目的 比较6种常见2型糖尿病动物模型的生化指标和胰岛、肝脏的组织病理学改变。方法 大鼠、小鼠各32只，随机分为8组：大鼠对照组、大鼠高脂高糖+四氧嘧啶组、大鼠高脂高糖+链脲佐菌素组、ZDF大鼠组、小鼠对照组、db/db小鼠组、ob/ob小鼠组和KK-ay小鼠组。制备2型糖尿病模型：高脂高糖+四氧嘧啶组和高脂高糖+链脲佐菌素组，喂饲高脂高糖饲料6周后，分别ip 1次150 mg/kg剂量的四氧嘧啶和30 mg/kg的链脲佐菌素，ZDF大鼠饲喂Purina#5008饲料6周；C57BL、db/db和ob/ob小鼠普通饲料、KK-ay小鼠高脂料喂养8周。每周测定体质量；腹主动脉取血，全自动生化分析仪测定血清空腹血糖（FBG）、胆固醇（TC）、三酰甘油（TG）、低密度脂蛋白胆固醇（LDL）和高密度脂蛋白胆固醇（HDL），Elisa法检测血清中空腹胰岛素（FINS）水平。剖取胰腺、肝脏进行HE染色，于光学显微镜下观察组织病理学变化。结果 与对照组比较，高脂高糖+四氧嘧啶及高脂高糖+链脲佐菌素组大鼠体质量增长幅度更大；ZDF大鼠组体质量缓慢降低；血脂、血糖和胰岛素测定结果显示，与大鼠对照组比较，高脂高糖+四氧嘧啶组和高脂高糖+链脲佐菌素组FBG、TC、TG均显著升高（P<0.01），FINS显著降低（P<0.01）；ZDF大鼠组FBG、TC、TG、HDL和FINS均显著升高（P<0.05、0.01）。与小鼠对照组比较，db/db、ob/ob、KK-ay小鼠组FBG、TC、TG、HDL、LDL和FINS均显著升高（P<0.05、0.01）（其中db/db小鼠LDL除外）。组织病理学检查结果显示，与大鼠对照组比较，高脂高糖+四氧嘧啶组与高脂高糖+链脲佐菌素组胰岛萎缩，体积减小，数量减少，分布稀疏，形态极不规则，胰岛细胞空泡样变，数目减少，β细胞坏死凋亡；肝脏可见不同程度的肝细胞空泡变性；ZDF大鼠组胰岛萎缩，体积减小，形状不规则，边界不清，炎细胞浸润，纤维组织增生，岛内β细胞凋亡，形态不清，排列紊乱；轻微至轻度肝细胞空泡变性。与小鼠对照组比较，db/db、ob/ob、KK-ay小鼠组均可见胰岛增生、肥大，岛内β细胞核增多、密集，胞浆减少，排列紊乱；中至重度肝细胞空泡变性。结论 6种大鼠2型糖尿病模型糖脂代谢紊乱，可致肝脏空泡变性和胰岛的病理改变。其中3种大鼠2型糖尿病模型可致胰岛的退行性病变，3种小鼠2型糖尿病早期模型可致胰岛的代偿性增生肥大的病变。

Objective The biochemical indexes and the histopathological changes of islet and liver in six common type 2 diabetic animal models were compared, providing help for the related experimental research of type 2 diabetes. Method Rats and mice of each 32, divided into eight groups, eight rats in each group, including control group of rats (SD rats), high fat and high glucose+ALX group (SD rats), high fat and high glucose+STZ group (SD rats), ZDF rats, control group of mice (C57BL mice), db/db mice, ob/ob mice and KK-ay mice. Type 2 diabetes mellitus models were established:rats in high fat and high glucose + ALX group and high fat and high glucose + STZ group were fed with high fat and high glucose diet for six weeks, and following with once ip of 150 mg/kg of ALX and 30 mg/kg of STZ, respectively, ZDF rats were fed with Purina#5008 diet for six weeks; C57BL, DB/DB and ob/ob mice were fed with normal diet and KKay mice were fed with high-fat diet for eight weeks. Fasting blood glucose (FBG), fasting insulin (FINS),TC, TG, HDL, LDL were measured in the anterior abdominal aorta, and the pathomorphological observation of the pancreas and liver was taken. Result The results of body weight measurement showed that:during the experiment, the body weight increased significantly in the control group of rats, high fat and high glucose+ALX group, high fat and high glucose+STZ group, and decreased slowly in the ZDF group; the body weight increased slowly in the control group of mice, db/db mice group, the ob/ob mice group and the KK-ay mice group.The results of blood lipid,blood glucose and fasting insulin showed that:compared with the control group of rats, FBG, TC and TG in high fat and high glucose+ALX group and high fat and high glucose+STZ group were significantly increased (P<0.01), FINS were significantly decreased (P<0.01); FBG, TC, TG,HDL and FINS in ZDF group were significantly increased (P<0.05、0.01). Compared with the control group of mice, the FBG, TC, TG, HDL, LDL and FINS in the db/db mice, the ob/ob mice and the KK-ay mice increased significantly (P<0.05,0.01). (except for the LDL value of db/db mice). The histopathological findings showed that, compared with the control group of rats, high fat and high glucose+ALX group and high fat and high glucose+STZ group islet atrophy, shape is irregular, sparse distribution, islet cell vacuolar degeneration, necrosis and apoptosis of beta cells; liver showed different degrees of liver cell degeneration; In the ZDF group, the islets were irregular in shape, unclear in boundary, inflammatory cell infiltration, fibrous tissue hyperplasia, apoptosis in the island cells, unclear morphology, disorder in arrangement, slight to mild vacuolar degeneration of hepatocytes. Compared with C57BL mice, db/db mice, ob/ob mice and KK-ay mice showed islet hyperplasia and hypertrophy, increased beta cells, decreased cytoplasm and arranged disorder; moderate to severe hepatocyte vacuolar degeneration. Conclusion The metabolic disorder of glucose and lipid in the six models of type 2 diabetic rats could lead to hepatic vacuolation and the pathological changes of islets. Among them, three kinds of rat models of type 2 diabetes can cause the degeneration of islets, and the early models of type 2 diabetes in three mice can cause compensatory hyperplasia and hypertrophy of the islets.

R965.1

国家科技重大新药创制项目（2015ZX09501004）