Lysine deacetylase inhibition prevents diabetes by chromatin-independent immunoregulation and β-cell protection

• Type 1 diabetes is due to immune-mediated pancreatic β-cell destruction. Lysine deacetylase inhibitors (KDACi) protect β-cells from inflammatory destruction in vitro and are promising immunomodulators. The orally active and clinically well-tolerated KDACi vorinostat and givinostat reverted diabetes in a mouse model of type 1 diabetes and counteracted inflammatory target cell damage. Importantly, these effects were achieved with doses that are safe and effective in human inflammatory diseases. Of note, the mechanism of action was compatible with transcription factor—rather than global chromatin—hyperacetylation, causing inhibition of transcription factor binding and reduction of proinflammatory gene expression in leukocytes and β-cells. These data provide a rationale for clinical trials of safety and efficacy of KDACi in patients with Type 1 diabetes.

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