Notch-mediated Ephrin signaling disrupts islet architecture and ß cell function.
JCI Insight
; 7(6)2022 03 22.
Article
en En
| MEDLINE
| ID: mdl-35167496
ABSTRACT
Altered islet architecture is associated with ß cell dysfunction and type 2 diabetes (T2D) progression, but molecular effectors of islet spatial organization remain mostly unknown. Although Notch signaling is known to regulate pancreatic development, we observed "reactivated" ß cell Notch activity in obese mouse models. To test the repercussions and reversibility of Notch effects, we generated doxycycline-dependent, ß cell-specific Notch gain-of-function mice. As predicted, we found that Notch activation in postnatal ß cells impaired glucose-stimulated insulin secretion and glucose intolerance, but we observed a surprising remnant glucose intolerance after doxycycline withdrawal and cessation of Notch activity, associated with a marked disruption of normal islet architecture. Transcriptomic screening of Notch-active islets revealed increased Ephrin signaling. Commensurately, exposure to Ephrin ligands increased ß cell repulsion and impaired murine and human pseudoislet formation. Consistent with our mouse data, Notch and Ephrin signaling were increased in metabolically inflexible ß cells in patients with T2D. These studies suggest that ß cell Notch/Ephrin signaling can permanently alter islet architecture during a morphogenetic window in early life.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Islotes Pancreáticos
/
Intolerancia a la Glucosa
/
Diabetes Mellitus Tipo 2
/
Células Secretoras de Insulina
Tipo de estudio:
Prognostic_studies
Límite:
Animals
/
Humans
Idioma:
En
Revista:
JCI Insight
Año:
2022
Tipo del documento:
Article
País de afiliación:
Estados Unidos