Glucagon receptor agonism and treatment withdrawal effect on liver transcriptomes of diet-induced obese mice

Glucagon is historically viewed as the main counter-regulatory hormone to insulin in glucose homeostasis. Although chronic glucagon receptor (GCGR) agonism induces hyperglycemia and glucose intolerance, acutely it also improves insulin secretion and action. Surprisingly, we found chronic treatment with the selective, long-acting GCGR agonist, IUB288, improved glycemia 4h after the last injection and hyperglycemia after 12h, compared to vehicle-treated controls, suggesting chronic GCGR agonism is not exclusively hyperglycemic. These periods of glycemic improvement were associated with enhanced AKT phosphorylation, despite control-like insulin levels, and could not be replicated by short acting GCGR agonists. Surprisingly, 4d IUB288 treatment in diet-induced obese (DIO) mice reduced ad libitum glycemia for a longer duration than observed in chow IUB288-treated mice. IUB288 treatment also increased glucose infusion rate, suppression of endogenous glucose production, and AKT phosphorylation during hyperinsulinemic-euglycemic clamps.