New mouse model to study islet transplantation in insulin-dependent diabetes mellitus
New mouse model to study islet transplantation in insulin-dependent diabetes mellitus
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DOI：
10.1097/00007890-200204270-00024
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发表时间：
2002-04-27
期刊：
影响因子：
6.2
通讯作者：
Leiter, EH
中科院分区：
文献类型：
--
作者：
Mathews, CE;Langley, SH;Leiter, EH
背景糖尿病啮齿类动物的胰岛移植研究经常使用致糖尿病药物（如四氧嘧啶或链脲佐菌素）治疗，以使宿主血糖升高。这些化学物质产生不必要的毒副作用，这使得高血糖症产生的损伤与直接毒素诱导的损伤的解释复杂化。自发发展胰岛素敏感型糖尿病而没有β细胞自身免疫的小鼠将为测试β细胞替代方案提供极好的载体。Ins 2（秋田）突变破坏正常的胰岛素加工并引起成熟胰岛素分泌的失败，这导致高血糖症的早期发展。本报告检测了携带Ins 2（秋田）的小鼠的胰岛素敏感性及其对同基因胰岛移植的反应性。给予10周龄的C57 BL/6 J-Ins 2（秋田/+）雄性1单位胰岛素以测定胰岛素敏感性。此外，10周龄高血糖B6-Ins 2（秋田/+）在肾包膜下接受了从同基因C57 BTL/6 J雄性（n=7）或异基因BALB/cJ雄性（n=5）分离的400个胰岛。这些小鼠在移植后随访8周或直至肿瘤缓解。对保持血糖正常的小鼠进行含移植肾的肾切除术。然后对这些小鼠进行2周的高血糖恢复随访。B6-Ins 2（秋田/+）小鼠是胰岛素响应性的。高血糖B6-Ins 2（秋田/+）雄性小鼠的胰岛素治疗在1小时内显著降低了血糖值。此外，同系胰岛移植物的B6-Ins 2（秋田/+）受体在不到72小时内逆转了其糖尿病状态。这些胰岛移植小鼠在移除含移植物的肾脏之前血糖保持正常。移除移植物导致高血糖症复发。接受同种异体移植物的小鼠有效地排斥移植物。我们的数据支持B6-Ins 2（秋田/+）小鼠是胰岛素敏感的并且为胰岛移植研究提供了极好的模型的假设。此外，减少的β-细胞质量和β-细胞自身免疫的缺乏，加上这些小鼠也排斥同种异体移植物的事实，表明这些小鼠可能用于各种其他应用，包括测试准备用于移植的人类胰岛的功能，也许还用于探索使用胰岛干细胞的β-细胞恢复疗法。
Background. Islet transplantation studies with diabetic rodents frequently use treatment with diabetogens such as alloxan or streptozotocin to render hosts hyperglycemic. These chemicals produce unwanted toxic side effects, which complicate interpretations of damage produced by hyperglycemia versus direct toxin-induced damage. A mouse that spontaneously developed insulin-sensitive diabetes without beta-cell autoimmunity would provide an excellent vehicle for testing beta-cell replacement protocols. The Ins2(Akita) mutation disrupts normal insulin processing and causes a failure in secretion of mature insulins, which results in the early development of hyperglycemia. This report examines the insulin sensitivity of mice that carry Ins2(Akita) and their responsiveness to engraftment with syngeneic pancreatic islets.Methods. Ten-week-old C57BL/6J-Ins2(Akita/+) males were given I unit of insulin to determine insulin sensitivity. Also, 10-week-old, hyperglycemic B6-Ins2(Akita/+) received either 400 islets isolated from syngeneic C57BTL/6J males (n=7) or from allogeneic BALB/cJ males (n=5) under the renal capsule. These mice were followed for 8 weeks after engraftment or until remission of euglycemia. Nephrectomy of the graft-containing kidney was performed on mice that remained euglycemic. These mice were then followed for 2 weeks for return of hyperglycemia.Results. B6-Ins2(Akita/+) mice are insulin responsive. Insulin treatment of hyperglycemic B6-Ins2(Akita/+) males significantly lowered blood glucose values within 1 hr. In addition, B6-Ins2(Akita/+) recipients of syngeneic islet grafts reversed their diabetic state in less than 72 hr. These islet-engrafted mice remained normoglycemic until removal of the graft-containing kidney. Removal of the graft resulted in a return to hyperglycemia. Mice that received allogeneic grafts efficiently rejected the graft.Conclusions. Our data support the hypothesis that B6-Ins2(Akita/+) mice are insulin sensitive and provide an excellent model for islet transplantation studies. In addition, the reduced beta-cell mass and the absence of beta-cell autoimmunity, coupled to the fact that these mice also reject allografts, suggest that these mice may be useful for a variety of other applications, including testing functionality of human islets prepared for transplantation and perhaps also for exploring beta-cell restorative therapy using pancreatic islet stem cells.