Metformin has a direct effect on ovarian cells that is dependent on organic cation transporters

Mol Cell Endocrinol. 2020 Jan 1:499:110591. doi: 10.1016/j.mce.2019.110591. Epub 2019 Sep 20.

Abstract

Metformin (MET) is the most widely prescribed hypoglycemic drug in type 2 diabetes and Polycystic Ovary Syndrome. Besides its effects on glucose metabolism, MET exerts beneficial effects on these patients' fertility. However, the exact mechanisms of action of MET on female fertility are still unclear. In this work, we analyzed a possible direct effect of MET on ovarian cells. We found expression of the organic cation transporters OCT1, OCT2 and OCT3, responsible for MET uptake into the cells, in rat granulosa cells and human cumulus cells. Furthermore, MET increased pAMPK and decreased VEGF levels both in vivo and in rat granulosa cells in culture. These last effects were reversed when OCTs were inhibited. Our results suggest that MET acts directly on ovarian cells regulating cell metabolism and VEGF expression. Our findings are relevant to optimize PCOS fertility treatment and to explore ovarian MET actions in other female pathologies.

Keywords: Granulosa cell; Metformin; Organic cation transporter; Ovary.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenylate Kinase / metabolism*
  • Adult
  • Animals
  • Cell Proliferation / drug effects
  • Cumulus Cells / cytology*
  • Cumulus Cells / drug effects
  • Cumulus Cells / metabolism
  • Female
  • Gene Expression Regulation / drug effects
  • Humans
  • Metformin / administration & dosage*
  • Metformin / pharmacology
  • Models, Animal
  • Octamer Transcription Factors / metabolism*
  • Phosphorylation / drug effects
  • Rats
  • Vascular Endothelial Growth Factor A / metabolism*

Substances

  • Octamer Transcription Factors
  • Vascular Endothelial Growth Factor A
  • Metformin
  • Adenylate Kinase