Loss of Endometrial Sodium Glucose Cotransporter SGLT1 is Detrimental to Embryo Survival and Fetal Growth in Pregnancy

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.

Na+/H+ exchanger 3 blockade ameliorates type 2 diabetes mellitus via inhibition of sodium‐glucose co‐transporter 1‐mediated glucose absorption in the small intestine

“…In addition, downregulation of SGLT1 in small intestine via inhibition of NHE3 may confer advantages in contrast to direct inhibition of SGLT1. This is suggested by recent literature, showing that absorption of SGLT1 inhibitors into the systemic circulation exerts its action on the heart, liver, lung, brain, and T‐lymphocytes, as well as the uterus, thereby possibly inducing serious side effects through localized SGLT1 inhibition. Moreover, SGLT1 inhibitors may compromise host defence against infection, as indicated by excessive bacterial loads in the liver, spleen, kidney and lung after Listeria monocytogenes infection, subsequently resulting in death of all SGLT1‐deficient mice .…”

“…In addition, downregulation of SGLT1 in small intestine via inhibition of NHE3 may confer advantages in contrast to direct inhibition of SGLT1. This is suggested by recent literature, showing that absorption of SGLT1 inhibitors into the systemic circulation exerts its action on the heart, liver, lung, brain, and Tlymphocytes, 27 as well as the uterus, 35 thereby possibly inducing serious side effects through localized SGLT1 inhibition. Moreover, SGLT1…”

Transcriptome analysis of the endometrium from Chinese Erhualian sows that differ in calcium ion concentration and litter size

“…Lack of Sglt1 compromises endometrial glycogen storage, resulting in reduced litter size and low birth weight in mice (Salker et al . ). The endometrial expression of interferon alpha and beta receptor subunit 1 ( IFNAR1 ) was influenced by different synchronization treatments, which could affect uterine response to pregnancy (Ruiz‐Gonzalez et al .…”

Sodium-glucose cotransporters: new targets of cancer therapy?

“…The limitation of the study however was the use of immunohistochemistry, which is a semi-quantitative method. Further research is needed to confirm whether SGLT1 has a role in the development and progression of ovarian cancer, especially because Salker et al (54) has recently reported SGLT1 activity in normal ovary tissue (human endometrium), where it controlled glycogen accumulation essential for embryo implantation.…”