目的 比較6種常見(jiàn)2型糖尿病動(dòng)物模型的生化指標(biāo)和胰島、肝臟的組織病理學(xué)改變。方法 大鼠、小鼠各32只，隨機(jī)分為8組：大鼠對(duì)照組、大鼠高脂高糖+四氧嘧啶組、大鼠高脂高糖+鏈脲佐菌素組、ZDF大鼠組、小鼠對(duì)照組、db/db小鼠組、ob/ob小鼠組和KK-ay小鼠組。制備2型糖尿病模型：高脂高糖+四氧嘧啶組和高脂高糖+鏈脲佐菌素組，喂飼高脂高糖飼料6周后，分別ip 1次150 mg/kg劑量的四氧嘧啶和30 mg/kg的鏈脲佐菌素，ZDF大鼠飼喂Purina#5008飼料6周；C57BL、db/db和ob/ob小鼠普通飼料、KK-ay小鼠高脂料喂養(yǎng)8周。每周測(cè)定體質(zhì)量；腹主動(dòng)脈取血，全自動(dòng)生化分析儀測(cè)定血清空腹血糖（FBG）、膽固醇（TC）、三酰甘油（TG）、低密度脂蛋白膽固醇（LDL）和高密度脂蛋白膽固醇（HDL），Elisa法檢測(cè)血清中空腹胰島素（FINS）水平。剖取胰腺、肝臟進(jìn)行HE染色，于光學(xué)顯微鏡下觀察組織病理學(xué)變化。結(jié)果 與對(duì)照組比較，高脂高糖+四氧嘧啶及高脂高糖+鏈脲佐菌素組大鼠體質(zhì)量增長(zhǎng)幅度更大；ZDF大鼠組體質(zhì)量緩慢降低；血脂、血糖和胰島素測(cè)定結(jié)果顯示，與大鼠對(duì)照組比較，高脂高糖+四氧嘧啶組和高脂高糖+鏈脲佐菌素組FBG、TC、TG均顯著升高（P<0.01），F(xiàn)INS顯著降低（P<0.01）；ZDF大鼠組FBG、TC、TG、HDL和FINS均顯著升高（P<0.05、0.01）。與小鼠對(duì)照組比較，db/db、ob/ob、KK-ay小鼠組FBG、TC、TG、HDL、LDL和FINS均顯著升高（P<0.05、0.01）（其中db/db小鼠LDL除外）。組織病理學(xué)檢查結(jié)果顯示，與大鼠對(duì)照組比較，高脂高糖+四氧嘧啶組與高脂高糖+鏈脲佐菌素組胰島萎縮，體積減小，數(shù)量減少，分布稀疏，形態(tài)極不規(guī)則，胰島細(xì)胞空泡樣變，數(shù)目減少，β細(xì)胞壞死凋亡；肝臟可見(jiàn)不同程度的肝細(xì)胞空泡變性；ZDF大鼠組胰島萎縮，體積減小，形狀不規(guī)則，邊界不清，炎細(xì)胞浸潤(rùn)，纖維組織增生，島內(nèi)β細(xì)胞凋亡，形態(tài)不清，排列紊亂；輕微至輕度肝細(xì)胞空泡變性。與小鼠對(duì)照組比較，db/db、ob/ob、KK-ay小鼠組均可見(jiàn)胰島增生、肥大，島內(nèi)β細(xì)胞核增多、密集，胞漿減少，排列紊亂；中至重度肝細(xì)胞空泡變性。結(jié)論 6種大鼠2型糖尿病模型糖脂代謝紊亂，可致肝臟空泡變性和胰島的病理改變。其中3種大鼠2型糖尿病模型可致胰島的退行性病變，3種小鼠2型糖尿病早期模型可致胰島的代償性增生肥大的病變。

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

國(guó)家科技重大新藥創(chuàng)制項(xiàng)目（2015ZX09501004）