%0 Journal Article 
%A Blandino-Rosano, Manuel
%A Barbaresso, Rebecca
%A Jiménez Palomares, Margarita
%A Bozadjieva, Nadejda
%A Werneck-de-Castro, Joao Pedro
%A Hatanaka, Masayuki
%A Mirmira, Raghavendra
%A Sonenberg, Nahum
%A Liu, Ming
%A Ruegg, Markus A.
%A Hall, Michael N.
%A Bernal-Mizrachi, Ernesto
%T Loss of mTORC1 signalling impairs β-cell homeostasis and insulin processing
%D 2017
%@ 2041-1723
%U http://hdl.handle.net/10498/34812
%X 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.
%K TRANSGENIC MICE
%K IN-VIVO
%K AUTOPHAGY REGULATION
%K S6 KINASE
%K PROINSULIN
%K BETA CELL MASS
%K BETA CELL FUNCTION
%K PHOSPHORYLATION
%K DIABETES
%K RESISTANCE
%~ Universidad de Cádiz