Date Published: July 20, 2017
Publisher: Public Library of Science
Author(s): Sanne D. van Otterdijk, Alexandra M. Binder, Katarzyna Szarc vel Szic, Julia Schwald, Karin B. Michels, Yvonne Böttcher.
The prevalence of type 2 diabetes (T2D) and the metabolic syndrome (MetS) is increasing and several studies suggested an involvement of DNA methylation in the development of these metabolic diseases. This study was designed to investigate if differential DNA methylation in blood can function as a biomarker for T2D and/or MetS.
Pyrosequencing analyses were performed for the candidate genes KCNJ11, PPARγ, PDK4, KCNQ1, SCD1, PDX1, FTO and PEG3 in peripheral blood leukocytes (PBLs) from 25 patients diagnosed with only T2D, 9 patients diagnosed with T2D and MetS and 11 control subjects without any metabolic disorders.
No significant differences in gene-specific methylation between patients and controls were observed, although a trend towards significance was observed for PEG3. Differential methylation was observed between the groups in 4 out of the 42 single CpG loci located in the promoters regions of the genes FTO, KCNJ11, PPARγ and PDK4. A trend towards a positive correlation was observed for PEG3 methylation with HDL cholesterol levels.
Altered levels of DNA methylation in PBLs of specific loci might serve as a biomarker for T2D or MetS, although further investigation is required.
The prevalence of metabolic diseases has been rising worldwide as a consequence of the increasing rate of obesity and sedentary lifestyles. Two prominent metabolic diseases are diabetes mellitus type 2 (T2D) and the metabolic syndrome (MetS). While T2D encompasses insulin resistance, MetS encompasses a more complex network of risk factors and symptoms that predisposes to diabetes and cardiovascular diseases. The symptoms of MetS include elevated blood pressure, dyslipidemia, raised fasting glucose and central obesity. The main risk factors for metabolic diseases, namely low physical activity, genetic predisposition and poor diet, are also factors which can modify DNA methylation and other epigenetic patterns[3,4].
In this study we analysed DNA methylation levels of a subset of candidate genes in PBL from patients diagnosed with T2D or MetS and control subjects without a metabolic disorder. All of the genes analysed in this study were previously reported to have a potential importance in the development of metabolic diseases and play critical roles in glucose metabolism, adipogenesis and/or insulin secretion[21–26]. Differential methylation was observed in previous studies for most of these genes between patients diagnosed with either T2D or MetS and control subjects in adipose tissues, muscles and/or pancreatic islets[12–16,28]. Our analyses in PBLs revealed no significant difference in methylation levels between the MetS patients, T2D patients and controls subjects, although a trend towards significance was observed for PEG3. A trend towards a positive correlation was also observed for PEG3 methylation with HDL cholesterol levels. PEG3 is a mediator of p53, which in turn directly influences various metabolic pathways, enabling cells to respond to metabolic stress. These functions are likely to be important for restraining the development of cancer but may also have a profound effect on the development of metabolic diseases, including diabetes. p53 plays a role in central carbon and lipid metabolism and it downregulates HDL[32,33]. As a mediator of P53, PEG3 methylation may contribute to the development of metabolic dysfunction by altering the response of cells to metabolic stress. Our study suggests that altered PEG3 DNA methylation may be present in PBL of patients with a metabolic disorder. Unfortunately our study only included 45 individuals, so additional studies are necessary to explore this relation in greater detail.