Ulster University, Sport and Exercise Sciences Research Institute, Newtownabbey, Northern Ireland, UK.
Ulster University, Genomic Medicine Research Group, Biomedical Sciences Research Institute, Coleraine, Northern Ireland, UK.
Free Radic Biol Med. 2021 Jul;170:194-206. doi: 10.1016/j.freeradbiomed.2020.12.025. Epub 2021 Jan 8.
The prevalence of type 2 diabetes mellitus (T2DM) continues to rise globally. Yet the aetiology and pathophysiology of this noncommunicable, polygenic disease, is poorly understood. Lifestyle factors, such as poor dietary intake, lack of exercise, and abnormal glycaemia, are purported to play a role in disease onset and progression, and these environmental factors may disrupt specific epigenetic mechanisms, leading to a reprogramming of gene transcription. The hyperglycaemic cell per se, alters epigenetics through chemical modifications to DNA and histones via metabolic intermediates such as succinate, α-ketoglutarate and O-GlcNAc. To illustrate, α-ketoglutarate is considered a salient co-factor in the activation of the ten-eleven translocation (TET) dioxygenases, which drives DNA demethylation. On the contrary, succinate and other mitochondrial tricarboxylic acid cycle intermediates, inhibit TET activity predisposing to a state of hypermethylation. Hyperglycaemia depletes intracellular ascorbic acid, and damages DNA by enhancing the production of reactive oxygen species (ROS); this compromised cell milieu exacerbates the oxidation of 5-methylcytosine alongside a destabilisation of TET. These metabolic connections may regulate DNA methylation, affecting gene transcription and pancreatic islet β-cell function in T2DM. This complex interrelationship between metabolism and epigenetic alterations may provide a conceptual foundation for understanding how pathologic stimuli modify and control the intricacies of T2DM. As such, this narrative review will comprehensively evaluate and detail the interplay between metabolism and epigenetic modifications in T2DM.
2 型糖尿病（T2DM）的患病率在全球范围内持续上升。然而，这种非传染性、多基因疾病的病因和病理生理学仍知之甚少。生活方式因素，如不良的饮食摄入、缺乏运动和异常的血糖水平，据称在疾病的发生和进展中发挥作用，这些环境因素可能会破坏特定的表观遗传机制，导致基因转录的重新编程。高血糖细胞本身通过代谢中间产物如琥珀酸、α-酮戊二酸和 O-GlcNAc 对 DNA 和组蛋白进行化学修饰，从而改变表观遗传学。例如，α-酮戊二酸被认为是激活 ten-eleven 易位（TET）双加氧酶的重要辅助因子，该酶驱动 DNA 去甲基化。相反，琥珀酸和其他线粒体三羧酸循环中间产物抑制 TET 活性，导致高甲基化状态。高血糖会消耗细胞内抗坏血酸，并通过增强活性氧（ROS）的产生来损伤 DNA；这种受损的细胞环境会加剧 5-甲基胞嘧啶的氧化，同时使 TET 不稳定。这些代谢联系可能调节 DNA 甲基化，影响 T2DM 中的基因转录和胰岛β细胞功能。代谢与表观遗传改变之间的这种复杂相互关系可能为理解病理刺激如何改变和控制 T2DM 的复杂性提供概念基础。因此，本综述将全面评估和详细阐述 T2DM 中代谢与表观遗传修饰之间的相互作用。
