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Inhibition of mTORC1 by ER stress impairs neonatal β-cell expansion and predisposes to diabetes in the Akita mouse

Unresolved ER stress followed by cell death is recognized as the main cause of a multitude of pathologies including neonatal diabetes. A systematic analysis of the mechanisms of β-cell loss and dysfunction in Akita mice, in which a mutation in the proinsulin gene causes a severe form of permanent ne...

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Autores principales: Riahi, Yael, Israeli, Tal, Yeroslaviz, Roni, Chimenez, Shoshana, Avrahami, Dana, Stolovich-Rain, Miri, Alter, Ido, Sebag, Marina, Polin, Nava, Bernal-Mizrachi, Ernesto, Dor, Yuval, Cerasi, Erol, Leibowitz, Gil
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6294551/
https://www.ncbi.nlm.nih.gov/pubmed/30412050
http://dx.doi.org/10.7554/eLife.38472
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author Riahi, Yael
Israeli, Tal
Yeroslaviz, Roni
Chimenez, Shoshana
Avrahami, Dana
Stolovich-Rain, Miri
Alter, Ido
Sebag, Marina
Polin, Nava
Bernal-Mizrachi, Ernesto
Dor, Yuval
Cerasi, Erol
Leibowitz, Gil
author_facet Riahi, Yael
Israeli, Tal
Yeroslaviz, Roni
Chimenez, Shoshana
Avrahami, Dana
Stolovich-Rain, Miri
Alter, Ido
Sebag, Marina
Polin, Nava
Bernal-Mizrachi, Ernesto
Dor, Yuval
Cerasi, Erol
Leibowitz, Gil
author_sort Riahi, Yael
collection PubMed
description Unresolved ER stress followed by cell death is recognized as the main cause of a multitude of pathologies including neonatal diabetes. A systematic analysis of the mechanisms of β-cell loss and dysfunction in Akita mice, in which a mutation in the proinsulin gene causes a severe form of permanent neonatal diabetes, showed no increase in β-cell apoptosis throughout life. Surprisingly, we found that the main mechanism leading to β-cell dysfunction is marked impairment of β-cell growth during the early postnatal life due to transient inhibition of mTORC1, which governs postnatal β-cell growth and differentiation. Importantly, restoration of mTORC1 activity in neonate β-cells was sufficient to rescue postnatal β-cell growth, and to improve diabetes. We propose a scenario for the development of permanent neonatal diabetes, possibly also common forms of diabetes, where early-life events inducing ER stress affect β-cell mass expansion due to mTOR inhibition.
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spelling pubmed-62945512018-12-15 Inhibition of mTORC1 by ER stress impairs neonatal β-cell expansion and predisposes to diabetes in the Akita mouse Riahi, Yael Israeli, Tal Yeroslaviz, Roni Chimenez, Shoshana Avrahami, Dana Stolovich-Rain, Miri Alter, Ido Sebag, Marina Polin, Nava Bernal-Mizrachi, Ernesto Dor, Yuval Cerasi, Erol Leibowitz, Gil eLife Human Biology and Medicine Unresolved ER stress followed by cell death is recognized as the main cause of a multitude of pathologies including neonatal diabetes. A systematic analysis of the mechanisms of β-cell loss and dysfunction in Akita mice, in which a mutation in the proinsulin gene causes a severe form of permanent neonatal diabetes, showed no increase in β-cell apoptosis throughout life. Surprisingly, we found that the main mechanism leading to β-cell dysfunction is marked impairment of β-cell growth during the early postnatal life due to transient inhibition of mTORC1, which governs postnatal β-cell growth and differentiation. Importantly, restoration of mTORC1 activity in neonate β-cells was sufficient to rescue postnatal β-cell growth, and to improve diabetes. We propose a scenario for the development of permanent neonatal diabetes, possibly also common forms of diabetes, where early-life events inducing ER stress affect β-cell mass expansion due to mTOR inhibition. eLife Sciences Publications, Ltd 2018-11-09 /pmc/articles/PMC6294551/ /pubmed/30412050 http://dx.doi.org/10.7554/eLife.38472 Text en © 2018, Riahi et al http://creativecommons.org/licenses/by/4.0/ http://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited.
spellingShingle Human Biology and Medicine
Riahi, Yael
Israeli, Tal
Yeroslaviz, Roni
Chimenez, Shoshana
Avrahami, Dana
Stolovich-Rain, Miri
Alter, Ido
Sebag, Marina
Polin, Nava
Bernal-Mizrachi, Ernesto
Dor, Yuval
Cerasi, Erol
Leibowitz, Gil
Inhibition of mTORC1 by ER stress impairs neonatal β-cell expansion and predisposes to diabetes in the Akita mouse
title Inhibition of mTORC1 by ER stress impairs neonatal β-cell expansion and predisposes to diabetes in the Akita mouse
title_full Inhibition of mTORC1 by ER stress impairs neonatal β-cell expansion and predisposes to diabetes in the Akita mouse
title_fullStr Inhibition of mTORC1 by ER stress impairs neonatal β-cell expansion and predisposes to diabetes in the Akita mouse
title_full_unstemmed Inhibition of mTORC1 by ER stress impairs neonatal β-cell expansion and predisposes to diabetes in the Akita mouse
title_short Inhibition of mTORC1 by ER stress impairs neonatal β-cell expansion and predisposes to diabetes in the Akita mouse
title_sort inhibition of mtorc1 by er stress impairs neonatal β-cell expansion and predisposes to diabetes in the akita mouse
topic Human Biology and Medicine
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6294551/
https://www.ncbi.nlm.nih.gov/pubmed/30412050
http://dx.doi.org/10.7554/eLife.38472
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