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

• Published in: eLife Vol. 7
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: England eLife Sciences Publications Ltd 09.11.2018; eLife Sciences Publications, Ltd
• Subjects: Animals; Animals, Newborn - genetics; Animals, Newborn - growth & development; Apoptosis; Apoptosis - genetics; Beta cells; Cell death; Cell growth; Diabetes; Diabetes mellitus; Diabetes Mellitus - genetics; Diabetes Mellitus - pathology; Endoplasmic Reticulum - genetics; Endoplasmic Reticulum Stress - genetics; ER stress; Genes; Human Biology and Medicine; Humans; Insulin; Insulin-Secreting Cells - pathology; Kinases; Mechanistic Target of Rapamycin Complex 1 - genetics; Medical research; Medicine; Metabolism; Mice; mTOR; Mutation; Neonates; Newborn babies; Pancreas; Proinsulin - genetics; proinsulin misfolding; proliferation; Protein Folding; Proteins; Software; Statistical analysis; TOR protein; Jerusalem Israel; United States > US; Israel; Beta cells; human biology; proinsulin misfolding; mouse; proliferation; ER stress; mTOR; medicine; diabetes
• ISSN: 2050-084X; 2050-084X
• DOI: 10.7554/eLife.38472

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 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.