Human metapneumovirus infection is a leading cause of respiratory tract infection in the first years of life, with a spectrum of disease similar to that of respiratory syncytial virus.

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Mammalian preimplantation blastocysts exhibit insulin-stimulated glucose uptake despite the absence of the only known insulinregulated transporter, GLUT4. We describe a previously unidentified member of the mammalian facilitative GLUT superfamily that exhibits Ϸ20 -25% identity with other murine facilitative GLUTs. Insulin induces a change in the intracellular localization of this protein, which translates into increased glucose uptake into the blastocyst, a process that is inhibited by antisense oligoprobes. Presence of this transporter may be necessary for successful blastocyst development, fuel metabolism, and subsequent implantation. Moreover, the existence of an alternative transporter may explain examples in other tissues of insulin-regulated glucose transport in the absence of GLUT4.

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We report that a decrease in facilitative glucose transporter (GLUT1) expression and reduced glucose transport trigger apoptosis in the murine blastocyst. Inhibition of GLUT1 expression either by high glucose conditions or with antisense oligodeoxynucleotides significantly lowers protein expression and function of GLUT1 and as a result induces a high rate of apoptosis at the blastocyst stage. Similar to wild-type mice, embryos from streptozotocin-induced diabetic Bax ؊/؊ mice experienced a significant decrease in glucose transport compared with embryos from non-diabetic Bax ؊/؊ mice. However, despite this decrease, these blastocysts demonstrate significantly fewer apoptotic nuclei as compared with blastocysts from hyperglycemic wild-type mice. This decrease in preimplantation apoptosis correlates with a decrease in resorptions and malformations among the infants of the hyperglycemic Bax ؊/؊ mice versus the Bax ؉/؉ and ؉/؊ mice. These findings suggest that hyperglycemia by decreasing glucose transport acts as a cell death signal to trigger a BAX-dependent apoptotic cascade in the murine blastocyst. This work also supports the hypothesis that increased apoptosis at a blastocyst stage because of maternal hyperglycemia may result in loss of key progenitor cells and manifest as a resorption or malformation, two adverse pregnancy outcomes more common in diabetic women.In prior studies, it has been shown that maternal hyperglycemia results in down-regulation of the embryonic facilitative glucose transporters (GLUT), 1 GLUT1, GLUT2, and GLUT3, at the blastocyst stage of mouse development (1). Culturing two-cell embryos for 72 h in high concentrations of glucose (30 or 52 mM) likewise causes a decrease in the expression of these facilitative transporters at the mRNA and protein levels. This decrease in transporter expression leads to a significant drop in intraembryonic free glucose levels in blastocysts obtained from mice made hyperglycemic by streptozotocin injection or after culturing two-cell embryos from normal mice in high glucose. Blastocysts cultured under similar conditions also experience a 6-fold increase in expression of the proapoptotic protein BAX, as compared with controls and undergo increased apoptosis (2). Approximately 40% of all nuclei from embryos from hyperglycemic mothers showed evidence of terminal dUTP nick-end labeling or TUNEL-positive staining compared with less than 10% among controls. This apoptotic event requires BAX expression because blastocysts recovered from diabetic Bax Ϫ/Ϫ mice are resistant to the hyperglycemia-induced apoptosis. Similarly, the hyperglycemia-induced event is inhibited partially with either the caspase inhibitor z-Val-Ala-Asp-fluoromethylketone (zVAD-FMK), or the ceramide synthase inhibitor, fumonisin B1, strongly suggesting that these apoptosis-associated pathways are involved. Apoptosis at this developmental stage may manifest later in pregnancy as a malformation or, if a significant cell loss occurs, as a miscarriage. Both these adverse pregnancy outcomes occur mor...