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

dc.contributor.authorBlandino-Rosano, Manuel
dc.contributor.authorBarbaresso, Rebecca
dc.contributor.authorJimenez-Palomares, Margarita
dc.contributor.authorBozadjieva, Nadejda
dc.contributor.authorWerneck-de-Castro, Joao Pedro
dc.contributor.authorHatanaka, Masayuki
dc.contributor.authorMirmira, Raghavendra G.
dc.contributor.authorSonenberg, Nahum
dc.contributor.authorLiu, Ming
dc.contributor.authorRüegg, Markus A.
dc.contributor.authorHall, Michael N.
dc.contributor.authorBernal-Mizrachi, Ernesto
dc.contributor.departmentPediatrics, School of Medicineen_US
dc.date.accessioned2018-05-01T16:13:10Z
dc.date.available2018-05-01T16:13:10Z
dc.date.issued2017-07-12
dc.description.abstractDeregulation 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-βraKOf/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.en_US
dc.eprint.versionFinal published version
dc.identifier.citationBlandino-Rosano, M., Barbaresso, R., Jimenez-Palomares, M., Bozadjieva, N., Werneck-de-Castro, J. P., Hatanaka, M., … Bernal-Mizrachi, E. (2017). Loss of mTORC1 signalling impairs β-cell homeostasis and insulin processing. Nature Communications, 8, 16014. http://doi.org/10.1038/ncomms16014en_US
dc.identifier.urihttps://hdl.handle.net/1805/15970
dc.language.isoen_USen_US
dc.publisherNature Communication Groupen_US
dc.relation.isversionof10.1038/ncomms16014en_US
dc.relation.journalNature Communicationsen_US
dc.rightsAttribution 3.0 United States
dc.rights.urihttps://creativecommons.org/licenses/by/3.0/us
dc.sourcePMC
dc.subjectMetabolism -- Disordersen_US
dc.subjectNon-insulin-dependent diabetesen_US
dc.subjectApoptosisen_US
dc.subjectCellular signal transductionen_US
dc.subjectRapamycinen_US
dc.titleLoss of mTORC1 signalling impairs β-cell homeostasis and insulin processingen_US
dc.typeArticleen_US
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