Historically, glucagon is proposed to be a key factor in the development of diabetes. However, we demonstrated that while chronic glucagon receptor (GCGR) agonism induces hyperglycemia and glucose intolerance, it also improves insulin secretion and insulin action. These paradoxical actions suggest the mechanisms regulating GCGR-mediated glucose metabolism have yet to be fully elucidated. Glucose metabolism and glucagon-stimulated glucose production are both regulated in a circadian manner. Thus, we hypothesized that chronic GCGR signaling regulates glycemia in a time-of-day dependent manner. We treated lean mice for 4d with vehicle or the GCGR agonist IUB288 administered either during the early (ZT 3) or late (ZT9) light period. Ad libitum glycemia was assessed every 4h over a 24h period after the last injection. Independent of the time injected, IUB288-treated mice displayed improved glycemia 4h after the last injection and hyperglycemia after 12h, compared to vehicle-treated controls. This suggests that chronic GCGR agonism is not exclusively hyperglycemic and variations in GCGR-stimulated glycemia are dependent on the time after treatment, rather than the time of day. Interestingly, ad libitum insulin levels were no different between IUB288 and vehicle-treated mice, suggesting differences in insulin sensitivity. Surprisingly, 4d IUB288 treatment in diet-induced obese (DIO) mice reduced ad libitum glycemia for a greater duration than chow IUB288-treated mice. We used hyperinsulinemic-euglycemic clamps to further dissect the mechanisms of these benefits. In DIO mice, IUB288 treatment increased glucose infusion rate, suppression of endogenous glucose production, and phosphorylation of AKT (S473 and T308) . Together, these data increase our understanding of GCGR pharmacology and its therapeutic role in diabetes and obesity treatment.
S.Nason: None. T.Kim: None. J.P.Antipenko: None. B.Finan: Employee; Novo Nordisk. R.Dimarchi: None. K.M.Habegger: Consultant; Glyscend Inc., Research Support; Eli Lilly and Company, Novo Nordisk, Stock/Shareholder; Glyscend Inc.