三黄糖肾康对早期DN大鼠微炎症状态影响的实验研究及临床疗效观察
摘要
目的：
1.三黄糖肾康颗粒对早期糖尿病肾病大鼠的药效学研究。
2.研究三黄糖肾康颗粒对早期糖尿病肾病的药物作用机制。
3.观察三黄糖肾康颗粒对早期糖尿病肾病患者的临床疗效。
材料与方法：
1.实验研究
1.1造模方法
采用高糖高脂饲料喂养结合腹腔注射链脲佐菌素(STZ)的造模方法，复制出糖尿病模型，引起胰岛素抵抗、高血糖，导致微量白蛋白尿的出现。
1.2分组和给药方法
SPF级Wistar大鼠90只，体重280±20g。将90只大鼠按体重编为1-90号，采用随机数字法将90只大鼠随机分为正常组和造模组，糖尿病模型成功后又按照血糖水平将造模组大鼠重新随机分组，最后共为6组，分别为A：正常组；B：模型组；C：中药预防组；D1：中药低剂量组；D2：中药高剂量组；E：西药组。除正常组外，其余各组采用高脂高糖饲料联合小剂量STZ（42mg/Kg.bw）的方法复制糖尿病肾病（DN）大鼠模型，模型复制成功2周后，除正常组和中药预防组外，分别给与相应药物经口灌胃干预，连续给药8周；中药预防组大鼠自模型复制之日起即开始给药，连续给药10周。中药预防组和中药低剂量组按照正常成人剂量(g/kg)的6.3倍给药；中药高剂量组按照低剂量的3倍给药。西药组给予贝那普利灌胃，给药量按照正常成人给药量等效换算成成年大鼠给药量，即0.9mg/kg.d。
1.3观察指标与测定方法
主要观察三黄糖肾康颗粒的药效学指标及对糖尿病肾病大鼠微炎症状态的影响，包括实验结束后，分别对各组大鼠糖化血红蛋白、肌酐、尿素氮、血β2-微球蛋白、血糖及尿中尿微量白蛋白含量进行检测。各组大鼠处死后摘取肾脏，以4%多聚甲醛溶液固定，采用HE染色和PAS染色的方法，观察各组大鼠肾脏病理变化情况。采用荧光定量PCR方法对各组大鼠肾脏组织中NF-κB、MCP-1和CCR2mRNA表达水平进行检测。采用western-blot方法对各组大鼠肾脏组织中NF-κB、MCP-1和CCR2蛋白表达水平进行检测。通过对以上效应指标的检测，进一步探讨了三黄糖肾康颗粒对糖尿病肾病大鼠的疗效及其部分作用机制。
2.临床研究
选择气虚血瘀型早期糖尿病肾病患者40例，采用随机对照的方法，将患者随机分为中药治疗组及西药对照组各20例。中药治疗组患者在基础治疗基础上，加用三黄糖肾康颗粒，每日一付，分两次口服；西药对照组患者在基础治疗基础上，给予口服洛汀新治疗，每次10mg，每日一次，疗程8周。完成治疗周期后，对两组患者进行一般体格检查、谷丙转氨酶（ALT）、血肌酐（Scr）、尿素氮（BUN）、空腹及餐后2小时血糖、糖化血红蛋白、24h尿微量白蛋白（U-mAlb）、中医症状疗效指数等检查，以观察三黄糖肾康颗粒对早期糖尿病肾病患者的临床疗效。
结果：
1.动物实验结果
1.1对大鼠一般情况的影响
实验过程中，正常组大鼠精神状态良好，未出现死亡；造模组大鼠食量减少，饮水量明显增多，共死亡6只。西药组大鼠死亡1只；中药高剂量组死亡1只；中药低剂量组死亡1只；模型组共死亡3只。
1.2对大鼠尿微量白蛋白的影响
与正常组比较，其余各组大鼠尿中微量白蛋白含量显著升高（p<0.01），有统计学差异；模型组尿微量白蛋白含量最高，与该组比较，各治疗组及预防组显著降低（p<0.05），有统计学意义；各治疗预防组组间比较，预防组低于各治疗组且其差异有统计学意义（p<0.01）；与西药组比较，预防组低于西药组且其差异有统计学意义（p<0.01），低剂量组高于西药组且其差异有统计学意义（p<0.05），高剂量组与西药组比较差异无统计学意义（p＞0.05）。
1.3对大鼠血糖的影响
除正常组，其余各组大鼠血糖均高于16.7mmol/L，与正常组比较，其余各组大鼠血糖显著增高（p<0.01），有统计学意义；与模型组比较，西药组、预防组、高剂量组、低剂量组血糖值均低于模型组，且其差异有统计学意义（p<0.01）；预防组血糖值最低，与其余各组比较差异有统计学意义（p<0.05）；与中药低剂量组比较，预防组及高剂量组均低于低剂量组，且其差异有统计学意义（p<0.01，p<0.05）；高剂量组与西药组组间比较差异无统计学意义（p＞0.05）。
1.4对大鼠糖化血红蛋白的影响
各组大鼠血清糖化血红蛋白含量测定结果显示，模型组及各治疗预防组均显著高于正常组（p＜0.01）有统计学意义；与模型组比较，预防组及各治疗组均显著降低（p＜0.01）有统计学意义；西药组、预防组、中药高剂量组及中药低剂量组组间比较差异无统计学意义（p＞0.05）。
1.5对血β2-微球蛋白的影响
与正常对照组比较，其余各组大鼠血清β2-微球蛋白含量升高，其差异有统计学意义（p<0.01）；模型对照组血清β2-微球蛋白含量最高，与该组比较，各治疗组及预防组显著降低（p<0.01），有统计学意义。
1.6对血肌酐、尿素氮的影响
各组间大鼠血清中肌酐含量比较无显著性差异（p＞0.05），没有统计学意义。模型组大鼠血清尿素氮含量显著升高，与模型组比较，其余各组大鼠血清尿素氮含量显著降低（p＜0.01），有统计学意义；与正常对照组比较，仅中药低剂量组有统计学差异（p＜0.05）。西药组、预防组、中药高剂量组、中药低剂量组组间比较差异无统计学意义（p＞0.05）。
1.7各组大鼠肾脏组织病理变化
HE染色：高倍镜下可见，模型组肾小球硬化，系膜细胞及系膜基质增生，肾小管上皮细胞空泡变形；各治疗组及中药预防组大鼠肾脏病理变化程度明显轻于模型对照组，中药预防组大鼠肾脏的肾小球及肾小管比正常组大鼠稍微增大；中药高剂量与西药组大鼠肾脏肾小球体积大小相当，但均大于正常组。
PAS染色：模型组大鼠肾脏组织可见广泛的PAS染色阳性物质，主要位于小叶中央部，肾小球基底膜增厚，系膜基质明显增多，肾小球弥漫性病变，小动脉玻璃样变，肾小球内部偶见圆形、椭圆形或锥形的结节，个别肾小球荒废；而各治疗组及中药预防组大鼠肾脏PAS染色呈弱阳性，西药组可见弥漫肾小球硬化，系膜基质和细胞外基质明显增多，肾小管萎缩；中药预防组可见肾小球系膜基质轻度增多，肾小球基底膜及肾小管无病变；中药高剂量组可见肾小球系膜基质及系膜细胞增多，肾小球基底膜无变化，肾小管无病变；中药低剂量组大鼠可见节断性肾小球硬化，肾小球系膜基质增多，基底膜增厚。
1.8对C反应蛋白含量的影响
各组大鼠血清及肾脏组织中C反应蛋白变化趋势相同，与正常组比较，模型组大鼠血清及肾脏组织中C反应蛋白含量显著升高（p＜0.01），有统计学意义；与模型组比较，中药预防及各治疗组大鼠血清及肾脏组织中C反应蛋白含量显著降低（p＜0.01），有统计学意义；与西药组比较，中药预防组、中药高、低剂量组大鼠血清中CRP含量显著下降（p＜0.01），有统计学意义。
1.9对肾脏组织中核转录因子NF-κB蛋白及基因的表达水平的影响
模型组大鼠肾脏组织中NF-κB mRNA及蛋白表达水平均较正常组显著上调（p＜0.01），有统计学意义；与模型组比较，中药预防组和各治疗组大鼠肾脏组织中NF-κBmRNA及蛋白表达水平均显著下调（p＜0.01），有统计学意义。与中药预防组比较，正常组、中药高剂量组、中药低剂量组大鼠肾脏组织中NF-κB蛋白及基因的表达水平均显著增高（p＜0.01），有统计学意义。西药组与中药低剂量、中药预防组比较，差异显著（p＜0.01），有统计学意义。中药高剂量组与西药组无显著性差异（p＞0.05）。
1.10对肾脏组织中MCP-1及CCR2蛋白及基因的表达水平的影响
各组大鼠肾脏组织中MCP-1mRNA及蛋白、CCR2mRNA及蛋白的表达水平测定结果，与正常对照组比较，模型组大鼠肾脏组织中MCP-1mRNA及蛋白、CCR2mRNA及蛋白的表达水平均显著上调（p＜0.01），有统计学意义；与模型组比较，中药预防组和各治疗组大鼠MCP-1和CCR2基因及蛋白表达水平均显著下调（p＜0.01）；中药预防组大鼠肾脏组织中MCP-1及CCR2蛋白及基因的表达水平显著低于西药组及中药高、低剂量组（p＜0.01或0.05）；西药组MCP-1及CCR2蛋白及基因的表达水平较中药高、低剂量组低（p＜0.05）；中药高剂量与低剂量组大鼠的CCR2蛋白及基因表达水平无显著性差异，但MCP-1mRNA及蛋白表达水平差异显著（p＜0.05）。
2.临床观察结果
2.1对疗效性指标的影响
中药治疗组与西药对照组患者24小时尿微量蛋白各时间点的组间比较，无显著性差异；与治疗前（0周比较），中药治疗组和西药对照组尿微量白蛋白显著降低（p＜0.01），有统计学意义；中药治疗组和西药对照组患者尿微量白蛋白随着治疗时间的延长而逐渐减少。
治疗前，中药治疗组与西药对照组患者症候积分组间比较，无显著性差异（p＞0.05）；治疗第6周及第8周，中药治疗组证候积分显著低于西药对照组（p＜0.05），两组间比较有统计学意义；与第0周比较，两组患者第4、6、8周的症候积分均显著降低（p＜0.05或p＜0.01），有统计学意义。
中药治疗组患者显效4例，有效8例，无效8例，总有效率60%；西药对照组患者显效4例，有效9例，无效7例，总有效率65%。
2.2对血糖和糖化血红蛋白的影响
两组患者FBG、2hPG和HbA1c水平无显著性差异（p＞0.05）；治疗前后比较，中药治疗组和西药对照组患者的FBG、2hPG和HbA1c水平无显著性差异（p＞0.05）。
2.3对安全性指标的影响
两组患者治疗前、后血清肌酐、尿素氮、谷丙转氨酶水平无显著性差异（p＞0.05）；每组的治疗前后比较，中药治疗组和西药对照组患者的血清肌酐、尿素氮、谷丙转氨酶水平无显著性差异（p＞0.05）。
结论：
1.三黄糖肾康颗粒可有效降低DN模型大鼠血糖、糖化血红蛋白、尿微量白蛋白、血β2-微球蛋白、尿素氮水平。
2．三黄糖肾康颗粒可有效降低DN模型大鼠血清及肾组织中C反应蛋白含量。
3.三黄糖肾康颗粒可有效降低DN模型大鼠肾脏皮质中NF-κB、MCP-1和CCR2mRNA及蛋白的表达水平。
4.三黄糖肾康颗粒对DN模型大鼠的防治作用可能是通过抑制NF-κB信号通路，从而抑制MCP-1与其受体CCR2结合而实现的。
5.三黄糖肾康颗粒可有效降低早期糖尿病肾病患者24小时尿微量蛋白、症候积分水平。
6.三黄糖肾康颗粒对早期糖尿病肾病患者血清肌酐、尿素氮、谷丙转氨酶、FBG、2hPG和HbA1c水平无显著影响。
7.三黄糖肾康颗粒在治疗第6周就能达到最佳中医疗效，对早期糖尿病肾病患者有较理想的防治作用。
Objective
1.The study of pharmacodynamics of San Huang Tang Shen Kang granular to earlydiabetic nephropathy rats.
2.The study of drug mechanism of San Huang Tang Shen Kang granular to earlydiabetic nephropathy rats.
3.Observe clinical curative effect of San Huang Tang Shen Kang granular inpatients with early diabetic nephropathy.Materials and methods
1. Trial Study
1.1Methods of modeling
With high fat, high sugar diet combined with intraperitoneal injection ofstreptozotocin(STZ),we duplicate diabetes model and lead insulin resistance,hyperglycemia, and miner albuminuria.
1.2Method of grouping and oral medication administering
SPF Wistar rats (90,280+20g weight). Only according to the weight, wenumbered90rats of1-90. By using random numbers,90rats were randomly dividedinto normal group and model group, when diabetes model was succeeded and thenthey were grouped according to their blood sugar levels, the total is6groups,respectively A: normal group; B: the model group; C: Chinese medicine preventiongroup; D1: low dose group; D2: the high dose group of TCM; E: the western medicinegroup. In addition to the normal group, the rest of the group using high fatand sugar feed in combination with small dose of STZ (42mg/Kg bw) method copyof diabetic nephropathy (DN) rats model, the model was copied in success after2weeks. In addition to the normal group and Chinese medicine prevention group,respectively we give the corresponding drug intervention to fill the stomachthrough the mouth, for eight consecutive weeks. Chinese medicine precautiousgroup rats from model replication which starts from the date of delivery, for10weeks in succession. According to the normal adult dose, Chinese medicine precautious group and low dose group of Chinese traditional medicine give6.3times dose. High dose group according to the3times of low dose group. Groupwas given western medicine that split lavage and dosage according to the normaladult dosage equivalent conversion into adult rats dosage, namely,0.9mg/kg.d.
1.3Observing index and measuring method
We should mainly observe pharmacodynamics indexes and San Huang Tang ShenKang particles to the influence of inflammation in diabetic nephropathy ratsincluding the experimental ended, separately for each group of rats serumglycosylated hemoglobin, blood urea nitrogen, creatinine, beta2-microglobulin,blood glucose and urine trace albumin content in urine test. Between groups ratswere randomly selected3only, after death, harvesting kidneys, fixed in4%paraformaldehyde solution, using the method of HE staining and PAS staining,observing their kidneys pathological changes. Using fluorescence quantitativepolymerase chain reaction (PCR), NF-κB, MCP-1and CCR2mRNA expression levelsin the kidney tissue of each group rats were detected. Using western blot method,NF-κB,MCP-1and CCR2protein expression levels in the kidney tissue of eachgroup rats were detected. Through the above effect index detection, we furtherdiscuss the San Huang Tang Shen Kang particles on the curative effect of diabeticnephropathy in rats and its mechanism.
2. Clinical research
Choosing40patients of blood deficiency type with early diabetic nephropathy,adopting the method of randomly contrast, patients were randomly divided intotraditional Chinese medicine treatment group and western medicine control groupfor20cases each. On the basis of foundation treatment, Chinese medicinetreatment group patients with San Huang Tang Shen Kang particles, a daily pay,two oral; On the basis of foundation treatment, western medicine control grouppatients give lotensin oral treatment,10mg each time, once per day, courseof8weeks. After completion of treatment on two groups of patients with generalmedical examination, cereal third transaminase (ALT), serum creatinine (Scr),urea nitrogen (BUN), fasting and postprandial2hours blood glucose, glycosylated hemoglobin,24h urine trace albumin (U-mAlb), TCM symptomscurative effect index, we observe San Huang Tang Shen Kang particles clinicalcurative effect in patients with early diabetic nephropathy.
Results
1. Results of animal experiments
1.1The affection on general situation of rats
In experiment process, the mental state of normal group rats is good andno death; Model group rats eat less, drink quantity obviously increased, anda total of6cases died. The western medicine group rats died in1case.Traditional Chinese medicine high dose group died in1case. Low dose group diedin1case. Model group in all3cases died.
1.2The affection to microalbuminuria on rats
Compared with normal group, urine trace albumin levels of the rest of thegroup rats increased significantly (p <0.01)and statistically different. Urinetrace albumin content of model group is the highest, compared with the group,the treatment group and prevention group decreased significantly (p <0.05).In Comparison among different treatment, prevention group is lower than thetreatment group. Compared with western medicine group, preventive group waslower than western medicine group and the difference was statisticallysignificant (p <0.01). Low dose group was higher than western medicine groupand the difference was statistically significant (p <0.05). Compared with thewestern medicine group, high dose group was no statistically significantdifference (p>0.05).
1.3The affection on blood sugar
Except for normal group, the blood sugar of other groups’ rats were higherthan16.7tendency for L. Compared with normal group, the rest of the group ratsblood glucose was significantly increased (p <0.01). Compared with model group,western medicine group, preventive group, high dose group, low dose group bloodglucose values were less than model group, and the difference was statistically significant (p <0.01). Prevention group had lowest blood sugar levels.Comparedwith the rest of the group, the difference was statistically significant (p <0.05). Compared with traditional Chinese medicine low dose group, preventivegroup and high dose group were lower than low dose group, and the differencewas statistically significant (p <0.01, p <0.05); Between the high dose groupand western medicine, there was no statistically significant difference (p>0.05).
1.4The affection on glycosylated hemoglobin
Serum glycosylated hemoglobin content of groups of rats determinated, modelgroup and prevention group were significantly higher than normal group (p <0.01)and was statistically significant. Compared with model group, preventive groupand each treatment group were significantly lower (p <0.01) and wasstatistically significant. In comparison between western medicine group,preventive group, high dose group and low dose, there was no statisticallysignificant difference (p>0.05).
1.5The affection on blood β2-micro globulin
Compared with normal control group, the rest of the group rats blood β2-micro globulin content increases, and the difference was statisticallysignificant (p <0.01). Blood β2-micro globulin content of model control groupis the highest. Compared with the group, the treatment group and prevention groupdecreased significantly (p <0.01) with statistical significance.
1.6The affection on serum creatinine and urea nitrogen
Serum creatinine content of each group of rats was no significant difference(p>0.05), no statistical significance. Serum urea nitrogen content of modelgroup rats increased significantly. Compared with model group, the rest of thegroup in the rat serum urea nitrogen content decreased significantly (p <0.01),and there was statistical significance. Compared with normal control group, onlyChinese medicine low dose was statistically difference (p <0.05). In comparisonbetween western medicine group, preventive group, high dose group and low dose,there was no statistically significant difference (p>0.05).
1.7The pathological changes of kidney tissue in each group
HE staining: At high magnification shows, model group of glomerularsclerosis, mesangial cell and mesangial matrix proliferation of renal tubularepithelial cell cavity deformation. Each treatment group and Chinese traditionalmedicine prevent group rats kidney pathological changes degree obviously lighterthan the control group. Chinese traditional medicine prevent group rats renalglomerulus and renal tubule increased slightly than normal group rats. Thewestern medicine group and high dose of Chinese medicine in the rat kidneyglomerular volume had the similar size, but bigger than the normal group.
PAS staining: Kidney tissue of model group rats is a wide range of PASpositive substances, mainly in the centrilobular, glomerular basement membranethickening, mesangial matrix increased obviously, glomerular diffuse lesions,arteriole hyaline changes, glomerulus internal occasional round, oval or conicaltubercles, individual glomerular waste, and each treatment group and Chinesetraditional medicine prevent group rats kidney PAS staining showed weaklypositive. Western medicine group is visible for diffuse glomerular hard,mesangial matrix and extracellular matrix increased obviously, and renal tubularatrophy. Chinese medicine prevention increased glomerular mesangial matrix setof visible light, the glomerular basement membrane and renal tubular lesion;Chinese medicine high dose group of glomerular mesangial matrix and mesangialcells increased, glomerular basement membrane changed. Chinese medicine low dosegroup is visible for section break in rats, increased glomerular mesangial matrix,and thickening of basement membrane.
1.8The affection on CRP levels
Groups of CRP in serum and kidney tissue of rats have the same change trend.Compared with normal group, model group rats CRP content in serum and kidneytissue increased significantly (p <0.01), and there was statisticalsignificance. Compared with model group, Chinese medicine prevention and thetreatment group rats CRP content in serum and kidney tissue decreasedsignificantly (p <0.01), and there was statistical significance. Compared with western medicine group, Chinese medicine prevention group, the Chinese medicinehigh, low dose group rats serum CRP levels decreased significantly (p <0.01)with statistical significance.
1.9The affection on Nuclear transcription factors in kidney tissue NF-κBprotein and gene expression level
Kidney tissue of model group rats in the NF-κB mRNA and protein expressionlevels were significantly raised in the normal group (p <0.01), and there wasstatistical significance. Compared with model control group, Chinese medicineprevention group and each treatment group in the rat kidney tissue in the NF-κB mRNA and protein expression levels were significantly lower (p <0.01).Compared with traditional Chinese medicine prevention group, normal group, highdose group, low dose group in the rat kidney tissue in the NF-κB protein andgene expression level were significantly increased (p <0.01) with statisticalsignificance. Western medicine group had significant difference in low doseChinese traditional medicine and Chinese traditional medicine prevent group (p<0.01) with statistical significance. Western medicine group and high dose groupof Chinese medicine has no significant difference (p>0.05).
1.10The affection on MCP-1and CCR2in kidney tissue protein and gene expressionlevel
Expression level determination results of each group MCP-1mRNA and protein,CCR2mRNA and protein in the kidney tissue, compared with normal control group,model group rats were significantly raised (p <0.01), and there was statisticalsignificance. Compared with model control group, Chinese medicine preventiongroup and each treatment group rats MCP-1and CCR2gene and protein expressionlevels were significantly lower (p <0.01). CCR2and MCP-1in the rat kidneytissue protein in Chinese medicine prevention group and gene expression levelwas significantly lower than western medicine group and Chinese medicine highand low dose group (p <0.01or0.05). CCR2and MCP-1protein and gene expressionlevel in western medicine group was lower than those of high and low dose ofChinese medicine (p <0.05). Low dose group and high dose of Chinese medicine in rats of CCR2protein and gene expression level has no significant difference,but the MCP-1mRNA and protein expression level was significant difference(p <0.05).
2. Result of clinical observation
2.1The affection on effect of indicators
Twenty-four hours urine micro protein in patients between traditionalChinese medicine treatment group and western medicine control group has nosignificant difference. Before treatment (0weeks), urine trace albumin betweenChinese medicine treatment group and western medicine control groupsignificantly reduced (p <0.01), and there was statistical significance.Patients' urine trace albumin between traditional Chinese medicine treatmentgroup and western medicine control group gradually reduce with the extensionof treatment time.
Before the treatment, patients symptoms between Chinese medicine treatmentgroup and western medicine control group were no significant difference (p>0.05);6weeks and8weeks treatment, TCM syndrome integral treatment group wassignificantly lower than western medicine control group (p <0.05). Thecomparison between the two groups was statistically significant; Compared withbefore treatment,4,6,8weeks in both groups of symptom scores weresignificantly lower (p <0.05or p <0.01) with statistical significance.
In Chinese medicine treatment group, there were4patients markedlyeffective,8patients effective,8non-effective, and the total effective ratewas60%. In western medicine control group there were4patient markedlyeffective,9patients effective,7non-effective, and the total effective ratewas65%.
2.2The affection on blood sugar and glycosylated hemoglobin
Two groups of FBG,2HPG and HbA1c levels in patients has no significantdifference. Compared before and after treatment, FBG,2HPG and HbA1c levelsin patients between Chinese medicine treatment group and western medicinecontrol group has no significant difference (p>0.05). 2.3The affection on Security indicators
Two groups of patients before and after treatment, serum creatinine, ureanitrogen, cereal third transaminase levels were no significant difference (p>0.05). In each group before and after treatment, serum urea nitrogen,creatinine, alanine aminotransferase levels in Chinese medicine treatment groupand western medicine control group were no significant difference (p>0.05).
Conclusion：
1. San Huang Tang Shen Kang particles can effectively reduce the DN rats’ bloodglucose, glycosylated hemoglobin, urine trace albumin, blood beta2-microglobulin, and urea nitrogen levels.
2. San Huang Tang Shen Kang particles can effectively reduce the DN model rats’CRP content in serum and kidney tissue.
3. San Huang Tang Shen Kang particles can effectively reduce the DN model rats’renal cortex of the NF-κB and CCR2, MCP-1mRNA and protein expression level.
4. San Huang Tang Shen Kang particles on prevention and cure of DN rats may bemediated by inhibiting the NF-κB pathway, thus inhibite MCP-1and its receptorCCR2combination.
5. San Huang Tang Shen Kang particles can effectively reduce the patients withearly diabetic nephropathy in24hour urine micro protein and symptom integrallevel.
6. San Huang Tang Shen Kang particles on early diabetic nephropathy patientsin serum urea nitrogen, creatinine, alanine aminotransferase, FBG,2HPG andHbA1c levels had no significant effect.
7. In the treatment of6weeks, San Huang Tang Shen Kang particles can achievethe best curative effect of traditional Chinese medicine, and it has the idealcontrol effect for patients with early diabetic nephropathy.
1.三黄糖肾康颗粒对早期糖尿病肾病大鼠的药效学研究。
2.研究三黄糖肾康颗粒对早期糖尿病肾病的药物作用机制。
3.观察三黄糖肾康颗粒对早期糖尿病肾病患者的临床疗效。
材料与方法：
1.实验研究
1.1造模方法
采用高糖高脂饲料喂养结合腹腔注射链脲佐菌素(STZ)的造模方法，复制出糖尿病模型，引起胰岛素抵抗、高血糖，导致微量白蛋白尿的出现。
1.2分组和给药方法
SPF级Wistar大鼠90只，体重280±20g。将90只大鼠按体重编为1-90号，采用随机数字法将90只大鼠随机分为正常组和造模组，糖尿病模型成功后又按照血糖水平将造模组大鼠重新随机分组，最后共为6组，分别为A：正常组；B：模型组；C：中药预防组；D1：中药低剂量组；D2：中药高剂量组；E：西药组。除正常组外，其余各组采用高脂高糖饲料联合小剂量STZ（42mg/Kg.bw）的方法复制糖尿病肾病（DN）大鼠模型，模型复制成功2周后，除正常组和中药预防组外，分别给与相应药物经口灌胃干预，连续给药8周；中药预防组大鼠自模型复制之日起即开始给药，连续给药10周。中药预防组和中药低剂量组按照正常成人剂量(g/kg)的6.3倍给药；中药高剂量组按照低剂量的3倍给药。西药组给予贝那普利灌胃，给药量按照正常成人给药量等效换算成成年大鼠给药量，即0.9mg/kg.d。
1.3观察指标与测定方法
主要观察三黄糖肾康颗粒的药效学指标及对糖尿病肾病大鼠微炎症状态的影响，包括实验结束后，分别对各组大鼠糖化血红蛋白、肌酐、尿素氮、血β2-微球蛋白、血糖及尿中尿微量白蛋白含量进行检测。各组大鼠处死后摘取肾脏，以4%多聚甲醛溶液固定，采用HE染色和PAS染色的方法，观察各组大鼠肾脏病理变化情况。采用荧光定量PCR方法对各组大鼠肾脏组织中NF-κB、MCP-1和CCR2mRNA表达水平进行检测。采用western-blot方法对各组大鼠肾脏组织中NF-κB、MCP-1和CCR2蛋白表达水平进行检测。通过对以上效应指标的检测，进一步探讨了三黄糖肾康颗粒对糖尿病肾病大鼠的疗效及其部分作用机制。
2.临床研究
选择气虚血瘀型早期糖尿病肾病患者40例，采用随机对照的方法，将患者随机分为中药治疗组及西药对照组各20例。中药治疗组患者在基础治疗基础上，加用三黄糖肾康颗粒，每日一付，分两次口服；西药对照组患者在基础治疗基础上，给予口服洛汀新治疗，每次10mg，每日一次，疗程8周。完成治疗周期后，对两组患者进行一般体格检查、谷丙转氨酶（ALT）、血肌酐（Scr）、尿素氮（BUN）、空腹及餐后2小时血糖、糖化血红蛋白、24h尿微量白蛋白（U-mAlb）、中医症状疗效指数等检查，以观察三黄糖肾康颗粒对早期糖尿病肾病患者的临床疗效。
结果：
1.动物实验结果
1.1对大鼠一般情况的影响
实验过程中，正常组大鼠精神状态良好，未出现死亡；造模组大鼠食量减少，饮水量明显增多，共死亡6只。西药组大鼠死亡1只；中药高剂量组死亡1只；中药低剂量组死亡1只；模型组共死亡3只。
1.2对大鼠尿微量白蛋白的影响
与正常组比较，其余各组大鼠尿中微量白蛋白含量显著升高（p<0.01），有统计学差异；模型组尿微量白蛋白含量最高，与该组比较，各治疗组及预防组显著降低（p<0.05），有统计学意义；各治疗预防组组间比较，预防组低于各治疗组且其差异有统计学意义（p<0.01）；与西药组比较，预防组低于西药组且其差异有统计学意义（p<0.01），低剂量组高于西药组且其差异有统计学意义（p<0.05），高剂量组与西药组比较差异无统计学意义（p＞0.05）。
1.3对大鼠血糖的影响
除正常组，其余各组大鼠血糖均高于16.7mmol/L，与正常组比较，其余各组大鼠血糖显著增高（p<0.01），有统计学意义；与模型组比较，西药组、预防组、高剂量组、低剂量组血糖值均低于模型组，且其差异有统计学意义（p<0.01）；预防组血糖值最低，与其余各组比较差异有统计学意义（p<0.05）；与中药低剂量组比较，预防组及高剂量组均低于低剂量组，且其差异有统计学意义（p<0.01，p<0.05）；高剂量组与西药组组间比较差异无统计学意义（p＞0.05）。
1.4对大鼠糖化血红蛋白的影响
各组大鼠血清糖化血红蛋白含量测定结果显示，模型组及各治疗预防组均显著高于正常组（p＜0.01）有统计学意义；与模型组比较，预防组及各治疗组均显著降低（p＜0.01）有统计学意义；西药组、预防组、中药高剂量组及中药低剂量组组间比较差异无统计学意义（p＞0.05）。
1.5对血β2-微球蛋白的影响
与正常对照组比较，其余各组大鼠血清β2-微球蛋白含量升高，其差异有统计学意义（p<0.01）；模型对照组血清β2-微球蛋白含量最高，与该组比较，各治疗组及预防组显著降低（p<0.01），有统计学意义。
1.6对血肌酐、尿素氮的影响
各组间大鼠血清中肌酐含量比较无显著性差异（p＞0.05），没有统计学意义。模型组大鼠血清尿素氮含量显著升高，与模型组比较，其余各组大鼠血清尿素氮含量显著降低（p＜0.01），有统计学意义；与正常对照组比较，仅中药低剂量组有统计学差异（p＜0.05）。西药组、预防组、中药高剂量组、中药低剂量组组间比较差异无统计学意义（p＞0.05）。
1.7各组大鼠肾脏组织病理变化
HE染色：高倍镜下可见，模型组肾小球硬化，系膜细胞及系膜基质增生，肾小管上皮细胞空泡变形；各治疗组及中药预防组大鼠肾脏病理变化程度明显轻于模型对照组，中药预防组大鼠肾脏的肾小球及肾小管比正常组大鼠稍微增大；中药高剂量与西药组大鼠肾脏肾小球体积大小相当，但均大于正常组。
PAS染色：模型组大鼠肾脏组织可见广泛的PAS染色阳性物质，主要位于小叶中央部，肾小球基底膜增厚，系膜基质明显增多，肾小球弥漫性病变，小动脉玻璃样变，肾小球内部偶见圆形、椭圆形或锥形的结节，个别肾小球荒废；而各治疗组及中药预防组大鼠肾脏PAS染色呈弱阳性，西药组可见弥漫肾小球硬化，系膜基质和细胞外基质明显增多，肾小管萎缩；中药预防组可见肾小球系膜基质轻度增多，肾小球基底膜及肾小管无病变；中药高剂量组可见肾小球系膜基质及系膜细胞增多，肾小球基底膜无变化，肾小管无病变；中药低剂量组大鼠可见节断性肾小球硬化，肾小球系膜基质增多，基底膜增厚。
1.8对C反应蛋白含量的影响
各组大鼠血清及肾脏组织中C反应蛋白变化趋势相同，与正常组比较，模型组大鼠血清及肾脏组织中C反应蛋白含量显著升高（p＜0.01），有统计学意义；与模型组比较，中药预防及各治疗组大鼠血清及肾脏组织中C反应蛋白含量显著降低（p＜0.01），有统计学意义；与西药组比较，中药预防组、中药高、低剂量组大鼠血清中CRP含量显著下降（p＜0.01），有统计学意义。
1.9对肾脏组织中核转录因子NF-κB蛋白及基因的表达水平的影响
模型组大鼠肾脏组织中NF-κB mRNA及蛋白表达水平均较正常组显著上调（p＜0.01），有统计学意义；与模型组比较，中药预防组和各治疗组大鼠肾脏组织中NF-κBmRNA及蛋白表达水平均显著下调（p＜0.01），有统计学意义。与中药预防组比较，正常组、中药高剂量组、中药低剂量组大鼠肾脏组织中NF-κB蛋白及基因的表达水平均显著增高（p＜0.01），有统计学意义。西药组与中药低剂量、中药预防组比较，差异显著（p＜0.01），有统计学意义。中药高剂量组与西药组无显著性差异（p＞0.05）。
1.10对肾脏组织中MCP-1及CCR2蛋白及基因的表达水平的影响
各组大鼠肾脏组织中MCP-1mRNA及蛋白、CCR2mRNA及蛋白的表达水平测定结果，与正常对照组比较，模型组大鼠肾脏组织中MCP-1mRNA及蛋白、CCR2mRNA及蛋白的表达水平均显著上调（p＜0.01），有统计学意义；与模型组比较，中药预防组和各治疗组大鼠MCP-1和CCR2基因及蛋白表达水平均显著下调（p＜0.01）；中药预防组大鼠肾脏组织中MCP-1及CCR2蛋白及基因的表达水平显著低于西药组及中药高、低剂量组（p＜0.01或0.05）；西药组MCP-1及CCR2蛋白及基因的表达水平较中药高、低剂量组低（p＜0.05）；中药高剂量与低剂量组大鼠的CCR2蛋白及基因表达水平无显著性差异，但MCP-1mRNA及蛋白表达水平差异显著（p＜0.05）。
2.临床观察结果
2.1对疗效性指标的影响
中药治疗组与西药对照组患者24小时尿微量蛋白各时间点的组间比较，无显著性差异；与治疗前（0周比较），中药治疗组和西药对照组尿微量白蛋白显著降低（p＜0.01），有统计学意义；中药治疗组和西药对照组患者尿微量白蛋白随着治疗时间的延长而逐渐减少。
治疗前，中药治疗组与西药对照组患者症候积分组间比较，无显著性差异（p＞0.05）；治疗第6周及第8周，中药治疗组证候积分显著低于西药对照组（p＜0.05），两组间比较有统计学意义；与第0周比较，两组患者第4、6、8周的症候积分均显著降低（p＜0.05或p＜0.01），有统计学意义。
中药治疗组患者显效4例，有效8例，无效8例，总有效率60%；西药对照组患者显效4例，有效9例，无效7例，总有效率65%。
2.2对血糖和糖化血红蛋白的影响
两组患者FBG、2hPG和HbA1c水平无显著性差异（p＞0.05）；治疗前后比较，中药治疗组和西药对照组患者的FBG、2hPG和HbA1c水平无显著性差异（p＞0.05）。
2.3对安全性指标的影响
两组患者治疗前、后血清肌酐、尿素氮、谷丙转氨酶水平无显著性差异（p＞0.05）；每组的治疗前后比较，中药治疗组和西药对照组患者的血清肌酐、尿素氮、谷丙转氨酶水平无显著性差异（p＞0.05）。
结论：
1.三黄糖肾康颗粒可有效降低DN模型大鼠血糖、糖化血红蛋白、尿微量白蛋白、血β2-微球蛋白、尿素氮水平。
2．三黄糖肾康颗粒可有效降低DN模型大鼠血清及肾组织中C反应蛋白含量。
3.三黄糖肾康颗粒可有效降低DN模型大鼠肾脏皮质中NF-κB、MCP-1和CCR2mRNA及蛋白的表达水平。
4.三黄糖肾康颗粒对DN模型大鼠的防治作用可能是通过抑制NF-κB信号通路，从而抑制MCP-1与其受体CCR2结合而实现的。
5.三黄糖肾康颗粒可有效降低早期糖尿病肾病患者24小时尿微量蛋白、症候积分水平。
6.三黄糖肾康颗粒对早期糖尿病肾病患者血清肌酐、尿素氮、谷丙转氨酶、FBG、2hPG和HbA1c水平无显著影响。
7.三黄糖肾康颗粒在治疗第6周就能达到最佳中医疗效，对早期糖尿病肾病患者有较理想的防治作用。
Objective
1.The study of pharmacodynamics of San Huang Tang Shen Kang granular to earlydiabetic nephropathy rats.
2.The study of drug mechanism of San Huang Tang Shen Kang granular to earlydiabetic nephropathy rats.
3.Observe clinical curative effect of San Huang Tang Shen Kang granular inpatients with early diabetic nephropathy.Materials and methods
1. Trial Study
1.1Methods of modeling
With high fat, high sugar diet combined with intraperitoneal injection ofstreptozotocin(STZ),we duplicate diabetes model and lead insulin resistance,hyperglycemia, and miner albuminuria.
1.2Method of grouping and oral medication administering
SPF Wistar rats (90,280+20g weight). Only according to the weight, wenumbered90rats of1-90. By using random numbers,90rats were randomly dividedinto normal group and model group, when diabetes model was succeeded and thenthey were grouped according to their blood sugar levels, the total is6groups,respectively A: normal group; B: the model group; C: Chinese medicine preventiongroup; D1: low dose group; D2: the high dose group of TCM; E: the western medicinegroup. In addition to the normal group, the rest of the group using high fatand sugar feed in combination with small dose of STZ (42mg/Kg bw) method copyof diabetic nephropathy (DN) rats model, the model was copied in success after2weeks. In addition to the normal group and Chinese medicine prevention group,respectively we give the corresponding drug intervention to fill the stomachthrough the mouth, for eight consecutive weeks. Chinese medicine precautiousgroup rats from model replication which starts from the date of delivery, for10weeks in succession. According to the normal adult dose, Chinese medicine precautious group and low dose group of Chinese traditional medicine give6.3times dose. High dose group according to the3times of low dose group. Groupwas given western medicine that split lavage and dosage according to the normaladult dosage equivalent conversion into adult rats dosage, namely,0.9mg/kg.d.
1.3Observing index and measuring method
We should mainly observe pharmacodynamics indexes and San Huang Tang ShenKang particles to the influence of inflammation in diabetic nephropathy ratsincluding the experimental ended, separately for each group of rats serumglycosylated hemoglobin, blood urea nitrogen, creatinine, beta2-microglobulin,blood glucose and urine trace albumin content in urine test. Between groups ratswere randomly selected3only, after death, harvesting kidneys, fixed in4%paraformaldehyde solution, using the method of HE staining and PAS staining,observing their kidneys pathological changes. Using fluorescence quantitativepolymerase chain reaction (PCR), NF-κB, MCP-1and CCR2mRNA expression levelsin the kidney tissue of each group rats were detected. Using western blot method,NF-κB,MCP-1and CCR2protein expression levels in the kidney tissue of eachgroup rats were detected. Through the above effect index detection, we furtherdiscuss the San Huang Tang Shen Kang particles on the curative effect of diabeticnephropathy in rats and its mechanism.
2. Clinical research
Choosing40patients of blood deficiency type with early diabetic nephropathy,adopting the method of randomly contrast, patients were randomly divided intotraditional Chinese medicine treatment group and western medicine control groupfor20cases each. On the basis of foundation treatment, Chinese medicinetreatment group patients with San Huang Tang Shen Kang particles, a daily pay,two oral; On the basis of foundation treatment, western medicine control grouppatients give lotensin oral treatment,10mg each time, once per day, courseof8weeks. After completion of treatment on two groups of patients with generalmedical examination, cereal third transaminase (ALT), serum creatinine (Scr),urea nitrogen (BUN), fasting and postprandial2hours blood glucose, glycosylated hemoglobin,24h urine trace albumin (U-mAlb), TCM symptomscurative effect index, we observe San Huang Tang Shen Kang particles clinicalcurative effect in patients with early diabetic nephropathy.
Results
1. Results of animal experiments
1.1The affection on general situation of rats
In experiment process, the mental state of normal group rats is good andno death; Model group rats eat less, drink quantity obviously increased, anda total of6cases died. The western medicine group rats died in1case.Traditional Chinese medicine high dose group died in1case. Low dose group diedin1case. Model group in all3cases died.
1.2The affection to microalbuminuria on rats
Compared with normal group, urine trace albumin levels of the rest of thegroup rats increased significantly (p <0.01)and statistically different. Urinetrace albumin content of model group is the highest, compared with the group,the treatment group and prevention group decreased significantly (p <0.05).In Comparison among different treatment, prevention group is lower than thetreatment group. Compared with western medicine group, preventive group waslower than western medicine group and the difference was statisticallysignificant (p <0.01). Low dose group was higher than western medicine groupand the difference was statistically significant (p <0.05). Compared with thewestern medicine group, high dose group was no statistically significantdifference (p>0.05).
1.3The affection on blood sugar
Except for normal group, the blood sugar of other groups’ rats were higherthan16.7tendency for L. Compared with normal group, the rest of the group ratsblood glucose was significantly increased (p <0.01). Compared with model group,western medicine group, preventive group, high dose group, low dose group bloodglucose values were less than model group, and the difference was statistically significant (p <0.01). Prevention group had lowest blood sugar levels.Comparedwith the rest of the group, the difference was statistically significant (p <0.05). Compared with traditional Chinese medicine low dose group, preventivegroup and high dose group were lower than low dose group, and the differencewas statistically significant (p <0.01, p <0.05); Between the high dose groupand western medicine, there was no statistically significant difference (p>0.05).
1.4The affection on glycosylated hemoglobin
Serum glycosylated hemoglobin content of groups of rats determinated, modelgroup and prevention group were significantly higher than normal group (p <0.01)and was statistically significant. Compared with model group, preventive groupand each treatment group were significantly lower (p <0.01) and wasstatistically significant. In comparison between western medicine group,preventive group, high dose group and low dose, there was no statisticallysignificant difference (p>0.05).
1.5The affection on blood β2-micro globulin
Compared with normal control group, the rest of the group rats blood β2-micro globulin content increases, and the difference was statisticallysignificant (p <0.01). Blood β2-micro globulin content of model control groupis the highest. Compared with the group, the treatment group and prevention groupdecreased significantly (p <0.01) with statistical significance.
1.6The affection on serum creatinine and urea nitrogen
Serum creatinine content of each group of rats was no significant difference(p>0.05), no statistical significance. Serum urea nitrogen content of modelgroup rats increased significantly. Compared with model group, the rest of thegroup in the rat serum urea nitrogen content decreased significantly (p <0.01),and there was statistical significance. Compared with normal control group, onlyChinese medicine low dose was statistically difference (p <0.05). In comparisonbetween western medicine group, preventive group, high dose group and low dose,there was no statistically significant difference (p>0.05).
1.7The pathological changes of kidney tissue in each group
HE staining: At high magnification shows, model group of glomerularsclerosis, mesangial cell and mesangial matrix proliferation of renal tubularepithelial cell cavity deformation. Each treatment group and Chinese traditionalmedicine prevent group rats kidney pathological changes degree obviously lighterthan the control group. Chinese traditional medicine prevent group rats renalglomerulus and renal tubule increased slightly than normal group rats. Thewestern medicine group and high dose of Chinese medicine in the rat kidneyglomerular volume had the similar size, but bigger than the normal group.
PAS staining: Kidney tissue of model group rats is a wide range of PASpositive substances, mainly in the centrilobular, glomerular basement membranethickening, mesangial matrix increased obviously, glomerular diffuse lesions,arteriole hyaline changes, glomerulus internal occasional round, oval or conicaltubercles, individual glomerular waste, and each treatment group and Chinesetraditional medicine prevent group rats kidney PAS staining showed weaklypositive. Western medicine group is visible for diffuse glomerular hard,mesangial matrix and extracellular matrix increased obviously, and renal tubularatrophy. Chinese medicine prevention increased glomerular mesangial matrix setof visible light, the glomerular basement membrane and renal tubular lesion;Chinese medicine high dose group of glomerular mesangial matrix and mesangialcells increased, glomerular basement membrane changed. Chinese medicine low dosegroup is visible for section break in rats, increased glomerular mesangial matrix,and thickening of basement membrane.
1.8The affection on CRP levels
Groups of CRP in serum and kidney tissue of rats have the same change trend.Compared with normal group, model group rats CRP content in serum and kidneytissue increased significantly (p <0.01), and there was statisticalsignificance. Compared with model group, Chinese medicine prevention and thetreatment group rats CRP content in serum and kidney tissue decreasedsignificantly (p <0.01), and there was statistical significance. Compared with western medicine group, Chinese medicine prevention group, the Chinese medicinehigh, low dose group rats serum CRP levels decreased significantly (p <0.01)with statistical significance.
1.9The affection on Nuclear transcription factors in kidney tissue NF-κBprotein and gene expression level
Kidney tissue of model group rats in the NF-κB mRNA and protein expressionlevels were significantly raised in the normal group (p <0.01), and there wasstatistical significance. Compared with model control group, Chinese medicineprevention group and each treatment group in the rat kidney tissue in the NF-κB mRNA and protein expression levels were significantly lower (p <0.01).Compared with traditional Chinese medicine prevention group, normal group, highdose group, low dose group in the rat kidney tissue in the NF-κB protein andgene expression level were significantly increased (p <0.01) with statisticalsignificance. Western medicine group had significant difference in low doseChinese traditional medicine and Chinese traditional medicine prevent group (p<0.01) with statistical significance. Western medicine group and high dose groupof Chinese medicine has no significant difference (p>0.05).
1.10The affection on MCP-1and CCR2in kidney tissue protein and gene expressionlevel
Expression level determination results of each group MCP-1mRNA and protein,CCR2mRNA and protein in the kidney tissue, compared with normal control group,model group rats were significantly raised (p <0.01), and there was statisticalsignificance. Compared with model control group, Chinese medicine preventiongroup and each treatment group rats MCP-1and CCR2gene and protein expressionlevels were significantly lower (p <0.01). CCR2and MCP-1in the rat kidneytissue protein in Chinese medicine prevention group and gene expression levelwas significantly lower than western medicine group and Chinese medicine highand low dose group (p <0.01or0.05). CCR2and MCP-1protein and gene expressionlevel in western medicine group was lower than those of high and low dose ofChinese medicine (p <0.05). Low dose group and high dose of Chinese medicine in rats of CCR2protein and gene expression level has no significant difference,but the MCP-1mRNA and protein expression level was significant difference(p <0.05).
2. Result of clinical observation
2.1The affection on effect of indicators
Twenty-four hours urine micro protein in patients between traditionalChinese medicine treatment group and western medicine control group has nosignificant difference. Before treatment (0weeks), urine trace albumin betweenChinese medicine treatment group and western medicine control groupsignificantly reduced (p <0.01), and there was statistical significance.Patients' urine trace albumin between traditional Chinese medicine treatmentgroup and western medicine control group gradually reduce with the extensionof treatment time.
Before the treatment, patients symptoms between Chinese medicine treatmentgroup and western medicine control group were no significant difference (p>0.05);6weeks and8weeks treatment, TCM syndrome integral treatment group wassignificantly lower than western medicine control group (p <0.05). Thecomparison between the two groups was statistically significant; Compared withbefore treatment,4,6,8weeks in both groups of symptom scores weresignificantly lower (p <0.05or p <0.01) with statistical significance.
In Chinese medicine treatment group, there were4patients markedlyeffective,8patients effective,8non-effective, and the total effective ratewas60%. In western medicine control group there were4patient markedlyeffective,9patients effective,7non-effective, and the total effective ratewas65%.
2.2The affection on blood sugar and glycosylated hemoglobin
Two groups of FBG,2HPG and HbA1c levels in patients has no significantdifference. Compared before and after treatment, FBG,2HPG and HbA1c levelsin patients between Chinese medicine treatment group and western medicinecontrol group has no significant difference (p>0.05). 2.3The affection on Security indicators
Two groups of patients before and after treatment, serum creatinine, ureanitrogen, cereal third transaminase levels were no significant difference (p>0.05). In each group before and after treatment, serum urea nitrogen,creatinine, alanine aminotransferase levels in Chinese medicine treatment groupand western medicine control group were no significant difference (p>0.05).
Conclusion：
1. San Huang Tang Shen Kang particles can effectively reduce the DN rats’ bloodglucose, glycosylated hemoglobin, urine trace albumin, blood beta2-microglobulin, and urea nitrogen levels.
2. San Huang Tang Shen Kang particles can effectively reduce the DN model rats’CRP content in serum and kidney tissue.
3. San Huang Tang Shen Kang particles can effectively reduce the DN model rats’renal cortex of the NF-κB and CCR2, MCP-1mRNA and protein expression level.
4. San Huang Tang Shen Kang particles on prevention and cure of DN rats may bemediated by inhibiting the NF-κB pathway, thus inhibite MCP-1and its receptorCCR2combination.
5. San Huang Tang Shen Kang particles can effectively reduce the patients withearly diabetic nephropathy in24hour urine micro protein and symptom integrallevel.
6. San Huang Tang Shen Kang particles on early diabetic nephropathy patientsin serum urea nitrogen, creatinine, alanine aminotransferase, FBG,2HPG andHbA1c levels had no significant effect.
7. In the treatment of6weeks, San Huang Tang Shen Kang particles can achievethe best curative effect of traditional Chinese medicine, and it has the idealcontrol effect for patients with early diabetic nephropathy.
引文
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