| First Author | Bartolomé A | Year | 2014 |
| Journal | Diabetes | Volume | 63 |
| Issue | 9 | Pages | 2996-3008 |
| PubMed ID | 24740570 | Mgi Jnum | J:229869 |
| Mgi Id | MGI:5754700 | Doi | 10.2337/db13-0970 |
| Citation | Bartolome A, et al. (2014) Pancreatic beta-cell failure mediated by mTORC1 hyperactivity and autophagic impairment. Diabetes 63(9):2996-3008 |
| abstractText | Hyperactivation of the mammalian target of rapamycin complex 1 (mTORC1) in beta-cells is usually found as a consequence of increased metabolic load. Although it plays an essential role in beta-cell compensatory mechanisms, mTORC1 negatively regulates autophagy. Using a mouse model with beta-cell-specific deletion of Tsc2 (betaTsc2(-/-)) and, consequently, mTORC1 hyperactivation, we focused on the role that chronic mTORC1 hyperactivation might have on beta-cell failure. mTORC1 hyperactivation drove an early increase in beta-cell mass that later declined, triggering hyperglycemia. Apoptosis and endoplasmic reticulum stress markers were found in islets of older betaTsc2(-/-) mice as well as accumulation of p62/SQSTM1 and an impaired autophagic response. Mitochondrial mass was increased in beta-cells of betaTsc2(-/-) mice, but mitophagy was also impaired under these circumstances. We provide evidence of beta-cell autophagy impairment as a link between mTORC1 hyperactivation and mitochondrial dysfunction that probably contributes to beta-cell failure. |
