Mitofusins Mfn1 and Mfn2 Are Required to Preserve Glucose- but Not Incretin-Stimulated beta-Cell Connectivity and Insulin Secretion
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2022-07
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Diabetes
Abstract
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 signaling has not previously been explored. Here, we generated mice with beta-cell-selective, adult-restricted deletion knock-out (dKO) of the mitofusin genes Mfn1 and Mfn2 (beta Mfn1/2 dKO). beta Mfn1/2-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 beta Mfn1/2-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 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.
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Only Vanderbilt University affiliated authors are listed on VUIR. For a full list of authors, access the version of record at https://diabetesjournals.org/diabetes/article/71/7/1472/145040/Mitofusins-Mfn1-and-Mfn2-Are-Required-to-Preserve
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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; Mitofusins Mfn1 and Mfn2 Are Required to Preserve Glucose- but Not Incretin-Stimulated β-Cell Connectivity and Insulin Secretion. Diabetes 1 July 2022; 71 (7): 1472–1489. https://doi.org/10.2337/db21-0800