AMP Kinase Activation Increases Glucose Uptake, Decreases Apoptosis, and Improves Pregnancy Outcome in Embryos Exposed to High IGF-I Concentrations

• Published in: Diabetes (New York, N.Y.) Vol. 56; no. 9; pp. 2228 - 2234
• Main Authors: ENG, Grace S, SHERIDAN, Rachael A, WYMAN, Amanda, CHI, Maggie M.-Y, BIBEE, Kristin P, JUNGHEIM, Emily S, MOLEY, Kelle H
• Format: Journal Article
• Language: English
• Published: Alexandria, VA American Diabetes Association 01.09.2007
• Subjects: Adenylate Kinase - metabolism; Aminoimidazole Carboxamide - analogs & derivatives; Aminoimidazole Carboxamide - pharmacology; Animals; Apoptosis; Apoptosis - drug effects; Apoptosis - physiology; Biological and medical sciences; Care and treatment; Diabetes; Diabetes. Impaired glucose tolerance; Embryos; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Enzyme Activation; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Female; Glucose; Glucose - metabolism; Health aspects; Infertility; Insulin resistance; Insulin-Like Growth Factor I - pharmacology; Insulin-like growth factors; Kinases; Medical sciences; Metformin - pharmacology; Mice; Mice, Inbred Strains; Miscarriage; Ovaries; Polycystic ovary syndrome; Pregnancy; Pregnancy Outcome; Pregnant women; Ribonucleotides - pharmacology; Risk factors; Stein-Leventhal syndrome; Superovulation; Endocrinopathy; Pregnancy; Embryo; Enzyme; Cell death; Kinase; Transferases; Diabetes mellitus; Glucose; Insulin like growth factor 1; Uptake; Apoptosis
• ISSN: 0012-1797; 1939-327X
• DOI: 10.2337/db07-0074

AMP Kinase Activation Increases Glucose Uptake, Decreases Apoptosis, and Improves Pregnancy Outcome in Embryos Exposed to High IGF-I Concentrations Grace S. Eng 1 , Rachael A. Sheridan 2 , Amanda Wyman 2 , Maggie M.-Y. Chi 2 , Kristin P. Bibee 2 , Emily S. Jungheim 2 and Kelle H. Moley 2 1 Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri 2 Department of Obstetrics and Gynecology, Division of Reproductive Endocrinology, Washington University, St. Louis, Missouri Address correspondence and reprint requests to Kelle H. Moley, Department of Obstetrics and Gynecology, Division of Reproductive Endocrinology, Washington University, 660 South Euclid Ave., Box 8064, St. Louis, MO 63110-1094. E-mail: moleyk{at}wustl.edu Abstract Women with polycystic ovarian syndrome are at increased risk of miscarriage. Although evidence exists that metformin reduces this risk, the mechanism is unknown. This study tests the hypothesis that AMP kinase (AMPK) activation with metformin directly improves insulin signaling within the blastocyst, leading to improved pregnancy outcomes. Murine embryos were exposed to 200 nmol/l IGF-I, similar to the concentrations that can occur during polycystic ovary syndrome (PCOS). Resulting blastocysts were compared with embryos cocultured with excess IGF-I plus metformin and embryos cultured in control medium for the following: AMPK phosphorylation, insulin-stimulated glucose uptake, and apoptosis. Study and control blastocysts were also transferred into control animals. On embryonic day (E) 14.5, resulting fetuses were examined for size and rates of fetal implantation and resorption. Compared with control blastocysts, blastocysts exposed to high concentrations of IGF-I showed a decrease in AMPK activation and insulin-stimulated glucose uptake and an increase in the number of apoptotic nuclei. Blastocysts cocultured in metformin and excess IGF-I performed as well as controls in all studies. 5-Aminoimidazole-4-carboxamide 1-β- d -ribofuranoside, another AMPK activator, also prevented the effects of excess IGF-I on blastocysts. Implantation rates and fetal size at day 14.5 were significantly lower among IGF-I–exposed embryos transferred into control mothers compared with control embryos transferred into control mothers. Both of these parameters were reversed by co-incubation with metformin and IGF-I before transfer. Activation of embryonic AMPK may be the mechanism responsible for the improved pregnancy outcomes seen in PCOS patients taking metformin. AICAR, 5-aminoimidazole-4-carboxamide 1-β-d-ribofuranoside AMPK, AMP kinase DPCPX, 1,3-dipropyl-8-cyclopentylxanthine E, embryonic day hCG, human chorionic gonadotropin HTF, human tubal fluid IGFBP-1, IGF binding protein-1 PCOS, polycystic ovary syndrome TBST, Tris-buffered saline with Tween TUNEL, transferase-mediated dUTP nick-end labeling Footnotes Published ahead of print at http://diabetes.diabetesjournals.org on 15 June 2007. DOI: 10.2337/db07-0074. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Accepted June 8, 2007. Received January 16, 2007. DIABETES