title: Glucagon receptor gene deletion in insulin knockout mice modestly reduces blood glucose and ketones but does not promote survival.
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.
  
  
  CONCLUSIONS
  Therefore, the metabolic manifestations associated with a complete lack of insulin cannot be overcome by glucagon receptor gene inactivation.
authors.affiliation: 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.
authors.forename: Ursula H
authors.initials: UH
authors.lastname: Neumann
authors.affiliation: 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.
authors.forename: Jessica S S
authors.initials: JSS
authors.lastname: Ho
authors.affiliation: 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.
authors.forename: Majid
authors.initials: M
authors.lastname: Mojibian
authors.affiliation: 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.
authors.forename: Scott D
authors.initials: SD
authors.lastname: Covey
authors.affiliation: Department of Biochemistry, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY, 10461, USA. Electronic address: maureen.charron@einstein.yu.edu.
authors.forename: Maureen J
authors.initials: MJ
authors.lastname: Charron
authors.affiliation: 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.
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Kieffer
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