The role of epigenetic modifications in the formation of heterogeneous phenotypes in diabetes mellitus (a literature review)

Abstract

This review article provides a summary and update on the role of epigenetic mechanisms in predisposition and progression of diabetes, analyzes the data concerning the cause-and-effect relationship between epigenetic changes and the emergence of distinct metabolic phenotypes. Extensive genetic research has enabled the isolation of a group of genes associated with a high risk of developing diabetes. However, numerous data point to the key role of so-called epigenetic modifications in the interaction between genes and the environment, which arise during ontogenesis based on the existing genotype under the influence of external factors. These modifications do not affect the primary DNA sequence, but influence gene expression through chemical modification and alteration of the secondary structure of DNA molecules and chromatin. Epigenetic mechanisms can program pathological phenotypes in subsequent generations. The main molecular mechanisms of epigenetic modifications are DNA methylation, histone and miRNA modification. Changes in the expression of genes that ensure the synthesis of key enzymes and regulatory molecules lead to disruption in the main signaling metabolic pathways. Deregulation of genes responsible for inflammatory, atherosclerotic and other pathological processes, in particular, leads to endothelial dysfunction and development of diabetic complications, such as cardiovascular diseases, diabetic nephropathy, retinopathy, neuropathy. Hyperglycemia, oxidative stress, inflammatory factors are known as mediators in the pathogenesis of type 2 diabetes and its complications. Since epigenetic modifications are reversible, the methylation process can be influenced by exercise, dietary, lifestyle changes and pharmacological agents such as methyl group donors. For example, S-adenosylmethionine, through participation in methylation reactions, can modulate the folate cycle function and production of homocysteine, an endothelium-toxic substance. Thus, the study of molecular modifications in chromatin structure and the features of activation and inhibition of various signaling pathways is a pressing task, the resolution of which will enable a deeper understanding of the pathogenesis of diabetes and the development of approaches to correct metabolic disorders.