Coordinate regulation of gluconeogenesis by the glucocorticoids and glucagon: evidence for acute and chronic regulation by glucagon.

The coordinate regulation of gluconeogenesis by the glucocorticoids and glucagon in primary cultures of adult rat liver parenchymal cells has been studied. The results suggest that glucagon stimulation of glucose production from 3-carbon precursors is composed of at least two components which the glucocorticoids differentially affect. Glucagon treatment of hepatocytes results in an immediate increase in glucose production which is not blocked by cycloheximide and occurs in the absence of any detectable increase of phosphoenolpyruvate carboxykinase activity. This component appears to be regulated by a post-translational mechanism and involves redirection of carbon flow from glycolysis to gluconeogenesis. The second component is characterized by the need for long-term glucagon treatment. This increase in glucose production can be blocked by cycloheximide and is correlated with an increase in phosphoenolpyruvate carboxykinase activity. The reaction that is accelerated by long-term glucagon incubation is located prior to the triose-phosphate level since long-term incubation with glucagon fails to increase glucose production from dihydroxyacetone any more than does short-term incubation. It is suggested that phosphoenolpyruvate carboxykinase rather than amino acid transport is the key pacemaker reaction in the long-term incubation since the direction and magnitude of the response for glucocorticoid and glucagon stimulation of glucose production is the same whether alanine or lactate is used as the 3-carbon precursor. The glucocorticoids exhibit an additive effect on glucagon-stimulated glucose production for the first component whereas they amplify the second component.