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

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 “re-activated” 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 post-natal ß cells impaired glucose stimulated insulin secretion (GSIS) 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 pseudo-islet formation. Consistent with our mouse data, Notch and Ephrin signaling are increased in metabolically-inflexible ß cells in patients with T2D. These studies suggest than islet architecture can be permanently altered by ß cell Notch/Ephrin signaling during a morphogenetic window in early life. Overall design: RNA-seq of pancreatic islets from beta cell NICD-gain of function model