Epigenetic regulation of insulin action and secretion - role in the pathogenesis of type 2 diabetes

Abstract

The prevalence of type 2 diabetes (T2D) is rapidly increasing worldwide. Obesity, physical inactivity and ageing increase the risk of T2D. Epigenetic modifications can change due to environmental exposures and may thereby predispose to disease. This review aims at summarizing recent advances in epigenetics related to T2D, with a special focus on impaired insulin action and secretion in humans. There will be an emphasis on analyses in human tissues; both from T2D case-control cohorts and intervention studies. Current data support an important role for epigenetics in the pathogenesis of T2D. Numerous studies have found differential DNA methylation and gene expression in skeletal muscle, adipose tissue, the liver and pancreatic islets from subjects with T2D compared with nondiabetic controls. For example, PDX1 has increased DNA methylation and decreased expression in pancreatic islets from patients with T2D compared with nondiabetic controls. Nongenetic risk factors for T2D such as ageing, unhealthy diets and physical activity do also impact the epigenome in human tissues. Interestingly, physical activity altered DNA methylation of candidate genes for T2D such as THADA in muscle and FTO, KCNQ1 and TCF7L2 in adipose tissue. There is also a strong interaction between genetic and epigenetic factors that together seem to affect T2D. mQTL studies in human adipose tissue and pancreatic islets showed that SNPs associated with DNA methylation levels in numerous sites. Several of these SNPs are also associated with T2D. Recent data also support that DNA methylation of some sites in blood may be developed into biomarkers that predict T2D since methylation of, for example TXNIP, ABCG1 and SREBF1 associated with future T2D. Future studies should use this information for development of new therapies and biomarkers and thereby improve prediction, prevention and treatment of T2D and its complications.

Keywords: ATAC-seq; DNA methylation; Epigenetics; Type 2 diabetes; chromatin structure; diet; exercise; histone modifications; insulin action; insulin resistance; insulin secretion; precision medicine.