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

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

Abstrakt

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.

OriginalsprogEngelsk
TidsskriftDiabetes
Vol/bind71
Udgave nummer7
Sider (fra-til)1472-1489
Antal sider18
ISSN0012-1797
DOI
StatusUdgivet - jul. 2022

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