325-LB: Circadian Clock Nuclear Receptor REV-ERBa Is a Novel Regulator of Beta-Cell Function, Survival, and Autophagy under Diabetogenic Conditions

The circadian clock regulates diverse cellular and molecular rhythms employing CLOCK-BMAL1 transcriptional heterodimer with nuclear receptor REV-ERBα (encoded by gene Nr1d1) playing an important role as a clock repressor through modulation of Bmal1 transcription. Importantly, in addition to its core circadian clock function, recent studies have identified REV-ERBα as a potent transcriptional repressor of autophagy. Therefore, in the current study we set out to address whether impaired beta-cell function and survival associated with exposure to diabetogenic stressors (e.g., glucotoxicity and inflammation) is attributed in part to REV-ERBα-mediated inhibition of autophagy. Exposure of beta-cells (INS-1E cell line) to either glucotoxicity (30 mM glucose) or cytokines (cytomix of IL-1β, TNFα and IFNγ) resulted in robust induction of REV-ERBα expression (1.5-2 fold, p