Molecular mechanisms of diabetic vascular complications.
Molecular mechanisms of diabetic vascular complications.
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DOI：
10.1111/j.2040-1124.2010.00018.x
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发表时间：
2010-06-01
影响因子：
3.2
通讯作者：
King GL
中科院分区：
文献类型：
--
作者：
Kitada M;Zhang Z;Mima A;King GL
糖尿病并发症是糖尿病患者发病和死亡的主要原因。微血管并发症包括视网膜病变、肾病和神经病变，它们是导致失明、终末期肾病和各种疼痛性神经病变的主要原因；而大血管并发症涉及动脉粥样硬化相关疾病，例如冠状动脉疾病、周围血管疾病和中风。糖尿病并发症是全身代谢变化（例如高血糖）、局部组织对葡萄糖代谢有毒代谢物的反应以及遗传和表观遗传调节剂之间相互作用的结果。慢性高血糖被认为是糖尿病并发症的主要引发因素。已提出多种分子机制来介导高血糖对血管组织的不利影响。这些包括多元醇途径增加、二酰基甘油/蛋白激酶 C 途径激活、氧化应激增加、晚期糖基化终产物的过量产生和作用以及己糖胺途径增加。此外，高血糖或有毒代谢物引起的信号转导途径的改变也可能通过改变基因表达和蛋白质功能导致细胞功能障碍并损害血管组织。与毒性机制相比，高血糖的研究较少，它还可能抑制内源性血管保护因子，如胰岛素、血管内皮生长因子、血小板衍生生长因子和活化蛋白 C，这些因子在维持血管稳态中发挥着重要作用。因此，糖尿病并发症的有效治疗需要抑制高血糖毒性作用诱导的机制，并增强内源性保护因子。本综述总结了高血糖激活的多种生化途径以及可能预防糖尿病并发症的潜在治疗干预措施。 （《糖尿病投资杂志》，doi：10.1111/j.2040-1124.2010.00018.x，2010）
Diabetic complications are the major causes of morbidity and mortality in patients with diabetes. Microvascular complications include retinopathy, nephropathy and neuropathy, which are leading causes of blindness, end‐stage renal disease and various painful neuropathies; whereas macrovascular complications involve atherosclerosis related diseases, such as coronary artery disease, peripheral vascular disease and stroke. Diabetic complications are the result of interactions among systemic metabolic changes, such as hyperglycemia, local tissue responses to toxic metabolites from glucose metabolism, and genetic and epigenetic modulators. Chronic hyperglycemia is recognized as a major initiator of diabetic complications. Multiple molecular mechanisms have been proposed to mediate hyperglycemia’s adverse effects on vascular tissues. These include increased polyol pathway, activation of the diacylglycerol/protein kinase C pathway, increased oxidative stress, overproduction and action of advanced glycation end products, and increased hexosamine pathway. In addition, the alterations of signal transduction pathways induced by hyperglycemia or toxic metabolites can also lead to cellular dysfunctions and damage vascular tissues by altering gene expression and protein function. Less studied than the toxic mechanisms, hyperglycemia might also inhibit the endogenous vascular protective factors such as insulin, vascular endothelial growth factor, platelet‐derived growth factor and activated protein C, which play important roles in maintaining vascular homeostasis. Thus, effective therapies for diabetic complications need to inhibit mechanisms induced by hyperglycemia’s toxic effects and also enhance the endogenous protective factors. The present review summarizes these multiple biochemical pathways activated by hyperglycemia and the potential therapeutic interventions that might prevent diabetic complications. (J Diabetes Invest, doi: 10.1111/j.2040‐1124.2010.00018.x, 2010)
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