ROLE OF DELTA/NOTCH-LIKE EGF-RELATED RECEPTOR (DNER) IN BLOOD GLUCOSE HOMEOSTASIS

Cell-cell interactions are necessary for optimal endocrine functions in the pancreas. β-cells, characterized by the expression and secretion of the hormone insulin, are a major constituent of functional micro-organs in the pancreas known as islets of Langerhans. β-cell-cell contacts are required to regulate insulin production and glucose stimulated insulin secretion, which are key determinants of blood glucose homeostasis. Contact-dependent interactions between β-cells are known to be mediated by gap junctions and cell adhesion molecules such as E-cadherin and N-CAM. I identified an essential role for Delta/Notch-like EGF-related receptor (DNER), a transmembrane protein and a proposed Notch ligand, in regulating β-cell contacts and function in mice. DNER begins to be expressed in β-cells at developmental stages coinciding with the onset of β-cell maturation and its expression is sustained throughout adulthood. DNER loss in adult β-cells result in disruptions in islet architecture, with perturbations in β-cell-cell contacts, decreased expression of N-CAM and E-cadherin. The morphological defects in β-Dner cKO mice are accompanied by impaired glucose tolerance, defects in glucose- and KCl-induced insulin secretion, and decreased insulin sensitivity. Recent genome-wide studies have implicated Dner as a potential susceptibility loci for type 2 diabetes in humans. Our studies in mice reveal the molecular and cellular underpinnings of DNER functions in regulating blood glucose homeostasis