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

Yael Riahi, Tal Israeli, Roni Yeroslaviz, Shoshana Chimenez, Dana Avrahami, Miri Stolovich-Rain, Ido Alter, Marina Sebag, Nava Polin, Ernesto Bernal-Mizrachi, Yuval Dor, Erol Cerasi, Gil Leibowitz

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10 Scopus citations

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 b-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 b-cell apoptosis throughout life. Surprisingly, we found that the main mechanism leading to b-cell dysfunction is marked impairment of b-cell growth during the early postnatal life due to transient inhibition of mTORC1, which governs postnatal b-cell growth and differentiation. Importantly, restoration of mTORC1 activity in neonate b-cells was sufficient to rescue postnatal b-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 b-cell mass expansion due to mTOR inhibition.

Original languageEnglish (US)
Article numbere38472
JournaleLife
Volume7
DOIs
StatePublished - Nov 1 2018

ASJC Scopus subject areas

  • Neuroscience(all)
  • Immunology and Microbiology(all)
  • Biochemistry, Genetics and Molecular Biology(all)

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    Riahi, Y., Israeli, T., Yeroslaviz, R., Chimenez, S., Avrahami, D., Stolovich-Rain, M., Alter, I., Sebag, M., Polin, N., Bernal-Mizrachi, E., Dor, Y., Cerasi, E., & Leibowitz, G. (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