| First Author | Blandino-Rosano M | Year | 2017 |
| Journal | Nat Commun | Volume | 8 |
| Pages | 16014 | PubMed ID | 28699639 |
| Mgi Jnum | J:250382 | Mgi Id | MGI:5920857 |
| Doi | 10.1038/ncomms16014 | Citation | Blandino-Rosano M, et al. (2017) Loss of mTORC1 signalling impairs beta-cell homeostasis and insulin processing. Nat Commun 8:16014 |
| abstractText | 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 (betaraKO) and inducible (MIP-betaraKOf/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 beta-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. |
