Both authors contributed equally.
Metformin and male reproduction: effects on Sertoli cell metabolism
Article first published online: 24 JAN 2014
© 2013 The British Pharmacological Society
British Journal of Pharmacology
Special Issue: Themed Section: Midkine. Guest Editors: Takashi Muramatsu and Kenji Kadomatsu
Volume 171, Issue 4, pages 1033–1042, February 2014
How to Cite
Alves, M. G., Martins, A. D., Vaz, C. V., Correia, S., Moreira, P. I., Oliveira, P. F. and Socorro, S. (2014), Metformin and male reproduction: effects on Sertoli cell metabolism. British Journal of Pharmacology, 171: 1033–1042. doi: 10.1111/bph.12522
- Issue published online: 24 JAN 2014
- Article first published online: 24 JAN 2014
- Accepted manuscript online: 22 NOV 2013 03:21AM EST
- Manuscript Accepted: 18 NOV 2013
- Manuscript Revised: 4 NOV 2013
- Manuscript Received: 13 JUN 2013
- ‘Fundação para a Ciência e a Tecnologia’ – FCT. Grant Numbers: PTDC/QUI-BIQ/121446/2010, PEst-C/SAU/UI0709/2011
- Fundo Europeu de Desenvolvimento Regional – FEDER via Programa Operacional Factores de Competitividade – COMPETE/QREN
- FCT. Grant Numbers: SFRH/BPD/80451/2011, SFRH/BD/70316/2010, SFRH/BD/60945/2009
- male reproductive function
Background and Purpose
Metformin is commonly used to treat type 2 diabetes (T2D). While new clinical applications have been ascribed to metformin, including treatment of anovulatory infertility, its effects on male reproduction have not been investigated. The Sertoli cell (SC) is crucial for germ cell development, exerting metabolic control of spermatogenesis, therefore, we investigated the effects of metformin on SC metabolism.
Rat SCs were cultured in the absence and presence of metformin (5, 50 and 500 μM). mRNA and protein levels of glucose transporters (GLUT1 and GLUT3), phosphofructokinase 1 (PFK 1), lactate dehydrogenase (LDH) and monocarboxylate transporter 4 (MCT4) were determined by quantitative PCR and Western blot respectively. LDH activity was assessed and metabolite production/consumption determined by 1H-NMR.
Metformin (50 μM) decreased mRNA and protein levels of GLUT1, GLUT3, MCT4 and PFK 1 but did not affect LDH mRNA or protein levels. However, although glucose consumption was maintained in metformin-treated cells, LDH activity, lactate and alanine production were increased, indicating an enhanced glycolytic flux. No metabolic cytotoxicity was detected in SCs exposed to supra-pharmacological concentration of metformin.
Conclusions and Implications
Our results indicate that metformin: (i) decreases mRNA and protein levels of glycolysis-related transporters in SCs but increases their activity; and (ii) stimulates alanine production, which induces antioxidant activity and maintains the NADH/NAD+ equilibrium. The increased lactate in metformin-treated SCs provides nutritional support and has an anti-apoptotic effect in developing germ cells. Thus, metformin can be considered as a suitable antidiabetic drug for male patients of reproductive age with T2D.