{"doi":"10.1101/2020.04.22.055384","title":"Mitofusins <i>Mfn1</i> and <i>Mfn2</i> are required to preserve glucose-but not incretin- stimulated beta cell connectivity and insulin secretion","abstract":"Abstract Aims/hypothesis Mitochondrial glucose metabolism is essential for stimulated insulin release from pancreatic beta cells. Whether mitochondrial networks may be important for glucose or incretin sensing has yet to be determined. Methods Here, we generated mice with beta cell-selective, adult-restricted deletion of the mitofusin genes Mfn1 and Mfn2 (β Mfn1/2 dKO). Whole or dissociated pancreatic islets were used for live beta cell fluorescence imaging of cytosolic or mitochondrial Ca 2+ concentration and ATP production or GSIS in response to increasing glucose concentrations or GLP-1 receptor agonists. Serum and blood samples were collected to examine oral and i.p. glucose tolerance. Results β Mfn1/2 dKO mice displayed elevated fed and fasted glycaemia (p&lt;0.01, p&lt;0.001) and a &gt;five-fold decrease (p&lt;0.0001) in plasma insulin. Mitochondrial length, glucose-induced polarisation, ATP synthesis and cytosolic Ca 2+ increases were all reduced (p&lt;0.05,p&lt;0.01,p&lt;0.0001) in dKO islets, and beta cell Ca 2+ dynamics were suppressed in vivo (p&lt;0.001). In contrast, oral glucose tolerance was near normal in β Mfn1/2 dKO mice (p&lt;0.05, p&lt;0.01) and GLP-1 or GIP receptor agonists largely corrected defective GSIS from isolated islets through an EPAC-dependent signalling activation. Conclusions/interpretation Mitochondrial fusion and fission cycles are thus essential in the beta cell to maintain normal glucose, but not incretin, sensing. Defects in these cycles in some forms of diabetes might therefore provide opportunities for novel incretin-based or other therapies. Graphical abstract Impact of Mfn1/2 deletion on glucose and incretin stimulated-insulin secretion in beta cells. (A) In control animals, glucose is taken up by beta cells through GLUT2 and metabolised by mitochondria (elongated structure) through the citrate (TCA) cycle, leading to an increased mitochondrial proton motive force (hyperpolarised Δψm), accelerated ATP synthesis and O2 consumption rate (OCR). Consequently, the cytoplasmic ATP:ADP ratio rises, which causes closure of KATP channels, depolarisation of plasma membrane potential (ψm), opening of VDCCs and influx of cytosolic Ca 2+ . Elevated [Ca 2+ ]cyt triggers a number of ATP-dependent processes including insulin secretion and improved beta-beta cell communication through connexin 36 (Cx36). (B) Following Mfn1/2 deletion (β Mfn1/2 dKO), highly fragmented mitochondria were associated with reduced mitochondrial Ca 2+ ([Ca 2+ ]m) accumulation, leading to a less polarised Δψm, weaker OCR, lower mtDNA copy number and decreased ATP synthesis. This is expected to result in weaker ψm depolarisation, cytosolic Ca 2+ influx and beta-beta cell connectivity due to lower expression of Cx36. Despite observing a higher number of docked insulin granules on the plasma membrane, insulin secretion was highly suppressed in these animals. This was also associated with increased beta cell death and reduced beta cell mass. (C) In response to incretins, insulin secretion is potentiated through the activation of GLP1-R and cAMP signalling involving PKA- and EPAC2-dependent pathways. Elevated [Ca 2+ ]cyt triggers a number of ATP-dependent processes including insulin secretion and Ca2+ removal into the endoplasmic reticulum (ER).(D) In β Mfn1/2 dKO cells, activation of the GLP1-R was shown to be linked with a potentiation of the EPAC2 pathway that is PKA independent, along with an increased ER Ca 2+ uptake and improved beta-beta cell communication. How these ‘amplifying’ signals of glucose metabolism for insulin secretion are linked with fragmented mitochondria remains unknown. Red and bold arrows represent enhanced pathways; dashed arrows represent impaired pathways. This figure was produced using illustrations from Servier Medical Art, http://smart.servier.com/ Research in context What is already known about this subject? Mitochondrial ultrastructural variations and number are altered in beta cells of human T2D pa","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2020,"id":125767,"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":2,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9577,"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":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":260266,"name":"Alejandra Tomás","orcid":"0000-0002-2290-8453","position":4,"is_corresponding":false},{"id":572618,"name":"Fiona Yong Su Wern","orcid":"0000-0003-1649-4386","position":5,"is_corresponding":false},{"id":572619,"name":"Elina Akalestou","orcid":"0000-0001-9316-6680","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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