Lysine deacetylases (KDACs) regulate posttranslational lysine acetylation of not only histone tails but of numerous other nuclear and cytosolic protein lysine residues in a balance with lysine acetyl transferases (KATs). The histone acetylation status is an important determinant of the epigenetic histone code that dynamically alters gene transcription. Gene expression is also affected by the acetylation of transcription factors and of signalling pathway proteins. Acetylation further regulates protein activity and thereby controls most cellular functions, including cell division, differentiation, stress responses and apoptosis. High-dose KDAC inhibitors are registered for certain neoplastic diseases and low-dose KDAC inhibitors are effective and safe in clinical trials in Systemic-onset juvenile idiopathic arthritis and Graft-versus-host disease.
Contrary to an expected increase in proinflammatory gene expression as a result of histone hyperacetylation, conventionally associated with open chromatin accessible to the transcriptional machinery, KDAC inhibition leads to potent inhibition of the expression of chemokines and proinflammatory cytokines including IL-1.
The preclinical evidence favouring that KDAC inhibitors fulfil the need for a novel class of safe and effective antidiabetic drugs is presented. Mechanisms of action are reviewed that suggest KDAC inhibition to target both immune effectors as well as to improve beta-cell protection against both metabolic and inflammatory insults. This evidence warrants development of selective KDAC inhibitors for clinical trials in diabetes.