Reddy Marpadga A, Natarajan Rama
Department of Diabetes, Beckman Research Institute of City of Hope, 1500 East Duarte Road, Duarte, CA, 91010, USA.
Subcell Biochem. 2013;61:435-54. doi: 10.1007/978-94-007-4525-4_19.
Diabetes and metabolic disorders are leading causes of micro- and macrovascular complications. Furthermore, efforts to treat these complications are hampered by metabolic memory, a phenomenon in which prior exposure to hyperglycemia predisposes diabetic patients to the continued development of vascular diseases despite subsequent glycemic control. Persistently increased levels of oxidant stress and inflammatory genes are key features of these pathologies. Biochemical and molecular studies showed that hyperglycemia induced activation of NF-κB, signaling and actions of advanced glycation end products and other inflammatory mediators play key roles in the expression of pathological genes. In addition, epigenetic mechanisms such as posttranslational modification of histones and DNA methylation also play central roles in gene regulation by affecting chromatin structure and function. Recent studies have suggested that dysregulation of such epigenetic mechanisms may be involved in metabolic memory leading to persistent changes in the expression of genes associated with diabetic vascular complications. Further exploration of these mechanisms by also taking advantages of recent advances in high throughput epigenomics technologies will greatly increase our understanding of epigenetic variations in diabetes and its complications. This in turn can lead to the development of novel new therapies.
糖尿病和代谢紊乱是微血管和大血管并发症的主要原因。此外，代谢记忆阻碍了对这些并发症的治疗，代谢记忆是一种现象，即先前暴露于高血糖会使糖尿病患者易患血管疾病的持续发展，尽管随后血糖得到了控制。氧化应激水平持续升高和炎症基因是这些病理状态的关键特征。生化和分子研究表明，高血糖诱导核因子κB的激活、晚期糖基化终产物的信号传导和作用以及其他炎症介质在病理基因的表达中起关键作用。此外，表观遗传机制，如组蛋白的翻译后修饰和DNA甲基化，也通过影响染色质结构和功能在基因调控中发挥核心作用。最近的研究表明，这种表观遗传机制的失调可能参与代谢记忆，导致与糖尿病血管并发症相关基因表达的持续变化。利用高通量表观基因组学技术的最新进展进一步探索这些机制，将大大增进我们对糖尿病及其并发症表观遗传变异的理解。这反过来又可以导致新疗法的开发。
