Incretin Drugs Effect On Epigenetic Machinery: New Potential Therapeutic Implications In Preventing Vascular Diabetic Complications

The effect of GLP-1R agonists on DNA methylation levels ofNF-kappa BandSOD2genes in human aortic endothelial cells exposed to high glucose and in diabetic patients treated and not with incretin-based drugs, was evaluated. Methylation levels, mRNA and protein expression ofNF-kappa BandSOD2genes were measured in human endothelial cells exposed to high glucose for 7 days and treated with GLP-1R agonists. Methylation status ofNF-kappa BandSOD2promoter was also analyzed in 128 diabetics and 116 nondiabetics and correlated with intima media thickness (ITM), an early marker of atherosclerotic process. Cells exposed to high glucose showed lowerNF-kappa BandSOD2methylation levels, increased NF-kappa B and reduced SOD2 expression compared to normal glucose cells. Co-treatment with GLP-1 agonists prevented methylation and genes expression changes induced by high glucose. Both high glucose and incretins exposure increased DNA methyltransferases and demethylases levels. In diabetics, incretin treatment resulted a significant predictor ofNF-kappa BDNA methylation, independently of age, sex, body mass index (BMI), glucose and plasma lipid levels.NF-kappa BDNA methylation inversely correlated with IMT after adjusting for multiple covariates. Our results firstly provide new evidences of an additional mechanism by which incretin drugs could prevent vascular diabetic complications.