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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.
- Source :
-
Diabetes [Diabetes] 2009 Mar; Vol. 58 (3), pp. 745-9. Date of Electronic Publication: 2009 Feb 19. - Publication Year :
- 2009
-
Abstract
- 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.<br />Research Design and 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.<br />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.<br />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.
- Subjects :
- Adenine
Aged
Aged, 80 and over
Bile chemistry
Blood Glucose metabolism
Cohort Studies
Creatinine blood
Diabetes Mellitus blood
Epithelial Cells metabolism
Female
Genotype
Glomerular Filtration Rate
Glycated Hemoglobin metabolism
Guanine
Hepatocytes metabolism
Humans
Kidney metabolism
Male
Metformin pharmacokinetics
Metformin therapeutic use
Metformin urine
White People
Diabetes Mellitus genetics
Drug Resistance, Multiple genetics
Genetic Variation
Organic Cation Transport Proteins genetics
Polymorphism, Single Nucleotide
Subjects
Details
- Language :
- English
- ISSN :
- 1939-327X
- Volume :
- 58
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- Diabetes
- Publication Type :
- Academic Journal
- Accession number :
- 19228809
- Full Text :
- https://doi.org/10.2337/db08-1028