Loss of mTORC1 signalling impairs β-cell homeostasis and insulin processing

Manuel Blandino-Rosano, Rebecca Barbaresso, Margarita Jimenez-Palomares, Nadejda Bozadjieva, Joao Pedro Werneck-de-Castro, Masayuki Hatanaka, Raghavendra G. Mirmira, Nahum Sonenberg, Ming Liu, Markus A. Rüegg, Michael N. Hall, Ernesto Bernal-Mizrachi

Research output: Contribution to journalArticle

44 Scopus citations

Abstract

Deregulation of mTOR complex 1 (mTORC1) signalling increases the risk for metabolic diseases, including type 2 diabetes. Here we show that β-cell-specific loss of mTORC1 causes diabetes and β-cell failure due to defects in proliferation, autophagy, apoptosis and insulin secretion by using mice with conditional (βraKO) and inducible (MIP-βraKO(f/f)) raptor deletion. Through genetic reconstitution of mTORC1 downstream targets, we identify mTORC1/S6K pathway as the mechanism by which mTORC1 regulates β-cell apoptosis, size and autophagy, whereas mTORC1/4E-BP2-eIF4E pathway regulates β-cell proliferation. Restoration of both pathways partially recovers β-cell mass and hyperglycaemia. This study also demonstrates a central role of mTORC1 in controlling insulin processing by regulating cap-dependent translation of carboxypeptidase E in a 4EBP2/eIF4E-dependent manner. Rapamycin treatment decreases CPE expression and insulin secretion in mice and human islets. We suggest an important role of mTORC1 in β-cells and identify downstream pathways driving β-cell mass, function and insulin processing.

Original languageEnglish (US)
Article number16014
JournalNature communications
Volume8
DOIs
StatePublished - Jul 12 2017

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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    Blandino-Rosano, M., Barbaresso, R., Jimenez-Palomares, M., Bozadjieva, N., Werneck-de-Castro, J. P., Hatanaka, M., Mirmira, R. G., Sonenberg, N., Liu, M., Rüegg, M. A., Hall, M. N., & Bernal-Mizrachi, E. (2017). Loss of mTORC1 signalling impairs β-cell homeostasis and insulin processing. Nature communications, 8, [16014]. https://doi.org/10.1038/ncomms16014