Skewed Epigenetics: An Alternative Therapeutic Option for Diabetes Complications

Abstract

Vascular complications are major causes of morbidity and mortality in type 2 diabetes patients. Mitochondrial reactive oxygen species (ROS) generation and a lack of efficient antioxidant machinery, a result of hyperglycaemia, mainly contribute to this problem. Although advances in therapy have significantly reduced both morbidity and mortality in diabetic individuals, diabetes-associated vascular complications are still one of the most challenging health problems worldwide. New healing options are urgently needed as current therapeutics are failing to improve long-term outcomes. Particular effort has recently been devoted to understanding the functional relationship between chromatin structure regulation and the persistent change in gene expression which is driven by hyperglycaemia and which accounts for long-lasting diabetic complications. A detailed investigation into epigenetic chromatin modifications in type 2 diabetes is underway. This will be particularly useful in the design of mechanism-based therapeutics which interfere with long-lasting activating epigenetics and improve patient outcomes. We herein provide an overview of the most relevant mechanisms that account for hyperglycaemia-induced changes in chromatin structure; the most relevant mechanism is called "metabolic memory."

Figure 1

Schematic representation of epigenetic mechanisms in diabetic setting. In the nucleus ROS-mediated histone acetylation/methylation as well as DNA methylation accounts for gene transcriptional activation or repression. In the cytoplasm ROS-mediated changes in miR expression drive posttranscriptional regulation of target genes. Such epigenetic changes impact long-term diabetes-associated complications. HTAs: histone acetyltransferases; HMTs: histone methyltransferases; DMT: DNA methyltransferase; ROS: reactive oxygen species; miRs: microRNAs; Lys: lysine; Arg: arginine; –COCH₃: acetyl radical; –CH₃: methyl radical.