title: SLC47A1 gene rs2289669 G>A variants enhance the glucose-lowering effect of metformin via delaying its excretion in Chinese type 2 diabetes patients.
abstract: OBJECTIVE
  The SLC47A1 gene encodes the multi-drug and toxic excretion-1(MATE1) protein, which plays a key role in the transport and excretion of metformin. This study is to clarify the influence of variants in SLC47A1 (rs2289669 G→A) on metformin pharmacokinetics and the long-term glucose-lowering effect of metformin.
  
  
  METHODS
  A total of 220 newly diagnosed type 2 diabetes patients were recruited, genotyped and divided into three groups by SLC47A1 genotypes (G/G, G/A, A/A). Ten patients in each group were randomly selected for metformin pharmacokinetics. All the participants received metformin oral treatment and were followed for one year.
  
  
  RESULTS
  After one-year follow-up, the decline of HbA1c level was significantly greater in subjects with variant genotype (AA) than other two groups (-2.32% [-25.4 mmol/mol] in AA vs. -1.16% [-12.7 mmol/mol] in GA, -1.07% [-11.7 mmol/mol] in GG, P<0.05). Then taking GG genotype as the referent, the association between AA genotype and change of HbA1c still existed after adjusted for age, sex, BMI, baseline HbA1c and diabetes duration (P<0.05). Pharmacokinetic parameters of metformin indicated that patients carrying MATE1 homozygous A had higher area under the plasma concentration versus time curve (AUC12h), but lower renal clearance (CLR) and renal clearance by secretion (CLSR) than other patients (all P<0.01). Multivariate lineal stepwise analysis further revealed that SLC47A1 genotype was an independent impact factor for urine excretion of metformin (P<0.01).
  
  
  CONCLUSIONS
  SLC47A1 rs2289669 G>A variants improve the glucose-lowering effect of metformin through slowing its excretion in 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, China.
authors.forename: Rui
authors.initials: R
authors.lastname: He
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, China.
authors.forename: Dandan
authors.initials: D
authors.lastname: Zhang
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, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Lu
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, China.
authors.forename: Taishan
authors.initials: T
authors.lastname: Zheng
authors.affiliation: Department of Pharmacy, Shanghai Jiaotong University Affiliated Sixth People's Hospital, Shanghai 200233, China.
authors.forename: Lili
authors.initials: L
authors.lastname: Wan
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, China. Electronic address: f-liu@sjtu.edu.cn.
authors.forename: Fang
authors.initials: F
authors.lastname: Liu
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, China. Electronic address: wpjia@sjtu.edu.cn.
authors.forename: Weiping
authors.initials: W
authors.lastname: Jia
mesh_terms: D000284:Administration, Oral; D000368:Aged; D044466:Asian People / Q000235:genetics; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000208:ethnology / Q000378:metabolism*; D005260:Female; D005838:Genotype; D006801:Humans; D007004:Hypoglycemic Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use; D008297:Male; D008687:Metformin / Q000493:pharmacokinetics* / Q000627:therapeutic use; D008875:Middle Aged; D027701:Organic Cation Transport Proteins / Q000235:genetics / Q000378:metabolism*; D020641:Polymorphism, Single Nucleotide
chemical_list: D007004:Hypoglycemic Agents; D027701:Organic Cation Transport Proteins; C521869:SLC47A1 protein, human; D008687:Metformin
keywords: MATE 1; Metformin; SLC47A1; Type 2 diabetes; rs2289669 G>A variants