Induction, maintenance, and reversal of streptozotocin-induced insulin-dependent diabetes mellitus in the juvenile cynomolgus monkey (Macaca fascilularis)
Induction, maintenance, and reversal of streptozotocin-induced insulin-dependent diabetes mellitus in the juvenile cynomolgus monkey (Macaca fascilularis)
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DOI：
10.1097/00007890-199908150-00003
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发表时间：
1999-08-15
期刊：
影响因子：
6.2
通讯作者：
Padrid, PA
中科院分区：
文献类型：
--
作者：
Theriault, BR;Thistlethwaite, JR;Padrid, PA
背景：胰岛素依赖型糖尿病(IDDM)是儿童第二常见的慢性病。由于缺乏可重复性和易维护的非人类灵长类疾病模型，阻碍了对IDDM治疗的研究。11只幼年食蟹猴静脉注射链脲佐菌素(STZ)150 mg/kg后诱发IDDM，所有糖尿病猴均采用滑动标尺每日两次胰岛素治疗。每只猴子的皮下血管通路都被外科手术放置，以便于连续采血和给药。来自无关供者的同种异体胰岛细胞随后被移植到所有注射STZ的猴的肠系膜循环中。结果注射STZ后，所有动物都出现了轻微的一过性恶心和呕吐，但没有出现额外的毒性迹象。在36小时内，所有猴子每天需要注射两次外源性胰岛素以维持非酮症状态。血清C-肽水平从STZ前的1.2 ng/ml降至STZ后的0.0~0.9 ng/ml，证实胰岛细胞被破坏。动物处于胰岛素依赖状态长达147天，无任何明显的临床并发症，皮下血管通畅长达136天，仅有一例局部感染。胰岛细胞移植后24小时内血糖正常，免疫功能正常动物移植后6~8天血清C肽水平升高(2~8 ng/ml)，免疫抑制猴移植后39~98天血清C肽水平升高。IDDM可以在幼年食蟹猴身上持续地诱导和安全地治疗。慢性血管通路可以在最少的监督和并发症的情况下维持。该模型适用于研究包括胰岛细胞移植在内的IDDM的潜在治疗方法。
Background, Insulin-dependent diabetes mellitus (IDDM) is the second most prevalent chronic illness of children. Investigation of the treatment of IDDM is hindered by the lack of a reproducible and easily maintained non-human primate model of this disorder.Methods. We induced IDDM in 11 juvenile cynomolgus monkeys after a single (150 mg/kg) intravenous injection of streptozotocin (STZ), All diabetic monkeys were treated with insulin twice daily, based on a sliding scale. Subcutaneous vascular access ports were surgically placed in each monkey to facilitate serial blood sampling and drug administration. Allogeneic pancreatic islet cells from unrelated donors were subsequently transplanted into the mesenteric circulation of all STZ-treated monkeys.Results, Mild, transient nausea and vomiting occurred in all animals after STZ injection; however, no additional signs of toxicity occurred. Within 36 hr, all monkeys required twice daily administration of exogenous insulin to maintain a non-ketotic state. Serum C-peptide levels decreased from >1.2 ng/ml before STZ, to between 0.0 and 0.9 ng/ml after STZ, confirming islet cell destruction. Animals were maintained in an insulin-dependent state for up to 147 days without any observable clinical complications, Subcutaneous vascular access port patency was maintained up to 136 days with a single incidence of local infection. Islet cell transplantation resulted in normoglycemia within 24 hr, Serum C-peptide levels increased (range: 2-8 ng/ml) for 6-8 days in immune competent animals, and for 39-98 days after transplant in immunosuppressed monkeys.Conclusions. IDDM can be consistently induced and safely treated in juvenile cynomolgus monkeys. Chronic vascular access can be maintained with minimal supervision and complications. This model is appropriate for studies investigating potential treatments for IDDM including islet cell transplantation.