New insight in molecular mechanisms regulating SIRT6 expression in diabetes: Hyperglycaemia effects on SIRT6 DNA methylation

Conflicting data are reported on the relationship between hyperglycaemia, diabetes and SIRT6 expression. To elucidate hyperglycaemia-induced molecular mechanisms regulating SIRT6 expression, the effect of hyperglycaemia on DNA methylation and SIRT6 expression has been evaluated in human aortic endothelial cells exposed to high glucose. DNA methylation of SIRT6 and any potential clinical implication was also evaluated in type 2 diabetic patients and compared with healthy controls. Endothelial cells exposed to high glucose showed lower methylation levels in SIRT6 promoter and increased SIRT6 and TET2 expression. The high glucose-induced epigenetic changes persisted after 48 h of glucose normalization. Diabetic patients showed lower levels of SIRT6 DNA methylation compared with nondiabetic patients. SIRT6 DNA methylation levels inversely correlated with plasma glucose. Our results firstly demonstrate the involvement of epigenetic mechanisms in regulating SIRT6 expression. Further experiments are necessary to clarify metabolic memory mechanisms driving to diabetic complications and how SIRT6 is potentially involved.

Automated summary

Conflicting data exist on the relationship between hyperglycaemia, diabetes, and SIRT6 expression. This study found that high glucose exposure led to lower DNA methylation in the SIRT6 promoter, increased expression of SIRT6 and TET2, and persisting epigenetic changes after glucose normalization. Diabetic patients had lower SIRT6 DNA methylation levels that correlated inversely with plasma glucose levels, indicating the involvement of epigenetic mechanisms in regulating SIRT6 expression.