LR11和SorCS1在糖尿病慢性并发症发生发展过程中的作用

Diabetic chronic complications(DCC) strongly impact the life of the patients and the quality of life. LR11(low density lipoprotein Receptor relative with 11 ligand binding repeats) is highly expressed in atherosclerotic plaque, intimal smooth muscle cells, macrophages, central and peripheral nerve system. LR11 may plays an important role in the adhesion of macrophages, the migration of smooth muscle cells and the regulation of nerve cells. Recent studies have shown that LR11 level is higher in coronary disease, diabetic retinopathy and Alzheimer's disease. It is positively correlated with intima media thickness of carotid arteries and glycated hemoglobin. The reason why glycated hemoglobin level promoting the expression of LR11 on the vascular intima is not available yet. Other studies found that, SorCS1(sortilin related Vps10 domain containing receptor 1) a novel gene risk factor for diabetes is associated with Alzheimer's disease and glycated hemoglobin level. These research indicated that the expression of LR11 and SorCS1 may be related to DCC, but a number of outstanding questions remains. In the present study, we observe that the defference levels of LR11 and SorCS1 in the macro and microvascular complications, and do stratification analysis for the affect of hyperglycemia and glucose fluctuation on the levels of LR11 and SorCS1 according to the level of glycated hemoglobin. The aim of this research is to explore the roles of LR11 and SorCS1 in the pathogenesis ans development of DCC. LR11 and SorCS1 may be expected to become a novel marker of DCC.

糖尿病慢性并发症(DCC)严重影响患者的寿命和生活质量。低密度脂蛋白受体11 (LR11)在粥样斑块、单核巨噬细胞、内膜平滑肌细胞、中枢及周围神经系统的表达丰富，对单核细胞的粘附、平滑肌细胞游走和神经细胞的调控起着重要作用。LR11水平在冠心病、糖尿病视网膜病变及阿尔兹海默病患者中呈显著高值，与颈动脉IMT、糖化血红蛋白正相关，高糖环境使血管内膜LR11表达增高的原因尚不清楚。分拣蛋白相关含Vps10域受体1(SorCS1)为糖尿病风险新基因，与阿尔兹海默病及糖化血红蛋白水平有密切关系。综上述，LR11和SorCS1可能与DCC有密切关系，目前关于这方面的研究报道甚少。本课题，研究LR11和SorCS1在DCC中的表达水平，根据糖化血红蛋白水平分层分析高血糖和血糖波动对二者的影响，探讨LR11和SorCS1在DCC发生发展过程中的作用。LR11和SorCS1有望成为DCC的新指标。

糖尿病慢性并发症严重影响患者的寿命和生活质量，尤其是心脑血管病变，其发病机制不十分清楚。低密度脂蛋白受体11(LR11)在粥样斑块、单核巨噬细胞、内膜平滑肌细胞的表达丰富，对单核细胞的黏附、平滑肌细胞游走和神经细胞的调控起着重要的作用，LR11在冠心病及高糖环境下的表达增高。分拣蛋白相关Vps10域受体(SorCS1)为糖尿病风险新基因。临床研究结果示，在2型糖尿病大血管病变中LR11、MCP-1、IL1β水平及MAGE显著增高，IL6、E-selectin、ICAM1、VCAM1、TNF-a水平无显著变化。LR11为因变量多元线性回归分析示与MCP-1、HbA1C%呈显著正相关。MAGE为因变量多元线性回归分析示与MBG、LR11呈显著正相关，但在大血管病变中与LR11无显著相关。在糖尿病患者中未见SorCS1水平的显著变化。细胞研究结果示，在持续性高血糖和剧烈血糖波动刺激下，大动脉内皮细胞的LR11、IL1β、E-selectin及MCP-1水平均显著增高， IL6、ICAM1、VCAM1、TNF-a水平无显著变化，LR11与IL1β、E-selectin、MCP-1单因素相关分析示r值分别为0.455、0740、0.757，多元线性回归分析示LR11与E-selectin显著正相关。当cAMP通路受抑制时，IL1β、E-selectin、MCP-1表达下调，但LR11表达未见下调，且未见血糖的变化对SorCS1表达水平的影响。结论: LR11和MAGE与2型糖尿病大血管并发症有着密切的关系，发病机制可能与MCP-1、E-selectin及IL1β的表达增高有关，其表达受cAMP通路的调控。LR11有可能成为2型糖尿病大血管病变发生发展过程中的新指标。