血糖波动对糖尿病大鼠肾脏病理改变及Ⅳ型胶原表达的影响
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摘要
目的：观察血糖波动对糖尿病大鼠肾脏病理改变及Ⅳ型胶原表达的影响。
方法：将75只雄性Sprague-Dawley(SD)大鼠随机分成正常组(NC)(n=20)和糖尿病模型组(DM)(n=55)。高糖高脂饲料喂养DM模型组大鼠4周后用小剂量链脲佐菌素(STZ) 35mg/Kg腹腔注射诱导建立糖尿病大鼠模型,取非同日两次测得的随机血糖>16.7mmol/L为模型制作成功。将DM组随机分为持续高血糖组(n=21)和血糖波动组(n=21)。血糖波动组大鼠给予每日2次皮下注射胰岛素诱导血糖波动,建立糖尿病大鼠血糖波动模型。正常组及持续性高血糖组予以等量蒸馏水腹腔注射。DM组继续喂以高糖高脂饲料,正常组喂普通饲料。观察各组大鼠存活率、体重、饮水量、尿量情况及检测血糖值。所有大鼠在进行干预12周后处死。处死前各组大鼠均留取空腹全血用于糖化血红蛋白(HbA1c)、肾功能、血脂等生化指标的检测,留取24小时尿做尿蛋白测定。
结果：1.高糖高脂饲料喂养SD大鼠4周后用小剂量链脲佐菌素35mg/Kg可成功诱导出糖尿病大鼠模型,所有成模大鼠非同日两次测得的随机血糖>16.7mmol/L。高糖高脂饮食喂养4周后的DM组大鼠比正常组大鼠体重有增高(P<0.05),胰岛素敏感指数都有下降(P<0.05)。
2.实验结束时,与正常组大鼠比较,血糖波动组和持续高血糖组大鼠存活率、体重显著下降(P<0.05),饮水量、尿量显著增多(P<0.05),而持续组和波动组无显著差异(P>0.05)。
3.与正常组大鼠比较,血糖波动组和持续高血糖组大鼠的平均血糖水平(MBG)、每日平均血糖的标准差(SDBG)、每日最大血糖波动幅度(LAGE)及M值均显著增高(P<0.05)。持续高血糖的MBG显著高于血糖波动组,血糖波动组的SDBG、LAGE及M值均显著高于持续高血糖组(P<0.05)。
4.与正常组大鼠比较,血糖波动组和持续高血糖组大鼠的HbA1c明显增高(P<0.05),而血糖波动组和持续高血糖组的HbA1c无显著差异(P>0.05)。与正常组大鼠比较,血糖波动组和持续高血糖组大鼠的血脂指标总胆固醇(TC)、甘油三酯(TG)、低密度脂蛋白(LDL)显著升高(P<0.05),高密度脂蛋白(HDL)显著下降(P<0.05)。血糖波动组和持续高血糖组比较无显著差异(P>0.05)。
5.与正常组大鼠比较,血糖波动组和持续高血糖组大鼠24小时尿蛋白量、血尿素氮(BUN)、血肌酐(SCr)均显著增高(P<0.01)。与持续高血糖组比较,血糖波动组大鼠24小时尿蛋白量、BUN、SCr有显著增高(P<0.05)。
6.与正常组大鼠比较,糖尿病组大鼠肾脏光镜检查可见肾小球体积增大、毛细血管基底膜增厚；肾小球囊腔扩张,系膜基质增多。肾小管体积增大,基底膜增厚。肾小球囊腔和肾小管管腔内可见管型蛋白,出现“高压力、高灌注和高滤过”的“三高”病理改变。血糖波动组较持续性高血糖组病变更为严重,“三高”症状更为明显。
7.正常组大鼠肾脏ColⅣ主要表达于肾小球毛细血管基底膜和系膜基质中。与正常组大鼠比较,血糖波动组和持续高血糖组大鼠肾脏ColⅣ均有显著增高(P<0.01)。与持续高血糖组比较,血糖波动组ColⅣ显著增加(P<0.05)。
结论：
1.糖尿病大鼠肾脏肾小球毛细血管基底膜增厚、系膜基质增多,肾小球体积增大、毛细血管扩张,肾小球通透性增强；肾小管体积增大、管腔扩张。血糖波动比持续性高糖更能加重对糖尿病大鼠肾脏的损伤。
2.糖尿病大鼠肾脏Ⅳ型胶原产生增多,且血糖波动比持续性高糖的作用更强。血糖波动有可能通过Ⅳ型胶原产生的增多而促进糖尿病肾病的发生发展。
Objective
To observe the effect of blood glucose fluctuation on renal pathological change and collagen IV expression of diabetic rats.
The male Sprague-Dawley (SD) rats were randomly assigned into normal group (NC) rats(n=20) and model group (DM) rats(n=55). Normal group rats were fed with normal diet, while diabetic model group rats were fed with high-sucrose-high-fat diet and after 4 weeks a low dose of streptozocin (STZ,35 mg/kg) was injected to induce diabetic model. And then the model group rats were divided randomly into two groups again:sustained high blood glucose group(n=21)and blood glucose fluctuation group(n=21).The latter group were induced by subcutaneous injecting insulin twice daily, while the other group were given equal dose physiological saline. We observed the survival rate, body weights, water intake, urine output, and detected the glucose level. All rats were executed after intervene 12 weeks, and collected the fasting blood and 24 hours urine before executed. The HbA1c, levels of lipid and renal functions were measured by the blood. The 24 hours protein uria were measured by the urine.
Results
1 The SD rats were successed induced into the diabetic models by fed with a high-sucrose-high-fat diet for four weeks and a low dose of STZ (35mg/Kg) was injected. The random glucose of all the diabetic model rats were more than 16.7mmol/L twice in different days. Compared with normal control group, the weights of diabetic group were increased. (p<0.05), while the insulin sensitive index was decreased (P<0.05)
2 Compared with normal control group, survival rate and body weight were significantly lower, while water intake and urine output were obviously higher in sustained high blood group and blood glucose fluctuation group after the experiments over (p<0.05). There was no significant difference between sustained high blood group and blood glucose fluctuation one (P>0.05)
3 Compared with normal control group, the average blood glucose levels(MBG), the standard deviation of daily average blood glucose (SDBG),the largest amplitude of glycemic excursions(LAGE) and the M-value were significantly increased in sustained high blood glucose group and blood glucose fluctuation group (p<0.05). Compared with sustained high glucose group, the MBG were significantly decreased in blood glucose fluctuation group, while the SDBG, LAGE, M-value were significantly increased (p<0.05). The blood glucose fluctuations could be induced by subcutaneous injecting insulin twice daily.
4 Compared with normal control group, HbA1c were significantly higher in sustained high blood group and blood glucose fluctuation group (P<0.05),while there was no significant difference between the two diabetic groups. Compared with normal control group, TC, TG and LDL were significantly increased in sustained high blood group and blood glucose fluctuation group (p<0.05),while the level of HDL were decreased.But both of them were no significantly difference between high blood group and blood glucose fluctuation group (P>0.05)
5 Compared with normal control group, the level of 24 hours proteinuria, BUN and SCr were significantly higher in sustained high blood group and blood glucose fluctuation group (p<0.01). Compared with sustained high blood group, the level of 24 hours proteinuria, BUN and SCr were significantly higher in blood glucose fluctuation group (p<0.05)
6 Compared with normal control group, it could be seen that the renal glomeruli became larger, capillary basal membrane became thicker, capsular space extended, ground substance increased, the volume of renal tubule extended in the diabetic rats' kidney under the light microscope. The diabetic rats' kidney has come out the change of "high pressure, hypertransfusion, high filtration". Compared with sustained high glucose group, the pathological changes were more serious in the blood glucose fluctuation group, and the symptom of "three high" was more obvious.
7 The normal control group rats' collagen IV immunohistochemical positive expression was mainly in membrane basement and mesenterium groundmass. The level of collagen IV was significantly increased in sustained high blood glucose group and blood glucose fluctuation group (P<0.01). Compared with sustained high blood glucose group, the level of Col IV was significantly increased in blood glucose fluctuation group(P<0.05).
Conclusion
1 The diabetic hyperglycemia circumstance could made the renal glomeruli larger, renal glomeruli capillary basal membrane thicker, ground substance increased, blood capillary broaden, permeability of renal glomeruli impaired, the renal tubule volume and lumina expanded. Compared with sustained high glucose group, the kidney's injury was more serious in blood glucose fluctuation group.
2 The diabetic hyperglycemia circumstance could made the expression of rats'renal collagen IV increased, and the product of collagen IV was more in blood glucose fluctuation group than in sustained high glucose group, which could contribute to the development of diabetic nephropathy.
方法：将75只雄性Sprague-Dawley(SD)大鼠随机分成正常组(NC)(n=20)和糖尿病模型组(DM)(n=55)。高糖高脂饲料喂养DM模型组大鼠4周后用小剂量链脲佐菌素(STZ) 35mg/Kg腹腔注射诱导建立糖尿病大鼠模型,取非同日两次测得的随机血糖>16.7mmol/L为模型制作成功。将DM组随机分为持续高血糖组(n=21)和血糖波动组(n=21)。血糖波动组大鼠给予每日2次皮下注射胰岛素诱导血糖波动,建立糖尿病大鼠血糖波动模型。正常组及持续性高血糖组予以等量蒸馏水腹腔注射。DM组继续喂以高糖高脂饲料,正常组喂普通饲料。观察各组大鼠存活率、体重、饮水量、尿量情况及检测血糖值。所有大鼠在进行干预12周后处死。处死前各组大鼠均留取空腹全血用于糖化血红蛋白(HbA1c)、肾功能、血脂等生化指标的检测,留取24小时尿做尿蛋白测定。
结果：1.高糖高脂饲料喂养SD大鼠4周后用小剂量链脲佐菌素35mg/Kg可成功诱导出糖尿病大鼠模型,所有成模大鼠非同日两次测得的随机血糖>16.7mmol/L。高糖高脂饮食喂养4周后的DM组大鼠比正常组大鼠体重有增高(P<0.05),胰岛素敏感指数都有下降(P<0.05)。
2.实验结束时,与正常组大鼠比较,血糖波动组和持续高血糖组大鼠存活率、体重显著下降(P<0.05),饮水量、尿量显著增多(P<0.05),而持续组和波动组无显著差异(P>0.05)。
3.与正常组大鼠比较,血糖波动组和持续高血糖组大鼠的平均血糖水平(MBG)、每日平均血糖的标准差(SDBG)、每日最大血糖波动幅度(LAGE)及M值均显著增高(P<0.05)。持续高血糖的MBG显著高于血糖波动组,血糖波动组的SDBG、LAGE及M值均显著高于持续高血糖组(P<0.05)。
4.与正常组大鼠比较,血糖波动组和持续高血糖组大鼠的HbA1c明显增高(P<0.05),而血糖波动组和持续高血糖组的HbA1c无显著差异(P>0.05)。与正常组大鼠比较,血糖波动组和持续高血糖组大鼠的血脂指标总胆固醇(TC)、甘油三酯(TG)、低密度脂蛋白(LDL)显著升高(P<0.05),高密度脂蛋白(HDL)显著下降(P<0.05)。血糖波动组和持续高血糖组比较无显著差异(P>0.05)。
5.与正常组大鼠比较,血糖波动组和持续高血糖组大鼠24小时尿蛋白量、血尿素氮(BUN)、血肌酐(SCr)均显著增高(P<0.01)。与持续高血糖组比较,血糖波动组大鼠24小时尿蛋白量、BUN、SCr有显著增高(P<0.05)。
6.与正常组大鼠比较,糖尿病组大鼠肾脏光镜检查可见肾小球体积增大、毛细血管基底膜增厚；肾小球囊腔扩张,系膜基质增多。肾小管体积增大,基底膜增厚。肾小球囊腔和肾小管管腔内可见管型蛋白,出现“高压力、高灌注和高滤过”的“三高”病理改变。血糖波动组较持续性高血糖组病变更为严重,“三高”症状更为明显。
7.正常组大鼠肾脏ColⅣ主要表达于肾小球毛细血管基底膜和系膜基质中。与正常组大鼠比较,血糖波动组和持续高血糖组大鼠肾脏ColⅣ均有显著增高(P<0.01)。与持续高血糖组比较,血糖波动组ColⅣ显著增加(P<0.05)。
结论：
1.糖尿病大鼠肾脏肾小球毛细血管基底膜增厚、系膜基质增多,肾小球体积增大、毛细血管扩张,肾小球通透性增强；肾小管体积增大、管腔扩张。血糖波动比持续性高糖更能加重对糖尿病大鼠肾脏的损伤。
2.糖尿病大鼠肾脏Ⅳ型胶原产生增多,且血糖波动比持续性高糖的作用更强。血糖波动有可能通过Ⅳ型胶原产生的增多而促进糖尿病肾病的发生发展。
Objective
To observe the effect of blood glucose fluctuation on renal pathological change and collagen IV expression of diabetic rats.
The male Sprague-Dawley (SD) rats were randomly assigned into normal group (NC) rats(n=20) and model group (DM) rats(n=55). Normal group rats were fed with normal diet, while diabetic model group rats were fed with high-sucrose-high-fat diet and after 4 weeks a low dose of streptozocin (STZ,35 mg/kg) was injected to induce diabetic model. And then the model group rats were divided randomly into two groups again:sustained high blood glucose group(n=21)and blood glucose fluctuation group(n=21).The latter group were induced by subcutaneous injecting insulin twice daily, while the other group were given equal dose physiological saline. We observed the survival rate, body weights, water intake, urine output, and detected the glucose level. All rats were executed after intervene 12 weeks, and collected the fasting blood and 24 hours urine before executed. The HbA1c, levels of lipid and renal functions were measured by the blood. The 24 hours protein uria were measured by the urine.
Results
1 The SD rats were successed induced into the diabetic models by fed with a high-sucrose-high-fat diet for four weeks and a low dose of STZ (35mg/Kg) was injected. The random glucose of all the diabetic model rats were more than 16.7mmol/L twice in different days. Compared with normal control group, the weights of diabetic group were increased. (p<0.05), while the insulin sensitive index was decreased (P<0.05)
2 Compared with normal control group, survival rate and body weight were significantly lower, while water intake and urine output were obviously higher in sustained high blood group and blood glucose fluctuation group after the experiments over (p<0.05). There was no significant difference between sustained high blood group and blood glucose fluctuation one (P>0.05)
3 Compared with normal control group, the average blood glucose levels(MBG), the standard deviation of daily average blood glucose (SDBG),the largest amplitude of glycemic excursions(LAGE) and the M-value were significantly increased in sustained high blood glucose group and blood glucose fluctuation group (p<0.05). Compared with sustained high glucose group, the MBG were significantly decreased in blood glucose fluctuation group, while the SDBG, LAGE, M-value were significantly increased (p<0.05). The blood glucose fluctuations could be induced by subcutaneous injecting insulin twice daily.
4 Compared with normal control group, HbA1c were significantly higher in sustained high blood group and blood glucose fluctuation group (P<0.05),while there was no significant difference between the two diabetic groups. Compared with normal control group, TC, TG and LDL were significantly increased in sustained high blood group and blood glucose fluctuation group (p<0.05),while the level of HDL were decreased.But both of them were no significantly difference between high blood group and blood glucose fluctuation group (P>0.05)
5 Compared with normal control group, the level of 24 hours proteinuria, BUN and SCr were significantly higher in sustained high blood group and blood glucose fluctuation group (p<0.01). Compared with sustained high blood group, the level of 24 hours proteinuria, BUN and SCr were significantly higher in blood glucose fluctuation group (p<0.05)
6 Compared with normal control group, it could be seen that the renal glomeruli became larger, capillary basal membrane became thicker, capsular space extended, ground substance increased, the volume of renal tubule extended in the diabetic rats' kidney under the light microscope. The diabetic rats' kidney has come out the change of "high pressure, hypertransfusion, high filtration". Compared with sustained high glucose group, the pathological changes were more serious in the blood glucose fluctuation group, and the symptom of "three high" was more obvious.
7 The normal control group rats' collagen IV immunohistochemical positive expression was mainly in membrane basement and mesenterium groundmass. The level of collagen IV was significantly increased in sustained high blood glucose group and blood glucose fluctuation group (P<0.01). Compared with sustained high blood glucose group, the level of Col IV was significantly increased in blood glucose fluctuation group(P<0.05).
Conclusion
1 The diabetic hyperglycemia circumstance could made the renal glomeruli larger, renal glomeruli capillary basal membrane thicker, ground substance increased, blood capillary broaden, permeability of renal glomeruli impaired, the renal tubule volume and lumina expanded. Compared with sustained high glucose group, the kidney's injury was more serious in blood glucose fluctuation group.
2 The diabetic hyperglycemia circumstance could made the expression of rats'renal collagen IV increased, and the product of collagen IV was more in blood glucose fluctuation group than in sustained high glucose group, which could contribute to the development of diabetic nephropathy.
引文
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