糖微康胶囊对早期糖尿病肾病的干预及疗效机理研究
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摘要
糖尿病肾病是糖尿病主要的微血管并发症之一,在糖尿病人群中的发生率约为20%-40%。糖尿病肾病又称糖尿病肾小球硬化症,是糖尿病患者致死的主要原因之一,严重性仅次于心脑血管病。在目前阶段,还没有明确的可完全防止或治愈糖尿病肾病的方法,许多临床研究表明中医药治疗糖尿病肾病有显著的优势和特色,能够减轻蛋白尿,改善肾功能,延缓糖尿病肾病的进展。导师根据数十年的临床经验,结合现代药理研制出糖微康胶囊,在糖尿病肾病的治疗中取得了良好的效果。本研究是导师的国家自然基金课题“糖微康抑制早期糖尿病肾病患者MTHFRC677T突变及其去甲基化作用”的一部分。亚甲基四氢叶酸还原酶C677T基因多态现象是2型糖尿病肾病的遗传危险因素,本研究旨在探讨糖微康胶囊的临床疗效,疗效与亚甲基四氢叶酸还原酶基因多态性的关系,以及糖微康胶囊对血浆Hcy、血清脂联素等的影响,揭示糖微康胶囊治疗糖尿病肾病的机制。
目的
观察糖微康胶囊的临床疗效,揭示糖微康胶囊治疗糖尿病肾病的机制。
方法
(1)研究方法
将新诊断为早期糖尿病肾病的130例患者随机分为两组：治疗组和对照组。两组患者均予糖尿病教育,饮食控制,均根据血糖、血压、血脂情况予以相应降糖、降压、调脂药治疗。饮食治疗给予糖尿病饮食,蛋白质摄入限量在0.8-1.0g/(kg·d)。降糖治疗一般选用胰岛素,避免使用有肾脏损害的口服降糖药。严格控制血压,使之尽量控制在正常范围以内,血压控制不理想可合并使用不影响糖脂代谢的降压药物。调脂治疗一般选择阿昔莫司。治疗期间发生感染的可以给与抗感染治疗,但疗程不大于7天。治疗组加用糖微康胶囊(由中国中医科学院广安门医院制剂室提供),用法：每次4粒,每日3次,饭后服用。以6个月为1个疗程,共观察1个疗程。
(2)观察指标
采集门诊和住院患者的资料,包括性别、年龄、职业、血型、个人史、既往史等情况。按中医证候调查表,对每一个观察者治疗前、治疗后的症状进行评分。常规实验室指标：治疗前、治疗后行电解质、糖化血红蛋白、血糖、血脂、24小时尿蛋白定量、尿微量白蛋白排泄率检查。安全性指标：治疗前、治疗后行肝、肾功,血、尿、便常规检查。特殊指标：MTHFR基因多态性,血浆Hcy,血清脂联素,血浆叶酸等检测。
(3)统计方法
采用SPSS 12.0统计软件处理,以P<0.05为差异具有统计学意义。
结果：
(1)糖微康胶囊的临床疗效
①两组患者的UAER比较
两组患者治疗前UAER经独立样本t检验,t=0.124,P=0.901,两组患者的UAER比较无统计学差异,具有可比性；治疗组治疗前后UAER经配对t检验,t=7.862,P=0.000,糖微康治疗后UAER显著降低,差异具有统计学意义,对照组治疗前后UAER经配对t检验,t=6.594,P=0.000,差异具有统计学意义；两组患者治疗后UAER经独立样本t检验,t=-2.045,P=0.043,糖微康治疗组UAER水平较对照组低,差异具有统计学意义。
②两组患者中医症状疗效比较
两组患者治疗前中医症状评分经独立样本t检验,t=-0.135,P=0.893,两组患者的中医症状评分无统计学差异,具有可比性；两组患者治疗后中医症状评分经独立样本t检验,t=2.330,P=0.022,治疗组较对照组中医症状评分低,两组患者治疗后中医症状评分差异具有统计学意义。
③两组患者血脂的比较
治疗前两组患者TG经独立样本t检验,t=-0.249,P=0.804,差异无统计学意义,治疗后两组患者TG经独立样本t检,t=1.320,P=0.190,差异无统计学意义,治疗组治疗前后TG经配对t检验,t=4.032,P=0.000,差异具有统计学意义,对照组治疗前后TG经配对t检验,t=2.796,P=0.007,差异具有统计学意义。
治疗前两组患者CHO经独立样本t检验,t=-0.025,P=0.980,差异无统计学意义,治疗后两组患者CHO经独立样本t检,t=-0.118,P=0.906,差异无统计学意义,治疗组治疗前后CHO经配对t检验,t=-1.805,P=0.076,差异无统计学意义,对照组治疗前后CHO经配对t检验,t=-1.208,P=0.232,差异无统计学意义。
治疗前两组患者HDL经独立样本t检验,t=-0.236,P=0.814,差异无统计学意义,治疗后两组患者HDL经独立样本t检,t=0.157,P=0.875,差异无统计学意义,治疗组治疗前后HDL经配对t检验,t=-2.132,P=0.037,差异具有统计学意义,对照组治疗前后HDL经配对t检验,t=-1.527,P=0.128,差异无统计学意义。
治疗前两组患者LDL经独立样本t检验,t=-0.062,P=0.951,差异无统计学意义,治疗后两组患者LDL经独立样本t检,t=-1.280,P=0.203,差异无统计学意义,治疗组治疗前后LDL经配对t检验,t=3.950,P=0.000,差异具有统计学意义,对照组治疗前后LDL经配对t检验,t=2.489,P=0.016,差异具有统计学意义。
④两组患者临床综合疗效比较
治疗组60例患者,显效24例,有效27例,无效9例,总有效率85.00%,对照组56例患者,显效13例,有效23例,无效19例,总有效率64.28%,两组患者经秩和检验,Z=2.539,P=0.011,差异具有统计学意义。
(2)糖微康胶囊治疗糖尿病肾病的机制
①亚甲基四氢叶酸还原酶基因多态性的分布
116例早期糖尿病肾病患者中CC基因型30例,CT基因型47例,TT基因型39例,CC基因型、CT基因型、TT基因型的频率分别为25.86%、40.52%、33.62%；T等位基因的频率为53.88%,C等位基因的频率为46.12%。两组患者治疗前后亚甲基四氢叶酸还原酶基因的基因型都未发生变化,
②亚甲基四氢叶酸还原酶3种基因型的血浆Hey比较
亚甲基四氢叶酸还原酶基因3种基因型的Hcy比较,经方差分析,F=4.961,P=0.009,早期糖尿病肾病患者亚甲基四氢叶酸还原酶基因3种基因型的血浆Hcy水平具有统计学差异,组间两两比较(Post Hoc Tests):CC基因型血浆Hey水平与CT基因型血浆Hey水平相比较,P=0.013,差异具有统计学意义,CC基因型血浆Hey水平与TT基因型血浆Hey水平相比较,P=0.003,差异具有统计学意义,CT基因型血浆Hey水平与TT基因型血浆Hcy水平相比较,P=0.674,差异无统计学意义。表明CC基因型血浆同型半胱氨酸水平明显低于TT或CT基因型。
③治疗组和对照组血浆Hcy水平的比较
两组患者治疗前血浆Hcy水平经独立样本t检验,t=-0.878,P=0.382,两组患者血浆Hcy水平无统计学差异,具有可比性,治疗组治疗前后血浆Hcy水平经配对t检验,t=7.592,P=0.000,差异具有统计学意义,糖微康胶囊治疗后血浆Hcy水平显著下降；对照组治疗前后血浆Hcy水平经配对t检验,t=4.800,P=0.000,差异具有统计学意义；两组患者治疗后血浆Hcy水平的比较,经独立样本t检验,t=-3.426,P=0.001,治疗组血浆Hcy水平较对照组低,差异具有统计学意义。
④两组患者亚甲基四氢叶酸还原酶三种基因型血浆Hcy水平的比较
治疗组治疗前不同基因型血浆Hcy水平经方差分析,F=3.459,P=0.038,3种基因型血浆Hcy水平差异具有统计学意义,经Post Hoc Tests:CC基因型血浆Hcy水平与CT基因型、TT基因型血浆Hcy水平相比较,P值分别为：P=0.029、P=0.018,差异具有统计学意义,CT基因型与TT基因型血浆Hcy水平相比较,差异无统计学意义,P=0.735。治疗组治疗后不同基因型血浆Hcy水平经方差分析,F=1.824,P=0.171,3种基因型血浆Hcy水平差异无统计学意义。治疗组CC基因型治疗前后血浆Hcy水平经配对t检验,t=2.599,P=0.021,差异具有统计学意义；CT基因型治疗前后血浆Hcy水平经配对t检验,t=6.503,P=0.000,差异具有统计学意义；TT基因型治疗前后血浆Hcy水平经配对t检验,t=4.113,P=0.001,差异具有统计学意义。对照组治疗前不同基因型血浆Hcy水平经方差分析,F=3.522,P=0.037,3种基因型血浆Hcy水平差异具有统计学意义,经Post Hoc Tests:CC基因型血浆Hcy水平与CT基因型、TT基因型血浆Hcy水平相比较,P值分别为：P=0.041、P=0.014,差异具有统计学意义,CT基因型与TT基因型血浆Hcy水平相比较,差异无统计学意义,P=0.687。对照组治疗后不同基因型血浆Hcy水平经方差分析,F=1.040,P=0.361,3种基因型血浆Hcy水平差异无统计学意义。对照组CC基因型治疗前后血浆Hcy水平经配对t检验,t=0.634,P=0.531,差异无统计学意义；CT基因型治疗前后血浆Hcy水平经配对t检验,t=4.455,P=0.000,差异具有统计学意义；TT基因型治疗前后血浆Hcy水平经配对t检验,t=4.127,P=0.000,差异具有统计学意义。
治疗组和对照组同一基因型血浆Hcy水平比较：两组患者CC基因型治疗前血浆Hcy水平经独立样本t检验,t=-0.493,P=0.626,差异无统计学意义,治疗后血浆Hcy水平经独立样本t检验,t=-1.441,P=0.161,差异虽然无统计学意义,但治疗组较对照组Hcy水平均值更低；两组患者CT基因型治疗前血浆Hcy水平经独立样本t检验,t=0.515,P=0.609,差异无统计学意义,治疗后两组血浆Hcy水平经独立样本t检验,t=2.449,P=0.019,治疗组血浆Hcy水平较对照组低,差异具有统计学意义；两组患者TT基因型治疗前血浆Hcy水平经独立样本t检验,t=0.608,P=0.547,差异无统计学意义,治疗后血浆Hcy水平经独立样本t检验,t=2.050,P=0.047,治疗组Hcy水平较对照组低,差异具有统计学意义。
⑤两组患者血浆叶酸水平的比较
治疗前两组患者血浆叶酸水平经独立样本t检验,t=-1.468,P=0.145,差异无统计学意义,治疗后两组患者血浆叶酸水平经独立样本t检验,t=-1.511,P=0.134,差异无统计学意义,治疗组治疗前后血浆叶酸水平经配对t检验,t=1.093,P=0.279,治疗组治疗前后血浆叶酸水平差异无统计学意义,对照组治疗前后血浆叶酸水平经配对t检验,t=1.463,P=0.149,对照组血浆叶酸水平治疗前后差异无统计学意义。
⑥治疗前总患者亚甲基四氢叶酸还原酶基因不同基因型UAER比较
亚甲基四氢叶酸还原酶基因不同基因型UAER比较经方差分析,F=3.589,P=0.031,3种基因型UAER水平差异具有统计学意义,组间两两比较(Post Hoc Tests):CC基因型UAER水平与CT基因型UAER水平相比较,P=0.043,差异具有统计学意义,CC基因型UAER水平与TT基因型UAER水平相比较,P=0.011,差异具有统计学意义,CT基因型UAER水平与TT基因型UAER水平相比较,P=0.482,差异无统计学意义。表明CC基因型UAER水平明显低于TT或CT基因型。
⑦两组患者亚甲基四氢叶酸还原酶三种基因型UAER的比较
治疗组治疗前不同基因型UAER比较经方差分析,F=1.150,P=0.324,3种基因型UAER水平差异不具有统计学意义,对照组治疗前不同基因型UAER比较经方差分析,F=2.537,P=0.089,3种基因型UAER水平差异不具有统计学意义；治疗组治疗后不同基因型UAER比较经方差分析,F=0.464,P=0.631,3种基因型UAER水平差异不具有统计学意义,对照组治疗后不同基因型UAER比较经方差分析,F=2.581,P=0.085,3种基因型UAER水平差异不具有统计学意义。两组患者的不同基因型UAER比较无统计学差异,这可能与样本量太小有关,但CC基因型UAER水平、CT基因型UAER水平、TT基因型UAER水平依次增高。治疗组CC基因型治疗前后UAER水平经配对t检验,t=4.969,P=0.000,治疗前后差异具有统计学意义,CT基因型治疗前后UAER水平经配对t检验,t=5.467,P=0.000,治疗前后差异具有统计学意义,TT基因型治疗前后UAER水平经配对t检验,t=2.972,P=0.008,治疗前后差异具有统计学意义；对照组CC基因型治疗前后UAER水平经配对t检验,t=3.471,P=0.004,治疗前后差异具有统计学意义,CT基因型治疗前后UAER水平经配对t检验,t=3.955,P=0.001,治疗前后差异具有统计学意义,TT基因型治疗前后UAER水平经配对t检验,t=3.984,P=0.001,治疗前后差异具有统计学意义。治疗组和对照组同一基因型UAER水平比较：两组患者CC基因型治疗前UAER水平经独立样本t检验,t=0.777,P=0.443,差异无统计学意义,治疗后UAER水平经独立样本t检验,t=0.037,P=0.971,差异无统计学意义；两组患者CT基因型治疗前UAER水平经独立样本t检验,t=0.215,P=0.830,差异无统计学意义,治疗后两组UAER水平经独立样本t检验,t=1.430,P=0.160,差异无统计学意义；两组患者TT基因型治疗前UAER水平经独立样本t检验,t=0.060,P=0.953,差异无统计学意义,治疗后UAER水平经独立样本t检验,t=1.386,P=0.174,差异无统计学意义。
⑧两组患者血清脂联素水平比较
治疗组治疗前后脂联素水平经配对t检验,t=6.881,P=0.000,治疗前后差异具有统计学意义,对照组治疗前后脂联素水平经配对t检验,t=5.046,P=0.000,治疗前后差异具有统计学意义。两组患者治疗前经独立样本t检验,t=1.248,P=0.214,脂联素水平差异无统计学意义,两组患者治疗后经独立样本t检验,t=-3.080,P=0.003,脂联素水平差异具有统计学意义。
结论：本研究的主要结论如下：
(1)导师提出的益气养阴,活血化瘀治则是糖尿病肾病的重要中医治则。
(2)导师为首的专家组研制的糖微康胶囊的临床研究表明：
①糖微康胶囊可以改善糖尿病肾病患者的症状。
②糖微康胶囊可以减少糖尿病肾病患者尿蛋白排泄率。
③糖微康胶囊可以改善糖尿病肾病患者的血脂紊乱。
(3)糖微康胶囊的机理研究表明：
①糖微康胶囊可以降低血浆Hcy水平。
②糖微康胶囊对MTHFR多态性的影响表明：糖微康胶囊可能改变了MTHFR的基因表型,影响遗传信息的表达,改变了基因的生物活性。
③糖微康胶囊可以降低血清脂联素水平。
(4) MTHFR基因多态性与血浆Hcy水平相关,MTHFR基因突变可引起高Hcy血症。
(5) MTHFR基因突变可能与糖尿病肾病的进展有关。
Diabetic nephropathy is one of the main microvascular complications of diabetes. The incidence of diabetic nephropathy is approximately 20-40% in diabetic crowd. Diabetic nephropathy is one of the leading causes of death in diabetic crowd. At present, no methods can completely prevent or cure diabetic nephropathy. Many clinical studies showed that TCM has obvious advantages, and can reduce albuminuria, improve renal function, delay the progress of diabetic nephropathy. According to decades of clinical experience, combining modern pharmacology, my teacher had developed TWK capsule. In the treatment of diabetic nephropathy, many clinical studies showed TWK capsule has good effect.
This research is from my teacher's national natural science fund project. The MTHFR C677T gene polymorphism is related with type 2 diabetic nephropathy. It is one of genetic risk factors of Diabetic nephropathy. In this study, we tried to investigate the clinical curative effect of TWK capsule, and the relation between TWK capsule's curative effect and MTHFR gene polymorphism. We also tried to investigate the influence of TWK capsule on plasma Hcy, serum adiponectin, and revealed the mechanism of TWK capsule on diabetic nephropathy.
Objective:
To observe the clinical curative effect of TWK capsule and reveal mechanism of TWK capsule on diabetic nephropathy.
Methods:
(1) research methods
The new diagnosed 130 cases of early diabetic nephropathy were randomly divided into two groups:treated group and control group. Diabetic education and diet control were guided by doctors in two groups. As far as diet therapy was considered, protein intake was limited in 0.8-1.0 g/(kg·d). Insulin was selected in first to control blood sugar, and avoided to use the oral medications that have kidney damage. Blood pressure of all patients need be controlled in the normal range. Acipimox was usually selected to retrieve abnormality of lipid. When infections occurred during treatment, anti-infection drugs were given to control infection, but the period of treatment is not more than 7 days. TWK capsule was added in treated group. Usage:4 grains/time,3 times/day. The course of treatment was six months.
(2) observation index
Materials of outpatient and inpatient were collected, including gender, age, occupation, blood type, personal history, past medical history, etc. According to the questionnaire, rating of the symptoms were conducted both before treatment and after completed treatment. Routine laboratory index:electrolytes, glycated hemoglobin, blood sugar, lipid and UAER were measured both before treatment and after completed treatment. Safety index:function of liver and kidney, regular inspection of blood, urine and stool. Special index:MTHFR gene polymorphism, plasma Hcy, serum adiponectin, etc.
(3) statistical method
Using SPSS 12.0 statistical software, P<0.05 is considered statistical significance.
Results:
(1) clinical curative effect of TWK capsule
①UAER comparison of the two groups
UAER of the two groups patients were tested by independent sample t-test before treatment, t=0.124, P=0.901.There was not statistically different between two groups. The UAER of before and after the treatment in treated group was tested by matching t test, t=7.862, P=0.000, and it was a statistically significant difference between before and after treatment. The UAER of before and after treatment in control group was tested by matching t test, t=6.594, P=0.000.There was a statistically significant difference. After the treatment, UAER of the two groups patients were tested by independent sample t-test, t=-2.045, P= 0.043, and it was a statistically significant difference between two groups.
②Compared TCM symptoms curative effect between the two groups
Scores of TCM symptoms of the two groups patients were tested by independent sample t-test before treatment, t=0.135,P=0.893. There was not statistically different between two groups. After the treatment, scores of TCM symptoms of the two groups patients were tested by independent sample t-test, t=2.330, P=0.022, and it was a statistically significant difference between two groups.
③Compared blood lipid in the two groups patients
TG was tested by independent sample t-test between two groups before treatment, t=-0.249, P=0.804, and difference was not statistically significant. TG of two groups patients was tested by independent sample t test after treatment, t=1.320, P=0.190, and difference was not statistically significant. TG in the treated group was tested by matching t test before and after treatment, t=4.032, P=0.000, and it showed a statistically significant difference between before and after treatment. TG in the control group was tested by matching t test before and after treatment, t=2.796, P=0.007, and it showed a statistically significant difference.
CHO was tested by independent sample t-test between two groups before treatment, t=-0.025, P=0.980, and difference was not statistically significant. CHO of two groups patients was tested by independent sample t test after treatment, t=-0.188, P=0.906, and difference was not statistically significant. CHO in the treated group was tested by matching t test before and after treatment, t=-1.085, P=0.076, and it showed a nearly statistically significant difference between before and after treatment. CHO in the control group was tested by matching t test before and after treatment, t=-1.208, P=0.232, and difference was not statistically significant.
HDL was tested by independent sample t-test between two groups before treatment, t=-0.236, P=0.814, and difference was not statistically significant. HDL of two groups patients was tested by independent sample t test after treatment, t=0.175, P=0.875, and difference was not statistically significant. HDL in the treated group was tested by matching t test before and after treatment, t=-2.132, P=0.037, and it showed a statistically significant difference between before and after treatment. HDL in the control group was tested by matching t test before and after treatment, t=-1.527, P=0.128, and difference was not statistically significant.
LDL was tested by independent sample t-test between two groups before treatment, t=-0.062, P=0.951, and difference was not statistically significant. LDL of two groups patients was tested by independent sample t test after treatment, t=-1.280, P=0.203, and difference was not statistically significant. LDL in the treated group was tested by matching t test before and after treatment, t=3.950, P=0.000, and it showed a statistically significant difference between before and after treatment. LDL in the control group was tested by matching t test before and after treatment, t=2.489, P=0.016, and difference was statistically significant.
④compared clinical total curative effect between two groups
60 patients in the treated group,27 cases were excellent effective, and 24 cases were effective, and 9 cases were invalid. The total effective rate was 85.00% in treated group.56 patients in the control group,13 cases were excellent effective, and 23 cases were effective, and 19 cases were invalid. The total effective rate was 64.28% in control group. Z= -2.539, P=0.011, and it showed a statistically significant difference between two groups.
(2) mechanism of TWK capsule on diabetic nephropathy
①MTHFR gene polymorphism of distribution
In 116 patients with early diabetic nephropathy,30 cases were CC genotype, and 47 cases were CT genotype, and 39 cases were TT genotype. Frequency of CC genotype, CT genotype, TT genotype were 25.86%,40.52%, 33.62% respectively. T allele frequency was 53.88%. C allele frequency was 46.12%. After treatment, all MTHFR gene genotypes were not changed。
②Compared Hey of MTHFR gene genotypes
Hey of 3 genotypes was tested by analysis of variance, F=4.961, P =0.009, and it showed plasma Hey levels of 3 genotypes have statistically significant. Compared CC genotype plasma Hcy level and CT genotype plasma Hey level, P=0.013, it showed a statistically significant difference. Compared CC genotype Hey level and TT genotype plasma Hey level, P=0.003 it showed a statistically significant differences. Compared CT genotypes Hey level and TT genotype plasma Hey level, P=0.674, it showed difference was not statistically significant.
③Effects of TWK capsule on plasma Hey levels of DN
Plasma Hey levels of two groups was tested by independent sample t test before treatment, t=-0.878, P=0.382, and it showed plasma Hey levels of two groups were not statistically different. Plasma Hey levels of two groups patients was tested by independent sample t test after treatment, t=-3.426, P=0.001, and difference was statistically significant. Plasma Hey levels in the treated group was tested by matching t test before and after treatment, t=7.952, P=0.000, and it showed a statistically significant difference between before and after treatment. Plasma Hey levels in the control group was tested by matching t test before and after treatment, t=4.800, P=0.000, and difference was statistically significant.
④Compared effects of TWK capsule on plasma Hey levels of MTHFRE different genotypes in DN
Plasma Hey of 3 genotypes in treated group was tested by analysis of variance, F=3.459, P=0.038, and it showed plasma Hey levels of 3 genotypes have statistically significant. Compared CC genotype plasma Hey level and CT genotype plasma Hey level, P=0.029, it showed a statistically significant difference. Compared CC genotype Hey level and TT genotype plasma Hey level, P=0.018, it showed a statistically significant differences. Compared CT genotypes Hey level and TT genotype plasma Hey level, P=0.735, it showed difference was not statistically significant. Plasma Hcy of 3 genotypes in treated group was tested by analysis of variance after treatment, F=1.824, P=0.171, and it showed plasma Hcy levels of 3 genotypes have not statistically significant. CC genotype plasma Hey level in the treated group was tested by matching t test before and after treatment, t=2.599, P=0.021, and it showed a statistically significant difference between before and after treatment. CT genotype plasma Hey level in the treated group was tested by matching t test before and after treatment, t=6.503, P=0.000, and it showed a statistically significant difference between before and after treatment. TT genotype plasma Hey level in the treated group was tested by matching t test before and after treatment, t=4.113, P=0.001, and it showed a statistically significant difference between before and after treatment. Plasma Hey of 3 genotypes in control group was tested by analysis of variance, F= 3.522, P=0.037, and it showed plasma Hey levels of 3 genotypes have statistically significant. Compared CC genotype plasma Hey level and CT genotype plasma Hey level, P=0.041, it showed a statistically significant difference. Compared CC genotype Hey level and TT genotype plasma Hey level, P=0.014, it showed a statistically significant differences. Compared CT genotypes Hey level and TT genotype plasma Hey level, P=0.687, it showed difference was not statistically significant. Plasma Hey of 3 genotypes in control group was tested by analysis of variance after treatment, F=1.040, P=0.361, and it showed plasma Hey levels of 3 genotypes have not statistically significant. CC genotype plasma Hey level in the control group was tested by matching t test before and after treatment, t=0.634, P=0.531, and it was not show a statistically significant difference between before and after treatment. CT genotype plasma Hey level in the control group was tested by matching t test before and after treatment, t=4.455, P=0.000, and it showed a statistically significant difference between before and after treatment. TT genotype plasma Hey level in the control group was tested by matching t test before and after treatment, t=4.127, P=0.000, and it showed a statistically significant difference between before and after treatment.
Compared effects of TWK capsule on plasma Hey levels of MTHFRE the same genotype:CC genotype plasma Hey levels of the two groups were tested by independent sample t-test before treatment, t=-0.493,P=0.626.There was not statistically different between two groups. After the treatment, CC genotype plasma Hey levels of the two groups were tested by independent sample t-test, t=-1.441,P=0.161, and it was not a statistically significant difference between two groups. CT genotype plasma Hey levels of the two groups were tested by independent sample t-test before treatment, t=0.515, P=0.609. There was not statistically different between two groups. After the treatment, CT genotype plasma Hey levels of the two groups were tested by independent sample t-test, t=2.449, P=0.019, and it was a statistically significant difference between two groups. TT genotype plasma Hey levels of the two groups were tested by independent sample t-test before treatment, t=0.608, P=0.547. There was not statistically different between two groups. After the treatment, TT genotype plasma Hey levels of the two groups were tested by independent sample t-test, t=2.050, P=0.047, and it was a statistically significant difference between two groups.
⑤Effects of TWK capsule on plasma folate levels of DN
Plasma folate levels of the two groups patients were tested by independent sample t-test before treatment, t=-1.468, P=0.145. There was not statistically different between two groups. The plasma folate levels of before and after the treatment in treated group was tested by matching t test, t=1.093, P=0.279, and it was not a statistically significant difference between before and after treatment. The plasma folate levels of before and after treatment in control group was tested by matching t test, t=1.463, P=0.149. There was not a statistically significant difference. After the treatment, The Plasma folate levels of the two groups patients were tested by independent sample t-test, t=-1.511, P=0.134, and it was not a statistically significant difference between two groups.
⑥Compared UAER of different MTHFR genotypes
UAER of 3 genotypes was tested by analysis of variance, F=3.589, P =0.031, and it showed UAER levels of 3 genotypes have statistically significant. Compared CC genotype UAER level and CT genotype UAER level, P=0.043, it showed a statistically significant difference. Compared CC genotype UAER level and TT genotype UAER level, P=0.011, it showed a statistically significant differences. Compared CT genotypes UAER level and TT genotype UAER level, P=0.482, it showed difference was not statistically significant.
⑦Compared effects of TWK capsule on adiponectin levels of two groups patients
Adiponectin levels of the two groups patients were tested by independent sample t-test before treatment, t=1.248, P=0.214. There was not statistically different between two groups. The adiponectin levels of before and after the treatment in treated group was tested by matching t test, t=6.811, P=0.000, and it was a statistically significant difference between before and after treatment. The adiponectin levels of before and after treatment in control group was tested by matching t test, t=5.064, P=0.000. There was a statistically significant difference. After the treatment, The adiponectin levels of the two groups patients were tested by independent sample t-test, t=-3.080, P= 0.003, and it was a statistically significant difference between two groups.
Conclusion:
(1)Replenishing qi and nourishing yin and invigorating blood circulation and removing blood stasis is a important principle in the treatment of diabetic nephropathy
(2) clinical research of TWK capsule:
①TWK capsule can improve the DN patient's symptoms.
②TWK capsule can reduce urinary albumin excretion rate of the DN patients.
③TWK capsule can improve blood lipid disorders of the DN patients.
(3) Mechanism research of TWK capsule:
①TWK capsule can reduce the level of plasma Hcy.
②TWK capsule may be altered MTHFR gene phenotype. TWK capsule may be affected expression of genetic information, and changed the gene's biological activity.
③TWK capsule can reduce serum adiponectin.
(4) MTHFR gene polymorphism are related with Hcy level. MTHFR gene mutations can lead to high blood Hcy.
(5) MTHFR gene mutations may be related with the progress of diabetic nephropathy.
目的
观察糖微康胶囊的临床疗效,揭示糖微康胶囊治疗糖尿病肾病的机制。
方法
(1)研究方法
将新诊断为早期糖尿病肾病的130例患者随机分为两组：治疗组和对照组。两组患者均予糖尿病教育,饮食控制,均根据血糖、血压、血脂情况予以相应降糖、降压、调脂药治疗。饮食治疗给予糖尿病饮食,蛋白质摄入限量在0.8-1.0g/(kg·d)。降糖治疗一般选用胰岛素,避免使用有肾脏损害的口服降糖药。严格控制血压,使之尽量控制在正常范围以内,血压控制不理想可合并使用不影响糖脂代谢的降压药物。调脂治疗一般选择阿昔莫司。治疗期间发生感染的可以给与抗感染治疗,但疗程不大于7天。治疗组加用糖微康胶囊(由中国中医科学院广安门医院制剂室提供),用法：每次4粒,每日3次,饭后服用。以6个月为1个疗程,共观察1个疗程。
(2)观察指标
采集门诊和住院患者的资料,包括性别、年龄、职业、血型、个人史、既往史等情况。按中医证候调查表,对每一个观察者治疗前、治疗后的症状进行评分。常规实验室指标：治疗前、治疗后行电解质、糖化血红蛋白、血糖、血脂、24小时尿蛋白定量、尿微量白蛋白排泄率检查。安全性指标：治疗前、治疗后行肝、肾功,血、尿、便常规检查。特殊指标：MTHFR基因多态性,血浆Hcy,血清脂联素,血浆叶酸等检测。
(3)统计方法
采用SPSS 12.0统计软件处理,以P<0.05为差异具有统计学意义。
结果：
(1)糖微康胶囊的临床疗效
①两组患者的UAER比较
两组患者治疗前UAER经独立样本t检验,t=0.124,P=0.901,两组患者的UAER比较无统计学差异,具有可比性；治疗组治疗前后UAER经配对t检验,t=7.862,P=0.000,糖微康治疗后UAER显著降低,差异具有统计学意义,对照组治疗前后UAER经配对t检验,t=6.594,P=0.000,差异具有统计学意义；两组患者治疗后UAER经独立样本t检验,t=-2.045,P=0.043,糖微康治疗组UAER水平较对照组低,差异具有统计学意义。
②两组患者中医症状疗效比较
两组患者治疗前中医症状评分经独立样本t检验,t=-0.135,P=0.893,两组患者的中医症状评分无统计学差异,具有可比性；两组患者治疗后中医症状评分经独立样本t检验,t=2.330,P=0.022,治疗组较对照组中医症状评分低,两组患者治疗后中医症状评分差异具有统计学意义。
③两组患者血脂的比较
治疗前两组患者TG经独立样本t检验,t=-0.249,P=0.804,差异无统计学意义,治疗后两组患者TG经独立样本t检,t=1.320,P=0.190,差异无统计学意义,治疗组治疗前后TG经配对t检验,t=4.032,P=0.000,差异具有统计学意义,对照组治疗前后TG经配对t检验,t=2.796,P=0.007,差异具有统计学意义。
治疗前两组患者CHO经独立样本t检验,t=-0.025,P=0.980,差异无统计学意义,治疗后两组患者CHO经独立样本t检,t=-0.118,P=0.906,差异无统计学意义,治疗组治疗前后CHO经配对t检验,t=-1.805,P=0.076,差异无统计学意义,对照组治疗前后CHO经配对t检验,t=-1.208,P=0.232,差异无统计学意义。
治疗前两组患者HDL经独立样本t检验,t=-0.236,P=0.814,差异无统计学意义,治疗后两组患者HDL经独立样本t检,t=0.157,P=0.875,差异无统计学意义,治疗组治疗前后HDL经配对t检验,t=-2.132,P=0.037,差异具有统计学意义,对照组治疗前后HDL经配对t检验,t=-1.527,P=0.128,差异无统计学意义。
治疗前两组患者LDL经独立样本t检验,t=-0.062,P=0.951,差异无统计学意义,治疗后两组患者LDL经独立样本t检,t=-1.280,P=0.203,差异无统计学意义,治疗组治疗前后LDL经配对t检验,t=3.950,P=0.000,差异具有统计学意义,对照组治疗前后LDL经配对t检验,t=2.489,P=0.016,差异具有统计学意义。
④两组患者临床综合疗效比较
治疗组60例患者,显效24例,有效27例,无效9例,总有效率85.00%,对照组56例患者,显效13例,有效23例,无效19例,总有效率64.28%,两组患者经秩和检验,Z=2.539,P=0.011,差异具有统计学意义。
(2)糖微康胶囊治疗糖尿病肾病的机制
①亚甲基四氢叶酸还原酶基因多态性的分布
116例早期糖尿病肾病患者中CC基因型30例,CT基因型47例,TT基因型39例,CC基因型、CT基因型、TT基因型的频率分别为25.86%、40.52%、33.62%；T等位基因的频率为53.88%,C等位基因的频率为46.12%。两组患者治疗前后亚甲基四氢叶酸还原酶基因的基因型都未发生变化,
②亚甲基四氢叶酸还原酶3种基因型的血浆Hey比较
亚甲基四氢叶酸还原酶基因3种基因型的Hcy比较,经方差分析,F=4.961,P=0.009,早期糖尿病肾病患者亚甲基四氢叶酸还原酶基因3种基因型的血浆Hcy水平具有统计学差异,组间两两比较(Post Hoc Tests):CC基因型血浆Hey水平与CT基因型血浆Hey水平相比较,P=0.013,差异具有统计学意义,CC基因型血浆Hey水平与TT基因型血浆Hey水平相比较,P=0.003,差异具有统计学意义,CT基因型血浆Hey水平与TT基因型血浆Hcy水平相比较,P=0.674,差异无统计学意义。表明CC基因型血浆同型半胱氨酸水平明显低于TT或CT基因型。
③治疗组和对照组血浆Hcy水平的比较
两组患者治疗前血浆Hcy水平经独立样本t检验,t=-0.878,P=0.382,两组患者血浆Hcy水平无统计学差异,具有可比性,治疗组治疗前后血浆Hcy水平经配对t检验,t=7.592,P=0.000,差异具有统计学意义,糖微康胶囊治疗后血浆Hcy水平显著下降；对照组治疗前后血浆Hcy水平经配对t检验,t=4.800,P=0.000,差异具有统计学意义；两组患者治疗后血浆Hcy水平的比较,经独立样本t检验,t=-3.426,P=0.001,治疗组血浆Hcy水平较对照组低,差异具有统计学意义。
④两组患者亚甲基四氢叶酸还原酶三种基因型血浆Hcy水平的比较
治疗组治疗前不同基因型血浆Hcy水平经方差分析,F=3.459,P=0.038,3种基因型血浆Hcy水平差异具有统计学意义,经Post Hoc Tests:CC基因型血浆Hcy水平与CT基因型、TT基因型血浆Hcy水平相比较,P值分别为：P=0.029、P=0.018,差异具有统计学意义,CT基因型与TT基因型血浆Hcy水平相比较,差异无统计学意义,P=0.735。治疗组治疗后不同基因型血浆Hcy水平经方差分析,F=1.824,P=0.171,3种基因型血浆Hcy水平差异无统计学意义。治疗组CC基因型治疗前后血浆Hcy水平经配对t检验,t=2.599,P=0.021,差异具有统计学意义；CT基因型治疗前后血浆Hcy水平经配对t检验,t=6.503,P=0.000,差异具有统计学意义；TT基因型治疗前后血浆Hcy水平经配对t检验,t=4.113,P=0.001,差异具有统计学意义。对照组治疗前不同基因型血浆Hcy水平经方差分析,F=3.522,P=0.037,3种基因型血浆Hcy水平差异具有统计学意义,经Post Hoc Tests:CC基因型血浆Hcy水平与CT基因型、TT基因型血浆Hcy水平相比较,P值分别为：P=0.041、P=0.014,差异具有统计学意义,CT基因型与TT基因型血浆Hcy水平相比较,差异无统计学意义,P=0.687。对照组治疗后不同基因型血浆Hcy水平经方差分析,F=1.040,P=0.361,3种基因型血浆Hcy水平差异无统计学意义。对照组CC基因型治疗前后血浆Hcy水平经配对t检验,t=0.634,P=0.531,差异无统计学意义；CT基因型治疗前后血浆Hcy水平经配对t检验,t=4.455,P=0.000,差异具有统计学意义；TT基因型治疗前后血浆Hcy水平经配对t检验,t=4.127,P=0.000,差异具有统计学意义。
治疗组和对照组同一基因型血浆Hcy水平比较：两组患者CC基因型治疗前血浆Hcy水平经独立样本t检验,t=-0.493,P=0.626,差异无统计学意义,治疗后血浆Hcy水平经独立样本t检验,t=-1.441,P=0.161,差异虽然无统计学意义,但治疗组较对照组Hcy水平均值更低；两组患者CT基因型治疗前血浆Hcy水平经独立样本t检验,t=0.515,P=0.609,差异无统计学意义,治疗后两组血浆Hcy水平经独立样本t检验,t=2.449,P=0.019,治疗组血浆Hcy水平较对照组低,差异具有统计学意义；两组患者TT基因型治疗前血浆Hcy水平经独立样本t检验,t=0.608,P=0.547,差异无统计学意义,治疗后血浆Hcy水平经独立样本t检验,t=2.050,P=0.047,治疗组Hcy水平较对照组低,差异具有统计学意义。
⑤两组患者血浆叶酸水平的比较
治疗前两组患者血浆叶酸水平经独立样本t检验,t=-1.468,P=0.145,差异无统计学意义,治疗后两组患者血浆叶酸水平经独立样本t检验,t=-1.511,P=0.134,差异无统计学意义,治疗组治疗前后血浆叶酸水平经配对t检验,t=1.093,P=0.279,治疗组治疗前后血浆叶酸水平差异无统计学意义,对照组治疗前后血浆叶酸水平经配对t检验,t=1.463,P=0.149,对照组血浆叶酸水平治疗前后差异无统计学意义。
⑥治疗前总患者亚甲基四氢叶酸还原酶基因不同基因型UAER比较
亚甲基四氢叶酸还原酶基因不同基因型UAER比较经方差分析,F=3.589,P=0.031,3种基因型UAER水平差异具有统计学意义,组间两两比较(Post Hoc Tests):CC基因型UAER水平与CT基因型UAER水平相比较,P=0.043,差异具有统计学意义,CC基因型UAER水平与TT基因型UAER水平相比较,P=0.011,差异具有统计学意义,CT基因型UAER水平与TT基因型UAER水平相比较,P=0.482,差异无统计学意义。表明CC基因型UAER水平明显低于TT或CT基因型。
⑦两组患者亚甲基四氢叶酸还原酶三种基因型UAER的比较
治疗组治疗前不同基因型UAER比较经方差分析,F=1.150,P=0.324,3种基因型UAER水平差异不具有统计学意义,对照组治疗前不同基因型UAER比较经方差分析,F=2.537,P=0.089,3种基因型UAER水平差异不具有统计学意义；治疗组治疗后不同基因型UAER比较经方差分析,F=0.464,P=0.631,3种基因型UAER水平差异不具有统计学意义,对照组治疗后不同基因型UAER比较经方差分析,F=2.581,P=0.085,3种基因型UAER水平差异不具有统计学意义。两组患者的不同基因型UAER比较无统计学差异,这可能与样本量太小有关,但CC基因型UAER水平、CT基因型UAER水平、TT基因型UAER水平依次增高。治疗组CC基因型治疗前后UAER水平经配对t检验,t=4.969,P=0.000,治疗前后差异具有统计学意义,CT基因型治疗前后UAER水平经配对t检验,t=5.467,P=0.000,治疗前后差异具有统计学意义,TT基因型治疗前后UAER水平经配对t检验,t=2.972,P=0.008,治疗前后差异具有统计学意义；对照组CC基因型治疗前后UAER水平经配对t检验,t=3.471,P=0.004,治疗前后差异具有统计学意义,CT基因型治疗前后UAER水平经配对t检验,t=3.955,P=0.001,治疗前后差异具有统计学意义,TT基因型治疗前后UAER水平经配对t检验,t=3.984,P=0.001,治疗前后差异具有统计学意义。治疗组和对照组同一基因型UAER水平比较：两组患者CC基因型治疗前UAER水平经独立样本t检验,t=0.777,P=0.443,差异无统计学意义,治疗后UAER水平经独立样本t检验,t=0.037,P=0.971,差异无统计学意义；两组患者CT基因型治疗前UAER水平经独立样本t检验,t=0.215,P=0.830,差异无统计学意义,治疗后两组UAER水平经独立样本t检验,t=1.430,P=0.160,差异无统计学意义；两组患者TT基因型治疗前UAER水平经独立样本t检验,t=0.060,P=0.953,差异无统计学意义,治疗后UAER水平经独立样本t检验,t=1.386,P=0.174,差异无统计学意义。
⑧两组患者血清脂联素水平比较
治疗组治疗前后脂联素水平经配对t检验,t=6.881,P=0.000,治疗前后差异具有统计学意义,对照组治疗前后脂联素水平经配对t检验,t=5.046,P=0.000,治疗前后差异具有统计学意义。两组患者治疗前经独立样本t检验,t=1.248,P=0.214,脂联素水平差异无统计学意义,两组患者治疗后经独立样本t检验,t=-3.080,P=0.003,脂联素水平差异具有统计学意义。
结论：本研究的主要结论如下：
(1)导师提出的益气养阴,活血化瘀治则是糖尿病肾病的重要中医治则。
(2)导师为首的专家组研制的糖微康胶囊的临床研究表明：
①糖微康胶囊可以改善糖尿病肾病患者的症状。
②糖微康胶囊可以减少糖尿病肾病患者尿蛋白排泄率。
③糖微康胶囊可以改善糖尿病肾病患者的血脂紊乱。
(3)糖微康胶囊的机理研究表明：
①糖微康胶囊可以降低血浆Hcy水平。
②糖微康胶囊对MTHFR多态性的影响表明：糖微康胶囊可能改变了MTHFR的基因表型,影响遗传信息的表达,改变了基因的生物活性。
③糖微康胶囊可以降低血清脂联素水平。
(4) MTHFR基因多态性与血浆Hcy水平相关,MTHFR基因突变可引起高Hcy血症。
(5) MTHFR基因突变可能与糖尿病肾病的进展有关。
Diabetic nephropathy is one of the main microvascular complications of diabetes. The incidence of diabetic nephropathy is approximately 20-40% in diabetic crowd. Diabetic nephropathy is one of the leading causes of death in diabetic crowd. At present, no methods can completely prevent or cure diabetic nephropathy. Many clinical studies showed that TCM has obvious advantages, and can reduce albuminuria, improve renal function, delay the progress of diabetic nephropathy. According to decades of clinical experience, combining modern pharmacology, my teacher had developed TWK capsule. In the treatment of diabetic nephropathy, many clinical studies showed TWK capsule has good effect.
This research is from my teacher's national natural science fund project. The MTHFR C677T gene polymorphism is related with type 2 diabetic nephropathy. It is one of genetic risk factors of Diabetic nephropathy. In this study, we tried to investigate the clinical curative effect of TWK capsule, and the relation between TWK capsule's curative effect and MTHFR gene polymorphism. We also tried to investigate the influence of TWK capsule on plasma Hcy, serum adiponectin, and revealed the mechanism of TWK capsule on diabetic nephropathy.
Objective:
To observe the clinical curative effect of TWK capsule and reveal mechanism of TWK capsule on diabetic nephropathy.
Methods:
(1) research methods
The new diagnosed 130 cases of early diabetic nephropathy were randomly divided into two groups:treated group and control group. Diabetic education and diet control were guided by doctors in two groups. As far as diet therapy was considered, protein intake was limited in 0.8-1.0 g/(kg·d). Insulin was selected in first to control blood sugar, and avoided to use the oral medications that have kidney damage. Blood pressure of all patients need be controlled in the normal range. Acipimox was usually selected to retrieve abnormality of lipid. When infections occurred during treatment, anti-infection drugs were given to control infection, but the period of treatment is not more than 7 days. TWK capsule was added in treated group. Usage:4 grains/time,3 times/day. The course of treatment was six months.
(2) observation index
Materials of outpatient and inpatient were collected, including gender, age, occupation, blood type, personal history, past medical history, etc. According to the questionnaire, rating of the symptoms were conducted both before treatment and after completed treatment. Routine laboratory index:electrolytes, glycated hemoglobin, blood sugar, lipid and UAER were measured both before treatment and after completed treatment. Safety index:function of liver and kidney, regular inspection of blood, urine and stool. Special index:MTHFR gene polymorphism, plasma Hcy, serum adiponectin, etc.
(3) statistical method
Using SPSS 12.0 statistical software, P<0.05 is considered statistical significance.
Results:
(1) clinical curative effect of TWK capsule
①UAER comparison of the two groups
UAER of the two groups patients were tested by independent sample t-test before treatment, t=0.124, P=0.901.There was not statistically different between two groups. The UAER of before and after the treatment in treated group was tested by matching t test, t=7.862, P=0.000, and it was a statistically significant difference between before and after treatment. The UAER of before and after treatment in control group was tested by matching t test, t=6.594, P=0.000.There was a statistically significant difference. After the treatment, UAER of the two groups patients were tested by independent sample t-test, t=-2.045, P= 0.043, and it was a statistically significant difference between two groups.
②Compared TCM symptoms curative effect between the two groups
Scores of TCM symptoms of the two groups patients were tested by independent sample t-test before treatment, t=0.135,P=0.893. There was not statistically different between two groups. After the treatment, scores of TCM symptoms of the two groups patients were tested by independent sample t-test, t=2.330, P=0.022, and it was a statistically significant difference between two groups.
③Compared blood lipid in the two groups patients
TG was tested by independent sample t-test between two groups before treatment, t=-0.249, P=0.804, and difference was not statistically significant. TG of two groups patients was tested by independent sample t test after treatment, t=1.320, P=0.190, and difference was not statistically significant. TG in the treated group was tested by matching t test before and after treatment, t=4.032, P=0.000, and it showed a statistically significant difference between before and after treatment. TG in the control group was tested by matching t test before and after treatment, t=2.796, P=0.007, and it showed a statistically significant difference.
CHO was tested by independent sample t-test between two groups before treatment, t=-0.025, P=0.980, and difference was not statistically significant. CHO of two groups patients was tested by independent sample t test after treatment, t=-0.188, P=0.906, and difference was not statistically significant. CHO in the treated group was tested by matching t test before and after treatment, t=-1.085, P=0.076, and it showed a nearly statistically significant difference between before and after treatment. CHO in the control group was tested by matching t test before and after treatment, t=-1.208, P=0.232, and difference was not statistically significant.
HDL was tested by independent sample t-test between two groups before treatment, t=-0.236, P=0.814, and difference was not statistically significant. HDL of two groups patients was tested by independent sample t test after treatment, t=0.175, P=0.875, and difference was not statistically significant. HDL in the treated group was tested by matching t test before and after treatment, t=-2.132, P=0.037, and it showed a statistically significant difference between before and after treatment. HDL in the control group was tested by matching t test before and after treatment, t=-1.527, P=0.128, and difference was not statistically significant.
LDL was tested by independent sample t-test between two groups before treatment, t=-0.062, P=0.951, and difference was not statistically significant. LDL of two groups patients was tested by independent sample t test after treatment, t=-1.280, P=0.203, and difference was not statistically significant. LDL in the treated group was tested by matching t test before and after treatment, t=3.950, P=0.000, and it showed a statistically significant difference between before and after treatment. LDL in the control group was tested by matching t test before and after treatment, t=2.489, P=0.016, and difference was statistically significant.
④compared clinical total curative effect between two groups
60 patients in the treated group,27 cases were excellent effective, and 24 cases were effective, and 9 cases were invalid. The total effective rate was 85.00% in treated group.56 patients in the control group,13 cases were excellent effective, and 23 cases were effective, and 19 cases were invalid. The total effective rate was 64.28% in control group. Z= -2.539, P=0.011, and it showed a statistically significant difference between two groups.
(2) mechanism of TWK capsule on diabetic nephropathy
①MTHFR gene polymorphism of distribution
In 116 patients with early diabetic nephropathy,30 cases were CC genotype, and 47 cases were CT genotype, and 39 cases were TT genotype. Frequency of CC genotype, CT genotype, TT genotype were 25.86%,40.52%, 33.62% respectively. T allele frequency was 53.88%. C allele frequency was 46.12%. After treatment, all MTHFR gene genotypes were not changed。
②Compared Hey of MTHFR gene genotypes
Hey of 3 genotypes was tested by analysis of variance, F=4.961, P =0.009, and it showed plasma Hey levels of 3 genotypes have statistically significant. Compared CC genotype plasma Hcy level and CT genotype plasma Hey level, P=0.013, it showed a statistically significant difference. Compared CC genotype Hey level and TT genotype plasma Hey level, P=0.003 it showed a statistically significant differences. Compared CT genotypes Hey level and TT genotype plasma Hey level, P=0.674, it showed difference was not statistically significant.
③Effects of TWK capsule on plasma Hey levels of DN
Plasma Hey levels of two groups was tested by independent sample t test before treatment, t=-0.878, P=0.382, and it showed plasma Hey levels of two groups were not statistically different. Plasma Hey levels of two groups patients was tested by independent sample t test after treatment, t=-3.426, P=0.001, and difference was statistically significant. Plasma Hey levels in the treated group was tested by matching t test before and after treatment, t=7.952, P=0.000, and it showed a statistically significant difference between before and after treatment. Plasma Hey levels in the control group was tested by matching t test before and after treatment, t=4.800, P=0.000, and difference was statistically significant.
④Compared effects of TWK capsule on plasma Hey levels of MTHFRE different genotypes in DN
Plasma Hey of 3 genotypes in treated group was tested by analysis of variance, F=3.459, P=0.038, and it showed plasma Hey levels of 3 genotypes have statistically significant. Compared CC genotype plasma Hey level and CT genotype plasma Hey level, P=0.029, it showed a statistically significant difference. Compared CC genotype Hey level and TT genotype plasma Hey level, P=0.018, it showed a statistically significant differences. Compared CT genotypes Hey level and TT genotype plasma Hey level, P=0.735, it showed difference was not statistically significant. Plasma Hcy of 3 genotypes in treated group was tested by analysis of variance after treatment, F=1.824, P=0.171, and it showed plasma Hcy levels of 3 genotypes have not statistically significant. CC genotype plasma Hey level in the treated group was tested by matching t test before and after treatment, t=2.599, P=0.021, and it showed a statistically significant difference between before and after treatment. CT genotype plasma Hey level in the treated group was tested by matching t test before and after treatment, t=6.503, P=0.000, and it showed a statistically significant difference between before and after treatment. TT genotype plasma Hey level in the treated group was tested by matching t test before and after treatment, t=4.113, P=0.001, and it showed a statistically significant difference between before and after treatment. Plasma Hey of 3 genotypes in control group was tested by analysis of variance, F= 3.522, P=0.037, and it showed plasma Hey levels of 3 genotypes have statistically significant. Compared CC genotype plasma Hey level and CT genotype plasma Hey level, P=0.041, it showed a statistically significant difference. Compared CC genotype Hey level and TT genotype plasma Hey level, P=0.014, it showed a statistically significant differences. Compared CT genotypes Hey level and TT genotype plasma Hey level, P=0.687, it showed difference was not statistically significant. Plasma Hey of 3 genotypes in control group was tested by analysis of variance after treatment, F=1.040, P=0.361, and it showed plasma Hey levels of 3 genotypes have not statistically significant. CC genotype plasma Hey level in the control group was tested by matching t test before and after treatment, t=0.634, P=0.531, and it was not show a statistically significant difference between before and after treatment. CT genotype plasma Hey level in the control group was tested by matching t test before and after treatment, t=4.455, P=0.000, and it showed a statistically significant difference between before and after treatment. TT genotype plasma Hey level in the control group was tested by matching t test before and after treatment, t=4.127, P=0.000, and it showed a statistically significant difference between before and after treatment.
Compared effects of TWK capsule on plasma Hey levels of MTHFRE the same genotype:CC genotype plasma Hey levels of the two groups were tested by independent sample t-test before treatment, t=-0.493,P=0.626.There was not statistically different between two groups. After the treatment, CC genotype plasma Hey levels of the two groups were tested by independent sample t-test, t=-1.441,P=0.161, and it was not a statistically significant difference between two groups. CT genotype plasma Hey levels of the two groups were tested by independent sample t-test before treatment, t=0.515, P=0.609. There was not statistically different between two groups. After the treatment, CT genotype plasma Hey levels of the two groups were tested by independent sample t-test, t=2.449, P=0.019, and it was a statistically significant difference between two groups. TT genotype plasma Hey levels of the two groups were tested by independent sample t-test before treatment, t=0.608, P=0.547. There was not statistically different between two groups. After the treatment, TT genotype plasma Hey levels of the two groups were tested by independent sample t-test, t=2.050, P=0.047, and it was a statistically significant difference between two groups.
⑤Effects of TWK capsule on plasma folate levels of DN
Plasma folate levels of the two groups patients were tested by independent sample t-test before treatment, t=-1.468, P=0.145. There was not statistically different between two groups. The plasma folate levels of before and after the treatment in treated group was tested by matching t test, t=1.093, P=0.279, and it was not a statistically significant difference between before and after treatment. The plasma folate levels of before and after treatment in control group was tested by matching t test, t=1.463, P=0.149. There was not a statistically significant difference. After the treatment, The Plasma folate levels of the two groups patients were tested by independent sample t-test, t=-1.511, P=0.134, and it was not a statistically significant difference between two groups.
⑥Compared UAER of different MTHFR genotypes
UAER of 3 genotypes was tested by analysis of variance, F=3.589, P =0.031, and it showed UAER levels of 3 genotypes have statistically significant. Compared CC genotype UAER level and CT genotype UAER level, P=0.043, it showed a statistically significant difference. Compared CC genotype UAER level and TT genotype UAER level, P=0.011, it showed a statistically significant differences. Compared CT genotypes UAER level and TT genotype UAER level, P=0.482, it showed difference was not statistically significant.
⑦Compared effects of TWK capsule on adiponectin levels of two groups patients
Adiponectin levels of the two groups patients were tested by independent sample t-test before treatment, t=1.248, P=0.214. There was not statistically different between two groups. The adiponectin levels of before and after the treatment in treated group was tested by matching t test, t=6.811, P=0.000, and it was a statistically significant difference between before and after treatment. The adiponectin levels of before and after treatment in control group was tested by matching t test, t=5.064, P=0.000. There was a statistically significant difference. After the treatment, The adiponectin levels of the two groups patients were tested by independent sample t-test, t=-3.080, P= 0.003, and it was a statistically significant difference between two groups.
Conclusion:
(1)Replenishing qi and nourishing yin and invigorating blood circulation and removing blood stasis is a important principle in the treatment of diabetic nephropathy
(2) clinical research of TWK capsule:
①TWK capsule can improve the DN patient's symptoms.
②TWK capsule can reduce urinary albumin excretion rate of the DN patients.
③TWK capsule can improve blood lipid disorders of the DN patients.
(3) Mechanism research of TWK capsule:
①TWK capsule can reduce the level of plasma Hcy.
②TWK capsule may be altered MTHFR gene phenotype. TWK capsule may be affected expression of genetic information, and changed the gene's biological activity.
③TWK capsule can reduce serum adiponectin.
(4) MTHFR gene polymorphism are related with Hcy level. MTHFR gene mutations can lead to high blood Hcy.
(5) MTHFR gene mutations may be related with the progress of diabetic nephropathy.
引文
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