Conversion of the death inhibitor ARC to a killer activates pancreatic ß cell death in diabetes.
Dev Cell
; 56(6): 747-760.e6, 2021 03 22.
Article
em En
| MEDLINE
| ID: mdl-33667344
ABSTRACT
Loss of insulin-secreting pancreatic ß cells through apoptosis contributes to the progression of type 2 diabetes, but underlying mechanisms remain elusive. Here, we identify a pathway in which the cell death inhibitor ARC paradoxically becomes a killer during diabetes. While cytoplasmic ARC maintains ß cell viability and pancreatic architecture, a pool of ARC relocates to the nucleus to induce ß cell apoptosis in humans with diabetes and several pathophysiologically distinct mouse models. ß cell death results through the coordinate downregulation of serpins (serine protease inhibitors) not previously known to be synthesized and secreted by ß cells. Loss of the serpin α1-antitrypsin from the extracellular space unleashes elastase, triggering the disruption of ß cell anchorage and subsequent cell death. Administration of α1-antitrypsin to mice with diabetes prevents ß cell death and metabolic abnormalities. These data uncover a pathway for ß cell loss in type 2 diabetes and identify an FDA-approved drug that may impede progression of this syndrome.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Núcleo Celular
/
Alfa 1-Antitripsina
/
Apoptose
/
Proteínas do Citoesqueleto
/
Diabetes Mellitus Experimental
/
Diabetes Mellitus Tipo 2
/
Células Secretoras de Insulina
/
Proteínas do Tecido Nervoso
Tipo de estudo:
Etiology_studies
/
Prognostic_studies
Limite:
Animals
/
Female
/
Humans
/
Male
Idioma:
En
Revista:
Dev Cell
Assunto da revista:
EMBRIOLOGIA
Ano de publicação:
2021
Tipo de documento:
Article
País de afiliação:
Estados Unidos