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

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.

Data availability

The RNA-seq data is available through NCBI. The accession number is: GSE114927

The following data sets were generated
The following previously published data sets were used

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.

Reviewing Editor

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

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.

Version history

  1. Received: May 19, 2018
  2. Accepted: November 7, 2018
  3. Accepted Manuscript published: November 9, 2018 (version 1)
  4. Version of Record published: December 14, 2018 (version 2)

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.

Metrics

  • 2,696
    Page views
  • 474
    Downloads
  • 38
    Citations

Article citation count generated by polling the highest count across the following sources: Scopus, Crossref, PubMed Central.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  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
(2018)
Inhibition of mTORC1 by ER stress impairs neonatal β-cell expansion and predisposes to diabetes in the Akita mouse
eLife 7:e38472.
https://doi.org/10.7554/eLife.38472

Share this article

https://doi.org/10.7554/eLife.38472

Further reading

    1. Stem Cells and Regenerative Medicine
    Honey Modi, James D Johnson
    Insight

    Exploring how proliferation and maturation of beta-cells can be impaired after birth will shed light on the origins of various forms of diabetes.

    1. Cell Biology
    2. Neuroscience
    Zhenyong Wu, Grant F Kusick ... Shigeki Watanabe
    Research Article

    Despite decades of intense study, the molecular basis of asynchronous neurotransmitter release remains enigmatic. Synaptotagmin (syt) 7 and Doc2 have both been proposed as Ca2+ sensors that trigger this mode of exocytosis, but conflicting findings have led to controversy. Here, we demonstrate that at excitatory mouse hippocampal synapses, Doc2α is the major Ca2+ sensor for asynchronous release, while syt7 supports this process through activity-dependent docking of synaptic vesicles. In synapses lacking Doc2α, asynchronous release after single action potentials is strongly reduced, while deleting syt7 has no effect. However, in the absence of syt7, docked vesicles cannot be replenished on millisecond timescales. Consequently, both synchronous and asynchronous release depress from the second pulse onward during repetitive activity. By contrast, synapses lacking Doc2α have normal activity-dependent docking, but continue to exhibit decreased asynchronous release after multiple stimuli. Moreover, disruption of both Ca2+ sensors is non-additive. These findings result in a new model whereby syt7 drives activity-dependent docking, thus providing synaptic vesicles for synchronous (syt1) and asynchronous (Doc2 and other unidentified sensors) release during ongoing transmission.