Ndip Agbor, Wilkinson Fiona L, Jude Edward B, Boulton Andrew J M, Alexander M Yvonne
Department of Medicine and Diabetes, Manchester Royal Infirmary, Manchester, UK,
Diabetologia. 2014 Nov;57(11):2251-60. doi: 10.1007/s00125-014-3348-z. Epub 2014 Aug 12.
Type 2 diabetes is associated with increased cardiovascular morbidity and mortality and early vascular ageing. This takes the form of atherosclerosis, with progressive vascular calcification being a major complication in the pathogenesis of this disease. Current research and drug targets in diabetes have hitherto focused on atherosclerosis, but vascular calcification is now recognised as an independent predictor of cardiovascular morbidity and mortality. An emerging regulatory pathway for vascular calcification in diabetes involves the receptor activator for nuclear factor κB (RANK), RANK ligand (RANKL) and osteoprotegerin (OPG). Important novel biomarkers of calcification are related to levels of glycation and inflammation in diabetes. Several therapeutic strategies could have advantageous effects on the vasculature in patients with diabetes, including targeting the RANKL and receptor for AGE (RAGE) signalling pathways, since there has been little success-at least in macrovascular outcomes-with conventional glucose-lowering therapy. There is substantial and relevant clinical and basic science evidence to suggest that modulating RANKL-RANK-OPG signalling, RAGE signalling and the associated proinflammatory milieu alters the natural course of cardiovascular complications and outcomes in people with diabetes. However, further research is critically needed to understand the precise mechanisms underpinning these pathways, in order to translate the anti-calcification strategies into patient benefit.
2型糖尿病与心血管疾病发病率和死亡率增加以及血管过早老化相关。其表现形式为动脉粥样硬化，进行性血管钙化是该疾病发病机制中的主要并发症。目前糖尿病领域的研究和药物靶点一直聚焦于动脉粥样硬化，但血管钙化现在被认为是心血管疾病发病率和死亡率的独立预测因子。糖尿病中血管钙化的一种新兴调节途径涉及核因子κB受体激活剂（RANK）、RANK配体（RANKL）和骨保护素（OPG）。重要的新型钙化生物标志物与糖尿病中的糖基化和炎症水平有关。几种治疗策略可能对糖尿病患者的血管系统产生有利影响，包括靶向RANKL和晚期糖基化终末产物受体（RAGE）信号通路，因为传统的降糖治疗至少在大血管结局方面收效甚微。有大量相关的临床和基础科学证据表明，调节RANKL-RANK-OPG信号通路、RAGE信号通路以及相关的促炎环境会改变糖尿病患者心血管并发症和结局的自然病程。然而，迫切需要进一步研究以了解这些途径的精确机制，从而将抗钙化策略转化为患者的益处。
