The reduction of pancreatic beta cell mass is one of the key factors for the onset of type 2 diabetes. Many reports have indicated that insulin signaling is important for type 2 diabetes, but the mechanism by which insulin signaling is altered in pancreatic beta cells remains unclear. This study was designed to examine the role of histone deacetylases (HDACs) in the regulation of insulin signaling in pancreatic beta cells. We found that insulin signaling was downregulated by inhibition of HDAC6. HDAC6 expression was specifically observed in pancreatic beta cells and was decreased in the pancreatic islets of a type 2 diabetes mouse model. When a mouse pancreatic beta cell line (MIN6 cells) was treated with palmitic acid to mimic the effect of a high-fat diet on pancreatic beta cells, HDAC6 was imported into the nucleus. These results suggest that HDAC6 plays an important role in the regulation of insulin signaling in pancreatic beta cells. Therefore, clarifying the regulation of insulin signaling by HDAC6 may be a valuable approach for the treatment of type 2 diabetes. (C) 2020 Elsevier Inc. All rights reserved.