{"doi":"10.1172/jci183741","title":"β Cell Gαs signaling is critical for physiological and pharmacological enhancement of insulin secretion","abstract":"The incretin peptides glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptors coordinate β cell secretion that is proportional to nutrient intake. This effect permits consistent and restricted glucose excursions across a range of carbohydrate intake. The canonical signaling downstream of ligand-activated incretin receptors involves coupling to Gαs protein and generation of intracellular cAMP. However, recent reports have highlighted the importance of additional signaling nodes engaged by incretin receptors, including other G proteins and β-arrestin proteins. Here, the importance of Gαs signaling was tested in mice with conditional, postdevelopmental β cell deletion of Gnas (encoding Gαs) under physiological and pharmacological conditions. Deletion of Gαs/cAMP signaling induced immediate and profound hyperglycemia that responded minimally to incretin receptor agonists, a sulfonylurea, or bethanechol. While islet area and insulin content were not affected in Gnasβcell-/-, perifusion of isolated islets demonstrated impaired responses to glucose, incretins, acetylcholine, and IBMX In the absence of Gαs, incretin-stimulated insulin secretion was impaired but not absent, with some contribution from Gαq signaling. Collectively, these findings validate a central role for cAMP in mediating incretin signaling, but also demonstrate broad impairment of insulin secretion in the absence of Gαs that causes both fasting hyperglycemia and glucose intolerance.","journal":"Journal of Clinical Investigation","year":2025,"id":518496,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":7,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9438,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1386389,"name":"David Bouslov","orcid":null,"position":1,"is_corresponding":false},{"id":814621,"name":"Ashot Sargsyan","orcid":"0000-0003-1662-7548","position":2,"is_corresponding":false},{"id":493973,"name":"Michelle Chan","orcid":"0000-0001-6037-7051","position":3,"is_corresponding":false},{"id":245064,"name":"Alex Chen","orcid":"0000-0003-2620-5066","position":4,"is_corresponding":false},{"id":259348,"name":"Sarah M. 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Foster","orcid":"0000-0003-0212-2346","position":14,"is_corresponding":false},{"id":292018,"name":"Lee S. Weinstein","orcid":"0000-0002-1899-5152","position":15,"is_corresponding":false},{"id":743820,"name":"Mehboob A. Hussain","orcid":null,"position":16,"is_corresponding":false},{"id":258194,"name":"Matthew J. Merrins","orcid":"0000-0003-1599-9227","position":17,"is_corresponding":false},{"id":226892,"name":"Francis S. Willard","orcid":"0000-0002-4260-2451","position":18,"is_corresponding":false},{"id":7355,"name":"Mark O. Huising","orcid":"0000-0002-6594-2205","position":19,"is_corresponding":false},{"id":63186,"name":"Kyle W. Sloop","orcid":"0000-0001-6748-9929","position":20,"is_corresponding":false},{"id":236999,"name":"David J. Hodson","orcid":"0000-0002-8641-8568","position":21,"is_corresponding":false},{"id":226899,"name":"David A. D’Alessio","orcid":"0000-0003-4155-4870","position":22,"is_corresponding":false},{"id":226902,"name":"Jonathan E. 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