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Mol Metab. 2016 May 30;5(8):731-736. doi: 10.1016/j.molmet.2016.05.014. eCollection 2016 Aug.

Glucagon receptor gene deletion in insulin knockout mice modestly reduces blood glucose and ketones but does not promote survival.

Author information

1
Department of Cellular and Physiological Sciences, University of British Columbia, 2350 Health Sciences Mall, Vancouver, British Columbia, V6T 1Z3, Canada. Electronic address: ursulahneumann@gmail.com.
2
Department of Cellular and Physiological Sciences, University of British Columbia, 2350 Health Sciences Mall, Vancouver, British Columbia, V6T 1Z3, Canada. Electronic address: h.jessica1@gmail.com.
3
Department of Cellular and Physiological Sciences, University of British Columbia, 2350 Health Sciences Mall, Vancouver, British Columbia, V6T 1Z3, Canada. Electronic address: mojibian@mail.ubc.ca.
4
Department of Biochemistry and Molecular Biology, University of British Columbia, 2350 Health Sciences Mall, Vancouver, British Columbia, V6T 1Z3, Canada. Electronic address: scott.covey@ubc.ca.
5
Department of Biochemistry, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY, 10461, USA. Electronic address: maureen.charron@einstein.yu.edu.
6
Department of Cellular and Physiological Sciences, University of British Columbia, 2350 Health Sciences Mall, Vancouver, British Columbia, V6T 1Z3, Canada; Department of Surgery, University of British Columbia, 2350 Health Sciences Mall, Vancouver, British Columbia, V6T 1Z3, Canada. Electronic address: tim.kieffer@ubc.ca.

Abstract

OBJECTIVE:

It has been thought that the depletion of insulin is responsible for the catabolic consequences of diabetes; however, evidence suggests that glucagon also plays a role in diabetes pathogenesis. Glucagon suppression by glucagon receptor (Gcgr) gene deletion, glucagon immunoneutralization, or Gcgr antagonist can reverse or prevent type 1 diabetes in rodents suggesting that dysregulated glucagon is also required for development of diabetic symptoms. However, the models used in these studies were rendered diabetic by chemical- or immune-mediated β-cell destruction, in which insulin depletion is incomplete. Therefore, it is unclear whether glucagon suppression could overcome the consequence of the complete lack of insulin.

METHODS:

To directly test this we characterized mice that lack the Gcgr and both insulin genes (GcgrKO/InsKO).

RESULTS:

In both P1 pups and mice that were kept alive to young adulthood using insulin therapy, blood glucose and plasma ketones were modestly normalized; however, mice survived for only up to 6 days, similar to GcgrHet/InsKO controls. In addition, Gcgr gene deletion was unable to normalize plasma leptin levels, triglycerides, fatty acids, or hepatic cholesterol accumulation compared to GcgrHet/InsKO controls.

CONCLUSION:

Therefore, the metabolic manifestations associated with a complete lack of insulin cannot be overcome by glucagon receptor gene inactivation.

KEYWORDS:

Gcgr, glucagon receptor; Glucagon; Glucose metabolism; Het, heterozygous; Ins1, insulin 1; Ins2, insulin 2; InsKO, insulin knockout; Insulin; KO, knockout; Lipid metabolism; Mice; P, post-natal day; STZ, streptozotocin; Type 1 diabetes; WT, wildtype

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