@misc{10498/34812,
year = {2017},
month = {7},
url = {http://hdl.handle.net/10498/34812},
abstract = {Deregulation of mTOR complex 1 (mTORC1) signalling increases the risk for metabolic diseases, including type 2 diabetes. Here we show that beta-cell-specific loss of mTORC1 causes diabetes and beta-cell failure due to defects in proliferation, autophagy, apoptosis and insulin secretion by using mice with conditional (beta raKO) and inducible (MIP-beta raKO(f/f)) raptor deletion. Through genetic reconstitution of mTORC1 downstream targets, we identify mTORC1/S6K pathway as the mechanism by which mTORC1 regulates beta-cell apoptosis, size and autophagy, whereas mTORC1/4E-BP2-eIF4E pathway regulates beta-cell proliferation. Restoration of both pathways partially recovers b-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 beta-cells and identify downstream pathways driving beta-cell mass, function and insulin processing.},
keywords = {TRANSGENIC MICE},
keywords = {IN-VIVO},
keywords = {AUTOPHAGY REGULATION},
keywords = {S6 KINASE},
keywords = {PROINSULIN},
keywords = {BETA CELL MASS},
keywords = {BETA CELL FUNCTION},
keywords = {PHOSPHORYLATION},
keywords = {DIABETES},
keywords = {RESISTANCE},
title = {Loss of mTORC1 signalling impairs β-cell homeostasis and insulin processing},
doi = {10.1038/ncomms16014},
author = {Blandino-Rosano, Manuel and Barbaresso, Rebecca and Jiménez Palomares, Margarita and Bozadjieva, Nadejda and Werneck-de-Castro, Joao Pedro and Hatanaka, Masayuki and Mirmira, Raghavendra and Sonenberg, Nahum and Liu, Ming and Ruegg, Markus A. and Hall, Michael N. and Bernal-Mizrachi, Ernesto},
}