Organic cation transporter 1 polymorphisms predict the metabolic response to metformin in women with the polycystic ovary syndrome.

CONTEXT

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.

DESIGN AND SETTING

We conducted a prospective study at an academic hospital.

PATIENTS

We studied 150 Italian PCOS patients aged 18-45 yr.

INTERVENTIONS

We administered two oral doses of metformin per day for 6 months.

MAIN OUTCOME MEASURES

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.