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Loss of mTORC1 signalling impairs β-cell homeostasis and insulin processing

Blandino-Rosano, Manuel and Barbaresso, Rebecca and Jimenez-Palomares, Margarita and Bozadjieva, Nadejda and Werneck-de-Castro, Joao Pedro and Hatanaka, Masayuki and Mirmira, Raghavendra G. and Sonenberg, Nahum and Liu, Ming and Rüegg, Markus A. and Hall, Michael N. and Bernal-Mizrachi, Ernesto. (2017) Loss of mTORC1 signalling impairs β-cell homeostasis and insulin processing. Nature Communications, 8. p. 16014.

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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-βraKO(f/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.
Faculties and Departments:05 Faculty of Science > Departement Biozentrum > Growth & Development > Biochemistry (Hall)
UniBasel Contributors:Hall, Michael N. and Rüegg, Markus A.
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:Nature Publishing Group
e-ISSN:2041-1723
Note:Publication type according to Uni Basel Research Database: Journal article
Language:English
Identification Number:
Last Modified:08 Nov 2017 13:31
Deposited On:19 Oct 2017 10:10

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