Browsing by Author "Alsabeeh, Nour"

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    Mitofusins Mfn1 and Mfn2 Are Required to Preserve Glucose- but Not Incretin-Stimulated β-Cell Connectivity and Insulin Secretion
    (American Diabetes Association, 2022) Georgiadou, Eleni; Muralidharan, Charanya; Martinez, Michelle; Chabosseau, Pauline; Akalestou, Elina; Tomas, Alejandra; Wern, Fiona Yong Su; Stylianides, Theodoros; Wretlind, Asger; Legido-Quigley, Cristina; Jones, Ben; Lopez-Noriega, Livia; Xu, Yanwen; Gu, Guoqiang; Alsabeeh, Nour; Cruciani-Guglielmacci, Céline; Magnan, Christophe; Ibberson, Mark; Leclerc, Isabelle; Ali, Yusuf; Soleimanpour, Scott A.; Linnemann, Amelia K.; Rodriguez, Tristan A.; Rutter, Guy A.; Biochemistry and Molecular Biology, School of Medicine
    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.