Inosine monophosphate dehydrogenase expression and activity are significantly lower in kidney transplant recipients with diabetes mellitus.
Inosine monophosphate dehydrogenase expression and activity are significantly lower in kidney transplant recipients with diabetes mellitus.
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DOI：
10.1097/ftd.0b013e3182852697
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发表时间：
2013-06
影响因子：
2.5
通讯作者：
Akhlaghi F
中科院分区：
文献类型：
--
作者：
Dostalek M;Gohh RY;Akhlaghi F
肌苷5′-单磷酸脱氢酶（IMPDH）是免疫抑制剂麦考酚酸（MPA）的作用靶点。进行12小时临床药代动力学和药效学研究以研究糖尿病对IMPDH I型和II型基因表达、蛋白水平和酶活性的影响。对非糖尿病（ND，n=11）和糖尿病（D，n=9）肾移植受者以及非移植非糖尿病（n=10）和糖尿病（n=10）志愿者的影响进行了研究。使用IMPDH-I效应曲线下面积，糖尿病显著降低了基因表达[ND：22.1（13.8-31.3）与D：4.5（2.3-6.5），P<0.001]和IMPDH-II [ND：15.3（11.0-21.7）与D：6.1（4.6-8.6），P<0.001]，蛋白水平[IMPDH-Ⅰ，ND：1.0（0.5-1.3）vs. 0.5（0.4-0.7），P=0.002; IMPDH-II，ND：1.0（0.6-1.6）vs. D：0.7（0.6-0.8）P<0.001]和酶活性[ND：180（105-245）vs. D：29.9（15.3-35.6）μmol/s/mol腺苷酸，P<0.001]。在非移植志愿者中也观察到了类似的结果。在非移植个体中，霉酚酸介导的IMPDH活性抑制的动力学研究显示，与非糖尿病志愿者相比，糖尿病志愿者的半数最大有效浓度（EC 50）约低2.5倍[ND：50.2（49.8-50.7）vs. D：15.8（15.6-16.3）nmol/l，P=0.004]。IMPDH基因多态性的差异不能解释糖尿病患者IMPDH基因表达或活性的降低。这项研究清楚地表明，IMPDH基因表达，蛋白质水平以及活性在糖尿病患者中的显着下调作用。需要在大量患者中进行进一步的临床研究，以验证MPA剂量是否需要优化用于糖尿病肾移植受者。
Inosine 5′-monophosphate dehydrogenase (IMPDH) is a target of the immunosuppressive drug, mycophenolic acid (MPA). A twelve hour clinical pharmacokinetic and pharmacodynamic study was conducted to study the effects of diabetes on IMPDH type I and -II gene expression, protein level and enzymatic activity. The effects were studied on nondiabetic (ND, n=11) and diabetic (D, n=9) kidney transplant recipients as well as on non-transplant nondiabetic (n=10) and diabetic (n=10) volunteers. Diabetes significantly reduced the gene expression using area under the effect curve of IMPDH-I [ND: 22.1 (13.8-31.3) vs. D: 4.5 (2.3-6.5), P<0.001] and IMPDH-II [ND: 15.3 (11.0-21.7) vs. D: 6.1 (4.6-8.6), P<0.001], protein level [IMPDH-I, ND: 1.0 (0.5-1.3) vs. 0.5 (0.4-0.7), P=0.002; IMPDH-II, ND: 1.0 (0.6-1.6) vs. D: 0.7 (0.6-0.8) P<0.001] and enzymatic activity [ND: 180 (105-245) vs. D: 29.9 (15.3-35.6) μmol/s/mol adenosine monophosphate, P<0.001] in transplant recipients. Similar results were observed in non-transplanted volunteers. Kinetic studies of mycophenolic acid-mediated suppression of IMPDH activity in non-transplanted individuals revealed an approximately 2.5-fold lower half-maximum effective concentration (EC50) for diabetic as compared with nondiabetic [ND: 50.2 (49.8-50.7) vs. D: 15.8 (15.6-16.3) nmol/l, P=0.004] volunteers. The lower IMPDH gene expression or activity in diabetic patients could not be explained by the difference in IMPDH gene polymorphism. This study clearly indicates a significant downregulation effect of IMPDH gene expression, protein level as well as activity in diabetic patients. Further clinical studies in a larger number of patients are warranted to verify whether MPA dosing require to be optimized for kidney transplant recipients with diabetes mellitus.