论文标题:实验性2型糖尿病大鼠脂代谢异常与2型糖尿病及糖尿病肾病的关系
The Relation between Dyslipidemia and Type 2 Diabetes Mellitus、Diabetic Nephropathy in the Rat Model of Type 2 Diabetes Mellitus
论文作者 宋庆芳
论文导师 王战建；刘宽芝,论文学位 硕士,论文专业 内科学
论文单位 河北医科大学,点击次数 89,论文页数 50页File Size1943k
2002-04-01论文网 http://www.lw23.com/lunwen_77134147/ 血脂;胰岛素抵抗;2型糖尿病;糖尿病肾病;转化生长因子－β
Hyperlipidemia,Insulin resistance,Type 2 diabetes mellitus,Diabetic nephropathy,Transfroming growth factor β
目的：脂代谢异常可以诱发胰岛素抵抗，而胰岛素抵抗是2型糖尿病的基本病理生理现象，是产生包括糖尿病、高血压病、冠心病等代谢综合征的基础，脂代谢异常也参与了糖尿病大血管和微血管并发症的发生发展。因此研究脂代谢异常在胰岛素抵抗、2型糖尿病和糖尿病慢性并发症发生发展中的作用有重要意义。本研究通过特殊膳食喂养SD雌性大鼠诱发出胰岛素抵抗，再注射小剂量链脲佐菌素(STZ)诱发高血糖，从而建立实验性2型糖尿病大鼠模型，该模型具有高血脂、高血糖，胰岛素水平不低，胰岛素抵抗等特点，其发病过程及特征与2型糖尿病的临床过程和代谢特征类似。在此基础上探讨脂代谢异常与胰岛素抵抗、2型糖尿病及糖尿病肾病的关系，以及转化生长因子-β(TGF-β)在糖尿病肾病中的作用。 方法：将实验动物随机分为正常对照组和实验组，对照组喂常规饲料，实验组大鼠喂高脂高糖饲料(主要为蔗糖和熟猪油；其中碳水化合物提供的热卡为40％，脂肪提供的热卡为47％，蛋白质提供的热卡为13％)4周，诱发胰岛素抵抗，然后小剂量链脲佐菌素(STZ，25mg/kg)腹腔注射，损伤部分胰腺，诱发胰岛素代偿性分泌障碍，不能克服胰岛素抵抗，出现高血糖。实验持续26周。于第4周、第8周、第26周分别采血测空腹血糖(FBG)、空腹血 中文摘要清胰岛素吓IN人血清甘油三酯门G人血清胆固醇门C人体重。第26周实验结柬时，代谢笼收集24小时尿，放免法测定尿微量白蛋白uAER），，断头处死后取右肾称重量，计算肾重／体重，01ympus 2700全自动生化分析仪测定 TG。TC、血肌酚门cr）及尿肌配ucr人计算内生肌配清除率 ＊cr人氧化酶法测定FBG，放免法测定FIN，计算胰岛素敏感性指数叮 SI人取左肾肾皮质进行 HE及 PAS染色，光镜、电镜下观察肾脏形态及病理变化，图象分析系统测量肾小球平均面积瞩MA入 肾小球平均体积uMV），用免疫组化的方法检测肾内TGF－p蛋白表达水平，分析TG、TC与 ISI、UAER、GMV的相关性。 结果：实验组大鼠高糖高脂饮食喂养4周后，大鼠体重较对照组增加（P＜0．05），TG、TC较对照组升高（P（．01，P＜0．01），FBG与对照组比较无显著性差异（P＞0．05），FIN较对照组明显升高，有显著性差异u④．01人ISI较对照组降低吓0．of人说明高糖高脂饮食喂养4周后出现胰岛素抵抗。小剂量STZ注射后4周，实验组FBG较对照组升高明显汀①．01人 FIN较注射前降低但与对照组比较无显著性差异 u川．05人 实验组 uI较对照组显著降低 吓N．01人说明胰岛素抵抗继续存在。体重较对照组增加但无显著差异卯川．05），TG、TC水平实验组较对照组升高（P＜0．of，P＜0．of）。此时实验组大鼠具有高血脂、高血糖、胰岛素抵抗的特征，至此已成功建立2型糖尿病大鼠模型。第26周实验结柬时，体重实验组与对照组比较无显著性差异u川．05人 FBG实验组较对照组升高u刃．of），但FIN两组之间无显著性差异印川．05），ISI实验组较对 2 中文摘要 照组降低uo．01），24小时尿微量白蛋白，实验组较对 照组升高Oo．01人Ccr实验组较对照组增高u刃．05）， 说明实验组大鼠存在肾小球高滤过。实验组大鼠肾重较对 照组增加u州．05人 肾重／体重与对照组比较有显著性差 异 汀④．05人 实验组大鼠删A、GMV与对照组比较有显著 性差异u．01，P川．of），光镜下叩S染色切片显示，实 验组肾小球较对照组PAS红染区明显扩大，系膜区增宽， 基底膜增厚。TGF－p免疫组化显示，实验组肾小球TGF－ p表达明显增强。其TGF－日平均阳性表达率与正常对照组 比较差异有显著性u州．01人相关分析表明，实验组大鼠 TG、TC与 ISI呈负相关（I’＝－0．7319，P＜0．01：I’＝－0．6514， P＜0．01），TG、TC与UAER呈正相关（r＝0．5629，P＜0．01 r＝0．6235，P（．01），TG、TC与MV呈正相关（r＝0．6032， P＜0．01 r＝0．6847，P＜0．01）。 结论： 1实验组雌性SD大鼠高糖高脂饮食喂养4周后，出现 高胰岛素血症，空腹血糖不高，胰岛素敏感指数降低，成 功诱发出胰岛素抵抗。 2在此基础上，再注射小剂量STZ，损伤部分胰腺， 诱发胰岛素分泌障碍，不能克服胰岛素抵抗，出现高血糖 症，此时胰岛素敏感指数低于对照组，仍存在胰岛素抵抗。 至此建立了实验性2型糖尿病大鼠模型，该模型具有高血 糖，空腹胰岛素不低，胰岛素敏感性降低，高血脂特点， 与人类2型糖尿的临床特征类似。 3比较实验组大鼠小剂量STZ注射前后胰岛素敏感指 数，可知在糖尿病发生后胰岛素抵抗继续存在，而且较前
Objective: Dyslipidemia induce insulin resistance. Insulin resistance is the basic pathologic physiology phenomenon of type 2 diabetes mellitus and is the bases of the metabolic syndrom such as diabetes mellitus ,hypertension and hyperlipidemia. Dyslipidemia also play an important role in the development of diabetic microvascuiar and macrovascular complications. So it is important to investigate the mechanism of dyslipidemia in the insulin resistance,type 2 diabetes mellitus and diabetic chronic complication. To feed SD femal rat with a high-sucrose-high-fat diet induce insulin resistance. After 4 weeks streptozotion (STZ,25mg/kg) was injected intrapenitoneally to induce hyperglycemia. So a rat model with the characteristics of hyperglycemia hyperlipidemia insulin resistance was set up , which stimulates the metabolic abnormalites of human type 2 diabetes mellitus. It may provide a particular advantage for investigating the relationship between dyslipidemia and insulin resistance,type 2 diabetes mellitus and diabetic nephropathy.Method: The rats were randomly assigened into twogroups :normal control rats(group A) and diabetic rats(group B). Group A was fed with normal diet .Group B was fed with a high-sucrose-high-faf diet and a low dose of STZ was injected to induce hyperglycemia after 4 weeks. Body weight, fasting blood glucose, fasting serum insulin, serum triglyceride, cholestrol were observed after 4 8 26 weeks After 26 weeks, kidney weight, serum creatinine, urinary albumin, urinary creatinine were observed? The expressions of protein of TGF- P was examined utilizing immunohistochemistyoThe renal tissue were observed by light microscopy and electronic microscope Morever , the correlation between insulin sensitivity index (ISI) and serum lipid level , the average positive expressing rate of TGF-P and urinary alumin were respectively analyzed To calculate kidney weight/body weight, creatinine clearance ratio (Ccr) and insulin sensitivity index, mean glomerular area (MGA), mean glomerular volume (MGV)Result: In the group B, fed with high-sucrose-high-fat diet for 4 weeks, body weight, fasting insulin, serum triglyceride, cholestrol were markedly increase as compared with those of group A ISI was reduced as compared with group A Fasting blood glucose had no difference with group A (p>0.05) . So insulin resistance was induced in group B. After 8 weeks, in group B, serum triglyceride, cholestrol, fasting blood glucose significantly increased. The fasting plasma inshlin, body weight were the same level comparedwith group A(p>0.05). ISI was markedly reduced as compared with group B(p<0.01). Insulin resistance also exist in group B o The rat model of type 2 diabetes mellitus has the characteristics of high blood glucose, hyperlipidemia, insulin resistance. After 26 weeks, compared with group A, there was a significantly increase in fasting blood glucose, urinary albumin, Ccr in group B. The body weight,fasting blood insulin in both groups had significance. The insulin sensitivity index in group B, kidney weight/body weight, GMA, GMV were significantly increase. Electronic microscopic finds showed expanded mesangial matrix, glomerular basement membrane thickening in group B. The PAS positive substance in glomeruli of group B was highly expressed than group A There was a significant positive correlation between the positive expressing ratio of TGF- 3 and urinary albumin in group B(r=0.7150, p<0.01). While there was a significant correlation between ISI and serum triglyceride, cholestrol(r=-0.7319, p<0.01;r=-0.6814, p<0.01). Conclusion:1 Insulin resistance was induced in femal SD rats fed with a high-sucrose-high-fat diet for 4 weeks.2 After streptozotion injected intraperitoneally hyperglycemia was induced. The rat model has hyperglycemia, hyperlidemia, insulin resistance, which stimulates the metabolic abnormalites of human type 2 diabetes mellitus.3 Compared the insulin sensitivity after injecting STZwith before injecting STZ , insulin resistance
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