Integration of metabolic flux with hepatic glucagon signaling and gene expression profiles in the conscious dog

Abstract

Glucagon rapidly and profoundly simulates hepatic glucose production (HGP), but for reasons which are unclear, this effect normally wanes after a few hours, despite sustained plasma glucagon levels. This study characterized the time course and relevance (to metabolic flux) of glucagon-mediated molecular events in the livers of conscious dogs. Glucagon was either infused into the hepato-portal vein at a 6-fold basal rate in the presence of somatostatin and basal insulin, or it was maintained at a basal level in control studies. In one control group glucose remained at basal while in the other glucose was infused to match the hyperglycemia that occurred in the hyperglucagonemic group. Elevated glucagon caused a rapid (30 min) but only partially sustained increase in hepatic cAMP over 4h, a continued elevation in G6P, and activation and deactivation of glycogen phosphorylase and synthase activities, respectively. Net hepatic glycogenolysis and HGP increased rapidly, peaking at 30 min, then returned to baseline over the next three hours (although glucagon’s stimulatory effect on HGP was sustained relative to the hyperglycemic control group). Hepatic gluconeogenic flux did not increase due to lack of glucagon effect on substrate supply to the liver. Global gene expression profiling highlighted glucagon-regulated activation of genes involved in cellular respiration, metabolic processes, and signaling, and downregulation of genes involved in extracellular matrix assembly and development.

Ultra-stable insulin-glucagon fusion protein exploits an endogenous hepatic switch to mitigate hypoglycemic risk

“…Physiological attenuation of glucagon signaling in the liver under euglycemic or hyperglycemic conditions is homeostatic and has been proposed to reflect multiple molecular mechanisms, including decreasing intracellular cAMP concentrations, changes in gluconeogenic and glycogenolytic fluxes, hormone-dependent programs of gene expression related to mitochondrial metabolism, and allosteric effects of glucose-6-phosphate accumulation on the enzymatic activities of glycogen synthase, glycogen phosphorylase and glucokinase. The contribution of the latter allosteric mechanisms to the waning of glucagon signaling (despite sustained glucagon concentrations in the blood) was highlighted in a recent dog study (73). From a translational perspective, the maintenance of glucagon signaling by the A/A FP under hypoglycemic conditions and its waning under euglycemic conditions would in principle enhance therapeutic efficacy.…”