Extrinsic and intrinsic factors influencing metabolic memory in type 2 diabetes.

Direct and indirect influence of pathological conditions in Type 2 Diabetes (T2D) on vasculature manifests in micro and/or macro vascular complications that act as a major source of morbidity and mortality. Although preventive therapies exist to control hyperglycemia, diabetic subjects are always at risk to accrue vascular complications. One of the hypotheses explained is 'glycemic' or 'metabolic' memory, a process of permanent epigenetic change in different cell types whereby diabetes associated vascular complications continue despite glycemic control by antidiabetic drugs. Epigenetic mechanisms including DNA methylation possess a strong influence on the association between environment and gene expression, thus indicating its importance in the pathogenesis of a complex disease such as T2D. The vascular system is more prone to environmental influences and present high flexibility in response to physiological and pathological challenges. DNA methylation based epigenetic changes during metabolic memory are influenced by sustained hyperglycemia, inflammatory mediators, gut microbiome composition, lifestyle modifications and gene-nutrient interactions. Hence, understanding underlying mechanisms in manifesting vascular complications regulated by DNA methylation is of high clinical importance. The review provides an insight into various extrinsic and intrinsic factors influencing the regulation of DNA methyltransferases contributing to the pathogenesis of vascular complications during T2D.