DNA methylation in the pathogenesis of type 2 diabetes in humans

Abstract

BackgroundType 2 diabetes (T2D) is a multifactorial, polygenic disease caused by impaired insulin secretion and insulin resistance. Genome-wide association studies (GWAS) were expected to resolve a large part of the genetic component of diabetes; yet, the single nucleotide polymorphisms identified by GWAS explain less than 20% of the estimated heritability for T2D. There was subsequently a need to look elsewhere to find disease-causing factors. Mechanisms mediating the interaction between environmental factors and the genome, such as epigenetics, may be of particular importance in the pathogenesis of T2D.Scope of ReviewThis review summarizes knowledge of the impact of epigenetics on the pathogenesis of T2D in humans. In particular, the review will focus on alterations in DNA methylation in four human tissues of importance for the disease; pancreatic islets, skeletal muscle, adipose tissue, and the liver. Case–control studies and studies examining the impact of non-genetic and genetic risk factors on DNA methylation in humans will be considered. These studies identified epigenetic changes in tissues from subjects with T2D versus non-diabetic controls. They also demonstrate that non-genetic factors associated with T2D such as age, obesity, energy rich diets, physical activity and the intrauterine environment impact the epigenome in humans. Additionally, interactions between genetics and epigenetics seem to influence the pathogenesis of T2D.ConclusionsOverall, previous studies by our group and others support a key role for epigenetics in the growing incidence of T2D.

Physical Exercise as Therapy for Type 2 Diabetes Mellitus: From Mechanism to Orientation

“…Based on these findings, it is speculated that an interaction between PA and susceptibility genes may also have a decreased effect on T2DM. Recently, DNA methylation is believed to be a potential epigenetic mechanism to explain the interactions between lifestyle changes and genetic variation [29,30]. Barrès et al [31] have observed that decreased DNA methylations in response to acute exercise intervention induced a dose-dependent expression of metabolic genes in human skeletal muscle.…”

DNMT3a and TET2 in adipocyte insulin sensitivity

“…It results from an intricate interaction between genetic make-up and environment, suggesting it's orchestrated by epigenetic mechanisms. In fact, a plethora of studies have found that changes in DNA methylation are associated with metabolic dysregulation [1, 2], but methylation's functional role is poorly understood.…”

IMAGE: high-powered detection of genetic effects on DNA methylation using integrated methylation QTL mapping and allele-specific analysis

“…DNA methylation is thus thought to play a key role in responding to the environment and generating trait variation, including variation in disease susceptibility. In support of this idea, methylation levels have been associated with diabetes [3,4], autoimmune diseases [5][6][7], metabolic disorders [8][9][10], neurological disorders [11,12], and various forms of cancer [13][14][15][16][17].…”