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J Clin Endocrinol Metab. 2009 Feb;94(2):670-7. doi: 10.1210/jc.2008-2025. Epub 2008 Nov 11.

Stimulation of lactate production in human granulosa cells by metformin and potential involvement of adenosine 5' monophosphate-activated protein kinase.

Author information

  • 1Developmental Origins of Health and Disease Research Division, Institute of Developmental Sciences, University of Southampton, Southampton General Hospital, Tremona Road, Southampton SO16 6YD, United Kingdom. mcr2@soton.ac.uk

Abstract

CONTEXT:

Production of 3-carbon units (as lactate) by granulosa cells (GCs) is important in follicular and oocyte development and may be modulated by metformin.

OBJECTIVE:

The aim of the study was to examine the action of metformin on GC lactate production and potential mediation via AMP-activated protein kinase (AMPK).

DESIGN:

GCs were prepared from follicular aspirates. After exposure to metformin and other potential modulators of AMPK in culture, aspects of cellular function were examined.

SETTING:

The study was conducted in a private fertility clinic/university academic center.

PATIENTS:

Women undergoing routine in vitro fertilization participated in the study.

INTERVENTIONS:

All agents were added in culture.

MAIN OUTCOME MEASURES:

Lactate output of GCs was measured. Cell extracts were prepared after culture, and phosphorylated forms of AMPK and acetyl CoA carboxylase (ACC) were assayed using Western analysis.

RESULTS:

Metformin led to a rapid increase in lactate production by GCs [minimum effective dose, 250 microm; maximum dose studied, 1 mm (1.22-fold; P < 0.01)]. This dose range of metformin was similar to that required for stimulation of phospho-AMPK in GCs [minimum effective dose, 250 microm; maximum effect, 500 microm (2.01-fold; P < 0.001)]. Increasing phospho-ACC, as a representative downstream target regulated by AMPK, was apparent over a lower range (minimum effective dose, 31 microm; maximum effect, 250 microm; P < 0.001). A level of metformin (125 microm) insufficient for the stimulation of lactate output when used alone potentiated the effects of suboptimal doses of insulin on lactate production. Adiponectin (2.5 microg/ml) had a small but significant effect on lactate output.

CONCLUSIONS:

Metformin activates AMPK in GCs, stimulating lactate production and increasing phospho-ACC. Metformin also enhances the action of suboptimal insulin concentrations to stimulate lactate production.

PMID:
19001513
[PubMed - indexed for MEDLINE]
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