1842-P: GLP-1 Receptor Agonists Induce Lasting Cyclic-AMP Generation and Insulin Secretion in Beta Cells

Introduction and Objective: Incretin-based drugs, derived from glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), are widely used to treat type 2 diabetes (T2D). However, GLP-1, not GIP, based therapies remain effective in treating T2D, suggesting they can induce different responses despite acting through the same Gαs signaling pathway. This study investigated the mechanisms underlying these differences, with a focus on cAMP, the crucial second messenger involved in incretin-induced potentiation of insulin secretion. Methods: Islets from mice expressing a genetically encoded cAMP sensor in beta cells were perfused with GIP and GLP-1 receptor (GLP-1R) agonists (GLP-1, exendin-4, and semaglutide), and kinetics of cAMP levels and glucose-stimulated insulin secretion were assessed. Results: Acute GIP treatment induced a transient cAMP response that dissipated with peptide washout. In contrast, GLP-1R agonists elicited a sustained cAMP response that persisted long after the peptide was washed out. The sustained cAMP response was most pronounced in response to the GLP-1R agonists exendin-4 and semaglutide. We further assessed that prolonged cAMP signaling induced by GLP-1R agonists was matched with prolonged PKA activity and glucose-stimulated insulin secretion. Furthermore, exendin(9-39) treatment failed to return the prolonged cAMP response back down to baseline, suggesting that a subset of internalized GLP-1Rs that is inaccessible to exendin(9-39) continue to generate cAMP. Conclusion: These data show that beta cells respond with distinct kinetics of cAMP generation in response to different incretins, with GLP-1R agonists capable of triggering lasting cAMP generation and insulin secretion. These findings reveal the mechanism(s) that underlie the effectiveness of incretin-based drugs. Disclosure M. Chan: None. H. Lee: None. M.H. Rehman: None. R. Hart: None. M.R. Flisher: None. J. Campbell: Research Support; Eli Lilly and Company, Novo Nordisk. Advisory Panel; Structure Therapeutics, Inc. Research Support; Structure Therapeutics, Inc. Consultant; Arrowhead Pharmaceuticals, Inc. Advisory Panel; Boehringer-Ingelheim, Neurocrine, Roche Pharmaceuticals, Prostasis. Research Support; Merck & Co., Inc. M.O. Huising: Research Support; Thermo Fisher. Funding American Diabetes Association (7-22-IBSPM-06); National Institutes of Health (F31DK136313)