Association Study Of The Genetic Polymorphisms Of KCNJ11 And TCF7L2 Genes And Repaglinide Response In Type 2 Diabetes Patients

Objectives:Gene encoding important proteins that take part in insulin secretion and glucose metabolism impairment often lead to the occurrence of type 2 diabetes mellitus(T2DM).Both Kir6.2 protein encoded by KCNJ11 gene and TCF7L2 play an important role in the insulin secretion and glucose metabolism as well as functional regulation ofβcell.The aims of this study were to explore the distributive characteristics of KCNJ11 rs5219 G/A and TCF7L2 rs290487 C/T mutations in Chinese T2DM patients and health control subjects,and investigate the relationship between the genetic polymorphisms of KCNJ11 and TCF7L2 genes and repaglinide response in Chinese T2DM patients.Methods:The genotypes of KCNJ11 and TCF7L2 were determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay in 295 T2DM patients and 188 healthy volunteers.Some samples were randomly selected for direct DNA sequencing to identify the results of PCR-RFLP assay.40 T2DM patients were randomly selected to administrate orally 3mg repaglinide daily for 8 consecutive weeks.Plasma concentrations of FPG,PPG,HbA1c and FINS,PINS levels were determined at 0 and 8th weekend after administration.The concentrations of blood glucose,insulin,and HbA1c were determined by enzymatic colorimetric assay,radioimmunoassay and high-performance liquid chromatography assay, respectively.Statistical analyses were performed by one-way ANOVA, wilcoxon rank sum test,two-sample T test,and paired T test andχ~2.Results:The genetic polymorphisms of KCNJ11 and TCF7L2 genes were consistent with Hardy-Weinberg equilibrium.There were no significant differences in the frequency distribution of the KCNJ11 and TCF7L2 polymorphisms between T2DM patients and health controls(P>0.05).Further study showed that the variation of KCNJ11 rs5219 was associated with the levels of FPG and PPG,the carriers with G allele in T2DM patients had significantly higher FPG and PPG level(P<0.05).Moreover,we found that the rs290487 mutation in TCF7L2 gene was markedly associated with the levels of BMI and CHO in T2DM patients,subjects with C allele had lower BMI and higher CHO values compared with TT genotypes(P<0.05).Finally, we found that patients with GA+AA genotypes in KCNJ11 gene had more decrease in FPG,PPG,and HbA1c than that in GG genotypes(P<0.05),and the carriers with CC+CT genotype in TCF7L2 gene had less increase in FINS and less decrease in TG and LDL-c(P<0.05) compared with TT genotypes after 8 weeks of repaglinide treatment.Conclusion:In the present study we found that there were not significant differences in the distributive frequencies of KCNJ11 rs5219 G/A and TCF7L2 rs290487 C/T mutations between T2DM patients and health subjects.However,the data showed that the genetic polymorphisms of KCNJ11 rs5219 G/A and TCF7L2 rs290487 C/T might have an effect on therapeutic efficacy of repaglinide in T2DM patients.