Core circadian transcription factor Bmal1 mediates β cell response and recovery from pro-inflammatory injury

The circadian clock plays a vital role in modulating the cellular immune response. However, its role in mediating pro-inflammatory diabetogenic β cell injury remains largely unexplored. Our studies demonstrate that the exposure of β cells to IL-1β-mediated inflammation alters genome-wide DNA binding of core circadian transcription factors BMAL1:CLOCK enriched for genomic sites important for cellular response to inflammation. Correspondingly, conditional deletion of Bmal1 in mouse β cells was shown to impair the ability of β cells to recover from streptozotocin-mediated pro-inflammatory injury in vivo, leading to β cell failure and the development of diabetes. Further data integration analysis revealed that the β cell circadian clock orchestrates the recovery from pro-inflammatory injury by regulating transcriptional responses to oxidative stress, DNA damage, and nuclear factor κB(NF-κB)-driven inflammation. Our study suggests that the β cell circadian clock mediates β cell response and recovery from pro-inflammatory injury common to the pathogenesis of diabetes mellitus.