摘要
目的探讨他克莫司(FK506)对胰岛的毒性作用以及其对肾移植患者的致糖尿病作用。方法依据临床肾移植患者术后不同阶段的血FK506浓度,设计体外实验分组,将分离、纯化的人胰岛分别与5μg/L(低浓度组)、15μg/L(中浓度组)和25μg/L(高浓度组)的FK506共培养3 d,测定其在2．8 mmol/L葡萄糖(低糖)和16．7 mmol/L葡萄糖(高糖)刺激下的胰岛素释放量。回顾分析461例肾移植患者的临床资料,患者术后采用FK506(或环孢素A)、硫唑嘌呤(或霉酚酸酯)及激素预防排斥反应,按照空腹血糖(FPG)水平将患者的糖代谢状态分为正常空腹血糖?(FPG＜5．55 mmol/L)、空腹血糖调节受损(FPG在5．55～6．88 mmol/L)和移植术后糖尿病(PTDM,FPG≥6．89 mmol/L)。结果体外实验中,低浓度组的胰岛在葡萄糖的刺激下胰岛素释放量未受影响,高浓度组的胰岛素释放量明显下降(P＜0．05)。肾移植后采用FK506者123例,采用环孢素A(CsA)者338例,二者术后12个月的PTDM累积发病率分别为13．8%和7．7%(P＞0．05),461例术后12个月的PTDM累积发病率为9．3%。肾移植术后并发PTDM的危险因素有年龄、糖尿病家族史、移植前空腹血糖调节受损和抗急性排斥反应治疗。结论FK506对人胰岛的毒性作用呈剂量相关性,且为可逆；肾移植患者避免长期维持较高血FK506浓度、激素用量最小化,对于减少PTDM有重要意义。
Objective To elucidate the deleterious diabetogenic effect of tacrolimus on Chinese Han people. Methods According to patients＇ whole blood trough levels, the concentration of tacrolimus was 5, 15 and 25 μg/L. Human islet cells cultured in vitro were exposed to various concentrations of tacrolimus for 72 h respectively, then stimulated by glucose at low （2. 8mmol/L） and high （16. 7 mmol/L） levels. Glucose-stimulating insulin secretion during subsequent static incubation was measured using the ultrasensitive human insulin ELISA kit. The assessment of islet cell viability was studied with acridine orange （AO）-propidium iodide （PI）. According to fasting plasma glucose, 461 subjects were divided into normal glucosetolerance group （FPG〈5.55 mmol/L）, impaired fasting glucose group （5.55 mmol/L〈FPG〈6. 88 mmol/L） and posttransplant diabetes mellitus group （FPG≥ 6. 89 mmol/L）. A retrospective review of 461 non-diabetic kidney recipients completing at least 12 months of follow-up was performed to determine risk factors, incidence, and characteristics of posttransplant diabetes mellitus （PTDM）. Results In vitro, lower tacrolimus concentration had not deleterious effect on insulin secretion and viability of islet; high tacrolimus impaired β-cell survival as well as insulin secretion. Of the 461 patients with no history of diabetes at transplantation over the study period of 12 months, 123 received tacrolimus and 338 received cyclosporine A （CsA）. For patients receiving tacrolimus the cumulative incidence of PTDM was 13. 8 %, compared with 7.7 % for patients receiving CsA, showing no significant difference between them. The reduced tacrolimus level within the therapeutic window resulted in an increase in better glucose metabolism. Older age, family history of diabetes, acute rejection episodes and pre-transplant impaired fasting glucose were identified as risk factors for PTDM. Conclusion The diabetogenic effect of TAC is dose-dependent, and in the majority is reversible. Low ini
出处
《中华器官移植杂志》
CAS
CSCD
北大核心
2006年第11期681-684,共4页
Chinese Journal of Organ Transplantation
基金
基金项目:吴阶平医学基金会临床科研资助基金资助(2003-32-B)
关键词
胰岛
他克莫司
药物毒性
肾移植
糖尿病
Islets of Langerhans
Tacrolimus
Drug toxicity
Kidney transplantation
Diabetes mellitus
