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

Authors

Teayoun Kim, University of Alabama - Birmingham
Cassie L. Holleman, University of Alabama - Birmingham
Shelly Nason, University of Alabama - Birmingham
Deanna M. Arble, Marquette UniversityFollow
Nickki Ottaway, University of Cincinnati
Joseph Chabenne, Novo Nordisk Research Center
Christine Loyd, University of Alabama - Birmingham
Jeong-a Kim, University of Alabama - Birmingham
Darleen A. Sandoval, University of Michigan - Ann ArborFollow
Daniel J. Drucker, University of Toronto
Richard DiMarchi, Novo Nordisk Research Center
Diego Perez-Tilve, University of Cincinnati
Kirk M. Habegger, University of Alabama - Birmingham

Document Type

Article

Language

eng

Publication Date

8-27-2018

Publisher

American Diabetes Association

Source Publication

Diabetes

Source ISSN

0012-1797

Abstract

Glucagon receptor (GCGR) agonists cause hyperglycemia but also weight loss. However, 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.

Comments

Accepted version. Diabetes, Vol. 67, No. 8, (August 27, 2018). DOI. © 2018 American Diabetes Association. Used with permission.

Recommended Citation

Kim, Teayoun; Holleman, Cassie L.; Nason, Shelly; Arble, Deanna M.; Ottaway, Nickki; Chabenne, Joseph; Loyd, Christine; Kim, Jeong-a; Sandoval, Darleen A.; Drucker, Daniel J.; DiMarchi, Richard; Perez-Tilve, Diego; and Habegger, Kirk M., "Hepatic Glucagon-Receptor Signaling Enhances Insulin-Stimulated Glucose Disposal in Rodents" (2018). Biological Sciences Faculty Research and Publications. 658.
https://epublications.marquette.edu/bio_fac/658