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.