Role of epigenetic mechanisms in the development of chronic complications of diabetes

Genetic factors cannot independently explain the causes of chronic complications associated with diabetes mellitus (DM). It indicates that epigenetic regulation of gene expression including posttranslational histone modifications (PTHMs), DNA methylation and microRNA (miRNA)-regulation of mRNA translation could play a crucial role in the development of chronic complications. Hyperglycemia (HG) induces an abnormal action of PTHMs and DNA methyltransferases as well as alters the levels of numerous miRNAs in endothelial cells, vascular smooth muscle cells, cardiomyocytes, retina, and renal cells. These epigenetic abnormalities result in changes in the expression of numerous genes contributing to development of chronic inflammation, impaired clearance of reactive oxygen species (ROS), endothelial cells dysfunction and/or accumulation of extracellular matrix in the kidney, causing development of retinopathy, nephropathy or cardiomyopathy. Some of epigenetic modifications, as PTHMs and DNA methylation, become over time irreversible. These epigenetic changes could explain the "metabolic memory", a phenomenon related to the harmful effect of HG which gives cells a constant pathogenic character causing development of chronic complications even after normoglycemia is achieved. In conclusion, the knowledge summarized in this review suggests that the treatment of chronic complications should focus on erasing metabolic memory by targeting chromatin modification enzymes and by restoring miRNAs levels