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

Diabetes
Teayoun KimKirk M Habegger

Abstract

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 Ser473; 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.

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Citations

Feb 6, 2019·JCI Insight·Megan E CapozziJonathan E Campbell
Aug 28, 2019·Applied Physiology, Nutrition, and Metabolism = Physiologie Appliquée, Nutrition Et Métabolisme·Scott A WillisJames A King
Jun 11, 2019·Diabetes·Brian FinanJonathan E Campbell
Jul 25, 2019·JCI Insight·Megan E CapozziJonathan E Campbell
Nov 27, 2020·Diabetes·Nadejda Bozadjieva KramerErnesto Bernal-Mizrachi
Nov 28, 2019·Journal of Medicinal Chemistry·Joseph ChabenneRichard D DiMarchi
Sep 24, 2020·Endocrinology·Kimberley ElJonathan E Campbell
Mar 10, 2020·Peptides·Mohan PatilGanesh V Sangle
Sep 29, 2020·Molecular Metabolism·Laurie L Baggio, Daniel J Drucker
Apr 20, 2021·Cellular Signalling·Siddharth SunilkumarMichael D Dennis
Jun 9, 2021·Nature Communications·Aijun QiaoGangjian Qin
Jul 2, 2021·Molecular Metabolism·Jessica D KeppleChad S Hunter

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