Notch-mediated Ephrin signaling disrupts islet architecture and β cell function

JCI Insight. 2022 Mar 22;7(6):e157694. doi: 10.1172/jci.insight.157694.


Altered islet architecture is associated with β 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" β cell Notch activity in obese mouse models. To test the repercussions and reversibility of Notch effects, we generated doxycycline-dependent, β cell-specific Notch gain-of-function mice. As predicted, we found that Notch activation in postnatal β 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 β cell repulsion and impaired murine and human pseudoislet formation. Consistent with our mouse data, Notch and Ephrin signaling were increased in metabolically inflexible β cells in patients with T2D. These studies suggest that β cell Notch/Ephrin signaling can permanently alter islet architecture during a morphogenetic window in early life.

Keywords: Cell migration/adhesion; Diabetes; Endocrinology; Islet cells.

MeSH terms

  • Animals
  • Diabetes Mellitus, Type 2* / metabolism
  • Doxycycline / metabolism
  • Ephrins / metabolism
  • Glucose Intolerance* / metabolism
  • Humans
  • Insulin-Secreting Cells*
  • Islets of Langerhans* / metabolism
  • Mice


  • Ephrins
  • Doxycycline