{"doi":"10.2337/db21-0800","title":"Mitofusins <i>Mfn1</i> and <i>Mfn2</i> Are Required to Preserve Glucose- but Not Incretin-Stimulated β-Cell Connectivity and Insulin Secretion","abstract":"Mitochondrial glucose metabolism is essential for stimulated insulin release from pancreatic β-cells. Whether mitofusin gene expression, and hence, mitochondrial network integrity, is important for glucose or incretin signaling has not previously been explored. Here, we generated mice with β-cell-selective, adult-restricted deletion knock-out (dKO) of the mitofusin genes Mfn1 and Mfn2 (βMfn1/2 dKO). βMfn1/2-dKO mice displayed elevated fed and fasted glycemia and a more than fivefold decrease in plasma insulin. Mitochondrial length, glucose-induced polarization, ATP synthesis, and cytosolic and mitochondrial Ca2+ increases were all reduced in dKO islets. In contrast, oral glucose tolerance was more modestly affected in βMfn1/2-dKO mice, and glucagon-like peptide 1 or glucose-dependent insulinotropic peptide receptor agonists largely corrected defective glucose-stimulated insulin secretion through enhanced EPAC-dependent signaling. Correspondingly, cAMP increases in the cytosol, as measured with an Epac-camps-based sensor, were exaggerated in dKO mice. Mitochondrial fusion and fission cycles are thus essential in the β-cell to maintain normal glucose, but not incretin, sensing. These findings broaden our understanding of the roles of mitofusins in β-cells, the potential contributions of altered mitochondrial dynamics to diabetes development, and the impact of incretins on this process.","journal":"Diabetes","year":2022,"id":247201,"datarank":0.782612298706411,"base_score":3.5553480614894135,"endowment":3.5553480614894135,"self_citation_contribution":0.5333022092234121,"citation_network_contribution":0.24931008948299896,"self_endowment_contribution":0.5333022092234121,"citer_contribution":0.24931008948299896,"corpus_percentile":null,"corpus_rank":null,"citation_count":34,"citer_count":20,"citers_with_citation_signal":15,"citers_with_endowment":15,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9586,"is_data_producer":true,"deposit_databanks":{"figshare":["10.2337/figshare.19607232"]},"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":563213,"name":"Charanya Muralidharan","orcid":"0000-0002-4909-7056","position":1,"is_corresponding":false},{"id":444272,"name":"Michelle Martínez","orcid":"0000-0002-6933-9905","position":2,"is_corresponding":false},{"id":572617,"name":"Pauline Chabosseau","orcid":"0000-0003-4048-0902","position":3,"is_corresponding":false},{"id":572619,"name":"Elina Akalestou","orcid":"0000-0001-9316-6680","position":4,"is_corresponding":false},{"id":260266,"name":"Alejandra Tomás","orcid":"0000-0002-2290-8453","position":5,"is_corresponding":false},{"id":572618,"name":"Fiona Yong Su Wern","orcid":"0000-0003-1649-4386","position":6,"is_corresponding":false},{"id":483201,"name":"Theodoros Stylianides","orcid":"0000-0002-9315-9787","position":7,"is_corresponding":false},{"id":572620,"name":"Asger Wretlind","orcid":"0000-0001-6083-5227","position":8,"is_corresponding":false},{"id":254762,"name":"Cristina Legido‐Quigley","orcid":"0000-0002-4018-214X","position":9,"is_corresponding":false},{"id":260262,"name":"Ben Jones","orcid":"0000-0003-0461-2584","position":10,"is_corresponding":false},{"id":350910,"name":"Livia López–Noriega","orcid":"0000-0002-2905-9490","position":11,"is_corresponding":false},{"id":86838,"name":"Yanwen Xu","orcid":"0000-0002-8308-9383","position":12,"is_corresponding":false},{"id":502802,"name":"Guoqiang Gu","orcid":"0000-0003-0772-9139","position":13,"is_corresponding":false},{"id":572621,"name":"Nour Alsabeeh","orcid":"0000-0001-7930-8013","position":14,"is_corresponding":false},{"id":572622,"name":"Céline Cruciani‐Guglielmacci","orcid":"0000-0002-2562-5360","position":15,"is_corresponding":false},{"id":427730,"name":"Chr̀istophe Magnan","orcid":"0000-0002-7044-2571","position":16,"is_corresponding":false},{"id":572623,"name":"Mark Ibberson","orcid":"0000-0003-3152-5670","position":17,"is_corresponding":false},{"id":350919,"name":"Isabelle Leclerc","orcid":"0000-0003-0044-7921","position":18,"is_corresponding":false},{"id":572624,"name":"Yusuf Ali","orcid":"0000-0002-0681-1125","position":19,"is_corresponding":false},{"id":428027,"name":"Scott A. 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