应用自发性高血压大鼠建立2型糖尿病早期肾损害模型

目的 应用自发性高血压大鼠（SHR）建立具有胰岛素抵抗和早期肾脏损害特征的2型糖尿病模型。 方法 采用高糖高脂饲料喂养SHR大鼠2周诱导胰岛素抵抗，同时用WKY大鼠作为对照组。测定大鼠收缩压、血糖、三酰甘油、胆固醇及胰岛素水平，计算稳态模型评价的胰岛素抵抗指数（HOMA-IR）。禁食12 h后，模型组予以腹腔注射链脲菌素（STZ）35 mg/kg，对照组予以相同剂量的柠檬酸缓冲液。注射STZ 72 h后测随机血糖，以血糖≥16.7 mmol/L为造模成功。观察8周后模型组与对照组的肾质量指数、收缩压、血脂、尿蛋白排泄以及肾脏病理变化情况。 结果 SHR大鼠高糖高脂饲料喂养2周后，与对照组相比，体质量、血脂、血糖均显著增加（均P ＜ 0.05），HOMA-IR也显著升高（5.03±0.38比2.61±0.34，P ＜ 0.05）。8周后，模型组大鼠多尿、多饮、体质量减轻，收缩压、血糖和糖化血红蛋白水平显著升高（P ＜ 0.01）。尿蛋白量（24 h）明显增加（57.58±16.54） mg/24 h比（5.35±1.90） mg/24 h，P ＜ 0.01]，肾质量指数（mg/g）也增加（P ＜ 0.05），造模成功率为81.8%。病理改变为肾脏肥大，肾小球系膜基质增多，毛细血管基底膜增厚，足细胞空泡变性，足突消失，部分融合。 结论 联合高糖高脂饲料及小剂量STZ注射SHR大鼠成功制备2型糖尿病特征的动物模型，并诱导出糖尿病早期肾脏损害，为进一步研究2型糖尿病肾病发生机制和药物干预提供了简单实用的动物模型。

Establishment of type 2 diabetes mellitus with early renal injury on spontaneously hypertensive rats

Objective To develop a model of type 2 diabetes with early renal injury on spontaneously hypertensive rats (SHR). Methods The 6-week old SHR were fed with the diets enriched with sucrose (20%, W/W), lard (10%, W/W), cholesterol (2.5%, W/W) and chleolate (1%, W/W) to induce insulin resistance. Hyperglycemia was developed by intraperitoneal injection of streptozotocin (STZ, 35 mg/kg). Wistar-Kyoto rats (WKY) were used as normal controls. Rats with plasma glucose (PGL) ≥ 16.7 mmol/L were diagnosed as diabetes. Eight weeks after the induction of diabetes, plasma triglyceride (TG), cholesterol (CHO), glucose, systolic pressure(SP), 24-h urine protein excretion (Upro) were examined in all the rats, and the homeostasis model assessment of insulin resistance (HOMA-IR) was analyzed. Renal pathological changes were studied by immunohistochemical staining and electron microscope. Results After 2 weeks on the high sucrose and fat diets, the model rats exhibited significant increase in basal PGL, TG and CHO levels as compared to control rats (P<0.05, respectively). The insulin resistance was developed in model rats demonstrated by the higher HOMA-IR (5.03±0.38 vs 2.61±0.34, P<0.05). At the end of the experiment, model rats were associated with hypertension. Upro level was significantly increased in model rats compared with that in controls (57.58±16.54) mg/24 h vs (5.35±1.90) mg/24 h, P<0.01]. The kidney hypertrophy index (KWI) was significantly increased in the model rats compared to controls (P <0.05). Moreover, the diabetic model rats showed glomerular hypertrophy, foot process effacement, micro villous transformation, glomerular basement membrane (GBM) thickening. Conclusion A rat model is successfully established, which presents typical features of human type 2 diabetes and can be served as an ideal model to study the diabetic nephropathy.