糖尿病视网膜病变病情进展与阳虚病机的相关性及其代谢组学研究
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摘要
目的:在探索糖尿病视网膜病变(DR)病情发展过程中的中医证候演变特征基础上,明确阳虚在其病情转化过程中的地位和作用,并利用系统生物学技术初步探索DR与阳虚病机的代谢组学基础,以期科学地阐释阳虚病机主导DR病情进展的作用机制,进而指导临床。
方法:①采用多中心临床研究方法,在全国9家医院收集603例2型DR患者,按照临床调查表观察和采集症状并量化,获得信息数据库后,运用频数分布、多元回归分析等统计方法,分析DR的证候特征及其演变规律,以及DR发生发展的危险因素。②基于前期临床研究结果,拟定DR阳虚证候调查表,根据阳虚证的有无,采集89例2型DR患者中医症状并分组为无阳虚证和有阳虚证组,并以及正常健康者30例作对照,统一收集所有观察对象血浆样本,应用气相色谱-飞行时间质谱(GC-TOFMS)技术进行血浆全代谢组学检测,建立DR分期、分证及正常人的血浆代谢组指纹图谱,运用不同化学计量学(OPLS及OSC-PLS)统计方法处理各图谱的信息,进行分期、分证组间的代谢组学差异及可能潜在生物标志物分析,建立相应代谢指纹图谱数据库。
结果:①DR中医症状频数分布排序结果中显示总体特征为随DR病情进展症状呈现多样化、复杂化趋势;症状及证候频数分布均表明三期均有气阴两虚基本证候特点,并随病情进展气虚表现逐渐加重,到增殖期出现明显阳虚证候。②DR增殖期发生的危险因素进行相关分析显示与年龄呈负相关,与DM病程、尿蛋白排泄率、糖化血红蛋白、高血脂、阳虚症状积分呈正相关;DR分期等级的相关因素分析中阳虚症状积分每增大1分,使得DR非增殖期转变到增殖期、临床前期发展到非增殖期的可能性增加0.068倍;③DR各组和正常人的代谢指纹图谱分类结果显示DR组同正常组完全分离,DR有阳虚证组和无阳虚证组基本分离,较少重叠,临床前期和非增殖期基本重叠,而增殖期和非增殖期基本分离,重叠较少;说明DR有阳虚证与无阳虚证、增殖期与非增殖期之间在代谢组学方面存在差异;另外,代谢组学分类及比对分析结果显示DR有阳虚证和增殖期的潜在生物标记物均为氨基酸类、有机酸类,此两类化合物均与能量代谢密切相关。
结论:气阴两虚是DR基本病机,贯穿疾病的始终,阳虚为DR进入增殖期的最关键危险因素之一。进一步的代谢组学研究结果提示阳虚的实质可能为机体能量相关代谢组学变化,阳虚可能通过影响机体能量代谢致使机体内环境发生重大变化,诱导引起DR增殖性改变的新生血管因子相关基因表达,使DR从非增殖期转化为增殖期.从多中心临床研究与代谢组学研究均说明阳虚为DR病情发展的关键病机。
Objective:To explore the effection of Yang deficiency in the disease aggravation based on studing characteristics of the Zheng of chinese medicine with diabetic retinopathy development and identify the metabonomics of DR and Yang deficiency in order to explain the mechanism of action for DR progress and guide clinical treatment.
Methods:Designed by multicentre,the clinical research was carried out in 9 hospitals all over the country.Totally,603 cases with type 2 diabetes were collected and its information database including the special questionnaire and experimental tests was recorded and established,then analyzed DR characteristic of the Zheng depending on the three different stages and the risk factors of DR occurrence process by data mining methods.Based on the former study results,we screened 89 DR patients and 30 normal subjects.These patients were divided in 2 groups as the difference of Yang deficiency.(yes\no). All subjects were collected blood serum which would determine the metabonomics changes by applying the GC\TOFMS technology.The metebonomics finger prints were analyzed by using the OPLS and OSC-PLS method in order to gaining distinction between the different groups and potential biological markers.
Results:The whole distribution characteristic showed that symptoms became diversity and complication with the development of DR from orders of Chinese symptoms and Zheng frequency analysis results,and both Qi and Yin deficiency were basic performance and Qi weakness gradually became worse with the DR condition development and Yang deficiency was present concurrently in PDR.The logistic regression analysis result for correlated danger factors of occurrence of PDR revealed that the relation was inverse correlation between age grade and PDR and positive correlation among DM duration,HblAc,Urine protein excretion rate,hyperlipemia and Yang asthenia scores.The result for DR stages displayed that the risk of a stage aggravation increased 0.068 times with Yang deficiency score added 1 point.The metabonomics outcomes of discrimination showed that DR drew off from normal group completely,Yang and non-Yang deficiency groups were basically separated with few overlap,DR preclinical and non-proliferative phase was overlap and hard to classify,but proliferative could divided from these phases in score plot.There had a certain difference between Yang deficiency and non Yang deficiency groups,and same as proliferative and non- proliferative DR groups.The potential biological markers for Yang deficiency and PDR stage classification belonged to amino acids and organic acids which correlated with human energy metabolism.
Conclusion:Both Qi and Yin deficiency was the basic Chinese medical mechanism of DR and throughout the whole duration.Yang deficiency was one of the vital risk factors correlated PDR.,and the essence might be organism energy metabolism diversity,induce the gene expression of new vessels factors by affecting the energy metabolism and internal environment great changes. Yang asthenia was the key pathogenesis of progress influence of DR from the research of the clinical obersavation and metabonolism.
方法:①采用多中心临床研究方法,在全国9家医院收集603例2型DR患者,按照临床调查表观察和采集症状并量化,获得信息数据库后,运用频数分布、多元回归分析等统计方法,分析DR的证候特征及其演变规律,以及DR发生发展的危险因素。②基于前期临床研究结果,拟定DR阳虚证候调查表,根据阳虚证的有无,采集89例2型DR患者中医症状并分组为无阳虚证和有阳虚证组,并以及正常健康者30例作对照,统一收集所有观察对象血浆样本,应用气相色谱-飞行时间质谱(GC-TOFMS)技术进行血浆全代谢组学检测,建立DR分期、分证及正常人的血浆代谢组指纹图谱,运用不同化学计量学(OPLS及OSC-PLS)统计方法处理各图谱的信息,进行分期、分证组间的代谢组学差异及可能潜在生物标志物分析,建立相应代谢指纹图谱数据库。
结果:①DR中医症状频数分布排序结果中显示总体特征为随DR病情进展症状呈现多样化、复杂化趋势;症状及证候频数分布均表明三期均有气阴两虚基本证候特点,并随病情进展气虚表现逐渐加重,到增殖期出现明显阳虚证候。②DR增殖期发生的危险因素进行相关分析显示与年龄呈负相关,与DM病程、尿蛋白排泄率、糖化血红蛋白、高血脂、阳虚症状积分呈正相关;DR分期等级的相关因素分析中阳虚症状积分每增大1分,使得DR非增殖期转变到增殖期、临床前期发展到非增殖期的可能性增加0.068倍;③DR各组和正常人的代谢指纹图谱分类结果显示DR组同正常组完全分离,DR有阳虚证组和无阳虚证组基本分离,较少重叠,临床前期和非增殖期基本重叠,而增殖期和非增殖期基本分离,重叠较少;说明DR有阳虚证与无阳虚证、增殖期与非增殖期之间在代谢组学方面存在差异;另外,代谢组学分类及比对分析结果显示DR有阳虚证和增殖期的潜在生物标记物均为氨基酸类、有机酸类,此两类化合物均与能量代谢密切相关。
结论:气阴两虚是DR基本病机,贯穿疾病的始终,阳虚为DR进入增殖期的最关键危险因素之一。进一步的代谢组学研究结果提示阳虚的实质可能为机体能量相关代谢组学变化,阳虚可能通过影响机体能量代谢致使机体内环境发生重大变化,诱导引起DR增殖性改变的新生血管因子相关基因表达,使DR从非增殖期转化为增殖期.从多中心临床研究与代谢组学研究均说明阳虚为DR病情发展的关键病机。
Objective:To explore the effection of Yang deficiency in the disease aggravation based on studing characteristics of the Zheng of chinese medicine with diabetic retinopathy development and identify the metabonomics of DR and Yang deficiency in order to explain the mechanism of action for DR progress and guide clinical treatment.
Methods:Designed by multicentre,the clinical research was carried out in 9 hospitals all over the country.Totally,603 cases with type 2 diabetes were collected and its information database including the special questionnaire and experimental tests was recorded and established,then analyzed DR characteristic of the Zheng depending on the three different stages and the risk factors of DR occurrence process by data mining methods.Based on the former study results,we screened 89 DR patients and 30 normal subjects.These patients were divided in 2 groups as the difference of Yang deficiency.(yes\no). All subjects were collected blood serum which would determine the metabonomics changes by applying the GC\TOFMS technology.The metebonomics finger prints were analyzed by using the OPLS and OSC-PLS method in order to gaining distinction between the different groups and potential biological markers.
Results:The whole distribution characteristic showed that symptoms became diversity and complication with the development of DR from orders of Chinese symptoms and Zheng frequency analysis results,and both Qi and Yin deficiency were basic performance and Qi weakness gradually became worse with the DR condition development and Yang deficiency was present concurrently in PDR.The logistic regression analysis result for correlated danger factors of occurrence of PDR revealed that the relation was inverse correlation between age grade and PDR and positive correlation among DM duration,HblAc,Urine protein excretion rate,hyperlipemia and Yang asthenia scores.The result for DR stages displayed that the risk of a stage aggravation increased 0.068 times with Yang deficiency score added 1 point.The metabonomics outcomes of discrimination showed that DR drew off from normal group completely,Yang and non-Yang deficiency groups were basically separated with few overlap,DR preclinical and non-proliferative phase was overlap and hard to classify,but proliferative could divided from these phases in score plot.There had a certain difference between Yang deficiency and non Yang deficiency groups,and same as proliferative and non- proliferative DR groups.The potential biological markers for Yang deficiency and PDR stage classification belonged to amino acids and organic acids which correlated with human energy metabolism.
Conclusion:Both Qi and Yin deficiency was the basic Chinese medical mechanism of DR and throughout the whole duration.Yang deficiency was one of the vital risk factors correlated PDR.,and the essence might be organism energy metabolism diversity,induce the gene expression of new vessels factors by affecting the energy metabolism and internal environment great changes. Yang asthenia was the key pathogenesis of progress influence of DR from the research of the clinical obersavation and metabonolism.
引文
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