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Inhibiting Class IIa Histone Deacetylase (HDAC) function is a promising approach to therapeutically enhance skeletal and cardiac muscle metabolic health in several chronic diseases including type 2 diabetes. However, the importance of Class IIa HDACs in the beta-cell remains unknown. As beta-cell function is vital to maintaining glycaemia it is essential that the importance of Class IIa HDACs in the beta-cell is determined. Here we used the INS-1E cell line cultured in normal glucose (11.1 mM) or hyperglycaemic (20 mM) conditions for 48 hrs to represent cells in a normal and diabetic environment respectively. Cells cultured in high glucose showed significantly reduced insulin secretory function and increased apoptotic signalling compared to cells cultured in normal glucose. Class IIa HDACS, HDAC-4 and -5, were not regulated at the transcript or protein level under normal or hyperglycaemic conditions suggesting that they may not play a role in beta-cell dysfunction. Furthermore, overexpression of wild-type HDAC-4 and -5 or dominant negative HDAC-4 and -5 did not alter insulin secretion, insulin mRNA expression or apoptotic signalling under normal or hyperglycaemic conditions. This suggests that Class IIa Histone Deacetylases do not play an important physiological role in the beta-cell under normal or diabetic conditions. Thus, Class IIa Histone Deacetylase inhibitors are not likely to have a detrimental effect on beta-cells supporting the use of these inhibitors to treat metabolic diseases such as type 2 diabetes.