Phenylbutyrate and β-cell function: contribution of histone deacetylases and ER stress inhibition

Incidences of diabetes are increasing globally due to involvement of genetic and epigenetic factors. Phenylbutyrate (PBA) is a US FDA approved drug for treatment of urea cycle disorder in children. PBA reduces endoplasmic reticulum (ER) stress and is proven as a potent histone deacetylases (HDACs) inhibitor. Chronic ER stress results in unfolding protein response, which triggers apoptosis. Abnormal ER homoeostasis is responsible for defective processing of several genes/proteins and contributes to beta-cell death/failure. Accumulated evidences indicated that HDACs modulate key biochemical pathways and HDAC inhibitors improve beta-cell function and insulin resistance by modulating multiple targets. This review highlights the role of PBA on beta-cell functions, insulin resistance for possible treatment of diabetes through inhibition of ER stress and HDACs.