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

Ursula H. Neumann, Jessica S.S. Ho, Majid Mojibian, Scott D. Covey, Maureen J. Charron, Timothy J. Kieffer

Research output: Contribution to journalArticle

18 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)731-736
Number of pages6
JournalMolecular Metabolism
Volume5
Issue number8
DOIs
StatePublished - Aug 1 2016

Keywords

  • Glucagon
  • Glucose metabolism
  • Insulin
  • Lipid metabolism
  • Mice
  • Type 1 diabetes

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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