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

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