Pancreatic ß-cell failure mediated by mTORC1 hyperactivity and autophagic impairment.
Diabetes
; 63(9): 2996-3008, 2014 Sep.
Article
em En
| MEDLINE
| ID: mdl-24740570
ABSTRACT
Hyperactivation of the mammalian target of rapamycin complex 1 (mTORC1) in ß-cells is usually found as a consequence of increased metabolic load. Although it plays an essential role in ß-cell compensatory mechanisms, mTORC1 negatively regulates autophagy. Using a mouse model with ß-cell-specific deletion of Tsc2 (ßTsc2(-/-)) and, consequently, mTORC1 hyperactivation, we focused on the role that chronic mTORC1 hyperactivation might have on ß-cell failure. mTORC1 hyperactivation drove an early increase in ß-cell mass that later declined, triggering hyperglycemia. Apoptosis and endoplasmic reticulum stress markers were found in islets of older ßTsc2(-/-) mice as well as accumulation of p62/SQSTM1 and an impaired autophagic response. Mitochondrial mass was increased in ß-cells of ßTsc2(-/-) mice, but mitophagy was also impaired under these circumstances. We provide evidence of ß-cell autophagy impairment as a link between mTORC1 hyperactivation and mitochondrial dysfunction that probably contributes to ß-cell failure.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Autofagia
/
Complexos Multiproteicos
/
Células Secretoras de Insulina
/
Serina-Treonina Quinases TOR
Limite:
Animals
/
Humans
/
Male
Idioma:
En
Revista:
Diabetes
Ano de publicação:
2014
Tipo de documento:
Article
País de afiliação:
Espanha