Epigenetics and Type 2 Diabetes Risk

Abstract

Purpose of review: The influence of environmental factors on type 2 diabetes (T2D) risk is now well recognized and highlights the contribution of epigenetic mechanisms. This review will focus on the role of epigenetic factors in the risk and pathogenesis of T2D.

Recent findings: Epigenetic dysregulation has emerged as a key mechanism underpinning the pathogenesis of T2D and its complications. Environmental variations, including alterations in lifestyle, nutrition, and metabolic demands during prenatal and postnatal life can induce epigenetic changes that may impact glucose homeostasis and the function of different metabolic organs. Accumulating data continues to uncover the specific pathways that are epigenetically dysregulated in T2D, providing an opportunity for therapeutic targeting. Environmental changes can disrupt specific epigenetic mechanisms underlying metabolic homeostasis, thus contributing to T2D pathogenesis. Such epigenetic changes can be transmitted to the next generation, contributing to the inheritance of T2D risk. Recent advances in epigenome-wide association studies and epigenetic editing tools present the attractive possibility of identifying epimutations associated with T2D, correcting specific epigenetic alterations, and designing novel epigenetic biomarkers and interventions for T2D.

Keywords: Biomarkers; Diabetes complications; Epigenetic therapies; Epigenetics; Glucose homeostasis; Type 2 diabetes.

Conflict of interest statement

Conflict of Interest

Sangeeta Dhawan declares no conflict of interest.

Rama Natarajan reports a pending patent on inhibitors of epigenetically modified targets.

Figures

Figure 1.

Variations in environmental factors such as nutritional status (diet), activity (sedentary lifestyle), circadian rhythms (sleep disruption), seasonal changes in temperature, and even aging can alter the cellular epigenome. These changes may occur in the histone modifications, DNA methylation patterns, chromatin accessibility, as well as the expression of non-coding RNA species such as lncRNAs and miRNAs. The epigenetic dysregulation in response to adverse environmental exposure in turn drives transcriptional changes across several tissues such as the insulin producing beta-cells and insulin sensitive organs including liver, muscle, and adipose. This can eventually induce a deficit of functional beta-cell mass and impaired insulin secretion, as well as drive insulin resistance, thus disrupting glucose homeostasis towards the pathogenesis of T2D. In addition, epigenetic alterations in vascular cells, kidney, retina, neurons, and immune cells can lead to multiple micro- and macro-vascular complications of diabetes. Finally, epigenetic changes in response to adverse environment can also occur in the germline and be potentially transmitted to the offspring, contributing to the inheritance of T2D risk.

Figure 2.

Hyperglycemia in T2D can activate multiple pathways such as signaling via AGEs, AngII and TGF-beta, as well as induce a milieu of cellular-stress. This can lead to dysregulation of different epigenetic mechanisms such as histone modifications, DNA methylation, and ncRNAs, and consequently alter chromatin accessibility and gene expression profiles in multiple tissues, resulting in the development of diabetes complications. Such aberrant epigenetic patterns can persist and lead to metabolic memory, such that there is increased risk of developing diabetes complications even after achieving glycemic control.