Permanent neonatal diabetes-causing insulin mutations have dominant negative effects on beta cell identity.
Mol Metab
; 80: 101879, 2024 Feb.
Article
em En
| MEDLINE
| ID: mdl-38237895
ABSTRACT
OBJECTIVE:
Heterozygous coding sequence mutations of the INS gene are a cause of permanent neonatal diabetes (PNDM), requiring insulin therapy similar to T1D. While the negative effects on insulin processing and secretion are known, how dominant insulin mutations result in a continued decline of beta cell function after birth is not well understood.METHODS:
We explored the causes of beta cell failure in two PNDM patients with two distinct INS mutations using patient-derived iPSCs and mutated hESCs.RESULTS:
we detected accumulation of misfolded proinsulin and impaired proinsulin processing in vitro, and a dominant-negative effect of these mutations on beta-cell mass and function after transplantation into mice. In addition to anticipated ER stress, we found evidence of beta-cell dedifferentiation, characterized by an increase of cells expressing both Nkx6.1 and ALDH1A3, but negative for insulin and glucagon.CONCLUSIONS:
These results highlight a novel mechanism, the loss of beta cell identity, contributing to the loss and functional failure of human beta cells with specific insulin gene mutations.Palavras-chave
Texto completo:
1
Bases de dados:
MEDLINE
Assunto principal:
Diabetes Mellitus
/
Insulina
Limite:
Animals
/
Humans
Idioma:
En
Revista:
Mol Metab
Ano de publicação:
2024
Tipo de documento:
Article
País de afiliação:
Estados Unidos