2564-P: Understanding the Implications of Incretin Receptor Desensitization

Introduction and Objective: Pairing GLP-1R agonism with either GIPR agonism or antagonism produces similar weight loss. One hypothesis to reconcile this paradox is that chronic GIPR agonism may induce a level of receptor desensitization and loss of function that mimics antagonism. While functional antagonism of the GIPR would provide a harmonious explanation to support both agonism and antagonism of the GIPR, it raises several questions: (1) can desensitization of the GIPR reach a level that can be classified as functional antagonism? (2) is this mechanism shared by the GLP-1R? (3) what is the underlying molecular mechanism? Addressing these will help understand how best to leverage either incretin receptor as a therapeutic target. We hypothesized that chronic agonism of either incretin receptor will lead to desensitization, but not to a level that can be classified as functional antagonism. Methods: We assessed incretin receptor activity in primary beta-cells, a physiologically relevant model for both GIPR and GLP-1R. Obese mice were treated with semaglutide (30 nmol/kg) for 5 days. GLP1R function in beta-cells was determined by glucose tolerance in response to acute treatment with exendin-4 (Ex4, 3 nmol/kg), before and after semaglutide treatment. A similar approach will be used with long-acting GIPR agonists and biased agonists for the incretin receptors. Results: Semaglutide treatment caused 12% weight loss over 5 days, that rebounded immediately after stopping treatment. Prior to semaglutide treatment, Ex4 lowered glycemia by 33% relative to PBS controls. Following chronic semaglutide treatment, Ex4 lowered glycemia by 34% in the control group, but had no effect in the semaglutide treated group. The desensitization induced by semaglutide treatment was no longer present 14 days after stopping treatment. Conclusion: This blunted effect of Ex4 following chronic semaglutide treatment indicates significant desensitization of the GLP1R in response to chronic semaglutide treatment. Assessing whether this achieves functional antagonism requires additional in vivo and ex vivo work. Disclosure R. Basu: None. J. Campbell: Research Support; Current; Eli Lilly and Company. Research Support; Ended; Novo Nordisk. Research Support; Current; Merck & Co., Inc., Structure Therapeutics, Protagonist Therapeutics, Prostasis. Consultant; Current; Roche Pharmaceuticals, Neurocrine Biosciences, Inc., Arrowhead Pharmaceuticals, Boehringer Ingelheim International GmbH. D.M. D'Alessio: Other - Clinical Trials; Current; Eli Lilly and Company. Consultant; Current; Sun Pharmaceutical Industries Ltd., Vertex Pharmaceuticals Incorporated.