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*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

38 Scopus citations


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 languageAmerican English
Article numbere38472
StatePublished - 1 Nov 2018

Bibliographical note

Funding Information:
Israel Science Foundation ISF-347/12 Gil LeibowitzIsrael Science Foundation ISF-1563/14 Gil LeibowitzIsrael Science Foundation 2323/17 Gil Leibowitz.

Publisher Copyright:
© Riahi et al.


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