Send to

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

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

Author information

Division of Endocrinology, Diabetes and Metabolism, University of Miami, Miller School of Medicine, Miami, Florida 33136, USA.
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.
Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA.
Department of Biochemistry, McGill University, Montreal, Quebec H3A 1A3, Canada.
Biozentrum, University of Basel, CH-4056 Basel, Switzerland.
Miami VA Health Care System, Miami, Florida 33136, USA.


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.

[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center