title: Polymorphism of organic cation transporter 2 improves glucose-lowering effect of metformin via influencing its pharmacokinetics in Chinese type 2 diabetic patients.
abstract: OBJECTIVE
  This study aimed to investigate how the organic cation transporter 2 nucleotide polymorphism at site 808 (G → T) affects metformin pharmacokinetics and its long-term anti-diabetic effect.
  
  
  METHODS
  A total of 220 newly diagnosed type 2 diabetes patients taking oral metformin were recruited, genotyped and then divided into three groups by SLC22A2 genotypes (G/G, G/T, T/T). Nine patients in the GG genotype group, five patients in the GT genotype group and four patients in the TT genotype group were randomly selected for the metformin pharmacokinetic study. A randomized cohort study with 1-year follow-up was performed to clarify the metformin pharmacodynamics.
  
  
  RESULTS
  After 1 year, the decrease in glycosylated hemoglobin (HbA1c) levels in subjects with the heterozygous variant genotype (GT) was significantly greater than in those with the wild-type homozygote (-2.2 % in GT vs. -1.1 % in GG, P < 0.05) after adjustment for baseline HbA1c levels, exercise and diet in each group. There were also differences in the pharmacokinetic parameters (95 % confidence interval) of metformin between these two groups [area under the concentration-time curve (AUC)0-∞ 19.7 (15.7-23.8) vs. 14.3 (11.7-16.9) μg h/L; renal clearance (CLr) 16.8 (8.5-25.0) vs. 34.1 (24.9-43.2) L/h; tubular secretion clearance (CLt) 8.1 (2.2-18.1) vs. 22.7 (15.5-29.8) L/h; all P < 0.05]. Multivariate analysis further revealed that the presence of T alleles and gender were independent influencing factors of urine excretion of metformin (P < 0.05).
  
  
  CONCLUSIONS
  As well as gender, the glucose-lowering efficiency of metformin can be enhanced by SLC22A2 808G > T variants through the delay of its transportation and CLr in Chinese type 2 diabetes populations.
authors.affiliation: Department of Endocrinology and Metabolism, Shanghai Jiaotong University Affiliated Sixth People's Hospital, Shanghai Clinical Medical Center of Diabetes, Shanghai Key Clinical Center of Metabolic Diseases, Shanghai Institute for Diabetes, Shanghai Key Laboratory of Diabetes, Shanghai, 200233, People's Republic of China.
authors.forename: Wolin
authors.initials: W
authors.lastname: Hou
authors.forename: Dandan
authors.initials: D
authors.lastname: Zhang
authors.forename: Wei
authors.initials: W
authors.lastname: Lu
authors.forename: Taishan
authors.initials: T
authors.lastname: Zheng
authors.forename: Lili
authors.initials: L
authors.lastname: Wan
authors.forename: Qing
authors.initials: Q
authors.lastname: Li
authors.forename: Yuqian
authors.initials: Y
authors.lastname: Bao
authors.forename: Fang
authors.initials: F
authors.lastname: Liu
authors.forename: Weiping
authors.initials: W
authors.lastname: Jia
mesh_terms: D000328:Adult; D000368:Aged; D019540:Area Under Curve; D001692:Biological Transport; D015331:Cohort Studies; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D005260:Female; D015870:Gene Expression; D006442:Glycated Hemoglobin / Q000378:metabolism; D006579:Heterozygote; D006801:Humans; D007004:Hypoglycemic Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use; D007668:Kidney / Q000378:metabolism; D008297:Male; D008687:Metformin / Q000493:pharmacokinetics* / Q000627:therapeutic use; D008875:Middle Aged; D027701:Organic Cation Transport Proteins / Q000235:genetics* / Q000378:metabolism; D000075102:Organic Cation Transporter 2; D020641:Polymorphism, Single Nucleotide; D012737:Sex Factors
chemical_list: D006442:Glycated Hemoglobin; D007004:Hypoglycemic Agents; D008687:Metformin; D027701:Organic Cation Transport Proteins; D000075102:Organic Cation Transporter 2; C491013:SLC22A2 protein, human; C517652:hemoglobin A1c protein, human