Transplantation of pancreatic islets to adrenal gland is promoted by agonists of growth-hormone-releasing hormone
Transplantation of pancreatic islets to adrenal gland is promoted by agonists of growth-hormone-releasing hormone
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DOI：
10.1073/pnas.1221505110
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发表时间：
2013-02-05
影响因子：
11.1
通讯作者：
Ludwig, Barbara
中科院分区：
文献类型：
--
作者：
Schubert, Undine;Schmid, Janine;Ludwig, Barbara
在这里，我们评估了一种替代的方法，预处理胰岛移植前使用一种有效的促生长激素释放激素（GHRH），以促进胰岛的活力和功能，我们探索肾上腺作为替代移植部位胰岛植入。肾上腺的内分泌微环境代表了一个有前途的利基市场，具有异常高氧张力和局部抗炎和免疫抑制特性的独特优势。GHRH激动剂已被证明可以促进胰岛移植物的存活和功能，这可能有助于减少逆转糖尿病所需的胰岛质量。在本研究中，最有效的GHRH激动剂MR403在体外对胰岛素瘤细胞、分离的大鼠胰岛和肾上腺β细胞共培养物进行了测试。GHRH受体在肾上腺细胞和胰岛上均有表达。MR403引起细胞活力和增殖的显着增加，并揭示了对胰岛素瘤细胞的抗凋亡作用。用激动剂处理后，大鼠胰岛的活力增加，并与肾上腺细胞共培养。将大鼠胰岛移植到糖尿病小鼠的肾上腺内移植部位，并与肾包膜下的经典移植进行比较。移植物的功能和整合通过代谢随访和肾上腺内移植物的免疫组织化学染色进行测试。两种模型中的血糖水平均迅速下降，所有动物在移植后的第一天内均达到正常血糖。我们的研究表明，肾上腺可能是一个有吸引力的网站胰岛移植和GHRH类似物可能允许减少胰岛质量需要扭转糖尿病状态。
Here, we evaluate an alternative approach of preconditioning pancreatic islets before transplantation using a potent agonist of growth-hormone-releasing hormone (GHRH) to promote islet viability and function, and we explore the adrenal gland as an alternative transplantation site for islet engraftment. The endocrine microenvironment of the adrenal represents a promising niche with the unique advantages of exceptional high oxygen tension and local anti-inflammatory and immunosuppressive properties. GHRH agonists have been shown to promote islet graft survival and function, which may help to reduce the islet mass necessary to reverse diabetes. In the present study, the most potent GHRH agonist MR403 was tested on insulinoma cells, isolated rat islets, and adrenal beta-cell cocultures in vitro. GHRH receptor is expressed on both adrenal cells and islets. MR403 caused a significant increase in cell viability and proliferation and revealed an antiapoptotic effect on insulinoma cells. Viability of rat islets was increased after treatment with the agonist and in coculture with adrenal cells. Rat islets were transplanted into diabetic mice to the intraadrenal transplant site and compared with the classical transplants underneath the kidney capsule. Graft function and integration were tested by metabolic follow-up and immunohistochemical staining of intraadrenal grafts. A rapid decrease occurred in blood glucose levels in both models, and all animals reached normoglycemia within the first days after transplantation. Our studies demonstrated that the adrenal may be an attractive site for islet transplantation and that GHRH analogs might allow reduction of the islet mass needed to reverse a diabetic status.