RT journal article
T1 Loss of mTORC1 signalling impairs β-cell homeostasis and insulin processing
A1 Blandino-Rosano, Manuel
A1 Barbaresso, Rebecca
A1 Jiménez Palomares, Margarita
A1 Bozadjieva, Nadejda
A1 Werneck-de-Castro, Joao Pedro
A1 Hatanaka, Masayuki
A1 Mirmira, Raghavendra
A1 Sonenberg, Nahum
A1 Liu, Ming
A1 Ruegg, Markus A.
A1 Hall, Michael N.
A1 Bernal-Mizrachi, Ernesto
A2 BiomedicinaBiotecnología y Salud Pública
K1 TRANSGENIC MICE
K1 IN-VIVO
K1 AUTOPHAGY REGULATION
K1 S6 KINASE
K1 PROINSULIN
K1 BETA CELL MASS
K1 BETA CELL FUNCTION
K1 PHOSPHORYLATION
K1 DIABETES
K1 RESISTANCE
AB 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.
SN 2041-1723
YR 2017
FD 2017-07-12
LK http://hdl.handle.net/10498/34812
UL http://hdl.handle.net/10498/34812
LA eng
DS Repositorio Institucional de la Universidad de Cádiz
RD 10-nov-2026