| Autor: |
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 |
| Předmět: |
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| Zdroj: |
Diabetes; 2022, Vol. 71 Issue 7, p1472-1489, 18p |
| 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. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
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