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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...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
eLife Sciences Publications, Ltd
2018
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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. |
format | Online Article Text |
id | pubmed-6294551 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | eLife Sciences Publications, Ltd |
record_format | MEDLINE/PubMed |
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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