Abstract
Embryo implantation requires a hospitable uterine environment. A key metabolic change that occurs during the peri-implantation period, and throughout early pregnancy, is the rise in endometrial glycogen content. Glycogen accumulation requires prior cellular uptake of glucose. Here we show that both human and murine endometrial epithelial cells express the high affinity Na+-coupled glucose carrier SGLT1. Ussing chamber experiments revealed electrogenic glucose transport across the endometrium in wild type (Slc5a1+/+) but not in SGLT1 deficient (Slc5a1−/−) mice. Endometrial glycogen content, litter size and weight of offspring at birth were significantly lower in Slc5a1−/− mice. In humans, SLC5A1 expression was upregulated upon decidualization of primary endometrial stromal cells. Endometrial SLC5A1 expression during the implantation window was attenuated in patients with recurrent pregnancy loss when compared with control subjects. Our findings reveal a novel mechanism establishing adequate endometrial glycogen stores for pregnancy. Disruption of this histiotrophic pathway leads to adverse pregnancy outcome.
Highlights
Human pregnancy is marred by early failure[1,2,3]
Endometrial cells cultured in glucose concentrations below 2.5 mM exhibit lower levels of decidualization, providing additional convincing data that increased glucose uptake is a prerequisite for decidualization[7]
Glycogen synthesis is accomplished by an intracellular glycogen synthase[12], which is upregulated by progesterone but inhibited by estrogens[13]
Summary
Human pregnancy is marred by early failure[1,2,3]. Approximately 15% of clinically recognized pregnancies miscarry[4,5]. Decidualization of endometrial stromal cells in vitro is dependent on adequate glucose concentrations. Intracellular glycogen synthesis requires cellular uptake of glucose, which could be accomplished by passive glucose carriers of the GLUT family[14]. Another possible mechanism to accumulate glucose involves the high affinity Na+-coupled glucose transporter SGLT1, a secondary active transporter driven by the steep electrochemical Na+ gradient across the cell membrane[15]. The present study explored whether SGLT1 is expressed in endometrial epithelium and decidualizing stroma, and if it affects glycogen accumulation during pregnancy and impacts on the growth and survival of the offspring
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