Elsevier

Molecular Metabolism

Volume 5, Issue 8, August 2016, Pages 731-736
Molecular Metabolism

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

https://doi.org/10.1016/j.molmet.2016.05.014Get rights and content
Under a Creative Commons license
open access

Highlights

  • Gcgr gene deletion does not promote survival of InsKO mice.

  • Gcgr gene deletion modestly reduces blood glucose and ketones in InsKO mice.

  • Gcgr gene deletion does not normalize perturbed lipid metabolism in InsKO mice.

  • Gcgr gene deletion does not prevent diabetes in the complete absence of insulin.

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.

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Keywords

Mice
Type 1 diabetes
Insulin
Glucagon
Glucose metabolism
Lipid metabolism

Abbreviations

Gcgr
glucagon receptor
Het
heterozygous
Ins1
insulin 1
Ins2
insulin 2
InsKO
insulin knockout
KO
knockout
P
post-natal day
STZ
streptozotocin
WT
wildtype

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