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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 investigate the toxic effects of tacrolimus (FK506) on pancreatic islets and its role in the diabetes mellitus in renal transplant recipients. Methods According to the concentration of FK506 in different stages of clinical renal transplant recipients, the experimental groups were designed in vitro. The isolated and purified human islets were incubated with 5μg / L (low concentration), 15μg / L (medium concentration) and 25μg / L (High concentration group) of FK506 for 3 days and measured the insulin release under the stimulation of 2.8 mmol / L glucose (low glucose) and 16.7 mmol / L glucose (high glucose). The clinical data of 461 renal transplant recipients were retrospectively analyzed. The patients were treated with FK506 (or cyclosporin A), azathioprine (or mycophenolate) and hormone to prevent rejection after the operation, and the patients were treated according to the level of fasting blood glucose (FPG) The state of glucose metabolism was divided into normal fasting blood glucose (FPG <5.55 mmol / L), impaired fasting glucose regulation (FPG 5.55-6.88 mmol / L) and posttransplantation diabetes mellitus (PTDM FPG≥6 .89 mmol / L). Results In vitro, insulin release was not affected by glucose stimulation in low concentration group, and insulin release was significantly decreased in high concentration group (P <0.05). 123 cases of FK506 after renal transplantation and 338 cases of cyclosporin A (CsA) had a cumulative incidence of PTDM of 13.8% and 7.7% at 12 months after operation (P> 0.05 ), And the cumulative incidence of PTDM in 461 patients at 12 months after operation was 9.3%. Risk factors for PTDM after renal transplantation are age, family history of diabetes, impaired fasting glucose regulation before transplantation, and anti-acute rejection therapy. Conclusions The toxic effect of FK506 on human islets is dose-dependent and reversible. It is important for renal transplant patients to avoid long-term maintenance of high blood FK506 concentration and minimize the dosage of hormones.