Liu Zhengzhao, Lu Ying, Hu Wenbao, Hara Hidetaka, Dai Yifan, Cai Zhiming, Mou Lisha
Shenzhen Xenotransplantation Medical Engineering Research and Development Center Institute of Translational Medicine Shenzhen Second People's Hospital The First Affiliated Hospital of Shenzhen University Health Science Center Shenzhen China.
Movement System Injury and Repair Research Center Xiangya Hospital of Central South University Changsha China.
Animal Model Exp Med. 2020 Mar 20;3(1):79-86. doi: 10.1002/ame2.12109. eCollection 2020 Mar.
Streptozotocin (STZ)- induced diabetic monkey is a wide used preclinical animal model for the investigation of diabetes such as islet transplantation and development of diabetic drugs. There are serious side effects of this method, including nausea, emesis, weight loss, liver damage, renal failure, and metabolic acidosis. In order to reduce the side effects, diabetic monkeys were induced using clinical-grade STZ. However, clinical-grade STZ is not available in China. Here, we establised a method by using 100 mg/kg analytical-grade STZ to induce complete diabetes in cynomolgus monkey without generating adverse effects to liver and renal.
Three cynomolgus monkeys were used in this study. 100 mg/kg STZ dissolved in normal saline and infused through vein line in 5 minutes after indwelling catheter in the carotid artery and jugular vein. After the STZ administration, blood glucose levels were examined every 1 or 2 hours in the first 48 hours. Then, blood glucose levels were examined twice per day during the first week after the STZ injection. Insulin and C-peptide levels were measured by ELISA. Blood chemistry of hepatic and renal function tests were performed. Insulin and glucagon expression in the islet of diabetic monkey and normal monkey were examined by immunohistochemistry assays.
The stimulated C-peptide level (Intravenous glucose tolerance test) which is less than 0.5 ng/mL, the triphasic blood glucose response and the destroyed β cell suggested the complete induction of diabetes model. No apparent adverse effects were observed including no signs of vomiting and toxicity after STZ injection.
In summary, we established a safe and reproducible STZ-induced diabetic cynomolgus monkey model for islet transplantation which will be used to develop novel approaches for the treatment of diabetes.
链脲佐菌素（STZ）诱导的糖尿病猴是一种广泛应用于临床前研究糖尿病的动物模型，用于胰岛移植和糖尿病药物研发等研究。该方法存在严重的副作用，包括恶心、呕吐、体重减轻、肝损伤、肾衰竭和代谢性酸中毒。为了减少副作用，采用临床级STZ诱导糖尿病猴。然而，临床级STZ在中国无法获得。在此，我们建立了一种使用100mg/kg分析级STZ诱导食蟹猴完全糖尿病的方法，且对肝脏和肾脏无不良影响。
本研究使用了3只食蟹猴。将100mg/kg STZ溶解于生理盐水中，在颈总动脉和颈静脉留置导管后5分钟内通过静脉输注。给予STZ后，在最初的48小时内每1或2小时检测一次血糖水平。然后，在注射STZ后的第一周内每天检测两次血糖水平。通过ELISA检测胰岛素和C肽水平。进行肝功能和肾功能的血液化学检测。通过免疫组织化学分析检测糖尿病猴和正常猴胰岛中胰岛素和胰高血糖素的表达。
刺激后的C肽水平（静脉葡萄糖耐量试验）低于0.5ng/mL、三相血糖反应以及β细胞破坏提示糖尿病模型诱导完全。未观察到明显的不良反应，包括注射STZ后无呕吐和毒性迹象。
总之，我们建立了一种安全且可重复的STZ诱导的糖尿病食蟹猴模型用于胰岛移植，该模型将用于开发治疗糖尿病的新方法。
