Integration of metabolic flux with hepatic glucagon signaling and gene expression profiles in the conscious dog.
Katie C Coate, Christopher J Ramnanan, Marta Smith, Jason J Winnick, Guillaume Kraft, Jose Irimia-Dominguez, Ben Farmer, E Patrick Donahue, Peter J Roach, Alan D Cherrington, Dale S Edgerton
Author Information
Katie C Coate: Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, United States. ORCID
Christopher J Ramnanan: Department of Innovation in Medical Education, University of Ottawa Faculty of Medicine, Ottawa, Ontario, Canada.
Marta Smith: Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee, United States.
Jason J Winnick: Division of Endocrinology, Diabetes and Metabolism, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio, United States.
Guillaume Kraft: Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee, United States. ORCID
Jose Irimia-Dominguez: Department of Molecular and Cellular Endocrinology, Beckman Research Institute, Duarte, California, United States.
Ben Farmer: Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee, United States.
E Patrick Donahue: Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, United States.
Peter J Roach: Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana, United States.
Alan D Cherrington: Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee, United States. ORCID
Dale S Edgerton: Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee, United States. ORCID
Glucagon rapidly and profoundly stimulates hepatic glucose production (HGP), but for reasons that are unclear, this effect normally wanes after a few hours, despite sustained plasma glucagon levels. This study characterized the time course of glucagon-mediated molecular events and their relevance to metabolic flux in the livers of conscious dogs. Glucagon was either infused into the hepato-portal vein at a sixfold 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, whereas in the other, glucose was infused to match the hyperglycemia that occurred in the hyperglucagonemic group. Elevated glucagon caused a rapid (30 min) and largely sustained increase in hepatic cAMP over 4 h, a continued elevation in glucose-6-phosphate (G6P), and activation and deactivation of glycogen phosphorylase and synthase activities, respectively. Net hepatic glycogenolysis increased rapidly, peaking at 15 min due to activation of the cAMP/PKA pathway, then slowly returned to baseline over the next 3 h in line with allosteric inhibition by glucose and G6P. Glucagon's stimulatory effect on HGP was sustained relative to the hyperglycemic control group due to continued PKA activation. Hepatic gluconeogenic flux did not increase due to the lack of glucagon's 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, as well as downregulation of genes involved in extracellular matrix assembly and development. Glucagon rapidly stimulates hepatic glucose production, but these effects are transient. This study links the molecular and metabolic flux changes that occur in the liver over time in response to a rise in glucagon, demonstrating the strength of the dog as a translational model to couple findings in small animals and humans. In addition, this study clarifies why the rapid effects of glucagon on liver glycogen metabolism are not sustained.
