Could targeting certain enzymes for diabetes treatment leave insulin-producing cells unharmed?

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Inhibiting Class IIa histone deacetylase (HDAC) function is a promising approach to improving skeletal and cardiac muscle metabolic health in several chronic diseases, including type 2 diabetes. However, the importance of these enzymes in beta-cells remained unknown. Because beta-cell function is vital to maintaining blood glucose levels, the researchers sought to determine the importance of Class IIa HDACs in these cells.

In this in vitro experiment, the researchers cultured the INS-1E cell line for 48 hours in normal glucose (11.1 mM) or high-glucose conditions (20 mM), representing normal and diabetic environments, respectively. Cells cultured in high glucose showed significantly reduced insulin secretory function and increased apoptotic signalling compared with cells cultured in normal glucose.

The Class IIa HDACs HDAC-4 and HDAC-5 showed no regulation at the transcript or protein level under normal or high-glucose conditions, suggesting that they may not play a role in beta-cell dysfunction. Overexpression of wild-type HDAC-4 and HDAC-5 or dominant-negative HDAC-4 and HDAC-5 did not alter insulin secretion, insulin mRNA expression or apoptotic signalling under either glucose condition.

The findings suggest that Class IIa HDACs do not play an important physiological role in beta-cells under normal or diabetic conditions. The authors therefore conclude that Class IIa HDAC inhibitors are unlikely to have a detrimental effect on beta-cells, supporting their use to treat metabolic diseases such as type 2 diabetes.