钙调磷酸酶抑制剂引起移植术后糖尿病的分子机制  

The molecular pathogenesis of post-transplantation diabetes mellitus induced by calcineurin inhibitors

作　　者：姚烨[1] 邢同海[1] 郭文城 龚婷[1] 金唯佳 

机构地区：[1]上海交通大学附属第一人民医院,上海200080

出　　处：《现代生物医学进展》2010年第10期1968-1970,共3页Progress in Modern Biomedicine

摘　　要：钙调磷酸酶抑制剂(calcineur ininhibitors,CNIs)是一类通过抑制钙调磷酸酶而发挥免疫抑制作用的药物。临床上以他克莫司(FK-506)及环孢素A(CsA)为代表。该类药物大大提高移植效果同时也增加了移植术后糖尿病(post-transplantation diabetes mellitus,PTDM)的发病率,研究发现CNIs引起PTDM主要与钙调磷酸酶被抑制有关。CNIs抑制钙调磷酸酶,导致胞浆内T细胞活化核因子(cytosolic nuclear factor of activated Tcells,NFATc)去磷酸化受阻,抑制了NFATc1诱导的β细胞增殖,使β细胞数量进行性减少,胰岛素分泌减少,最终导致PTDM的发生。在高血糖的环境中,CNIs抑制钙调磷酸酶,可引起cAMP介导的反应结合蛋白活性调节转导子(transducer of regulated CRE Bactivity2,TORC2)持续磷酸化,抑制TORC2的入核及cAMP介导的反应结合蛋白(cAMP response element binding protein,CREB)的激活,引起靶基因的转录受抑,加重PTDM。此外,胰岛β细胞中含量很高的FK-506结合蛋白12(FK506-binding protein,FKBP-12)可导致FK506在β细胞聚集,而同等剂量的CsA无此分布规律,这可能是服用FK506的患者比服用CsA的患者PTDM的发病率更高的原因。Calcineurin Inhibitors（CNIs） are sort of medicine that inhibits calcineurin in order to suppress immunologic system,representing by FK506 and CsA.Many studies demonstrate that CNIs are at greater risk of post-transplantation diabetes mellitus（PTDM） while making effect on suppression of immunologic system.Its pathogenesis is mainly associated with inhibition of calcineurin.CNIs inhibit calcineurin,the activator of cytosolic nuclear factor of activated T cells 1（NFATc1） in beta-cell,which result in an absolute deficiency in beta-cell mass and insulin.In high glucose,transducer of regulated CREB activity 2（TORC2） is continuously phosphorylated,on the basis of inhibition of calcineurin,which prevents TORC2 dephosphorylation,nuclear entry and cAMP response element binding protein（CREB） activation,leading to PTDM.Furthermore,the studies find more FK506-binding protein（FKBP-12）in beta-cell,which result in congregation of FK506.But there is no evidence to show the same rule with CsA.It can explain why FK506 is more diabetogenic than CsA.

关 键 词：CNIs PTDM NFATC TORC 免疫亲和蛋白 

分 类 号：R587.1[医药卫生—内分泌]