109-OR: Notch Signaling Controls Islet Architecture and ß-Cell Function in the Developed Pancreas

Abstract

Although β cell dysfunction is a well-appreciated contributor to type 2 diabetes (T2D) pathophysiology, determinants of β cell function are incompletely understood. For instance, disrupted islet architecture is associated with T2D progression in humans and rodent models, but the identity of the molecular elements that govern islet architecture remain mostly unknown. Nevertheless, data suggest that the spatial arrangement of the different cell types that form the endocrine islets influences cell-to-cell communication and β cell function. The Notch pathway transduces signals between neighboring cells in pancreas development, then thought to be silenced in the developed endocrine islet. However, recent reports have uncovered a maladaptive Notch response in adult β cells in T2D patients and obese rodent models. To test the repercussions of Notch activity, we created β cell-specific gain-of-function mice that express a constitutively-active Notch intracellular domain (β-NICD). β-NICD mice show a profound disorganization of islet architecture, loss of β cell maturity and marked glucose intolerance. Importantly, we generated a second model that allows doxycycline-dependent expression of NICD (β-TetO-NICD), which recapitulates the phenotypes of β-NICD mice, even when NICD is induced in adulthood. Upon doxycycline withdrawal, β-TetO-NICD mice recover markers of β cell maturity, but disrupted islet architecture and glucose intolerance persist in β-TetO-NICD mice as compared to controls. To assess the molecular mechanisms of these findings, we performed unbiased transcriptomic screening of adult islets, which identified differentially expressed pathways that regulate cell-to-cell communication in different systems. These studies uncover β cell Notch signaling as a novel determinant of islet architecture, and suggest that Notch inhibitors repurposed from oncology pipelines may have potential application to correct obesity-related β cell dysfunction in patients with T2D. Disclosure A. Bartolome: None. U. Pajvani: Research Support; Self; Sanofi. Funding American Diabetes Association (1-17-PMF-025 to A.B.)