Dipeptidyl peptidase IV inhibition with MK0431 improves islet graft survival in diabetic NOD mice partially via T-cell modulation.
Dipeptidyl peptidase IV inhibition with MK0431 improves islet graft survival in diabetic NOD mice partially via T-cell modulation.
复制标题
DOI：
10.2337/db08-1101
复制
发表时间：
2009-03
期刊：
影响因子：
7.7
通讯作者：
McIntosh, Christopher H. S.
中科院分区：
文献类型：
--
作者：
Kim, Su-Jin;Nian, Cuilan;Doudet, Doris J.;McIntosh, Christopher H. S.
目的：研究表明，内肽酶二肽基肽酶- iv （DPP-IV）可在nh2末端截断肠促胰岛素激素、葡萄糖依赖性胰岛素性多肽和胰高血糖素样肽-1，从而削弱它们增强葡萄糖刺激胰岛素分泌的能力。因此，通过给予DPP-IV抑制剂来增加肠促胰岛素的循环水平已被引入作为治疗2型糖尿病的一种治疗方法。DPP-IV抑制剂治疗也被证明可以保护1型糖尿病啮齿动物模型中的胰岛质量。目前的研究旨在确定DPP-IV抑制剂西格列汀（MK0431）对非肥胖糖尿病（NOD）小鼠（一种自身免疫性1型糖尿病模型）移植胰岛存活的影响。研究设计和方法：通过代谢研究和微正电子发射断层扫描成像，研究MK0431对糖尿病NOD小鼠胰岛移植存活的影响，并评估其潜在的分子机制。结果：在胰岛移植前后用MK0431治疗NOD小鼠可延长胰岛移植存活，而在移植后单独治疗与未治疗对照组相比，有益效果较小。随后的研究表明，MK0431预处理可降低糖尿病NOD小鼠的胰岛素炎症，并减少离体脾CD4+ t细胞的体外迁移。此外，用DPP-IV体外处理脾CD4+ t细胞可导致蛋白激酶A （PKA）和Rac1的迁移和活化增加。结论：MK0431通过cAMP/PKA/Rac1激活途径减少CD4+ t细胞归巢到胰腺β细胞，从而部分降低自身免疫对移植物存活的影响。
OBJECTIVE—The endopeptidase dipeptidyl peptidase-IV (DPP-IV) has been shown to NH2-terminally truncate incretin hormones, glucose-dependent insulinotropic polypeptide, and glucagon-like peptide-1, thus ablating their ability to potentiate glucose-stimulated insulin secretion. Increasing the circulating levels of incretins through administration of DPP-IV inhibitors has therefore been introduced as a therapeutic approach for the treatment of type 2 diabetes. DPP-IV inhibitor treatment has also been shown to preserve islet mass in rodent models of type 1 diabetes. The current study was initiated to define the effects of the DPP-IV inhibitor sitagliptin (MK0431) on transplanted islet survival in nonobese diabetic (NOD) mice, an autoimmune type 1 diabetes model. RESEARCH DESIGN AND METHODS—Effects of MK0431 on islet graft survival in diabetic NOD mice were determined with metabolic studies and micropositron emission tomography imaging, and its underlying molecular mechanisms were assessed. RESULTS—Treatment of NOD mice with MK0431 before and after islet transplantation resulted in prolongation of islet graft survival, whereas treatment after transplantation alone resulted in small beneficial effects compared with nontreated controls. Subsequent studies demonstrated that MK0431 pretreatment resulted in decreased insulitis in diabetic NOD mice and reduced in vitro migration of isolated splenic CD4+ T-cells. Furthermore, in vitro treatment of splenic CD4+ T-cells with DPP-IV resulted in increased migration and activation of protein kinase A (PKA) and Rac1. CONCLUSIONS—Treatment with MK0431 therefore reduced the effect of autoimmunity on graft survival partially by decreasing the homing of CD4+ T-cells into pancreatic β-cells through a pathway involving cAMP/PKA/Rac1 activation.
登录
查看更多内容
影响因子：
4.8
作者：
Ehses, JA;Casilla, VR;McIntosh, CHS
通讯作者：
McIntosh, CHS
DOI：
10.1073/pnas.0507072102
发表时间：
2005-10-04
影响因子：
11.1
作者：
Howe, AK;Baldor, LC;Hogan, BP
通讯作者：
Hogan, BP
影响因子：
4.8
作者：
Kim, SJ;Choi, WS;McIntosh, CHS
通讯作者：
McIntosh, CHS
影响因子：
7.7
作者：
Kim, Su-Jin;Nian, Cuilan;McIntosh, Christopher H. S.
通讯作者：
McIntosh, Christopher H. S.
影响因子：
16.2
作者：
Aschner, Pablo;Kipnes, Mark S.;Williams-Herman, Debora E.
通讯作者：
Williams-Herman, Debora E.