Relationship Between The Blood Concentration Of Calcineurin Inhibitors, Single Nucleotide Polymorphisms Of Diabetes Mellitus And Posttransplantation Diabetes Mellitus In Renal Transplantation Patients

AIMS:Posttransplant diabetes mellitus (PTDM) is the common complication following renal transplantation, yet the exact mechanism(s) of pathogenesis remains unclear. Since the usage of CNI plays a role in occurrence of PTDM, the present study was designed to investigate the relation between PTDM and the genetic polymorphism of CYP3A4 and CYP3A5(metabolism related enzymes of CNI), GCK(the key enzyme in glucose metabolism) and SUR1(the target of insulin secretion).Furthermore, it is aimed to analyze the risk factors of PTDM (e.g. plasma concentration of CNI, blood glucose, polymorphism of relative gene)and provide theoretical basis for choosing and using CNI correctly.METHODS:The age, gender, BMI, family history of diabetes, application of CNI of 613 renal transplant patients were recorded. The correlations between PTDM and these indexes were analyzed. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis was applied to determine the genotype of CYP3A4*18B, CYP3A5*3, SUR1 exon 16-3C/T and GCK promoter 30-G/A in 207 patients (162 subjects received transplantation and 45 subjects without operation). The concentrations of FK506 and CsA in plasma were determined by ELISA and Polarized Immunofluorescence Assay (PIFA), respectively. All patients received fasting blood glucose monitoring. All measurement data was expressed as the mean±SD and treated with the student's t-test. All enumeration data was treated with the Chi-square test. Logistic regression analysis was used to control the confounding factor. RESULTS:1. The incidence of PTDM is 24.1%, and the onset of PTDM is correlated with age, family history of diabetes, BMI of patients. The blood concentration/dose (C/D) ratio of CNI in patients of PTDM group is significantly higher than that of non-PTDM patients. Compared with CsA, the fasting blood glucose in PTDM patients was remarkably elevated while coadministration with FK506.2. The genotype mutation frequency of CYP3A4*18B, CYP3A5*3, SUR1 exon 16-3C/T and GCK promoter 30-G/A is 28.5%, 80.0%, 24.4% and 42.5% respectively in 207 patients.3. The C/D ratio and blood glucose in renal transplantation patients with SUR1 exon 16-TT type is significantly higher than that of subjects with SUR1 exon 16-CC type when treated with FK506.4. The C/D ratio in PTDM and non PTDM patients with *3/*3(CYP3A5*3) is evidently higher than that of subjects with *1/*1(CYP3A5*3) when treated with FK506 or CsA.5. The G/A variant at position-30 of GCK gene promoter and CYP3A5*18B have no significant correlation with PTDM of renal transplant recipients.CONCLUSION:1. Compared with age, BMI, family history of diabetes of patients, application of CNI is the most important risk factor for the progression of PTDM in renal transplantation patients. In addition, FK506 is more easily to induce PTDM.2. The genetic polymorphism of CYP3A5*3 and SUR1 is a partial determinant of PTDM, while polymorphism of GCK and CYP3A4*18B is not associated with PTDM. Various factors may contribute to the development of PTDM in transplantation subjects.