Chronic hyperglucagonemia in rats: Effects on insulin, substrates, and hepatic enzymes of intermediary metabolism

Abstract

The effects of chronic exogenous hyperglucagonemia were evaluated in 120–140 g rats given 0.8 or 0.4 mg glucagon per day for seven days by constant infusion through the use of subcutaneously implanted, osmotically driven minipumps. Untreated animals, with and without dietary restriction, served as controls. Glucagon infusion resulted in plasma glucagon concentrations ranging from 1000 to more than 4000 pg/mL. The experimental animals had decreased food intake resulting in poor weight gain. Plasma insulin, glucose, and β-hydroxybutyrate concentrations were unchanged in the experimental animals. Glucagon administration was associated with generalized hypoaminoacidemia (75% reduction from the control mean total amino acid concentration). Hepatic glycogen content decreased to the level seen in the dietary-restricted animals, which were matched for weight gain. In vitro activities of total hepatic glycogen phosphorylase, pyruvate kinase (measured at saturating PEP concentrations), acetyl-CoA carboxylase and fatty acid synthase were decreased in the experimental animals. Total glycogen synthase and PEP carboxykinase activities increased. These results are not consistent with previously described effects of glucagon mediated through enzyme phosphorylation and are interpreted as suggesting changes in total enzyme content. From these studies we conclude that chronic hyperglucagonemia of 1 week's duration in young rats has persistent metabolic effects. It does not, however, result in persistent changes in plasma glucose or β-hydroxybutyrate concentrations when insulin secretion is preserved. The observed hypoaminoacidemia is analogous to that seen in the glucagonoma syndrome. Long-term effects of glucagon on in vitro hepatic enzyme activities are possibly due to changes in enzyme protein content and not protein phosphorylation.