2型糖尿病者视网膜病变代谢记忆的人群及分子流行病学研究

The well-accepted strategy for prevention and early-stage treatment of diabetic retinopathy (DR) is maintaining blood glucose in a proper low level. In our previous population-based study, we observed the existence of metabolic memory phenomenon, which describes DR progression in diabetic patients with proper low blood glucose level. Because the related factors of DR metabolic memory incidence in type 2 diabetic patients are still unknown, it is quite difficult to find out high risk patients, and that obviously limits the effects of DR prevention and early-stage treatment strategy. Increasing experimental evidence has shown that unbalanced mitochondrial reactive oxygen species (ROS) activates DR metabolic memory. In our previous and other scientists' studies, uncoupling protein 2 (UCP-2) gene expression are found to regulate retinal mitochondrial ROS balance; UCP-2, UCP-1 and manganese superoxide dismutase 2 (MnSOD2) gene loci polymorphisms are found relevant to DR development. Therefore, we suppose that gene polymorphisms are also correlate with DR metabolic memory phenomenon. However, up til now, there was neither epidemiology report on DR metabolic memory in Chinese population nor association study of specific gene polymorphisms and DR metabolic memory. In the present study, we plan to conduct a 4-year perspective cohort observation of 3267 Chinese type 2 diabetic residents under proper blood glucose control, trying to find out related physical and biochemical risk factors. The results will facilitate discriminating DR high risk groups in diabetic patients who maintain low blood glucose level. In the same time, a prior case-control study and a following cohort study will demonstrate the specific UCP-2, UCP-1 or MnSOD2 gene polymorphism relevant to DR metabolic memory, and that will provide important theoretic evidence of diabetic metabolic memory blocking agents which target on gene polymorphism. The present grant application is in line with the guideline of National Science Foundation of China (NSFC) which now supports cohort epidemiology study on eye diseases.

目前对糖尿病视网膜病变(DR）预防和早期干预主要通过血糖控制。我们近期研究发现糖尿病居民中存在血糖控制稳定后DR仍发生发展的"代谢记忆"现象,其危险因素不明，但已影响到干预效果。代谢记忆分子发病机制关键点是线粒体活性氧（ROS）失衡，前期我们研究已证实UCP-2基因的表达直接调控ROS平衡，而UCP-2、UCP-1或MnSOD2基因位点多态性与DR患病相关，故推测DR代谢记忆发病的个体差异也源于基因多态性，但至今尚无相关研究。鉴于国家自然科学基金现支持眼科流行病学队列研究，本研究拟对已建档的3267名血糖控制稳定的2型糖尿病居民进行连续4年前瞻性队列研究，得到个体特征、生化等预测指标，从而实现DR代谢记忆高危人群早期发现。同时，通过前期病例对照研究和后续队列研究确认与DR代谢记忆相关的UCP-2、UCP-1或MnSOD2基因型，为实现以特定基因型为靶点的DR代谢记忆早期阻断提供理论依据。

糖尿病性视网膜病变（DR）是糖尿病常见的致盲性并发症。我国尚缺以社区人群为对象的流行病学研究来探究DR的发病、进展、好转及其影响因素。DR代谢记忆指在血糖血压控制稳定后DR仍可持续进展，其影响因素不明，可能受易感基因影响。解偶联蛋白（UCP）能减少线粒体活性氧（ROS）的生成，可能与代谢记忆相关。本研究对上海市新泾地区2型糖尿病患者开展为期5年的前瞻性流行病学调查研究，收集受试者一般资料、予以血压测量，糖化血红蛋白（HbA1C）、甘油三酯、总胆固醇和血肌酐检验，视力、裂隙灯、直接检眼镜和眼底照相检查。结果发现，DR的5年累积发病率为46.89%，高基线HbA1C水平和高血压是其独立危险因素。糖尿病黄斑水肿（DME）的5年累积发病率为19.71%，高基线HbA1C水平是其独立危险因素。5年后DR自发好转率30.48%，低基线HbA1c和低血肌酐是其促进因素。5年后DME自发好转率12.75%，高基线HbA1C水平是其影响因素。血糖稳定的2型糖尿病居民中5年后DR进展率32.23%，基线时的HbA1c是DR进展的影响因素。在5.2%≤HbA1C＜6.4%和HbA1C≥6.4%的人群中DR进展的发生率分别为24.41%和76.83%。同时，采用横断面调查进行DR代谢记忆的基因型相关研究。将UCP1、UCP2和UCP3的共计18个位点选为标签位点。提取染色体后，使用Taqman探针和Sequenom Mass Array分析平台检测基因型。使用SAS和SHEsis软件在所有参试者中，及血糖控制良好/不佳的参试者中，分析各位点与DR的相关性。在UCP1、UCP2和UCP3候选基因中发现UCP1基因rs10011540和rs3811787与DR有关，且在排除了血压、血糖和糖尿病病程的影响之后仍独立存在。在血糖控制良好的受试者中未能找到与DR相关的基因位点。既往血糖控制不佳的受试者中UCP1基因rs7688743，rs10011540和rs3811787与DR相关。本研究的意义在于：首先提出传统的HbA1C低于7.0%的控制标准并不足以防控DR的发展，为减少DR代谢记忆的发生，建议全身状态良好的糖尿病患者在不发生低血糖等严重副反应的前提下，尽量在病程的早期就把血糖降到接近正常水平（HbA1c＜6.4%）。发现的UCP1基因多态性与DR的相关性，为筛查DR高危人群提供了理论依据。