{Reference Type}: Journal Article
{Title}: Glucagon receptor gene deletion in insulin knockout mice modestly reduces blood glucose and ketones but does not promote survival.
{Author}: Neumann UH;Ho JSS;Mojibian M;Covey SD;Charron MJ;Kieffer TJ;
{Journal}: Mol Metab
{Volume}: 5
{Issue}: 8
{Year}: Aug 2016
{Factor}: 8.568
{DOI}: 10.1016/j.molmet.2016.05.014
{Abstract}: <B>OBJECTIVE: </B>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.<BR><B>METHODS: </B>To directly test this we characterized mice that lack the Gcgr and both insulin genes (GcgrKO/InsKO).<BR><B>RESULTS: </B>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.<BR><B>CONCLUSIONS: </B>Therefore, the metabolic manifestations associated with a complete lack of insulin cannot be overcome by glucagon receptor gene inactivation.