{"doi":"10.1101/2020.07.10.197863","title":"EP3 signaling is decoupled from regulation of glucose-stimulated insulin secretion in β-cells compensating for obesity and insulin resistance","abstract":"ABSTRACT Of the β-cell signaling pathways altered by non-diabetic obesity and insulin resistance, some are adaptive while others actively contribute to β-cell failure and demise. Cytoplasmic calcium (Ca 2+ ) and cyclic AMP (cAMP), which control the timing and amplitude of insulin secretion, are two important signaling intermediates that can be controlled by stimulatory and inhibitory G protein-coupled receptors. Previous work has shown the importance of the cAMP-inhibitory EP3 receptor in the beta-cell dysfunction of type 2 diabetes. To examine alterations in β-cell cAMP during diabetes progression we utilized a β-cell specific cAMP biosensor in tandem with islet Ca 2+ recordings and insulin secretion assays. Three groups of C57BL/6J mice were used as a model of the progression from metabolic health to type 2 diabetes: wildtype, normoglycemic Leptin Ob , and hyperglycemic Leptin Ob . Here, we report robust increases in β-cell cAMP and insulin secretion responses in normoglycemic Leptin ob mice as compared to wild-type: an effect that was lost in islets from hyperglycemic Leptin ob mice, despite elevated Ca 2+ duty cycle. Yet, the correlation of EP3 expression and activity to reduce cAMP levels and Ca 2+ duty cycle with reduced insulin secretion only held true in hyperglycemic Leptin Ob mice. Our results suggest alterations in beta-cell EP3 signaling may be both adaptive and maladaptive and define β-cell EP3 signaling as much more nuanced than previously understood.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2020,"id":123862,"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":3,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9452,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":568068,"name":"Jeffrey M. Harrington","orcid":null,"position":1,"is_corresponding":false},{"id":568069,"name":"Grant M. Kelly","orcid":null,"position":2,"is_corresponding":false},{"id":260984,"name":"Sophia M. Sdao","orcid":null,"position":3,"is_corresponding":false},{"id":258194,"name":"Matthew J. Merrins","orcid":"0000-0003-1599-9227","position":4,"is_corresponding":false},{"id":380536,"name":"Michelle E. Kimple","orcid":"0000-0003-0869-9699","position":5,"is_corresponding":false},{"id":506837,"name":"Michael D. Schaid","orcid":"0000-0002-3633-5748","position":0,"is_corresponding":true}],"reference_count":51,"raw_metadata":null,"created_at":"2026-07-18T23:15:03.403566Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}