Jin Long, Lim Sun Woo, Jin Jian, Chung Byung Ha, Yang Chul Woo
Convergent Research Consortium for Immunologic Disease, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea; Transplant Research Center, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.
Convergent Research Consortium for Immunologic Disease, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea; Transplant Research Center, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea; Division of Nephrology, Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.
Transl Res. 2016 Aug;174:122-39. doi: 10.1016/j.trsl.2016.03.012. Epub 2016 Mar 22.
The guideline for the management of new-onset diabetes after transplantation recommends metformin (MET) as a first-line drug, and addition of a second-line drug is needed to better control of hyperglycemia. We tested the effect of addition of a dipeptidyl peptidase IV (DPP IV) inhibitor to MET on sirolimus (SRL)-induced diabetes mellitus (DM). In animal model of SRL-induced DM, MET treatment improved pancreatic islet function (blood glucose level and insulin secretion) and attenuated oxidative stress and apoptotic cell death. Addition of a DPP IV inhibitor to MET improved these parameters more than MET alone. An in vitro study showed that SRL treatment increased pancreas beta cell death and production of reactive oxygen species (ROS), and pretreatment of ROS inhibitor, or p38MAPK inhibitor effectively decreased SRL-induced islet cell death. Exendin-4 (EXD), a substrate of DPP IV or MET significantly improved cell viability and decreased ROS production compared with SRL treatment, and combined treatment with the 2 drugs improved both parameters. At the subcellular level, impaired mitochondrial respiration by SRL were partially improved by MET or EXD and much improved further after addition of EXD to MET. Our data suggest that addition of a DPP IV inhibitor to MET decreases SRL-induced oxidative stress and improves mitochondrial respiration. This finding provides a rationale for the combined use of a DPP IV inhibitor and MET in treating SRL-induced DM.
移植后新发糖尿病管理指南推荐二甲双胍（MET）作为一线用药，如需更好地控制高血糖则需加用二线药物。我们测试了在MET基础上加用二肽基肽酶IV（DPP IV）抑制剂对西罗莫司（SRL）诱导的糖尿病（DM）的影响。在SRL诱导的DM动物模型中，MET治疗改善了胰岛功能（血糖水平和胰岛素分泌），并减轻了氧化应激和凋亡性细胞死亡。在MET基础上加用DPP IV抑制剂比单独使用MET更能改善这些参数。一项体外研究表明，SRL治疗增加了胰腺β细胞死亡和活性氧（ROS）的产生，而ROS抑制剂或p38丝裂原活化蛋白激酶（p38MAPK）抑制剂预处理可有效减少SRL诱导的胰岛细胞死亡。与SRL治疗相比，DPP IV的底物艾塞那肽-4（EXD）或MET显著提高了细胞活力并减少了ROS的产生，两种药物联合治疗进一步改善了这两个参数。在亚细胞水平上，SRL导致的线粒体呼吸受损被MET或EXD部分改善，在MET基础上加用EXD后进一步显著改善。我们的数据表明，在MET基础上加用DPP IV抑制剂可降低SRL诱导的氧化应激并改善线粒体呼吸。这一发现为联合使用DPP IV抑制剂和MET治疗SRL诱导的DM提供了理论依据。
