title: Organic cation transporter 1 polymorphisms predict the metabolic response to metformin in women with the polycystic ovary syndrome.
abstract: BACKGROUND
  The determinants of the variability in the clinical response to metformin in women with the polycystic ovary syndrome (PCOS) are enigmatic. Organic cation transporter 1 (OCT1) plays a trigger role in the hepatic uptake of metformin. In cellular studies, it was recently shown that seven polymorphisms of OCT1 exhibit reduced transport of metformin. It is noteworthy that four of the seven variants, R61C (C>T), G401S (G>A), G465R (G>A), and 420del, are present in individuals of European descent.
  
  
  OBJECTIVE
  The aim was testing the hypothesis that polymorphisms in OCT1 may contribute to the variability in the response to metformin in PCOS.
  
  
  METHODS
  We conducted a prospective study at an academic hospital.
  
  
  METHODS
  We studied 150 Italian PCOS patients aged 18-45 yr.
  
  
  METHODS
  We administered two oral doses of metformin per day for 6 months.
  
  
  METHODS
  We measured the genotype distribution of R61C, G401S, G465R, and 420del and the influence of genotypes on response to metformin.
  
  
  RESULTS
  Eighty-four PCOS women had the reference allele at all four positions and were classified as "References," whereas 66 PCOS women carried at least one copy of the four polymorphisms (52 carried one polymorphism, 13 carried two polymorphisms, and one carried three polymorphisms) and were classified as "Variants." Only the References reduced their total cholesterol [-14 mg/dl (-22 to -5); P = 0.002] and triglycerides [-17 mg/dl (-29 to -5); P = 0.008]. Insulin(AUC) decreased in References and in Variants carrying one polymorphism, but it did not change in Variants carrying two or more polymorphisms.
  
  
  CONCLUSIONS
  Genetic variation in OCT1 may be associated with heterogeneity in the metabolic response to metformin in women with PCOS.
authors.affiliation: Division of Endocrinology, Department of Clinical Medicine, S. Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Gambineri
authors.forename: Federica
authors.initials: F
authors.lastname: Tomassoni
authors.forename: Daniela Ibarra
authors.initials: DI
authors.lastname: Gasparini
authors.forename: Antonio
authors.initials: A
authors.lastname: Di Rocco
authors.forename: Vilma
authors.initials: V
authors.lastname: Mantovani
authors.forename: Uberto
authors.initials: U
authors.lastname: Pagotto
authors.forename: Paola
authors.initials: P
authors.lastname: Altieri
authors.forename: Stefania
authors.initials: S
authors.lastname: Sanna
authors.forename: Anna Maria
authors.initials: AM
authors.lastname: Fulghesu
authors.forename: Renato
authors.initials: R
authors.lastname: Pasquali
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D054316:Biomarkers, Pharmacological / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004351:Drug Resistance / Q000235:genetics; D005260:Female; D018740:Genetic Heterogeneity; D005838:Genotype; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D055442:Metabolome / Q000187:drug effects / Q000235:genetics; D008687:Metformin / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D008875:Middle Aged; D027702:Organic Cation Transporter 1 / Q000235:genetics* / Q000378:metabolism; D011085:Polycystic Ovary Syndrome / Q000175:diagnosis* / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D011110:Polymorphism, Genetic / Q000502:physiology; D011379:Prognosis; D055815:Young Adult
chemical_list: D054316:Biomarkers, Pharmacological; D007004:Hypoglycemic Agents; D027702:Organic Cation Transporter 1; D008687:Metformin