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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., Competing Interests: The authors declare no competing interests., (© 2024 The Author(s).)

Coordinated communication among pancreatic islet cells is necessary for maintenance of glucose homeostasis. In diabetes, chronic exposure to pro-inflammatory cytokines has been shown to perturb β cell communication and function. Compelling evidence has implicated extracellular vesicles (EVs) in modulating physiological and pathological responses to β cell stress. We report that pro-inflammatory β cell small EVs (cytokine-exposed EVs [cytoEVs]) induce β cell dysfunction, promote a pro-inflammatory islet transcriptome, and enhance recruitment of CD8 + T cells and macrophages. Proteomic analysis of cytoEVs shows enrichment of the chemokine CXCL10, with surface topological analysis depicting CXCL10 as membrane bound on cytoEVs to facilitate direct binding to CXCR3 receptors on the surface of β cells. CXCR3 receptor inhibition reduced CXCL10-cytoEV binding and attenuated β cell dysfunction, inflammatory gene expression, and leukocyte recruitment to islets. This work implies a significant role of pro-inflammatory β cell-derived small EVs in modulating β cell function, global gene expression, and antigen presentation through activation of the CXCL10/CXCR3 axis., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)