Beneficial effect of insulin treatment on islet transplantation outcomes in Akita mice.
Beneficial effect of insulin treatment on islet transplantation outcomes in Akita mice.
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DOI：
10.1371/journal.pone.0095451
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Kume S
中科院分区：
文献类型：
--
作者：
Kikawa K;Sakano D;Shiraki N;Tsuyama T;Kume K;Endo F;Kume S
胰岛移植是治疗1型糖尿病的一种很有前途的治疗方法。胰岛移植的结果取决于移植足够量的β细胞团。然而，移植后胰岛的初始损失是有问题的。我们假设受体的高血糖状态可能会对移植物存活产生负面影响。因此，在本研究中，我们评估了胰岛素治疗对秋田小鼠胰岛移植的影响，所述小鼠是具有胰岛素2基因错义突变的糖尿病模型小鼠，所述胰岛移植涉及次优量的胰岛。将50个胰岛移植到接受或未接受胰岛素治疗的受体小鼠的左肾包膜下。对于胰岛素治疗，在移植前2周将缓释胰岛素植入物皮下植入受体小鼠并维持4周。不加胰岛素治疗的胰岛移植不能逆转高血糖。相比之下，接受移植联合胰岛素治疗的组在移植后18周内表现出空腹血糖水平的改善，即使在胰岛素治疗停止后也是如此。接受胰岛移植联合胰岛素治疗的组比未接受胰岛素治疗的组具有更好的糖耐量。胰岛素治疗从急性期（即，移植后1天）至慢性期（即，移植后18周）。在体外培养和体内移植实验中，胰岛细胞凋亡随着培养基或血液中葡萄糖浓度的增加而增加。移植物的表达谱分析表明，与免疫反应，趋化性和炎症反应相关的基因被特异性上调时，胰岛移植到小鼠与高血糖症相比，那些与正常血糖症。因此，结果表明，胰岛素治疗保护胰岛免于移植后通常观察到的初始快速损失，并对秋田小鼠中胰岛移植的结果产生积极影响。
Islet transplantation is a promising potential therapy for patients with type 1 diabetes. The outcome of islet transplantation depends on the transplantation of a sufficient amount of β-cell mass. However, the initial loss of islets after transplantation is problematic. We hypothesized the hyperglycemic status of the recipient may negatively affect graft survival. Therefore, in the present study, we evaluated the effect of insulin treatment on islet transplantation involving a suboptimal amount of islets in Akita mice, which is a diabetes model mouse with an Insulin 2 gene missense mutation. Fifty islets were transplanted under the left kidney capsule of the recipient mouse with or without insulin treatment. For insulin treatment, sustained-release insulin implants were implanted subcutaneously into recipient mice 2 weeks before transplantation and maintained for 4 weeks. Islet transplantation without insulin treatment did not reverse hyperglycemia. In contrast, the group that received transplants in combination with insulin treatment exhibited improved fasting blood glucose levels until 18 weeks after transplantation, even after insulin treatment was discontinued. The group that underwent islet transplantation in combination with insulin treatment had better glucose tolerance than the group that did not undergo insulin treatment. Insulin treatment improved graft survival from the acute phase (i.e., 1 day after transplantation) to the chronic phase (i.e., 18 weeks after transplantation). Islet apoptosis increased with increasing glucose concentration in the medium or blood in both the in vitro culture and in vivo transplantation experiments. Expression profile analysis of grafts indicated that genes related to immune response, chemotaxis, and inflammatory response were specifically upregulated when islets were transplanted into mice with hyperglycemia compared to those with normoglycemia. Thus, the results demonstrate that insulin treatment protects islets from the initial rapid loss that is usually observed after transplantation and positively affects the outcome of islet transplantation in Akita mice.
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