1648-P: Triagonism Targeting GCGR/GLP-1/GIP-1 Receptors Improves Insulin Sensitivity in Obese Mice

Abstract

Glucagon is best known as the primary counter-regulatory hormone against insulin action. Glucagon secretion is likewise elevated in Diabetes and thus it is often implicated as a diabetogenic hormone. However, emerging data from our group and others have uncovered that Glucagon receptor (GCGR) agonism improves insulin sensitivity in both lean and obese mice. Mechanistically, this improvement is associated with enhanced AKT phosphorylation and mTOR signaling in the liver. Novel, single-molecule, triagonists targeting GCG/GLP-1/GIP receptors (GGG) have recently been described to exert stronger anti-obesity effects than dual or single agonism in obese mice. Thus, we evaluated the effect of these agonists on insulin sensitivity using hyperinsulinemic euglycemic clamp. Diet-induced obese (DIO) mice were randomly assigned to 4d treatment (10 nmole/kg subcutaneous injection) of vehicle, GGG, GCGR agonism (IUB288), GLP-1R agonism (Semaglutide), or a long-acting GIP-1R agonist (GIP-FA 085). On the fourth day, mice were fasted for 5 hours, continuously infused with 1.2mU/kg/min insulin, and blood glucose levels clamped around 80-100 mg/dL. Under these conditions Semaglutide and GGG treatments stimulated the greatest glucose infusion rate (p<0.0001) and significantly improved insulin-mediated suppression of Endo Ra (p<0.01). Smaller, but significant, enhancement was also observed in the IUB288-treated mice. Moreover, [14C]-2GDp uptake into brown adipose tissue was improved in GGG, Semaglutide, and IUB288 treated mice compared to Vehicle treated mice. Importantly, these improvements in insulin sensitivity and glucose dynamics were body-weight independent. Therefore, GCGR and GLP-1R signaling combine in GGG triagonism to improve insulin sensitivity mainly via suppression of hepatic glucose production. Disclosure T.Kim: None. S.Nason: None. J.Antipenko: None. K.M.Habegger: Consultant; Glyscend Inc., Research Support; Eli Lilly and Company, Novo Nordisk, Glyscend Inc., Stock/Shareholder; Glyscend Inc. Funding Eli Lilly and Company