{"doi":"10.1101/2020.11.03.366179","title":"RESTORING CONNEXIN-36 FUNCTION IN DIABETOGENIC ENVIRONMENTS PRECLUDES MOUSE AND HUMAN ISLET DYSFUNCTION","abstract":"ABSTRACT The secretion of insulin from β-cells in the islet of Langerhans is governed by a series of metabolic and electrical events, which can fail during the progression of type2 diabetes (T2D). β-cells are electrically coupled via Cx36 gap junction channels, which coordinates the pulsatile dynamics of [Ca 2+ ] and insulin release across the islet. Factors such as pro-inflammatory cytokines and free fatty acids disrupt gap junction coupling under invitro conditions. Here we test whether gap junction coupling and coordinated [Ca 2+ ] dynamics are disrupted in T2D, and whether recovery of gap junction coupling can recover islet function. We examine islets from donors with T2D, from db/db mice, and islets treated with proinflammatory cytokines (TNF-α, IL-1β, IFN-ɣ) or free fatty acids (palmitate). We modulate gap junction coupling using Cx36 over-expression or pharmacological activation via modafinil. We also develop a peptide mimetic (S293) of the c-terminal regulatory site of Cx36 designed to compete against its phosphorylation. Cx36 gap junction permeability and [Ca 2+ ] dynamics were disrupted in islets from both human donors with T2D and db/db mice, and in islets treated with proinflammatory cytokines or palmitate. Cx36 over-expression, modafinil treatment and S293 peptide all enhanced Cx36 gap junction coupling and protected against declines in coordinated [Ca 2+ ] dynamics. Cx36 over-expression and S293 peptide also reduced apoptosis induced by proinflammatory cytokines. Critically S293 peptide rescued gap junction coupling and [Ca 2+ ] dynamics in islets from both db/db mice and a sub-set of T2D donors. Thus, recovering or enhancing Cx36 gap junction coupling can improve islet function in diabetes. KEY POINTS - Cx36 gap junction permeability and associated coordination of [Ca2+] dynamics is diminished in human type 2 diabetes (T2D) and mouse models of T2D. - Enhancing Cx36 gap junction permeability protects against disruptions to the coordination of [Ca2+] dynamics. - A novel peptide mimetic of the Cx36 c-terminal regulatory region protects against declines in Cx36 gap junction permeability. - Pharmacological elevation in Cx36 or Cx36 peptide mimetic recovers [Ca2+] dynamics and GSIS in human T2D and mouse models of T2D.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2020,"id":123096,"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":4,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9495,"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":565711,"name":"Matthew J. Westacott","orcid":"0000-0001-6049-2420","position":1,"is_corresponding":false},{"id":566495,"name":"J.M. Miranda","orcid":null,"position":2,"is_corresponding":false},{"id":565712,"name":"Nikki L. Farnsworth","orcid":"0000-0002-9834-9168","position":3,"is_corresponding":false},{"id":542244,"name":"Vira Kravets","orcid":"0000-0002-5147-309X","position":4,"is_corresponding":false},{"id":553748,"name":"Wolfgang E. Schleicher","orcid":"0000-0001-6054-3435","position":5,"is_corresponding":false},{"id":553747,"name":"JaeAnn M. Dwulet","orcid":"0000-0003-2519-5193","position":6,"is_corresponding":false},{"id":566496,"name":"Claire H Levitt","orcid":null,"position":7,"is_corresponding":false},{"id":566497,"name":"Audrey Heintz","orcid":null,"position":8,"is_corresponding":false},{"id":566498,"name":"Nurin W.F. Ludin","orcid":null,"position":9,"is_corresponding":false},{"id":7356,"name":"Richard K.P. Benninger","orcid":"0000-0002-5063-6096","position":10,"is_corresponding":false},{"id":566494,"name":"Joshua R. St. Clair","orcid":null,"position":0,"is_corresponding":true}],"reference_count":70,"raw_metadata":null,"created_at":"2026-07-18T23:14:59.547352Z","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":[]}