The nuclear receptor REV-ERBα is implicated in the alteration of β-cell autophagy and survival under diabetogenic conditions

Pancreatic beta-cell failure in type 2 diabetes mellitus (T2DM) is associated with impaired regulation of autophagy which controls beta-cell development, function, and survival through clearance of misfolded proteins and damaged organelles. However, the mechanisms responsible for defective autophagy in T2DM beta-cells remain unknown. Since recent studies identified circadian clock transcriptional repressor REV-ERB alpha as a novel regulator of autophagy in cancer, in this study we set out to test whether REV-ERB alpha-mediated inhibition of autophagy contributes to the beta-cell failure in T2DM. Our study provides evidence that common diabetogenic stressors (e.g., glucotoxicity and cytokine-mediated inflammation) augment beta-cell REV-ERB alpha expression and impair beta-cell autophagy and survival. Notably, pharmacological activation of REV-ERB alpha was shown to phenocopy effects of diabetogenic stressors on the beta-cell through inhibition of autophagic flux, survival, and insulin secretion. In contrast, negative modulation of REV-ERB alpha was shown to provide partial protection from inflammation and glucotoxicity-induced beta-cell failure. Finally, using bioinformatic approaches, we provide further supporting evidence for augmented REV-ERB alpha activity in T2DM human islets associated with impaired transcriptional regulation of autophagy and protein degradation pathways. In conclusion, our study reveals a previously unexplored causative relationship between REV-ERB alpha expression, inhibition of autophagy, and beta-cell failure in T2DM.