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

Abstract

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

Circadian desynchronization desensitizes insulin-producing cells to cytokine-mediated transcriptomic remodeling and cell death: a novel beta-cell anti-apoptotic response to inflammation

“…REV-ERBα mRNA and protein expressions were cytokine-coregulated and both potentiated by synchronization. Pharmacological activation of REV-ERBα impairs autophagy and insulin expression and secretion while promoting apoptosis in β-cells, likely through clock-independent transcriptional effects [24, 47]. The loss of β-cell function and increased apoptosis might be an effect of impaired autophagy, as loss of autophagy results in loss of β-cell mass in mice [48].…”

The role of autophagy in the treatment of type II diabetes and its complications: a review

“…BartoloméA et al (47) demonstrated that chronic overactivation of mTORC1 in a mouse model (b-tsc2 -/-) led to increased pancreatic b-cell death and impaired autophagy. In a separate study, Matthew R. Brown et al (48) found that negative regulation of REV-ERBa may improve b-cell function under glucotoxicity by enhancing autophagy. This was achieved by investigating the link between the core circadian clock nuclear receptor REV-ERBa, autophagy, and b-cell failure.…”

“…In a separate study, Matthew R. Brown et al. ( 48 ) found that negative regulation of REV-ERBα may improve β-cell function under glucotoxicity by enhancing autophagy. This was achieved by investigating the link between the core circadian clock nuclear receptor REV-ERBα, autophagy, and β-cell failure.…”

The relationship between HMGB1 and autophagy in the pathogenesis of diabetes and its complications

“…Therefore, inhibiting excessive apoptosis in pancreatic β cells is crucial for the treatment of DM. Studies have confirmed that impaired autophagy regulation is associated with pancreatic β-cell failure in type 2 diabetes (T2DM) ( 15 ). However, the mechanism of autophagy in type 1 diabetes remains unclear.…”