Mitofusins Mfn1 and Mfn2 are required to preserve glucose- but not incretin-stimulated β-cell connectivity and insulin secretion

• Main Authors: Georgiadou, Eleni, Muralidharan, Charanya, Martinez, Michelle, Chabosseau, Pauline, Akalestou, Elina, Tomas, Alejandra, Yong, Fiona Su Wern, 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.
• Other Authors: Lee Kong Chian School of Medicine (LKCMedicine)
• Format: Article
• Language: English
• Published: 2022
• Subjects: Science::Medicine; Adenosine Triphosphate; Diabetes Mellitus
• Online Access: https://hdl.handle.net/10356/163808
• Institution: Nanyang Technological University

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.