Abstract
BackgroundAccumulating evidence suggests that epigenetic changes play key roles in the pathogenesis of type 2 diabetes mellitus (T2DM). However, the dynamic regulation of 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC) in diabetic peripheral blood DNA remains to be elucidated.ResultsWe collected fasting blood samples (104 patients and 108 healthy controls) and glucose-stimulated blood samples at different time points (11 patients and 5 healthy controls underwent oral glucose tolerance test (OGTT)), as well as blood samples from six couples of diabetic and control rats. A HPLC-MS/MS system was used for quantifying global 5mC and 5hmC in genomic DNA from white blood cells (WBCs), and qPCR was performed for detecting mRNA expression of SIRT6 and TETs. We found that global 5mC decreased, while global 5hmC increased in both patients and diabetic rats, with lower 5mC being a risk factor of T2DM (OR = 0.524, 95%CI 0.402–0.683, p = 1.64 × 10−6). The OGTT data from patients showed that 5mC declined within 1 h and then returned to the fasting status at 2 h, while 5hmC rose from 0.5 h to 3 h with increasing glucose. However, the similar patterns were not found in the controls. The mRNA expression of TET2, TET3, and SIRT6 was upregulated in patients (p = 0.012, p = 0.026, and p = 0.035, respectively). The similar results were observed in diabetic OGTT and rats. Correlation analysis indicated that SIRT6 was positively correlated with TET2 in humans (r = 0.277, p < 0.001) and rats (r = 0.942, p < 0.001), in addition to a correlation between glucose and SIRT6 (r = 0.162, p = 0.045) and TET2 (r = 0.174, p = 0.036).ConclusionsHyperglycemia appeared to promote the mRNA expression of SIRT6 and TETs, which in turn might cause the dynamic changes of 5mC and 5hmC in WBCs from T2DM patients.
Highlights
Accumulating evidence suggests that epigenetic changes play key roles in the pathogenesis of type 2 diabetes mellitus (T2DM)
Pearson correlation analysis indicated that glucose was correlated with TG, total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C) and Glycated hemoglobin (HbA1c) (Additional file 1: Table S1)
Our results demonstrated that 5mC decrease and 5hmC increase were mediated by glucose in T2DM patients and diabetic rats through upregulation of Sirtuin 6 (SIRT6) and Ten-eleven translocation proteins (TETs)
Summary
Accumulating evidence suggests that epigenetic changes play key roles in the pathogenesis of type 2 diabetes mellitus (T2DM). The dynamic regulation of 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC) in diabetic peripheral blood DNA remains to be elucidated. With an increasing incidence of obesity, diabetes has become a worldwide epidemic [1], which represents the sixth leading cause of disability, an overwhelming burden on individuals and global healthcare systems [2]. 2017, with an estimated increase to 629 million by 2045. About > 90% of patients have type 2 diabetes mellitus (T2DM) [2], which is a chronic, complex metabolic syndrome caused by the interaction of genetics, epigenetics, and environmental factors, including obesity, physical inactivity, and aging [3,4,5]. DNA methylation modification is a dynamic process in which methylation could be synthesized de
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