Discovery of a drug candidate for GLIS3-associated diabetes.
Nat Commun
; 9(1): 2681, 2018 07 11.
Article
em En
| MEDLINE
| ID: mdl-29992946
ABSTRACT
GLIS3 mutations are associated with type 1, type 2, and neonatal diabetes, reflecting a key function for this gene in pancreatic ß-cell biology. Previous attempts to recapitulate disease-relevant phenotypes in GLIS3-/- ß-like cells have been unsuccessful. Here, we develop a "minimal component" protocol to generate late-stage pancreatic progenitors (PP2) that differentiate to mono-hormonal glucose-responding ß-like (PP2-ß) cells. Using this differentiation platform, we discover that GLIS3-/- hESCs show impaired differentiation, with significant death of PP2 and PP2-ß cells, without impacting the total endocrine pool. Furthermore, we perform a high-content chemical screen and identify a drug candidate that rescues mutant GLIS3-associated ß-cell death both in vitro and in vivo. Finally, we discovered that loss of GLIS3 causes ß-cell death, by activating the TGFß pathway. This study establishes an optimized directed differentiation protocol for modeling human ß-cell disease and identifies a drug candidate for treating a broad range of GLIS3-associated diabetic patients.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Fatores de Transcrição
/
Diabetes Mellitus
/
Descoberta de Drogas
/
Hipoglicemiantes
Tipo de estudo:
Prognostic_studies
/
Risk_factors_studies
Limite:
Animals
/
Humans
/
Male
Idioma:
En
Revista:
Nat Commun
Assunto da revista:
BIOLOGIA
/
CIENCIA
Ano de publicação:
2018
Tipo de documento:
Article
País de afiliação:
Estados Unidos