实验恒河猴糖尿病动物模型建立及视网膜并发症的研究

作者:代解杰;孙晓梅;匡德宣;高家红;唐东红;叶尤松;仝品芬;江勤芳 刊名:中国实验动物学报 上传者:杨柳

【摘要】[Objective] To study the development, prevention and cure of diabetes mellitus, we established the experimental diabetic animal models by streptozotocin (STZ)-induced in rhesus monkeys. This disease animal model is useful for evaluation of security and effectivity of treating diabetic disease drugs. [Methods] Nine mature male rhesus monkeys were be randomly assigned three groups (1 animal, high-dosage group, 60mg/kg STZ; 3 animals, mid-dosage group, 45mg/kg STZ; 3 animals, low-dosage group, 30mg/kg STZ, and 2 animals in control group ), the experimental animals were injected intravenously with different doses of STZ. For diabetic monkeys, to test water intake、food intake and urine every day, to test body weight, blood glucose, urine glucose every week, to test TG、Chol、HDL、GHb、insulin、C-peptide、biochemical index of urine and IV-GTT (Intravenous glucose tolerance test) every month,and to detect clinical index of diabetic monkeys and the development of diabetes mellitus. The diabetic animals were observed the pathological changes of eyeground.and histopathological observation of their heart, kidney, pancreas and spleen. [Results] The seven animals in experimental groups compared with two animals in control group, which showed the same clinical features as those of diabetes mellitus patients at a different time and extent, such as polyphagia, polydipsia, polyuria, hyperglycemia, hyperglycosuria and body weight loss. The 7/9 animals insulin and C- peptide were reduced obviously, but the clinical characteristics in 7/9 animals were lighten and controlled by using insulin, especially the animal clinical symptoms of mid-dosage and high-dosage of STZ were more obvious than those in low-dosage group animals . The body weight in low-dosage group animals rose in a short time, then dropped rapidly. Plasma glucose and glycosuria of animals in experimental groups were increased with STZ injection, especially, which of the animals in mid-dosage and high--dosage group varied obviously. All clinical characteristics and histopathological study in 7/9 animals showed obviously diabetic disease after STZ-inducing. All of 7/9 the animals were induced animal models of the Insulin Dependent Diabetes Mellitus (IDDM) and the state of chronic hyperglycemia (SCH), these diabetic monkeys had long-term higher preprandial plasma glucose, they showed tiny blood vessel dilation in eyeground, early retinal hemorrhage dot, tiny angioma and cataract, They were resulted in different extent diabetic retinopathy after inducing STZ among 63-91day. [Conclusion] The study showed that rhesus monkeys were resulted in IDDM disease animal model after STZ-inducing, otherwise, the rhesus monkeys were induced with 60mg/kg and 45 mg/kg STZ, they resulted in rapidly diabetes mellitus animal model, which clinical characteristic resembled human IDDM disease. The rhesus monkeys were induced with 30mg/kg STZ, they resulted in animal model of diabetic retinopathy complication disease after 2-3 months, it was useful on studying the mechanism of diabetes mellitus and it's complication, meanwhile it was significant for observing the effective, safety of the diabetic drugs instead of human being.

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实际上 ,现在所有欧洲国家新安装的设施、设备 ,包括世界上许多其它地区都已经接受了尚未得到正式批准的 ETS 123 草案。 实验恒河猴糖尿病动物模型建立及视网膜并发症的研究 代解杰  孙晓梅  匡德宣  高家红  唐东红  叶尤松  仝品芬  江勤芳中国医学科学院Π中国协和医科大学 医学生物学研究所 ,昆明  560118[ 目的]  糖尿病是由于多种因素和遗传因素导致体内胰岛素相对或绝对分泌不足 ,而引起的代谢性内分泌疾病 ,它以血糖、尿糖升高为特点 ,起病隐蔽 ,通过并发症使人致残致死 ,是继心血管、癌症之后的第三大致死性疾病 ,很可能成为 21 世纪人类的“第一杀手” (1 ,2) 。本文采用人工诱导的方法 ,建立恒河猴糖尿病动物模型 ,研究糖尿病疾病的发展和及其并发症的发生、发展规律和防治措施 ,同时对于治疗糖尿病新药的安全性评价和药物疗效的观察具有广阔的运用前景。[方法]  选用成熟的、健康的、雄性恒河猴 9 只 ,随机分成三个组 ,其中高剂量组(60mgΠkg) 1 只 ,中剂量组(45mgΠkg) 3 只 , 低剂量组(30mgΠkg) 3 只和对照组 2 只 ,静 脉注射链脲佐菌素(STZ,streptozotocin) ,定时检测动物血糖、尿糖、尿蛋白、胰岛素、 C2肽、特殊的血液生化值、静脉葡萄糖耐量试验(IV. GTT)和详细记录动物的摄食量、饮水量、排尿量及体重的变化等与糖尿病相关的 临床指标 ,并 对模型动物进行组织病理学检查。对于已成糖尿病模型的动物 ,随时观察眼底变化 ,必要时做眼底镜检查和视网膜荧光血管造影 ,以诊断动物糖尿病并发视网膜病变疾病 ,并分析其疾病发生原因及发展规律。[结果]  用不同剂量的 STZ静脉注射 7 只恒河猴后 ,不同程度地引起胰腺β细胞上的 ADP 核糖体合成酶损伤 ,胰腺β细胞数量明显减少 ,造成胰岛素分泌减少。同时引起体内糖、脂肪和蛋白质代谢紊乱 ,导致糖尿病(3 ,4 ,5) 疾病。实验组的 7 只猴在给药 1 月后摄食量、饮水量、排尿量均明显增加 ,体重减少 1Kg 左右 , “三多一少”症状显著 ,且有嗜睡、消瘦、四肢无力等临床症状 ;血糖值(20 - 45mmolL) 、尿糖值、糖化血红蛋白 值(3 - 4mmolL)显著增加 ,而胰岛素和 C2肽则明显下降 ,尿中免疫球蛋白(4 - 6. 3mgΠdl) 、α 12微球蛋白(1 - 1.3mgdl) , 白蛋白(1. 3mgdl) 、食量与对照组相比明显增加 ,其中高剂量组的动物在给药后第 108 天出现尿酮。 实验组的动物甘油三酯、胆固醇在给药后 2 月平均增加 1mmolΠL ,而脂蛋白则有所下降。值得注意的是低剂 量组(30mgΠkg)与高剂量组(60mgΠkg)相比 ,糖尿病临床指标及症状出现得晚一些 ,并且程度没有高剂量组的 严重 ,主要是 STZ部分损伤胰腺β细胞 ,出现慢性持续性高血糖 ,血糖值在 15 - 25mmolΠL 范围可持续 1 个月 左右。同时在 2 个月后出现早期眼底微血管动脉扩张或出血点 ,而引发白内障及其它糖尿病并发症。在不采取治疗措施的情况下 ,低剂量组中的 3 只猴在 5 月后已产生了晚期白内障 ,动物存活周期较长可达 2 年以上 ;而高剂量组的动物则存活周期短(在 1 年左右) ,不利开展糖尿病并发症的研究 ,并表现出 1 型糖尿病的特征 ,而低剂量组的动物能否成为 2 型糖尿病模型有待进一步研究。[结论]本研究通过 STZ人工诱导恒河猴 ,引起动物发生持续性血糖升高 ,胰岛素和 C2

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