruvate but not from dihydroxyacetone or fructose, suggesting a point of action in the gluconeogenic pathway between pyruvate and triose phosphate. The maximum rate of gluconeogenesis from oxalacetate was about the same as that from pyruvate. Because lactate production from oxalacetate was substantial and the same tissue level of malate was found with pyruvate or oxalacetate, it appeared that oxalacetate was not metabolized as such by the liver but only after breakdown to pyruvate. Ethanol stimulated gluconeogenesis and lactate formation from pyruvate. The effects of ethanol and glucagon were additive indicating that glucagon does not act by increasing NADH supply. The gluconeogenic effect of glucagon was observed with concentrations of lactate in the physiological range. It is proposed that glucagon plays a physiological role in the maintenance of the blood glucose through control of gluconeogenesis as well as glycogenolysis in the liver. Sympathetic nervous activity, leading to the intrahepatic release of catecholamine, may also play an important role in increasing glucose output and lactate uptake by the liver, particularly during exercise or hypoglycemia.