Type 2 diabetes is a polygenic disease characterized by hyperglycaemia due to impaired pancreatic beta-cell function and insulin resistance in peripheral target tissues such as skeletal muscle, adipose tissue and the liver. The disease develops as a conspiracy between the genetic background and the environment. Recent genome-wide association studies have identified more than 60 genetic variants associated with type 2 diabetes. Moreover, ageing, physical inactivity and obesity represent non-genetic risk factors for type 2 diabetes. The interaction between genes and environment may involve epigenetic factors, such as DNA methylation and histone modifications, to promote type 2 diabetes. Indeed, recent studies from our group and others propose that epigenetic factors play an important role in the growing incidence of type 2 diabetes. We were the first to demonstrate that DNA methylation plays a role in gene regulation in pancreatic islets from patients with type 2 diabetes. Additionally, we have performed genome-wide analyses of DNA methylation in pancreatic islets, skeletal muscle, adipose tissue and the liver from subjects with type 2 diabetes and non-diabetic controls. In these studies, we identified epigenetic alterations that are likely to contribute to the development of diabetes. We have also shown that age, diet, physical activity, birth weight and genetic variation influence the DNA methylation pattern in human pancreatic islets, skeletal muscle, adipose tissue and the liver. Nevertheless, our knowledge about the epigenetic mechanisms linking environmental factors and type 2 diabetes remains limited.
The overall objective of our research is to identify the key epigenetic mechanisms influencing the pathogenesis of T2D.
We are currently analysing DNA methylation and histone modifications in a number of human cohorts. Here, we examine if non-genetic and genetic factors as well as type 2 diabetes affect epigenetic variation in human tissues (Figure 1). We are further relating DNA methylation to gene expression, in vivo metabolism and type 2 diabetes. Furthermore, we are dissecting the role of epigenetic enzymes in development of type 2 diabetes.
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