Control of Gluconeogenesis in Liver

Abstract

The isolated perfused rat liver preparation was employed to study the effects of glucagon, fasting, and diabetes on the flow of exogenous lactate or endogenous substrates into the pathways of gluconeogenesis, glycogenesis, ketogenesis, lipogenesis, and the Krebs cycle in the liver. Measurements were made of the utilization of substrates and oxygen, the formation of glucose, glycogen, ketone bodies, and urea, and the incorporation of isotope from [14C]lactate into glucose, glycogen, protein, CO2, ketone bodies, cholesterol, and other lipids. Glucose synthesis from lactate was enhanced in livers treated with glucagon or from fasted or diabetic rats. The increased gluconeogenesis was associated with increased lactate utilization and was not the result of inhibition of alternative pathways of lactate metabolism. The disposition of isotope between glucose and glycogen indicated impaired glycogen synthesis in these livers. The changes in glucose and glycogen synthesis in livers from diabetic rats were reversed by insulin treatment in vivo. CO2 was the major product of lactate metabolism in livers from fed rats, whereas glucose was the major product in livers treated with glucagon or from fasted or diabetic rats. Ketone bodies, fatty acids, and cholesterol were minor products of lactate metabolism in all situations examined. Glucagon, fasting, and diabetes had negligible effects on the oxidation of lactate to CO2, but inhibited the synthesis of fatty acid and cholesterol from this substrate. Fasting and diabetes also reduced lactate ketogenesis. Urea production was increased about 2-fold by glucagon and diabetes and by about 30% by fasting. It was minimally changed by lactate. The alterations in ureogenesis indicated enhancement of gluconeogenesis from endogenous protein by glucagon, fasting, and diabetes. Ketone body production was increased about 10-fold in livers from fasted or diabetic rats perfused without lactate. The increase was apparently due to increased lipid utilization and decreased Krebs cycle activity. Glucagon produced a 2-fold increase in ketone bodies and it is suggested that these were mainly derived from protein. Lactate markedly suppressed ketogenesis and increased respiration in livers from fasted or diabetic rats. Both effects were attributable to an increase in the Krebs cycle. Lactate also replaced lipid as the major fuel oxidized by livers from fed rats and it is suggested that it acted by diverting endogenous fatty acid from oxidation to esterification. The metabolic changes observed in the present study are discussed from the viewpoints of underlying mechanisms and physiological implications. It is concluded that changes in the disposition of substrate (pyruvate or fatty acid) within the liver may be as important as changes in substrate supply in the alterations in gluconeogenesis and ketogenesis during fasting and diabetes.