复方丹参滴丸防治大鼠早期糖尿病肾脏损害的研究.pdf

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1、复方丹参滴丸防治大鼠早期糖尿病肾脏损害的研究 李佑生，王文健，马宇滢，刘 毅，何春燕，何燕铭，陈伟华，应 健(复旦大学附属华山医院中医科复旦大学中西医结合研究所，上海 200040)关键词：复方丹参滴丸；糖尿病肾病；微量白蛋白尿；胰岛紊抵抗；大鼠 摘要：目的：考察复方丹参滴丸对大鼠早期糖尿病肾脏损害的疗效。方法：采用高糖高脂喂饲加低剂量STZ 建立大鼠2型糖尿病肾病模型，给予复方丹参滴丸治疗 12周，动态观察血糖及尿微量白蛋白尿等指标。结果：复方丹参滴丸大剂量时可降低血糖、减少尿微量白蛋白、减轻肾脏肥大、减少尿量，而中低剂量可降低血清甘油三酯水平，疗效优于氯沙坦。结论：复方丹参滴丸大剂量时有改

2、善实验性大鼠 2型糖尿病肾脏病变，主要是改善微量白蛋白尿的作用。Effect of Compound Danshen Drop Pills on early stage diabetic nephropathy in rat models LI You-sheng，WANG Wen-Jian，MA Yu-ying，LIU Yi，HE Chun-yan，HE Yan-ming，CHEN Wei-hua，YING Jian(Dept of TCMHuashan Hospital Affiliated to Fudan University，Shanghai 200040，China)KEY WOR

3、DS：Compound Danshen Drop Pills；diabetic nephropathy；microalbuminuria；insulin resistance；rat ABSTRACT：AIM：To explore the effect of Compound Danshen Drop Pills(CDDP)on early stage of diabetic nephropathy in rat modelsMETHODS：Diabetic nephropathy of type 2 diabetes rat model was established by feeding

4、with high glucose high fat diet with low dose STZ injectionRats were treated with CDDP then and blood glucose，urinary micro-albumin and other targets were measured at different time points RESULTS：High dose of CDDP decreased blood glucose level，reduced urinary micro-albumin，glomerular hypertrophy an

5、d urinary volumeMiddle and low dose of CDDP decreased blood triglyceride leve1These effects were better than Losartan CONCLUSION：High dose of CDDP could ameliorate diabetic nephropathy in type 2 diabetes rat models，and the main effect Was reducing urinary micro-albuimn 糖尿病肾病是糖尿病的主要并发症，也是导致终未肾脏疾病(ESR

6、D)的主要原因之一，目前在我国是导致需要透析治疗的第二位原因。复方丹参滴丸具有活血化瘀的功效，是目前治疗心血管疾病的常用中成药。现有研究表明1，微量白蛋白尿作为糖尿病肾病早期的主要表现，也是心血管疾病的独立危因素。为此我们对复方丹参滴丸防治伴胰岛素抵抗的大鼠2型糖尿病肾脏损害的疗效，主要是其对微量白蛋白尿的疗效进行了 l2 周的观察，现将结果报告如下。1 实验材料与方法 11 动物：清洁级 Wistar 大鼠90只，体重(20020)g，由复旦大学上海医学院实验动物中心提供，动物合格证号：O10232。12 高糖高脂饲料配方：碳水化合物65.2，脂肪15.0，胆固醇2.5，胆酸1.0，蛋白质8

7、.1，其它8.2。热能含量为14.6kJkg。13 药物：(1)复方丹参滴丸，由天津天士力制药有限公司提供浸膏。实验中以蒸馏水溶解成相应的浓度，以便灌胃。(2)氯沙坦：市售，杭州默沙东制药有限公司生产，含量：50mg 片，实验中配成与复方丹参滴丸等容积的浓度。批号：S1063。14 胰岛素抑制试验(IST)：参照文献方法2，大鼠以1戊巴比妥钠30mg/kg 腹腔注射麻醉后固定于手术台上，自颈部正中切开皮肤，暴露颈动脉及静脉，于右颈静脉、左颈动脉分别置PE-50 导管。大鼠清醒后，用微量泵自右颈静脉以 20ml/min速度持续注射葡萄糖0.22mmol/(kg min)、胰岛素3OnmoL/(k

8、g min)、和生长抑素920pmoL(kg min)共150min。于灌注90、120、150 min时从左颈动脉取血标本3次，每次0.3mL，备测胰岛素及血糖，取其平均值作为稳态血糖(steady-state plasma glucose，SSPG)、稳态胰岛素(steady-state plasma insulin，SSPI)值，以衡量胰岛素敏感性的程度。15 模拟胰岛素抵抗状态：造模鼠喂饲高糖高脂饲料，正常鼠喂饲普通饲料，4周后按上述方法进行胰岛素抑制试验，以确认胰岛素抵抗。16 伴胰岛素抵抗的2型糖尿病肾病(DN)动物模型的建立：确认存在胰岛素抵抗后，按30mg/kg 予大鼠腹腔注射

9、链脲佐菌素(STZ，美国Sigma 公司产品)，并继续给予高糖高脂饲料，l 周后所有造模大鼠割尾采血测血糖，以割尾采血测血糖大于 l6.7mmoL/L者作为糖尿病肾病模型成功。17 实验分组：清洁级 Wistar 大鼠90只，体重(20020)g，由复旦大学上海医学院实验动物中心提供。按1：6的比例进行随机分组，其中l5 只作为正常对照组，予普通标准饲料，其余75只予高糖高脂饮食，4周后从两种饲料喂饲的动物中各取5只大鼠经IST确认存在胰岛素抵抗，再按前述方法给予 STZ 制备伴胰岛素抵抗的2型糖尿病肾病模型，造模成功率为82，将达标的造模大鼠随机分为5组，分别为：模型组(N=11)、氯沙坦治

10、疗组(N=11，氯沙坦1mg/(kgd)、复方丹参滴丸小剂量组(N=11，复方丹参滴丸20mg/(kgd)、复方丹参滴丸中剂量组(N=11，复方丹参滴丸80mg/(kgd)、复方丹参滴丸大剂量组(N=11，复方丹参滴丸180mg/(kgd)。各组按上述药物及剂量治疗12周。18 观测指标及检测方法 在治疗前，治疗后的第4周、第8周、第10周代谢笼收集24h尿液，检测尿微量白蛋文档编码:CG2L9B5H10K5 HT9W3G1Q6E7 ZD8B4V8M2T4文档编码:CG2L9B5H10K5 HT9W3G1Q6E7 ZD8B4V8M2T4文档编码:CG2L9B5H10K5 HT9W3G1Q6E7

11、 ZD8B4V8M2T4文档编码:CG2L9B5H10K5 HT9W3G1Q6E7 ZD8B4V8M2T4文档编码:CG2L9B5H10K5 HT9W3G1Q6E7 ZD8B4V8M2T4文档编码:CG2L9B5H10K5 HT9W3G1Q6E7 ZD8B4V8M2T4文档编码:CG2L9B5H10K5 HT9W3G1Q6E7 ZD8B4V8M2T4文档编码:CG2L9B5H10K5 HT9W3G1Q6E7 ZD8B4V8M2T4文档编码:CG2L9B5H10K5 HT9W3G1Q6E7 ZD8B4V8M2T4文档编码:CG2L9B5H10K5 HT9W3G1Q6E7 ZD8B4V8M2T4文

12、档编码:CG2L9B5H10K5 HT9W3G1Q6E7 ZD8B4V8M2T4文档编码:CG2L9B5H10K5 HT9W3G1Q6E7 ZD8B4V8M2T4文档编码:CG2L9B5H10K5 HT9W3G1Q6E7 ZD8B4V8M2T4文档编码:CG2L9B5H10K5 HT9W3G1Q6E7 ZD8B4V8M2T4文档编码:CG2L9B5H10K5 HT9W3G1Q6E7 ZD8B4V8M2T4文档编码:CG2L9B5H10K5 HT9W3G1Q6E7 ZD8B4V8M2T4文档编码:CG2L9B5H10K5 HT9W3G1Q6E7 ZD8B4V8M2T4文档编码:CG2L9B5H1

13、0K5 HT9W3G1Q6E7 ZD8B4V8M2T4文档编码:CG2L9B5H10K5 HT9W3G1Q6E7 ZD8B4V8M2T4文档编码:CG2L9B5H10K5 HT9W3G1Q6E7 ZD8B4V8M2T4文档编码:CG2L9B5H10K5 HT9W3G1Q6E7 ZD8B4V8M2T4文档编码:CG2L9B5H10K5 HT9W3G1Q6E7 ZD8B4V8M2T4文档编码:CG2L9B5H10K5 HT9W3G1Q6E7 ZD8B4V8M2T4文档编码:CG2L9B5H10K5 HT9W3G1Q6E7 ZD8B4V8M2T4文档编码:CG2L9B5H10K5 HT9W3G1Q6

14、E7 ZD8B4V8M2T4文档编码:CG2L9B5H10K5 HT9W3G1Q6E7 ZD8B4V8M2T4文档编码:CG2L9B5H10K5 HT9W3G1Q6E7 ZD8B4V8M2T4文档编码:CG2L9B5H10K5 HT9W3G1Q6E7 ZD8B4V8M2T4文档编码:CG2L9B5H10K5 HT9W3G1Q6E7 ZD8B4V8M2T4文档编码:CG2L9B5H10K5 HT9W3G1Q6E7 ZD8B4V8M2T4文档编码:CG2L9B5H10K5 HT9W3G1Q6E7 ZD8B4V8M2T4文档编码:CG2L9B5H10K5 HT9W3G1Q6E7 ZD8B4V8M2T

15、4文档编码:CG2L9B5H10K5 HT9W3G1Q6E7 ZD8B4V8M2T4文档编码:CG2L9B5H10K5 HT9W3G1Q6E7 ZD8B4V8M2T4文档编码:CG2L9B5H10K5 HT9W3G1Q6E7 ZD8B4V8M2T4文档编码:CG2L9B5H10K5 HT9W3G1Q6E7 ZD8B4V8M2T4文档编码:CG2L9B5H10K5 HT9W3G1Q6E7 ZD8B4V8M2T4文档编码:CG2L9B5H10K5 HT9W3G1Q6E7 ZD8B4V8M2T4文档编码:CG2L9B5H10K5 HT9W3G1Q6E7 ZD8B4V8M2T4文档编码:CG2L9B5

16、H10K5 HT9W3G1Q6E7 ZD8B4V8M2T4文档编码:CG2L9B5H10K5 HT9W3G1Q6E7 ZD8B4V8M2T4文档编码:CG2L9B5H10K5 HT9W3G1Q6E7 ZD8B4V8M2T4文档编码:CG2L9B5H10K5 HT9W3G1Q6E7 ZD8B4V8M2T4文档编码:CG2L9B5H10K5 HT9W3G1Q6E7 ZD8B4V8M2T4文档编码:CG2L9B5H10K5 HT9W3G1Q6E7 ZD8B4V8M2T4文档编码:CG2L9B5H10K5 HT9W3G1Q6E7 ZD8B4V8M2T4文档编码:CG2L9B5H10K5 HT9W3G1

17、Q6E7 ZD8B4V8M2T4文档编码:CG2L9B5H10K5 HT9W3G1Q6E7 ZD8B4V8M2T4白和肌酐(免疫比浊法，由南京聚力生物医学研究所提供试剂盒)，并同时取尾静脉血测血糖。第12周即处死动物的前一天禁食16h，收集尿液，次日以2戊巴比妥钠麻醉大鼠，腹主动脉收集血标本，测胰岛素(elisa 法)、胆固醇(TC)、甘油三酯(TG)、血肌酐(cr)、血尿素氮(BUN)及血糖(均为常规生化方法)，取肾脏做组织学观察。19 统计方法：建立EPI数据库，所有实验数据均录人数据库中，再用 SPSS 13.0 统计软件进行统计，计数资料采用卡方检验或秩和检验，计量资料采用方差分析。数

18、据用xs表示，组间差异采用多因素方差分析。2 结果 21 胰岛素抵抗检测：大鼠在高糖高脂饮食4周后，发生高胰岛素血症，血糖不但不降，反而略有升高，表明已成功诱发出胰岛素抵抗。模型组与正常组大鼠胰岛素钳夹试验的结果见表1。Table 1 Insulin suppression test Groups SSPI/IU/L SSPG/mmol/L Normal 15.423.23 14.393.09 Model 554.2463.3821.274.71Data are means SE.P0.05 vs Normal；P0.01 vs Normal.22 实验过程中血糖及尿量变化：与模型组一样，治疗

19、各组血糖水平在实验过程中均维持在一个较高的水平，但复方丹参滴丸大剂量组在治疗12 周后血糖水平较模型组明显降低，差异有统计学意义(P0.05)，且已接近正常，与正常对照组差异无统计学意义。各组血糖水平见表2。Table 2 Glucose level at different time course/mmol/L Groups Baseline 4 Weeks 8 Weeks 10 Weeks 12 Weeks Normal 5.380.16(10)6.000.08(10)5.740.17(10)5.210.12(10)5.520.15#(10)Model 24.792.23*(11)25.7

20、61.97*(10)24.542.92*(10)21.405.16*(8)22.832.66*(7)Losartan 26.102.04*(11)27.801.97*(11)26.722.24*(11)23.883.59*(10)17.573.17*(10)Low dos.28.011.42*(11)26.761.73*(11)25.102.50*(11)24.163.39*(10)14.852.78*(10)Middle dos 27.762.01*(11)22.071.51*(10)20.572.32*(9)22.393.89*(9)13.733.23*#(9)High dos.26.41

21、1.87*(11)22.312.79*(10)19.493.40*(9)16.014.33*(8)10.142.67#(8)Date are means SE.#P0.05 vs Model；#P0.01 vs Model.*P0.05 vs Normal；*P0.01 vs Normal.实验过程中各组大鼠饮水量较正常组明显增多，尿量亦明显增多，进食量增多；至造模后4周，随着尿量明显增加，体重明显下降。而与模型组比较，复方丹参滴丸大剂量组尿量增加一直不明显，其它治疗组尿量增多也较模型组晚，约在第 8周才开始明显增多。见表3。文档编码:CG2L9B5H10K5 HT9W3G1Q6E7 ZD8B

22、4V8M2T4文档编码:CG2L9B5H10K5 HT9W3G1Q6E7 ZD8B4V8M2T4文档编码:CG2L9B5H10K5 HT9W3G1Q6E7 ZD8B4V8M2T4文档编码:CG2L9B5H10K5 HT9W3G1Q6E7 ZD8B4V8M2T4文档编码:CG2L9B5H10K5 HT9W3G1Q6E7 ZD8B4V8M2T4文档编码:CG2L9B5H10K5 HT9W3G1Q6E7 ZD8B4V8M2T4文档编码:CG2L9B5H10K5 HT9W3G1Q6E7 ZD8B4V8M2T4文档编码:CG2L9B5H10K5 HT9W3G1Q6E7 ZD8B4V8M2T4文档编码:C

23、G2L9B5H10K5 HT9W3G1Q6E7 ZD8B4V8M2T4文档编码:CG2L9B5H10K5 HT9W3G1Q6E7 ZD8B4V8M2T4文档编码:CG2L9B5H10K5 HT9W3G1Q6E7 ZD8B4V8M2T4文档编码:CG2L9B5H10K5 HT9W3G1Q6E7 ZD8B4V8M2T4文档编码:CG2L9B5H10K5 HT9W3G1Q6E7 ZD8B4V8M2T4文档编码:CG2L9B5H10K5 HT9W3G1Q6E7 ZD8B4V8M2T4文档编码:CG2L9B5H10K5 HT9W3G1Q6E7 ZD8B4V8M2T4文档编码:CG2L9B5H10K5 H

24、T9W3G1Q6E7 ZD8B4V8M2T4文档编码:CG2L9B5H10K5 HT9W3G1Q6E7 ZD8B4V8M2T4文档编码:CG2L9B5H10K5 HT9W3G1Q6E7 ZD8B4V8M2T4文档编码:CG2L9B5H10K5 HT9W3G1Q6E7 ZD8B4V8M2T4文档编码:CG2L9B5H10K5 HT9W3G1Q6E7 ZD8B4V8M2T4文档编码:CG2L9B5H10K5 HT9W3G1Q6E7 ZD8B4V8M2T4文档编码:CG2L9B5H10K5 HT9W3G1Q6E7 ZD8B4V8M2T4文档编码:CG2L9B5H10K5 HT9W3G1Q6E7 ZD

25、8B4V8M2T4文档编码:CG2L9B5H10K5 HT9W3G1Q6E7 ZD8B4V8M2T4文档编码:CG2L9B5H10K5 HT9W3G1Q6E7 ZD8B4V8M2T4文档编码:CG2L9B5H10K5 HT9W3G1Q6E7 ZD8B4V8M2T4文档编码:CG2L9B5H10K5 HT9W3G1Q6E7 ZD8B4V8M2T4文档编码:CG2L9B5H10K5 HT9W3G1Q6E7 ZD8B4V8M2T4文档编码:CG2L9B5H10K5 HT9W3G1Q6E7 ZD8B4V8M2T4文档编码:CG2L9B5H10K5 HT9W3G1Q6E7 ZD8B4V8M2T4文档编码

26、:CG2L9B5H10K5 HT9W3G1Q6E7 ZD8B4V8M2T4文档编码:CG2L9B5H10K5 HT9W3G1Q6E7 ZD8B4V8M2T4文档编码:CG2L9B5H10K5 HT9W3G1Q6E7 ZD8B4V8M2T4文档编码:CG2L9B5H10K5 HT9W3G1Q6E7 ZD8B4V8M2T4文档编码:CG2L9B5H10K5 HT9W3G1Q6E7 ZD8B4V8M2T4文档编码:CG2L9B5H10K5 HT9W3G1Q6E7 ZD8B4V8M2T4文档编码:CG2L9B5H10K5 HT9W3G1Q6E7 ZD8B4V8M2T4文档编码:CG2L9B5H10K5

27、 HT9W3G1Q6E7 ZD8B4V8M2T4文档编码:CG2L9B5H10K5 HT9W3G1Q6E7 ZD8B4V8M2T4文档编码:CG2L9B5H10K5 HT9W3G1Q6E7 ZD8B4V8M2T4文档编码:CG2L9B5H10K5 HT9W3G1Q6E7 ZD8B4V8M2T4文档编码:CG2L9B5H10K5 HT9W3G1Q6E7 ZD8B4V8M2T4文档编码:CG2L9B5H10K5 HT9W3G1Q6E7 ZD8B4V8M2T4文档编码:CG2L9B5H10K5 HT9W3G1Q6E7 ZD8B4V8M2T4文档编码:CG2L9B5H10K5 HT9W3G1Q6E7

28、ZD8B4V8M2T4文档编码:CG2L9B5H10K5 HT9W3G1Q6E7 ZD8B4V8M2T4文档编码:CG2L9B5H10K5 HT9W3G1Q6E7 ZD8B4V8M2T4文档编码:CG2L9B5H10K5 HT9W3G1Q6E7 ZD8B4V8M2T4Table 3 Urine volume at different time course/mL/24h Groups Baseline 4 Weeks 8 Weeks 10 Weeks 12 Weeks Normal 12.061.64(10)9.251.72(10)13.972.64(10)16.113.12(10)30.80

29、1.36(10)Model 40.757.09*(11)72.8311.35*(10)72.3711.66*(8)69.2910.72*(8)76.5713.93*(7)Losartan 35.395.33*(11)39.039.88*#(11)94.6524.02*(11)95.7014.63*(10)97.6017.11*(10)Low dos.27.756.03*(11)40.6912.83*(11)71.4416.90*(11)80.7020.11*(10)73.2013.40*(10)Middle dos 33.866.16*(11)37.1611.22*#(10)66.8917.9

30、3*(9)66.2216.26*(9)57.8912.72*(9)High dos.31.157.49*(11)30.2010.75#(10)38.4416.04(9)36.2212.73(8)35.5014.24(8)Date are means SE.#P0.05 vs Model；#P0.01 vs Model.*P0.05 vs Normal；*P0.01 vs Normal.23 对一般状况及血脂肾功能的影响：见表 4。从表中可见造模后大鼠体质量下降，肾脏肥大；复方丹参滴丸治疗各组肾脏肥大有改善，肾质量体质量比值有所降低，但只有大剂量组与模型组比较差异均有统计学意义(P0.05)。对

31、照药氯沙坦亦有一定的改善肾脏肥大的作用，但肾质量体质量降低较模型组差异亦无统计学意义。Table 4 General state at the end of the experiment Groups Body weight/g Kidney weight/mg Kidney/body TG/mmol/L Cho/mmol/L BUN/mmol/L Cr/mol/L Normal(10)611.2014.621409 0.230.01 0.750.11 1.390.07 5.620.20 30.800.93Model(7)271.715.75*14410 0.530.03*0.660.10 8

32、.641.85*7.141.22 37.718.93Losartan(10)277.4012.77*1148 0.410.03*0.620.17 7.852.54*7.571.00 32.002.65Low dos(10)289.609.22*1207 0.420.02*0.370.05 4.400.60*6.351.32 29.501.00Mid.dos(9)313.789.19*1368 0.430.02*0.700.24 4.620.73*6.011.28 26.891.37High dos(8)304.7510.95*1218 0.400.02*0.360.05 6.411.05*4.

33、321.06 28.751.31Date are means SE.#P0.05 vs Model；#P0.01 vs Model.*P0.05 vs Normal；*P0.01 vs Normal.造模后动物出现明显的高胆固醇血症。复方丹参滴丸有较好的降低血清胆固醇的作用，其中以中、低剂量作用较好，疗后与模型组比较差异有统计学意义(P0.05)，但大剂量反作用较差。造模后肾功能无明显改变，血肌酐及血尿素氮基本均在正常范围内，说明这一模型是处于糖尿病肾病的早期阶段。24 改善尿蛋白的作用：通过造模后多个时点的观察，发现模型组大鼠尿微量白蛋白呈一定的与时间一致的上升趋势。与模型组比较，各复方丹参

34、滴丸治疗组尿微量白蛋白有降低，至治疗的第8周，大剂量组降低有统计学意义(P0.05)，通过比较尿微量白蛋白与尿肌酐的比值，至疗程结束时，3种剂量的疗效均有统计学差异(P0.05或P0.O1)，说明复方丹参滴丸须在长期的应用前提下方可获得一定的疗效。氯沙坦治疗组与模型组比较，治疗1O 周后尿微量白蛋白出现有统计学意义的降低，其疗效与复方丹参滴丸大剂量组基本一致。见表5。文档编码:CG2L9B5H10K5 HT9W3G1Q6E7 ZD8B4V8M2T4文档编码:CG2L9B5H10K5 HT9W3G1Q6E7 ZD8B4V8M2T4文档编码:CG2L9B5H10K5 HT9W3G1Q6E7 ZD8

35、B4V8M2T4文档编码:CG2L9B5H10K5 HT9W3G1Q6E7 ZD8B4V8M2T4文档编码:CG2L9B5H10K5 HT9W3G1Q6E7 ZD8B4V8M2T4文档编码:CG2L9B5H10K5 HT9W3G1Q6E7 ZD8B4V8M2T4文档编码:CG2L9B5H10K5 HT9W3G1Q6E7 ZD8B4V8M2T4文档编码:CG2L9B5H10K5 HT9W3G1Q6E7 ZD8B4V8M2T4文档编码:CG2L9B5H10K5 HT9W3G1Q6E7 ZD8B4V8M2T4文档编码:CG2L9B5H10K5 HT9W3G1Q6E7 ZD8B4V8M2T4文档编码:

36、CG2L9B5H10K5 HT9W3G1Q6E7 ZD8B4V8M2T4文档编码:CG2L9B5H10K5 HT9W3G1Q6E7 ZD8B4V8M2T4文档编码:CG2L9B5H10K5 HT9W3G1Q6E7 ZD8B4V8M2T4文档编码:CG2L9B5H10K5 HT9W3G1Q6E7 ZD8B4V8M2T4文档编码:CG2L9B5H10K5 HT9W3G1Q6E7 ZD8B4V8M2T4文档编码:CG2L9B5H10K5 HT9W3G1Q6E7 ZD8B4V8M2T4文档编码:CG2L9B5H10K5 HT9W3G1Q6E7 ZD8B4V8M2T4文档编码:CG2L9B5H10K5

37、HT9W3G1Q6E7 ZD8B4V8M2T4文档编码:CG2L9B5H10K5 HT9W3G1Q6E7 ZD8B4V8M2T4文档编码:CG2L9B5H10K5 HT9W3G1Q6E7 ZD8B4V8M2T4文档编码:CG2L9B5H10K5 HT9W3G1Q6E7 ZD8B4V8M2T4文档编码:CG2L9B5H10K5 HT9W3G1Q6E7 ZD8B4V8M2T4文档编码:CG2L9B5H10K5 HT9W3G1Q6E7 ZD8B4V8M2T4文档编码:CG2L9B5H10K5 HT9W3G1Q6E7 ZD8B4V8M2T4文档编码:CG2L9B5H10K5 HT9W3G1Q6E7 Z

38、D8B4V8M2T4文档编码:CG2L9B5H10K5 HT9W3G1Q6E7 ZD8B4V8M2T4文档编码:CG2L9B5H10K5 HT9W3G1Q6E7 ZD8B4V8M2T4文档编码:CG2L9B5H10K5 HT9W3G1Q6E7 ZD8B4V8M2T4文档编码:CG2L9B5H10K5 HT9W3G1Q6E7 ZD8B4V8M2T4文档编码:CG2L9B5H10K5 HT9W3G1Q6E7 ZD8B4V8M2T4文档编码:CG2L9B5H10K5 HT9W3G1Q6E7 ZD8B4V8M2T4文档编码:CG2L9B5H10K5 HT9W3G1Q6E7 ZD8B4V8M2T4文档编

39、码:CG2L9B5H10K5 HT9W3G1Q6E7 ZD8B4V8M2T4文档编码:CG2L9B5H10K5 HT9W3G1Q6E7 ZD8B4V8M2T4文档编码:CG2L9B5H10K5 HT9W3G1Q6E7 ZD8B4V8M2T4文档编码:CG2L9B5H10K5 HT9W3G1Q6E7 ZD8B4V8M2T4文档编码:CG2L9B5H10K5 HT9W3G1Q6E7 ZD8B4V8M2T4文档编码:CG2L9B5H10K5 HT9W3G1Q6E7 ZD8B4V8M2T4文档编码:CG2L9B5H10K5 HT9W3G1Q6E7 ZD8B4V8M2T4文档编码:CG2L9B5H10K

40、5 HT9W3G1Q6E7 ZD8B4V8M2T4文档编码:CG2L9B5H10K5 HT9W3G1Q6E7 ZD8B4V8M2T4文档编码:CG2L9B5H10K5 HT9W3G1Q6E7 ZD8B4V8M2T4文档编码:CG2L9B5H10K5 HT9W3G1Q6E7 ZD8B4V8M2T4文档编码:CG2L9B5H10K5 HT9W3G1Q6E7 ZD8B4V8M2T4文档编码:CG2L9B5H10K5 HT9W3G1Q6E7 ZD8B4V8M2T4文档编码:CG2L9B5H10K5 HT9W3G1Q6E7 ZD8B4V8M2T4文档编码:CG2L9B5H10K5 HT9W3G1Q6E7

41、 ZD8B4V8M2T4文档编码:CG2L9B5H10K5 HT9W3G1Q6E7 ZD8B4V8M2T4Table 5 The excretion of 24 hours urinary microalbumin(UMB,g/24h)at different time course Before treatment Normal(10)Model(11)Losartan(11)Low dos(11)Mid.dos(11)High dos(11)24h UMa(g)64.4824.63678.5785.59*638.6798.61*616.9992.23*638.89111.23*725.97

42、123.46*24h urinary Cr 1.080.20 2.610.31 2.390.61 3.070.84 1.820.25 1.370.29 AIb/Cr 0.550.18 3.860.75*4.201.00 3.440.88 3.850.75 5.870.65 After treatment 4 weeks Normal(10)Model(10)Losartan(11)Low dos(11)Mid.dos(10)High dos(10)24h UMa(g)57.8019.901634.52242.61*1208.25205.41*979.00166.83*1533.30316.24

43、*1369.73302.15*24h urinary Cr 1.290.19 2.120.38 1.550.24 2.060.78 2.570.62 1.540.26 AIb/Cr 0.610.26 11.082.72*8.171.25*7.671.69*7.501.47*8.851.77*After treatment 8 weeks Normal(10)Model(8)Losartan(11)Low dos(11)Mid.dos(9)High dos(9)24h UMa(g)64.3315.751693.41483.50*1364.22366.63*1445.31436.38*895.70

44、278.13*911.98226.89*24h urinary Cr 1.840.35 1.920.38 2.980.56 2.720.64 1.840.42 2.150.49 AIb/Cr 0.480.12 8.031.38*4.730.97*7.132.91*4.511.06*5.151.48*After treatment 10 weeks Normal(10)Model(8)Losartan(10)Low dos(10)Mid.dos(9)High dos(8)24h UMa(g)64.3418.712385.62411.40*1504.42352.76*1739.22286.86*1

45、709.86241.66*1247.87274.37*24h urinary Cr 1.840.35 2.090.30 3.110.52 3.440.48 3.300.50 2.230.40 AIb/Cr 0.400.11 11.641.57*5.761.10*7.762.36*5.620.92*6.121.28*After treatment 12 weeks Normal(10)Model(7)Losartan(10)Low dos(10)Mid.dos(9)High dos(8)24h UMa(g)56.8115.472067.21304.04*1089.92186.82*1316.56

46、329.25*1142.80302.59*571.21171.10*24h urinary Cr 1.840.17 1.160.18 2.470.99 1.530.21 1.260.23 1.550.55 AIb/Cr 0.410.14 20.083.89*7.041.30*7.871.60*9.061.96*4.701.23*Date are means SE.#P0.05 vs Model；#P0.01 vs Model.*P0.05 vs Normal；*P0.01 vs Normal.25 对肾脏组织学的影响：造模12周后，肉眼观察模型组肾脏明显肥大，光镜下观察肾脏组织学改变不明显，只

47、存在轻度的系膜增生，表明本实验的模型为 2型糖尿病肾病的早期。治疗的各组肾脏组织学改变不明显。3 讨论 31 2型糖尿病早期肾病的动物模型特点 传统的单纯给予STZ 的造模方法 是应用STZ 破坏胰岛细胞，这种造模方法更近似于临床的1型糖尿病。我们采用预先喂饲高糖高脂饮食的方法，通过 4周的喂饲，可稳定地诱导出大鼠胰岛素抵抗，从实验结果分析，模型组即使有明显较正常组高的胰岛素水平，亦只能维持血糖在一个较正常对照组更高的水平。而在此基础，只需给予低剂量的STZ 即可达到诱导大鼠糖尿病的目的。这种造模方法可能只是部分地破坏了大鼠的胰岛细胞，而其血糖的升高在很大程度上与之前诱导的胰岛素抵抗有较大的关

48、系，其血糖水平也大多在2535mmol L之间。这种造模方法所诱导的伴胰岛素抵抗的大鼠糖尿病更近似于临床上的2型糖尿病。微量白蛋白尿是糖尿病肾病的早期临床表现，在这一阶段，仍有希望通过适当的治疗改善肾脏病变，减少尿蛋白的排出。本研究通过造模后多个时点的观察，发现模型组大鼠尿微量白蛋白呈一定的与时间一致的上升趋势，表明该模型符合临床 2型糖尿病早文档编码:CG2L9B5H10K5 HT9W3G1Q6E7 ZD8B4V8M2T4文档编码:CG2L9B5H10K5 HT9W3G1Q6E7 ZD8B4V8M2T4文档编码:CG2L9B5H10K5 HT9W3G1Q6E7 ZD8B4V8M2T4文档编码

49、:CG2L9B5H10K5 HT9W3G1Q6E7 ZD8B4V8M2T4文档编码:CG2L9B5H10K5 HT9W3G1Q6E7 ZD8B4V8M2T4文档编码:CG2L9B5H10K5 HT9W3G1Q6E7 ZD8B4V8M2T4文档编码:CG2L9B5H10K5 HT9W3G1Q6E7 ZD8B4V8M2T4文档编码:CG2L9B5H10K5 HT9W3G1Q6E7 ZD8B4V8M2T4文档编码:CG2L9B5H10K5 HT9W3G1Q6E7 ZD8B4V8M2T4文档编码:CG2L9B5H10K5 HT9W3G1Q6E7 ZD8B4V8M2T4文档编码:CG2L9B5H10K5

50、 HT9W3G1Q6E7 ZD8B4V8M2T4文档编码:CG2L9B5H10K5 HT9W3G1Q6E7 ZD8B4V8M2T4文档编码:CG2L9B5H10K5 HT9W3G1Q6E7 ZD8B4V8M2T4文档编码:CG2L9B5H10K5 HT9W3G1Q6E7 ZD8B4V8M2T4文档编码:CG2L9B5H10K5 HT9W3G1Q6E7 ZD8B4V8M2T4文档编码:CG2L9B5H10K5 HT9W3G1Q6E7 ZD8B4V8M2T4文档编码:CG2L9B5H10K5 HT9W3G1Q6E7 ZD8B4V8M2T4文档编码:CG2L9B5H10K5 HT9W3G1Q6E7