Pinzón-Cortés Jairo Arturo, Perna-Chaux Angelina, Rojas-Villamizar Nicolás Steven, Díaz-Basabe Angélica, Polanía-Villanueva Diana Carolina, Jácome María Fernanda, Mendivil Carlos Olimpo, Groot Helena, López-Segura Valeriano
Biological Sciences DepartmentLaboratory of Human Genetics, Universidad de los Andes, Bogotá, Colombia.
School of MedicineUniversidad de los Andes, Bogotá, Colombia.
Endocr Connect. 2017 Nov;6(8):708-725. doi: 10.1530/EC-17-0199. Epub 2017 Oct 9.
Type 2 diabetes mellitus (T2DM) is characterized by oxidative stress that could lead to chronic micro- and macrovascular complications. We hypothesized that some of the target organ damage is mediated by oxidative alterations in epigenetic mechanisms involving DNA methylation (5mC) and DNA hydroxymethylation (5hmC). We analyzed global DNA methylation and hydroxymethylation in peripheral blood cells in well-controlled and poorly controlled patients with T2DM and compared them with healthy controls. We also analyzed microarrays of DNA methylation and gene expression of other important tissues in the context of diabetes from the GEO database repository and then compared these results with our experimental gene expression data. DNA methylation and, more importantly, DNA hydroxymethylation levels were increased in poorly controlled patients compared to well-controlled and healthy individuals. Both 5mC and 5hmC measurements were correlated with the percentage of glycated hemoglobin, indicating a direct impact of hyperglycemia on changes over the epigenome. The analysis of methylation microarrays was concordant, and 5mC levels were increased in the peripheral blood of T2DM patients. However, the DNA methylation levels were the opposite of those in other tissues, such as the pancreas, adipose tissue and skeletal muscle. We hypothesize that a process of DNA oxidation associated with hyperglycemia may explain the DNA demethylation in which the activity of ten-eleven translocation (TET) proteins is not sufficient to complete the process. High levels of glucose lead to cellular oxidation, which triggers the process of DNA demethylation aided by TET enzymes, resulting in epigenetic dysregulation of the damaged tissues.
2型糖尿病（T2DM）的特征是氧化应激，这可能导致慢性微血管和大血管并发症。我们推测，一些靶器官损伤是由涉及DNA甲基化（5mC）和DNA羟甲基化（5hmC）的表观遗传机制中的氧化改变介导的。我们分析了血糖控制良好和控制不佳的T2DM患者外周血细胞中的整体DNA甲基化和羟甲基化，并将其与健康对照进行比较。我们还从GEO数据库存储库中分析了糖尿病背景下其他重要组织的DNA甲基化微阵列和基因表达，然后将这些结果与我们的实验基因表达数据进行比较。与血糖控制良好的患者和健康个体相比，控制不佳的患者的DNA甲基化水平，更重要的是DNA羟甲基化水平升高。5mC和5hmC测量值均与糖化血红蛋白百分比相关，表明高血糖对表观基因组变化有直接影响。甲基化微阵列分析结果一致，T2DM患者外周血中的5mC水平升高。然而，DNA甲基化水平与胰腺、脂肪组织和骨骼肌等其他组织中的情况相反。我们推测，与高血糖相关的DNA氧化过程可能解释了DNA去甲基化，即十一-易位（TET）蛋白的活性不足以完成该过程。高水平的葡萄糖会导致细胞氧化，从而触发由TET酶辅助的DNA去甲基化过程，导致受损组织的表观遗传失调。
