Vujcic Sanja, Kotur-Stevuljevic Jelena, Vujcic Zoran, Stojanovic Sanja, Beljic Zivkovic Teodora, Vuksanovic Miljanka, Marjanovic Petkovic Milica, Perovic Blagojevic Iva, Koprivica-Uzelac Branka, Ilic-Mijailovic Sanja, Rizzo Manfredi, Zeljkovic Aleksandra, Stefanovic Tatjana, Bosic Srecko, Vekic Jelena
Department of Medical Biochemistry, University of Belgrade-Faculty of Pharmacy, 11000 Belgrade, Serbia.
Department of Biochemistry, University of Belgrade-Faculty of Chemistry, 11000 Belgrade, Serbia.
Int J Mol Sci. 2025 Jul 13;26(14):6716. doi: 10.3390/ijms26146716.
Although emerging evidence suggests that epigenetic mechanisms contribute to the pathogenesis and progression of type 2 diabetes mellitus (T2DM), data remain limited for patients with suboptimal metabolic control. The aim of this study was to assess global DNA methylation in patients with poorly controlled T2DM and to identify diabetes-related factors associated with DNA methylation levels. The study included 107 patients and 50 healthy controls. Global DNA methylation (5mC) was measured by UHPLC-DAD method. Pro-oxidant and antioxidant biomarkers, advanced glycation end-products, high-sensitivity C-reactive protein (hsCRP) and complete blood count were determined and leukocyte indices calculated. Patients had a significantly lower 5mC than controls (3.56 ± 0.31% vs. 4.00 ± 0.68%; < 0.001), with further reductions observed in those with longer disease duration and diabetic foot ulcers. Oxidative stress and inflammatory biomarkers were higher in the patient group. DNA hypomethylation was associated with a higher monocyte-to-lymphocyte ratio and hsCRP, pro-oxidant-antioxidant balance, ischemia-modified albumin, and advanced oxidation protein products levels. Conversely, 5mC levels showed positive correlations with total antioxidant status and total sulfhydryl groups. Principal component analysis identified five key factors: proinflammatory, pro-oxidant, aging, hyperglycemic, and antioxidant. The pro-oxidant factor emerged as the sole independent predictor of global DNA hypomethylation in T2DM (OR = 2.294; = 0.027). Our results indicate that global DNA hypomethylation could be a biomarker of T2DM progression, reflecting the complex interactions between oxidative stress, inflammation, and epigenetic modifications in T2DM.
尽管新出现的证据表明表观遗传机制在2型糖尿病（T2DM）的发病机制和进展中起作用，但对于代谢控制欠佳的患者，相关数据仍然有限。本研究的目的是评估T2DM控制不佳患者的全基因组DNA甲基化情况，并确定与DNA甲基化水平相关的糖尿病相关因素。该研究纳入了107例患者和50名健康对照。采用超高效液相色谱-二极管阵列检测法（UHPLC-DAD）测定全基因组DNA甲基化（5mC）。测定促氧化剂和抗氧化生物标志物、晚期糖基化终产物、高敏C反应蛋白（hsCRP）及全血细胞计数，并计算白细胞指数。患者的5mC水平显著低于对照组（3.56±0.31%对4.00±0.68%；P<0.001），病程较长和患有糖尿病足溃疡的患者中5mC水平进一步降低。患者组的氧化应激和炎症生物标志物水平较高。DNA低甲基化与较高的单核细胞与淋巴细胞比值、hsCRP、促氧化剂-抗氧化剂平衡、缺血修饰白蛋白及晚期氧化蛋白产物水平相关。相反，5mC水平与总抗氧化状态和总巯基呈正相关。主成分分析确定了五个关键因素：促炎、促氧化、衰老、高血糖和抗氧化。促氧化因素是T2DM全基因组DNA低甲基化的唯一独立预测因子（OR=2.294；P=0.027）。我们的结果表明，全基因组DNA低甲基化可能是T2DM进展的生物标志物，反映了T2DM中氧化应激、炎症和表观遗传修饰之间的复杂相互作用。
