Please use this identifier to cite or link to this item: https://hdl.handle.net/10356/163808
Title: Mitofusins Mfn1 and Mfn2 are required to preserve glucose- but not incretin-stimulated β-cell connectivity and insulin secretion
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.
Keywords: Science::Medicine
Issue Date: 2022
Source: Georgiadou, E., Muralidharan, C., Martinez, M., Chabosseau, P., Akalestou, E., Tomas, A., Yong, F. S. W., Stylianides, T., Wretlind, A., Legido-Quigley, C., Jones, B., Lopez-Noriega, L., Xu, Y., Gu, G., Alsabeeh, N., Cruciani-Guglielmacci, C., Magnan, C., Ibberson, M., Leclerc, I., ...Rutter, G. A. (2022). Mitofusins Mfn1 and Mfn2 are required to preserve glucose- but not incretin-stimulated β-cell connectivity and insulin secretion. Diabetes, 71(7), 1472-1489. https://dx.doi.org/10.2337/db21-0800
Journal: Diabetes
Abstract: 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.
URI: https://hdl.handle.net/10356/163808
ISSN: 0012-1797
DOI: 10.2337/db21-0800
Rights: © 2022 by the American Diabetes Association. All rights reserved.
Fulltext Permission: none
Fulltext Availability: No Fulltext
Appears in Collections:LKCMedicine Journal Articles

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