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

Citation
Kim, T., et al. “Hepatic Glucagon Receptor Signaling Enhances Insulin-Stimulated Glucose Disposal In Rodents.”. Diabetes, pp. 2157-2166.
Center University of Michigan University of Alabama at Birmingham
Multicenter
Multicenter
Author Teayoun Kim, Cassie L Holleman, Shelly Nason, Deanna M Arble, Nickki Ottaway, Joseph Chabenne, Christine Loyd, Jeong-A Kim, Darleen Sandoval, Daniel J Drucker, Richard DiMarchi, Diego Perez-Tilve, Kirk 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 Ser; 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.

Year of Publication
2018
Journal
Diabetes
Volume
67
Issue
11
Number of Pages
2157-2166
Date Published
12/2018
ISSN Number
1939-327X
DOI
10.2337/db18-0068
Alternate Journal
Diabetes
PMID
30150304
PMCID
PMC6198333
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