Type 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 Review
This 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.
Conclusions
Overall, previous studies by our group and others support a key role for epigenetics in the growing incidence of T2D.
Keywords
Epigenetics
DNA methylation
Type 2 diabetes
Abbreviations
BMI
body mass index
CIT
causal inference test
DMR
differentially methylated region
DNMT
DNA methyltransferase
eQTL
expression quantitative trait loci
EWAS
epigenome-wide association study
FH
family history
GWAS
genome-wide association study
HbA1c
glycated hemoglobin A1c
HDAC
histone deacetylase
HDL
high-density lipoprotein
HFD
high-fat diet
HOMA-IR
homeostatic model assessment for insulin resistance