Mitofusins Mfn1 and Mfn2 Are Required to Preserve Glucose- but Not Incretin-Stimulated β-Cell Connectivity and Insulin Secretion

• Main Authors: Akalestou, E. (Author), Ali, Y. (Author), Alsabeeh, N. (Author), Chabosseau, P. (Author), Cruciani-Guglielmacci, C. (Author), Georgiadou, E. (Author), Gu, G. (Author), Ibberson, M. (Author), Jones, B. (Author), Leclerc, I. (Author), Legido-Quigley, C. (Author), Linnemann, A.K (Author), Lopez-Noriega, L. (Author), Magnan, C. (Author), Martinez, M. (Author), Muralidharan, C. (Author), Rodriguez, T.A (Author), Rutter, G.A (Author), Soleimanpour, S.A (Author), Stylianides, T. (Author), Tomas, A. (Author), Wern, F.Y.S (Author), Wretlind, A. (Author), Xu, Y. (Author)
• Format: Article
• Language: English
• Published: NLM (Medline) 2022
• Subjects: animal; Animals; genetics; glucose; Glucose; GTP Phosphohydrolases; guanine nucleotide exchange factor; Guanine Nucleotide Exchange Factors; guanosine triphosphatase; incretin; Incretins; insulin; Insulin; insulin release; Insulin Secretion; Insulin-Secreting Cells; knockout mouse; metabolism; Mfn1 protein, mouse; Mfn2 protein, mouse; Mice; Mice, Knockout; mouse; pancreas islet beta cell
• Online Access: View Fulltext in Publisher

 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. © 2022 by the American Diabetes Association.