Hepatic Glucagon Receptor Signaling Enhances Insulin-Stimulated Glucose Disposal in Rodents.

Autor:	Kim T; Comprehensive Diabetes Center and Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL., Holleman CL; Comprehensive Diabetes Center and Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL., Nason S; Comprehensive Diabetes Center and Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL., Arble DM; Department of Biological Sciences, Marquette University, Milwaukee, WI., Ottaway N; Metabolic Diseases Institute and Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Cincinnati, Cincinnati, OH., Chabenne J; Novo Nordisk Research Center, Indianapolis, IN., Loyd C; Comprehensive Diabetes Center and Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL., Kim JA; Comprehensive Diabetes Center and Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL., Sandoval D; Department of Surgery, University of Michigan, Ann Arbor, MI., Drucker DJ; Lunenfeld-Tanenbaum Research Institute, Mt. Sinai Hospital, Department of Medicine, University of Toronto, Toronto, Ontario, Canada., DiMarchi R; Novo Nordisk Research Center, Indianapolis, IN.; Department of Chemistry, Indiana University, Bloomington, IN., Perez-Tilve D; Metabolic Diseases Institute and Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Cincinnati, Cincinnati, OH kirkhabegger@uabmc.edu pereztdo@ucmail.uc.edu., Habegger KM; Comprehensive Diabetes Center and Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL kirkhabegger@uabmc.edu pereztdo@ucmail.uc.edu.
Jazyk:	angličtina
Zdroj:	Diabetes [Diabetes] 2018 Nov; Vol. 67 (11), pp. 2157-2166. Date of Electronic Publication: 2018 Aug 27.
DOI:	10.2337/db18-0068
Abstrakt:	Glucagon receptor (GCGR) agonists cause hyperglycemia but also weight loss. However, GCG-like peptide 1 receptor (GLP1R)/GCGR mixed agonists do not exhibit the diabetogenic effects often attributed to GCGR activity. Thus, we sought to investigate the effect of glucagon agonism on insulin action and glucose homeostasis. Acute GCGR agonism induced immediate hyperglycemia, followed by improved glucose tolerance and enhanced glucose-stimulated insulin secretion. Moreover, acute GCGR agonism improved insulin tolerance in a dose-dependent manner in both lean and obese mice. Improved insulin tolerance was independent of GLP1R, FGF21, and hepatic glycogenolysis. Moreover, we observed increased glucose infusion rate, disposal, uptake, and suppressed endogenous glucose production during euglycemic clamps. Mice treated with insulin and GCGR agonist had enhanced phosphorylation of hepatic AKT at Ser 473 ; this effect was reproduced in isolated mouse primary hepatocytes and resulted in increased AKT kinase activity. These data reveal that GCGR agonism enhances glucose tolerance, in part, by augmenting insulin action, with implications for the use of GCGR agonism in therapeutic strategies for diabetes. (© 2018 by the American Diabetes Association.)
Databáze:	MEDLINE
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