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Nat Commun. 2017 Jul 12;8:16014. doi: 10.1038/ncomms16014.

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

Author information

1
Division of Endocrinology, Diabetes and Metabolism, University of Miami, Miller School of Medicine, Miami, Florida 33136, USA.
2
Department of Internal Medicine, Division of Metabolism, Endocrinology and Diabetes, Brehm Center for Diabetes Research, University of Michigan Medical Center, Ann Arbor, Michigan 48105, USA.
3
Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA.
4
Department of Biochemistry, McGill University, Montreal, Quebec H3A 1A3, Canada.
5
Biozentrum, University of Basel, CH-4056 Basel, Switzerland.
6
Miami VA Health Care System, Miami, Florida 33136, USA.

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-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.

PMID:
28699639
PMCID:
PMC5510183
DOI:
10.1038/ncomms16014
[Indexed for MEDLINE]
Free PMC Article

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