Loss of mTORC1 signalling impairs β-cell homeostasis and insulin processing.
- Blandino-Rosano M Division of Endocrinology, Diabetes and Metabolism, University of Miami, Miller School of Medicine, Miami, Florida 33136, USA.
- Barbaresso R 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.
- Jimenez-Palomares M 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.
- Bozadjieva N 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.
- Werneck-de-Castro JP Division of Endocrinology, Diabetes and Metabolism, University of Miami, Miller School of Medicine, Miami, Florida 33136, USA.
- Hatanaka M Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA.
- Mirmira RG Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA.
- Sonenberg N Department of Biochemistry, McGill University, Montreal, Quebec H3A 1A3, Canada.
- Liu M 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.
- Rüegg MA Biozentrum, University of Basel, CH-4056 Basel, Switzerland.
- Hall MN Biozentrum, University of Basel, CH-4056 Basel, Switzerland.
- Bernal-Mizrachi E Division of Endocrinology, Diabetes and Metabolism, University of Miami, Miller School of Medicine, Miami, Florida 33136, USA.
- 2017-07-13
Published in:
- Nature communications. - 2017
Animals
Autophagy
Blood Glucose
Carboxypeptidase H
Diabetes Mellitus, Experimental
Eukaryotic Initiation Factor-4E
Eukaryotic Initiation Factors
Homeostasis
Humans
Insulin
Insulin-Secreting Cells
Mechanistic Target of Rapamycin Complex 1
Mice
Mice, Transgenic
Regulatory-Associated Protein of mTOR
Ribosomal Protein S6 Kinases
Sirolimus
English
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.
- Language
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- English
- Open access status
- gold
- Identifiers
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- DOI 10.1038/ncomms16014
- PMID 28699639
- Persistent URL
- https://sonar.ch/global/documents/232442
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