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Mitofusins Mfn1 and Mfn2 are Required to Preserve Glucose- But Not Incretin-Stimulated Beta Cell Connectivity and Insulin Secretion

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posted on 26.04.2022, 21:28 authored by Eleni Georgiadou, Charanya Muralidharan, Michelle Martinez, Pauline Chabosseau, Elina Akalestou, Alejandra Tomas, Fiona Yong Su Wern, Theodoros Stylianides, Asger Wretlind, Cristina Legido-Quigley, Ben Jones, Livia Lopez Noriega, Yanwen Xu, Guoqiang Gu, Nour Alsabeeh, Céline Cruciani-Guglielmacci, Christophe Magnan, Mark Ibberson, Isabelle Leclerc, Yusuf Ali, Scott A. Soleimanpour, Amelia K. Linnemann, Tristan A. Rodriguez, Guy A. Rutter

Mitochondrial glucose metabolism is essential for stimulated insulin release from pancreatic beta cells.  Whether mitofusin gene expression, and hence mitochondrial network integrity, is important for glucose or incretin signalling has not previously been explored. Here, we generated mice with beta cell-selective, adult-restricted deletion of the mitofusin genes Mfn1 and Mfn2 Mfn1/2 dKO). βMfn1/2 dKO mice displayed elevated fed and fasted glycaemia and a >five-fold decrease in plasma insulin. Mitochondrial length, glucose-induced polarisation, ATP synthesis, 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 GLP-1 or GIP receptor agonists largely corrected defective GSIS through enhanced EPAC-dependent signalling. 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 beta cell to maintain normal glucose, but not incretin, sensing. These findings broaden our understanding of the roles of mitofusins in beta cells, the potential contributions of altered mitochondrial dynamics to diabetes development and the impact of incretins on this process. 

Funding

GAR was supported by a Wellcome Trust Senior Investigator Award (098424AIA) and Investigator Award (212625/Z/18/Z), MRC Programme grants (MR/R022259/1, MR/J0003042/1, MR/L020149/1), an Experimental Challenge Grant (DIVA, MR/L02036X/1), an MRC grant (MR/N00275X/1), and a Diabetes UK grant (BDA/11/0004210, BDA/15/0005275, BDA16/0005485). IL was supported by a Diabetes UK project grant (16/0005485). This project has received funding from the Innovative Medicines Initiative 2 Joint Undertaking, under grant agreement no. 115881 (RHAPSODY). This Joint Undertaking receives support from the European Union’s Horizon 2020 research and innovation programme and EFPIA. This work is supported by the Swiss State Secretariat for Education‚ Research and Innovation (SERI), under contract no. 16.0097. AT was supported by MRC project grant MR/R010676/1. Intravital imaging was performed using resources and/or funding provided by National Institutes of Health grants R03 DK115990 (to AKL), Human Islet Research Network UC4 DK104162 (to AKL; RRID:SCR_014393). BJ acknowledges support from the Academy of Medical Sciences, Society for Endocrinology, The British Society for Neuroendocrinology, the European Federation for the Study of Diabetes, an EPSRC capital award and the MRC (MR/R010676/1). SAS was supported by the JDRF (CDA-2016-189, SRA-2018-539, COE-2019-861), the NIH (R01 DK108921, U01 DK127747), and the US Department of Veterans Affairs (I01 BX004444).

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