Loss of mTORC1 signalling impairs β-cell homeostasis and insulin processing
dc.contributor.author | Blandino-Rosano, Manuel | |
dc.contributor.author | Barbaresso, Rebecca | |
dc.contributor.author | Jimenez-Palomares, Margarita | |
dc.contributor.author | Bozadjieva, Nadejda | |
dc.contributor.author | Werneck-de-Castro, Joao Pedro | |
dc.contributor.author | Hatanaka, Masayuki | |
dc.contributor.author | Mirmira, Raghavendra G. | |
dc.contributor.author | Sonenberg, Nahum | |
dc.contributor.author | Liu, Ming | |
dc.contributor.author | Rüegg, Markus A. | |
dc.contributor.author | Hall, Michael N. | |
dc.contributor.author | Bernal-Mizrachi, Ernesto | |
dc.contributor.department | Pediatrics, School of Medicine | en_US |
dc.date.accessioned | 2018-05-01T16:13:10Z | |
dc.date.available | 2018-05-01T16:13:10Z | |
dc.date.issued | 2017-07-12 | |
dc.description.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-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.version | Final published version | |
dc.identifier.citation | Blandino-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/ncomms16014 | en_US |
dc.identifier.uri | https://hdl.handle.net/1805/15970 | |
dc.language.iso | en_US | en_US |
dc.publisher | Nature Communication Group | en_US |
dc.relation.isversionof | 10.1038/ncomms16014 | en_US |
dc.relation.journal | Nature Communications | en_US |
dc.rights | Attribution 3.0 United States | |
dc.rights.uri | https://creativecommons.org/licenses/by/3.0/us | |
dc.source | PMC | |
dc.subject | Metabolism -- Disorders | en_US |
dc.subject | Non-insulin-dependent diabetes | en_US |
dc.subject | Apoptosis | en_US |
dc.subject | Cellular signal transduction | en_US |
dc.subject | Rapamycin | en_US |
dc.title | Loss of mTORC1 signalling impairs β-cell homeostasis and insulin processing | en_US |
dc.type | Article | en_US |