Genetic variation in the multidrug and toxin extrusion 1 transporter protein influences the glucose-lowering effect of metformin in patients with diabetes: a preliminary study.
OBJECTIVE
Metformin, an oral glucose-lowering drug, is taken up in hepatocytes by the organic cation transporter (OCT) 1 and in renal epithelium by OCT2. In these cells, the multidrug and toxin extrusion (MATE) 1 protein, encoded by the SLC47A1 gene, is responsible for the excretion of metformin into the bile and urine, respectively. We studied the effect of single nucleotide polymorphisms (SNPs) in the SLC47A1 gene on the A1C-lowering effect of metformin.


METHODS
We identified all incident metformin users in the Rotterdam Study, a population-based cohort study. Associations between 12 tagging SNPs in the SLC47A1 gene and change in A1C level were analyzed.


RESULTS
One hundred and sixteen incident metformin users were included in the study sample. The rs2289669 G>A SNP was significantly associated with metformin response. For the other SNPs, no associations were found. For each minor A allele at rs2289669, the A1C reduction was 0.30% (95% CI -0.51 to -0.10; P = 0.005) larger. After Bonferroni correction for multiple testing, the P value was 0.045.


CONCLUSIONS
The rs2289669 G>A SNP is associated with a reduction in A1C level, consistent with a reduction in MATE1 transporter activity. These results suggest that the transporter MATE1, encoded by SLC47A1, may have an important role in the pharmacokinetics of metformin, although replication is necessary.
Becker
Matthijs L
ML
Department of Epidemiology and Biostatistics, Erasmus Medical Center, Rotterdam, The Netherlands.
Visser
Loes E
LE
van Schaik
Ron H N
RH
Hofman
Albert
A
Uitterlinden
André G
AG
Stricker
Bruno H Ch
BH
D000225:Adenine; D000368:Aged; D000369:Aged, 80 and over; D001646:Bile / Q000737:chemistry; D001786:Blood Glucose / Q000378:metabolism; D015331:Cohort Studies; D003404:Creatinine / Q000097:blood; D003920:Diabetes Mellitus / Q000097:blood / Q000235:genetics*; D018432:Drug Resistance, Multiple / Q000235:genetics*; D004847:Epithelial Cells / Q000378:metabolism; D005260:Female; D014644:Genetic Variation; D005838:Genotype; D005919:Glomerular Filtration Rate; D006442:Glycated Hemoglobin / Q000378:metabolism; D006147:Guanine; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D007668:Kidney / Q000378:metabolism; D008297:Male; D008687:Metformin / Q000493:pharmacokinetics / Q000627:therapeutic use / Q000652:urine; D027701:Organic Cation Transport Proteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D044465:White People
D000225:Adenine; D001786:Blood Glucose; D003404:Creatinine; D006442:Glycated Hemoglobin; D006147:Guanine; D008687:Metformin; D027701:Organic Cation Transport Proteins; C521869:SLC47A1 protein, human