1559-P: Glucagon Receptor–Mediated Improvements in Glycemia Are Dependent on Agonist Pharmacodynamics

Abstract

Glucagon is considered the main glucose counter-regulatory hormone to insulin. Although, chronic glucagon receptor (GCGR) agonism induces hyperglycemia and glucose intolerance, it also improves insulin secretion and action. Surprisingly, we found chronic treatment with the selective, long-acting GCGR agonist, IUB288, improves ad libitum glycemia and glucose tolerance 4h after treatment. These glycemic improvements were associated with enhanced AKT phosphorylation, despite control-like insulin levels. We next tested if these results could be replicated with a short acting GCGR agonist. IUB94 displays improved aqueous solubility but maintains the short half-life and potency of native glucagon. 4h glucose excursion was monitored in lean mice after injection of IUB288, IUB94, or vehicle. We observed a transient rise in blood glucose (BG) 15min after either IUB288 or IUB94 compared to vehicle. Intriguingly, IUB288-treated mice exhibited improved BG from 120-240min, while BG in IUB94-treated mice was similar to vehicle controls. These data suggest that acute BG regulation is agonist-dependent yet, it remains unclear if pharmacodynamics or some inherent difference in potency is influencing the 4h BG. We next treated lean mice for 4d with vehicle or IUB288, measuring ad libitum glycemia over the final 24h period. IUB288-treated mice displayed improved glycemia 4h after the last injection and hyperglycemia after 12h, compared to vehicle-treated controls, suggesting chronic GCGR agonism is not exclusively hyperglycemic. 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. These data provide insight into the potential therapeutic use of sustained-acting GCGR agonists against diabetes and obesity. Disclosure S.Nason: None. T.Kim: None. J.Antipenko: None. B.Yang: None. R.Dimarchi: None. K.M.Habegger: Consultant; Glyscend Inc., Research Support; Eli Lilly and Company, Novo Nordisk, Glyscend Inc., Stock/Shareholder; Glyscend Inc. Funding National Institutes of Health