Organic cation transporter 1 polymorphisms predict the metabolic response to metformin in women with the polycystic ovary syndrome.
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.
Gambineri
Alessandra
A
Division of Endocrinology, Department of Clinical Medicine, S. Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy.
Tomassoni
Federica
F
Gasparini
Daniela Ibarra
DI
Di Rocco
Antonio
A
Mantovani
Vilma
V
Pagotto
Uberto
U
Altieri
Paola
P
Sanna
Stefania
S
Fulghesu
Anna Maria
AM
Pasquali
Renato
R
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
D054316:Biomarkers, Pharmacological; D007004:Hypoglycemic Agents; D027702:Organic Cation Transporter 1; D008687:Metformin