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Diabetes Publish Ahead of Print published online ahead of print June 15, 2007
DOI: 10.2337/db07-0074
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Original Research

AMPK activation increases glucose uptake, decreases apoptosis and improves pregnancy outcome in embryos exposed to high IGF-1 concentrations

Grace S. Eng1, Rachael A. Sheridan2, Amanda Wyman2, Maggie M-Y Chi2, Kristin P. Bibee2, Emily S. Jungheim2, and Kelle H. Moley2

1Department of Internal Medicine, Washington University School of Medicine, St Louis, MO 63110
2Department of Obstetrics Gynecology, Washington University School of Medicine, St Louis, MO 63110

Correspondence: moleyk{at}wustl.edu

Objective:Women with polycystic ovarian syndrome are at increased risk of miscarriage. While evidence exists that metformin reduces this risk, the mechanism is unknown. This study tests the hypothesis that AMPK activation with metformin directly improves insulin signaling within the blastocyst leading to improved pregnancy outcomes.

Research Design & Methods:Murine embryos were exposed to 200nM IGF-1, similar to the concentrations which can occur during Polycystic Ovary Syndrome (PCOS). Resulting blastocysts were compared to embryos co-cultured with excess IGF-1 plus metformin, and embryos cultured in control media for the following: AMPK phosphorylation, insulin-stimulated glucose uptake, and apoptosis. Study and control blastocysts were also transferred into control animals. On embryonic day 14.5 resulting fetuses were examined for size, and rates of fetal implantation and resorption.

Results:Compared to control blastocysts, blastocysts exposed to high concentrations of IGF-1 showed a decrease in AMPK activation and insulin-stimulated glucose uptake, and an increase in number of apoptotic nuclei. Blastocysts co-cultured in metformin and excess IGF-1 performed as well as controls in all studies. AICAR, another AMPK-activator, also prevented the effects of excess IGF-1 on blastocysts. Implantation rates and fetal size at day 14.5 were significantly lower among IGF-1 exposed embryos transferred into control mothers as compared to control embryos transferred into control mothers. Both these parameters were reversed by co-incubation with metformin and IGF-1 prior to transfer.

Conclusions:Activation of embryonic AMPK may be the mechanism responsible for the improved pregnancy outcomes seen in PCOS patients taking metformin.


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Copyright © 2007 by the American Diabetes Association.