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

  1. Yael Riahi
  2. Tal Israeli
  3. Roni Yeroslaviz
  4. Shoshana Chimenez
  5. Dana Avrahami
  6. Miri Stolovich-Rain
  7. Ido Alter
  8. Marina Sebag
  9. Nava Polin
  10. Ernesto Bernal-Mizrachi
  11. Yuval Dor
  12. Erol Cerasi
  13. Gil Leibowitz  Is a corresponding author
  1. The Hadassah-Hebrew University Medical Center, Israel
  2. The Hebrew University-Hadassah Medical School, Israel
  3. Miller School of Medicine, University of Miami, United States
Research Article
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Cite this article as: eLife 2018;7:e38472 doi: 10.7554/eLife.38472

Abstract

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.

Article and author information

Author details

  1. Yael Riahi

    The Diabetes Unit and the Endocrine Service, The Hadassah-Hebrew University Medical Center, Jerusalem, Israel
    Competing interests
    The authors declare that no competing interests exist.
  2. Tal Israeli

    The Diabetes Unit and the Endocrine Service, The Hadassah-Hebrew University Medical Center, Jerusalem, Israel
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9293-0827
  3. Roni Yeroslaviz

    The Diabetes Unit and the Endocrine Service, The Hadassah-Hebrew University Medical Center, Jerusalem, Israel
    Competing interests
    The authors declare that no competing interests exist.
  4. Shoshana Chimenez

    The Diabetes Unit and the Endocrine Service, The Hadassah-Hebrew University Medical Center, Jerusalem, Israel
    Competing interests
    The authors declare that no competing interests exist.
  5. Dana Avrahami

    The Diabetes Unit and the Endocrine Service, The Hadassah-Hebrew University Medical Center, Jerusalem, Israel
    Competing interests
    The authors declare that no competing interests exist.
  6. Miri Stolovich-Rain

    Department of Developmental Biology and Cancer Research, The Hebrew University-Hadassah Medical School, Jerusalem, Israel
    Competing interests
    The authors declare that no competing interests exist.
  7. Ido Alter

    The Diabetes Unit and the Endocrine Service, The Hadassah-Hebrew University Medical Center, Jerusalem, Israel
    Competing interests
    The authors declare that no competing interests exist.
  8. Marina Sebag

    The Diabetes Unit and the Endocrine Service, The Hadassah-Hebrew University Medical Center, Jerusalem, Israel
    Competing interests
    The authors declare that no competing interests exist.
  9. Nava Polin

    The Diabetes Unit and the Endocrine Service, The Hadassah-Hebrew University Medical Center, Jerusalem, Israel
    Competing interests
    The authors declare that no competing interests exist.
  10. Ernesto Bernal-Mizrachi

    Department of Internal Medicine, Division of Endocrinology, Metabolism and Diabetes, Miller School of Medicine, University of Miami, Miami, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. Yuval Dor

    Department of Developmental Biology and Cancer Research, The Hebrew University-Hadassah Medical School, Jerusalem, Israel
    Competing interests
    The authors declare that no competing interests exist.
  12. Erol Cerasi

    The Diabetes Unit and the Endocrine Service, The Hadassah-Hebrew University Medical Center, Jerusalem, Israel
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8234-3618
  13. Gil Leibowitz

    The Diabetes Unit and the Endocrine Service, The Hadassah-Hebrew University Medical Center, Jerusalem, Israel
    For correspondence
    gleib@hadassah.org.il
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6915-4361

Funding

Israel Science Foundation (ISF-347/12)

  • Gil Leibowitz

Israel Science Foundation (ISF-1563/14)

  • Gil Leibowitz

Israel Science Foundation (2323/17)

  • Gil Leibowitz

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the Hebrew University. All of the animals were handled according to approved institutional animal care and use committee of the Hebrew University. The protocol was approved by the Committee on the Ethics of Animal Experiments of the Hebrew University (Permit Number: MD-17-15065-4). Every effort was made to minimize animal suffering.

Reviewing Editor

  1. Anna L Gloyn, University of Oxford, United Kingdom

Publication history

  1. Received: May 19, 2018
  2. Accepted: November 7, 2018
  3. Accepted Manuscript published: November 9, 2018 (version 1)

Copyright

© 2018, Riahi et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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