The Role of Variants Regulating Metformin Transport and Action in Women with Polycystic Ovary Syndrome

Abstract

Aims: Variants in genes encoding metformin transport proteins and the ATM gene are associated with metformin response. We hypothesized that these gene variants contribute to variable metformin treatment response in polycystic ovary syndrome. Materials & methods: The discovery cohort (n = 38) was studied in an open-label study. Results were replicated in two additional cohorts (n = 26 and n = 131). Response was assessed after 3–6 months of treatment with metformin extended-release 1500–2000 mg/day. Results: The rs683369 variant was associated with less weight loss in the discovery cohort (p = 0.003), but these results were not replicated (p = 0.8). There were no differences in glucose parameters, testosterone levels or ovulatory frequency as a function of genotype. Conclusion: Variants in organic ion transporters do not explain the variable metformin response in polycystic ovary syndrome.

Keywords::

• glucose
• insulin
• MATE
• OCT
• testosterone

Acknowledgements

The authors thank the NICHD, Reproductive Medicine Network (RMN) and its Protocol Subcommittee for making the database available on behalf of this project. The RMN Steering Committee provided samples but was not involved in analysis, data interpretation or manuscript preparation. The contents of this report represent the views of the authors and do not represent the views of the NICHD RMN.

Financial & competing interests disclosure

This work was supported by the NIH 1F32HD081844 (CT Pau) and 1R01HD065029 (CK Welt), the American Diabetes Association 1-10-CT-57 (CK Welt), the 1 UL1 RR025758 Harvard Clinical and Translational Science Center, the U54 HD034449 from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (JE Nestler, JF Strauss) and the UL1RR031990 VCU Center for Clinical and Translational Research. CT Pau, KI Cheang, BP Modi, T Kasippillai, CC Keefe, M Shulleeta, WS Evans, L Pal and JE Nestler have nothing to declare. CK Welt and JF Strauss III consulted for Takeda. Clinical trial’s number: NCT01389778. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Ethical conduct of research

The authors state that they have obtained appropriate institutional review board approval or have followed the principles outlined in the Declaration of Helsinki for all human or animal experimental investigations. In addition, for investigations involving human subjects, informed consent has been obtained from the participants involved.

Additional information

Funding

This work was supported by the NIH 1F32HD081844 (CT Pau) and 1R01HD065029 (CK Welt), the American Diabetes Association 1-10-CT-57 (CK Welt), the 1 UL1 RR025758 Harvard Clinical and Translational Science Center, the U54 HD034449 from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (JE Nestler, JF Strauss) and the UL1RR031990 VCU Center for Clinical and Translational Research. CT Pau, KI Cheang, BP Modi, T Kasippillai, CC Keefe, M Shulleeta, WS Evans, L Pal and JE Nestler have nothing to declare. CK Welt and JF Strauss III consulted for Takeda. Clinical trial’s number: NCT01389778. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.