Blandino-Rosano, ManuelBarbaresso, RebeccaJimenez-Palomares, MargaritaBozadjieva, NadejdaWerneck-de-Castro, Joao PedroHatanaka, MasayukiMirmira, Raghavendra G.Sonenberg, NahumLiu, MingRüegg, Markus A.Hall, Michael N.Bernal-Mizrachi, Ernesto2018-05-012018-05-012017-07-12Blandino-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/ncomms16014https://hdl.handle.net/1805/15970Deregulation 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-USAttribution 3.0 United StatesMetabolism -- DisordersNon-insulin-dependent diabetesApoptosisCellular signal transductionRapamycinArticle