The Regulating Effect Of Gonadal Hormones On The Etabolism Of Metformin In Type2Diabetics With Different SLC47A1Genotypes

ObjectiveThe SLC47A1gene encodes for multidrug and toxin extrusion1(MATE1) which playsa dominant role in the metabolism and excretion of metformin through liver and kidney.The present study is to investigate the effect of sex hormone levels on plasma lactic acid(LA) levels, and to elucidate the relationship between the SLC47A1gene polymorphismand plasma lactate levels in Chinese Hans who suffered from type2diabetes mellitus(T2DM) with and without metformin therapy.MethodsFasting whole blood samples of392type2diabetes patients treated with metformin(n=199) or not (n=193) were collected. The SLC47A1single nucleotide polymorphism(SNP) rs2289669G/A was genotyped in232T2DM patients, including a metformin treatedgroup (n=128) and a non-metformin-treated group (n=104) with PCR-restrictionfragment length polymorphism method. LA was measured with an enzyme-electrode assay.Levels of sex hormones, including testosterone (T) and estradiol (E2), were measured witha chemiluminescence microparticle immunoassay. Spearman’s or Pearson’s correlation andlogistic regression analysis were performed for the factors associated with LA.Results:1. The LA level in the metformin group was significantly higher than that in thenon-metformin group (1.26±0.43vs.1.14±0.49mmol/L). The incidence ofhyperlactatemia of the metformin group was higher than that of the non-metformin group(7.5%vs.3.11%), but no lactic acidosis cases were found.2. LA levels of females were significantly higher than those of males. The plasma lactatelevels of menopausal women were significantly higher than that of postmenopausal women.However, in men, there was no significant difference in blood lactate levels among thethree age subgroups. 3. LA concentrations were positively correlated with E2level but negatively correlatedwith metformin and T levels. The logistic regression analysis further showed that gender,creatinine, E2, metformin, and T were independent factors influencing lactate levels.4. Three SLC47A1genotypes at site rs2289669, GA, GG and AA were found in T2DMpatients of Chinese Hans. The proportions of patients carring with AA genotype is19%,and the frequency of the A allele was50.6%.5. Female patients with the AA genotype had higher lactic acid concentrations(1.26±0.35mmol/L) than males with AA genotype (0.99±0.36mmol/L) in total patients.However, there were no gender differences of lactate levels in patients with GA, GGgenotype in total patients. Patients with the variant genotype (AA) of metformin group hada higher blood lactate concentration than those of non-metformin group (1.26±0.40mmol/Lvs0.94±0.27mmol/L), whereas there were no obvious differences of lactate levels inpatients with GA, GG genotype between the two groups.6. In the metformin-treated group, there were significant gender differences in lactateconcentrations carried with AA genotype (1.43±0.33in women vs1.12±0.41mmol/L inmen,) but not with GG, GA genotype. The lactate levels of women with the AA genotypewere the highest (1.43±0.33vs GA1.19±0.32and GG1.09±0.24mmol/L). But differencesin lactate levels among the three genotypes were not observed in the non-metformin group.Conclusions:1. Metformin increases blood lactate levels. Different levels of T and E2are the maincauses that lead to gender difference of blood lactate. E2up-regulates but T tends todown-regulate lactate levels.2. The non-synonymous SLC47A1SNP, rs2289669G> A, was found in T2DM patientsof Chinese Hans. The AA genotype is to19%and the frequency of the A allele was50.6%.3. The SLC47A1gene rs2289669G>A variant influences the plasma lactateconcentrations in T2DM patients with metformin therapy, the lactic acid levels offemale patients carrying the AA genotype was the highest.