Induction of diabetes with signs of autoimmunity in primates by the injection of multiple-low-dose streptozotocin.
Induction of diabetes with signs of autoimmunity in primates by the injection of multiple-low-dose streptozotocin.
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DOI：
10.1016/j.bbrc.2011.07.105
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发表时间：
2011-08
影响因子：
3.1
通讯作者：
Ling-ling Wei;Yanrong Lu;Sirong He;Xi Jin;L. Zeng;Shuang Zhang;Younan Chen;B. Tian;G. Mai;Guang Yang;Jie Zhang;Li Wang;Hongxia Li;J. Markmann;Jingqiu Cheng;S. Deng
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作者：
Ling-ling Wei;Yanrong Lu;Sirong He;Xi Jin;L. Zeng;Shuang Zhang;Younan Chen;B. Tian;G. Mai;Guang Yang;Jie Zhang;Li Wang;Hongxia Li;J. Markmann;Jingqiu Cheng;S. Deng
目的建立自身免疫性糖尿病的临床前大动物模型，为自身免疫性糖尿病的转化研究提供实验依据。材料与方法用链脲佐菌素（STZ）多次低剂量（MLD）静脉注射，连续5d，间隔1 wk再加强注射STZ。通过常规代谢试验、胰岛反应性自身抗体的血清学评估和胰腺组织的组织学检查来评估自身免疫性糖尿病的诱导。所有糖尿病动物均表现出严重的葡萄糖耐量受损，胰岛功能受限，需要胰岛素治疗以维持相对正常的葡萄糖代谢和健康状态。血清学试验表明，所有糖尿病猴的胰岛素和胰岛抗原特异性自身抗体。此外，对糖尿病动物胰腺的组织学检查揭示了胰岛β细胞和T淋巴细胞浸润的胰岛的特异性破坏的证据。注射MLD-STZ可诱导幼年恒河猴发生显性和持续性糖尿病，对胰岛细胞的自身免疫反应可能参与了糖耐量异常和糖尿病的发生。这可以作为研究人类自身免疫性糖尿病的发病机制和潜在治疗的有价值的临床前模型。
AIMTo develop a preclinical large animal model of autoimmune diabetes to facilitate the translational research of autoimmune diabetes in human.MATERIALS AND METHODSNine young rhesus monkeys received multiple-low-dose (MLD) intravenous injections of streptozotocin for five consecutive days, followed by two additional boosting injections of STZ given 1week apart. The induction of autoimmune diabetes was evaluated by regular metabolic testing, serological assessment of islet-reactive autoantibodies and histological examination of pancreatic tissues.RESULTSSeven of nine treated animals became diabetic with moderate hyperglycemia initially and more severe hyperglycemia thereafter. All diabetic animals exhibited severely impaired glucose tolerance, limited islet function, and required insulin therapy to maintain relatively normal glucose metabolism and healthy status. Serological tests showed that all diabetic monkeys developed autoantibodies specifically against insulin and islet antigens. Furthermore, histological examination of the pancreata from diabetic animals revealed evidence of specific destruction of islet β cells and islets infiltrated with T lymphocytes. Overt and persistent diabetes can be induced in young rhesus monkeys by the injection of MLD-STZ, and autoimmune responses to pancreatic islet cells seem to be involved in the development of glucose intolerance and diabetes.CONCLUSIONThese data indicate for the first time that autoimmune diabetes can be induced in primates; this may serve as a valuable preclinical model for studying the pathogenesis of and potential therapies for autoimmune diabetes in humans.