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MICROSCOPY RESEARCH AND TECHNIQUE 38:145–152 (1997)
Mechanism of Glucose Transport Across the Human
and Rat Placental Barrier: A Review
KUNIAKI TAKATA,1* AND HIROSHI HIRANO2
1Laboratory
of Molecular and Cellular Morphology, Institute for Molecular and Cellular Regulation, Gunma University,
Maebashi, Gunma 371, Japan
2Department of Anatomy, Kyorin University School of Medicine, Mitaka, Tokyo 181, Japan
KEY WORDS
glucose transporter GLUT1; glucose transporter GLUT3; placental barrier;
gap junction; human; rat
ABSTRACT
Glucose is one of the most important substances transferred from the maternal
blood to the fetal circulation in the placenta, and its transport across the cellular membranes is
mediated by glucose transporters. Facilitated-diffusion glucose transporter GLUT1 is abundant in
the placental barrier, as is the case in other blood–tissue barriers, where GLUT1 is present at the
critical plasma membranes of the barrier cells. In the human placenta, the microvillous apical and
the basal plasma membranes of the syncytiotrophoblast are rich in GLUT1, which molecule seems to
be responsible for the transcellular transport of glucose across the placental barrier. In the rat
placental labyrinth, two layers of syncytiotrophoblasts (termed syncytiotrophoblasts I and II from
the maternal side) serve as a barrier. GLUT1 is abundant at the plasma membrane of syncytiotrophoblast I facing the maternal side, and the plasma membrane of syncytiotrophoblast II facing the
fetal side. Numerous gap junctions, made of connexin 26, connect syncytiotrophoblasts I and II,
comprising a channel for the transfer of glucose between them. GLUT1 in combination with the gap
junction, therefore, seems to serve as the structural basis for the transport of glucose across the rat
placental barrier. Microsc. Res. Tech. 38:145–152, 1997. r 1997 Wiley-Liss, Inc.
GLUCOSE TRANSPORTERS
Glucose serves as one of the most important substances in nourishing animal cells, where it is used to
generate ATP and is metabolized to become various
cellular molecules. The plasma membrane encloses the
cell body against the extracellular environment, while
the phospholipid bilayer, the framework of the plasma
membrane, by itself is practically impermeable to hydrophilic substances such as glucose. In most cells, the
plasma membrane has rapid and efficient sugar transport activity. Glucose transporters, which are integral
membrane proteins, are mainly responsible for the
transport of glucose and its analogues across the membranes. Two types of glucose transport systems are
known to exist: Na1-dependent active glucose transporters and facilitated-diffusion glucose transporters (Baldwin, 1993; Bell et al., 1990, 1993; Mueckler, 1994;
Silverman, 1991; Takata et al., 1993a; Wright, 1993).
The Na1-dependent glucose transport is found in the
absorptive epithelial cells of the small intestine (Hediger et al., 1987; Takata et al., 1992b) and in the urinary
tubules of the kidney (Takata et al., 1991a). Glucose is
transported across the plasma membrane into the
cytoplasm by the chemical gradient of Na1. Since Na1
inside cells is pumped out by the Na1, K1-ATPase at the
expense of ATP, the Na1-dependent glucose transporter
is an active transporter.
The first transport protein shown to facilitate the
transport of glucose across the plasma membranes was
purified from human erythrocyte ghosts as zone 4.5
protein, and was named the glucose transporter (Kasahara and Hinkle, 1977). It is a hydrophobic glycoprotein
r 1997 WILEY-LISS, INC.
of Mr 55 kD with a broad profile in SDS-polyacrylamide
gel electrophoresis, mainly due to various degrees of
glycosylation. The human erythrocyte glucose transporter is specifically inhibited by phloretin and cytochalasin B. Kinetic analysis using inside-out and rightsideout erythrocyte membrane showed that erythrocyte
glucose transporter can transport glucose through the
membrane in a bidirectional manner, depending on the
concentration gradient of glucose across the membrane
(Carruthers, 1990). Since transport is carried out by the
chemical gradient of glucose itself, this transport system does not consume ATP, and thus is referred to as a
passive facilitated-diffusion transport system. A cDNA
of the human erythrocyte glucose transporter was
cloned and sequenced from a human hepatoma cell
HepG2 cDNA library (Mueckler et al., 1985). The
human erythrocyte glucose transporter was later termed
‘‘GLUT1.’’
Facilitated-diffusion glucose transporters comprise a
family. By the use of the nucleotide sequence data on
GLUT1, or specific antibodies against transporters,
structurally related facilitated-diffusion glucose transporter isoforms have been cloned from various mammalian species (Baldwin, 1993; Bell et al., 1990; Mueckler,
1994). GLUT1 is found in human erythrocytes, kidney,
and cells of blood–tissue barriers, including the placenta (Takata et al., 1990, 1993a). It is also considered
*Correspondence to: Kuniaki Takata, Ph.D., Laboratory of Molecular and
Cellular Morphology, Institute for Molecular and Cellular Regulation, Gunma
University, Maebashi, Gunma 371, Japan.
Received 1 March 1995; Accepted 4 September 1995
146
K. TAKATA AND H. HIRANO
to be a ubiquitous house-keeping transporter responsible for the entry of glucose into the cytoplasm in most
animal cells. GLUT2 is a low-affinity, high-capacity
glucose transporter expressed in liver, intestine, and
pancreatic ¬-cells (Thorens, 1992). In ¬-cells, it is a part
of the blood-glucose sensing machinery coupled to the
secretion of insulin (Unger, 1991). Northern blot analyses showed that GLUT3 is mainly expressed in the
nervous system in rodents (Nagamatsu et al., 1992).
GLUT3 transcript, however, was reported to be ubiquitous in human tissues, including placenta (Bell et al.,
1990). GLUT4, which is found mainly in muscle and fat
cells (Birnbaum, 1992), is responsible for the insulinstimulated glucose transport activity in these cells.
GLUT5 is expressed in intestine and testis, and is
responsible for the transport of fructose. GLUT6 is a
pseudogene, while GLUT7 is a glucose transporter in
the endoplasmic reticulum membrane in hepatocytes
and other cells (Burchell et al., 1994; Waddell et al.,
1992). These GLUT isoforms exhibit cell- and tissuespecific expression and localization that seem to be
closely related to their function (Takata et al., 1993a;
Thomas et al., 1992). Among the glucose transporter
isoforms, GLUT1 and GLUT3 have been found to be
major isoforms expressed in placenta.
GLUT1, A GLUCOSE TRANSPORTER
ISOFORM IN BLOOD–TISSUE BARRIERS
In most tissues and organs, soluble constituents of
blood pass freely through the endothelium of the capillary, and are available to the tissue cells. Such permeability has been demonstrated using tracers such as
dyes, ferritin, and horseradish peroxidase injected into
the bloodstream. There are specialized regions in the
mammalian body, however, where such free access from
the bloodstream to the surrounding parenchymal cells
is blocked. These impermeable barriers between blood
and tissue cells have been termed ‘‘blood–tissue barriers’’ (Takata et al., 1990, 1993a). These barriers are
found in the brain (blood–brain barrier), the ciliary
body of the eye (blood–aqueous barrier), the retina of
the eye (blood–retinal barrier), the placenta (placental
barrier), the peripheral nerves (blood–nerve barrier),
the testis (blood–testis barrier), etc. Histologically, the
blood–tissue barriers are classified into two types: the
endothelium type and the epithelium type. In the
endothelium-type barrier, endothelial cells connected
by impermeable tight junctions serve as the structural
basis of the barrier. In this case, blood contents are
blocked in the blood vessels. In the epithelium-type
barrier, instead of the blood vessel walls, the continuous epithelial cell layer sealed by tight junctions constitutes the structural basis of the barrier. Endothelial
cells adjacent to such an epithelium are usually of the
fenestrated type and show extremely high permeability. GLUT1 is especially abundant at the critical plasma
membranes of the cells of the blood–tissue barriers
(Farrell et al., 1992; Harik et al., 1990; Takata et al.,
1990, 1993a). In the endothelium type, GLUT1 is
present in both the luminal and contra-luminal plasma
membranes. In the epithelium-type barrier, GLUT1 is
abundant in both the apical and the basolateral plasma
membranes. Since GLUT1 transports glucose across
the membrane in both inward and outward directions,
according to the concentration gradient of glucose,
glucose can easily and efficiently pass through these
barrier cell layers transcellularly with the help of
GLUT1. Being in high concentration at such critical
plasma membranes of the blood–tissue barriers, GLUT1
serves as a key molecule in the supply of glucose to
these tissues.
GLUCOSE TRANSPORT IN THE HUMAN
PLACENTA
In the human placenta, placental villous trees are
directly surrounded by the maternal blood (Fig. 1).
Each villus is covered by the trophoblastic surface.
During the first trimester, the villus is lined by double
trophoblastic epithelial cell layers (hemodichorial placenta). At term, a single layer of syncytiotrophoblast
covers the villi (hemomonochorial placenta) (Benirschke and Kaufmann, 1995). A continuous, uninterrupted, multinucleated syncytiotrophoblast layer constitutes the structural basis of the placental barrier. The
plasma membrane of this syncytium serves as a barrier
for the free transfer of hydrophilic substances. Glucose
is a major nutrient of fetal development, and is supplied
from the maternal blood through the placenta. Glucose
passes the placental barrier not by simple diffusion but
by the action of facilitated-diffusion transport machinery (Morris and Boyd, 1988).
Northern blot analysis showed that GLUT1 mRNA is
especially abundant in the human placenta (Bell et al.,
1990; Fukumoto et al., 1988). The level of GLUT1
mRNA is five-fold higher in the first trimester than in
the term placenta, which may correspond to the cellular
hyperplasia (Hauguel-De Mouzon et al., 1994).
By the use of antibodies against the human erythrocyte glucose transporter and the C-terminal peptide of
the HepG2 glucose transporter, a high level of GLUT1
protein was detected in human term placental villus
homogenates (Jansson et al., 1993; Takata et al., 1992a).
The 50-kD protein detected in such homogenates exhibited a broad range of Mr, similar to that of the protein in
the human erythrocyte ghost, which is characteristic of
highly glycosylated GLUT1.
The human placenta has been shown to be also rich
in GLUT3 mRNA (Bell et al., 1990). By immunoblotting, Shepherd et al. (1992) detected a substantial
amount of human GLUT3 protein in the human placenta. Immunohistochemically, GLUT3 protein was
detected at the apical side of the syncytiotrophoblast
(Arnott et al., 1994). Maher et al. (1992), however, failed
to detect the human GLUT3 protein in human placenta. Haber et al. (1993), who also employed immunoblotting, suggested that a very low level of GLUT3
protein, if any, may be present in human placenta.
Jansson et al. (1993) also showed that GLUT1, but not
GLUT3, protein was abundantly present in syncytiotrophoblast membranes in human placenta, although
abundant GLUT3 protein was successfully detected in
the brain. These observations suggest that in the
human placenta GLUT3 protein is not present or at
least is not as abundant as in the brain and that
GLUT1 is the major glucose transporter isoform in the
human placenta. The inconsistent results may be attributed to the specificity of the anti-GLUT3 antibodies
used or to the difference of the methods used, such as
sample preparation and detection of signals. The reason for the discrepancy between the mRNA level and
GLUCOSE TRANSPORT IN PLACENTA
147
Fig. 1. Schema showing possible pathway of glucose transport
across the placental barrier in human (top) and rat (bottom) placentae.
In the human placenta, the syncytiotrophoblast layer (Syn) serves as
the structural basis of the placental barrier. Glucose passes the
syncytiotrophoblast via GLUT1 localized at both the apical and basal
plasma membranes. Glucose may cross endothelial cells paracellularly. A possible trans-endothelial route via GLUT1 is also shown. In
the rat placenta, a double layer of syncytiotrophoblasts (Syn I and Syn
II) serves as the barrier. Glucose passes the barrier via the combination of GLUT1 action and gap junctions (GJ). Glucose easily crosses
endothelial cells through numerous fenestrae. M: maternal blood;
F: fetal blood; Cap: fetal capillary; Cyt: cytotrophoblast; BL: basal
lamina; End: endothelial cell.
the protein level in GLUT3 is not clear at this moment.
It might be due to the post-transcriptional regulation of
GLUT3 expression.
Human placenta is rich in insulin receptors (Desoye,
1993; Fujita-Yamaguchi et al., 1983; Siegel et al., 1981).
GLUT4, an isoform of the GLUT family, is a major
insulin-responsive glucose transporter. It is mainly
expressed in adipocytes and muscle cells, whose glucose
uptake is regulated by insulin. GLUT4 is localized in
the cytoplasmic vesicles. Upon insulin stimulation,
these vesicles fuse with the plasma membrane, thereby
increasing cell-surface GLUT4, and subsequently increase the glucose transport activity in these cells. We
used anti-GLUT4 antibody to see whether GLUT4 is
present in human placental villi. By immunohistochemistry, we did not find any GLUT4 staining (Takata et al.,
1992a). Furthermore, Northern blot analyses showed
that only a very low level of GLUT4, if any, is expressed
in the human placenta (Fukumoto et al., 1989; Hauguel-de Mouzon et al., 1994). These results agree well
with the lack of insulin sensitivity of placental glucose
transport (Challier et al., 1986; Johnson and Smith,
1980).
Fig. 2. Immunolocalization of glucose transporter GLUT1 in the
human term placenta. GLUT1 is localized at both the apical microvillous (a) and the basal (b) plasma membranes of the syncytiotrophoblast (arrowheads). Immunogold staining of an LR White-embedded
specimen. Bar: 0.1 µm.
Location of the GLUT1 glucose transporter protein
has been investigated by immunohistochemical techniques. Immunofluorescence staining of semithin frozen sections showed that the plasma membrane of the
syncytiotrophoblast covering the surface of the placental villi is rich in GLUT1 (Takata et al., 1992a). GLUT1
was concentrated at both the microvillous apical and
the infolded basal plasma membranes. Immunoelectron microscopic examination of immunogold-labeled
specimens confirmed that GLUT1 is localized at both
the apical and basal plasma membranes (Takata et al.,
1992a) (Fig. 2).
Glucose uptake by facilitated-diffusion was observed
in the apical plasma membrane vesicles prepared from
148
K. TAKATA AND H. HIRANO
the human placental syncytiotrophoblast (Bissonnette
et al., 1981; Johnson and Smith, 1980, 1982). It was
inhibited by cytochalasin B and phloretin. D-glucosesensitive, cytochalasin B-binding protein, whose Mr
was within the range of GLUT1, was detected in the
microvillous plasma membranes of human placenta
(Ingermann et al., 1983). Similar uptake of glucose was
seen in the basal plasma membrane vesicles (Bissonnette et al., 1982; Johnson and Smith, 1985).
Jansson et al. (1993) showed that GLUT1 is highly
abundant in the microvillous apical membrane, and
present to a lesser extent in the basal membrane, by the
immunoperoxidase staining of semithin Araldite sections. By the immunoblotting of purified microvillous
and basal plasma membranes of the syncytiotrophoblast, GLUT1 was detected in both membranes, but in a
different amount in each; i.e., GLUT1 density was 3
times higher in the apical than in the basal plasma
membrane of the syncytiotrophoblast (Jansson et al.,
1993). Taking the surface area difference between the
two syncytiotrophoblast membranes into account, the
total amount of GLUT1 of the microvillous apical
membrane was estimated to be up to 20-fold higher
than that of the basal membrane (Jansson et al., 1993).
Such semi-polarized distribution, i.e., relatively preferential localization at the microvillous apical membrane,
in addition to the abundance of GLUT1 protein, may
contribute to the efficient transfer of glucose while
fuelling the placental cells.
Abundant GLUT1 is also present at the plasma
membrane of the cytotrophoblasts situated beneath the
syncytiotrophoblast layer (Hahn et al., 1995; Takata
et al., 1992a). This observation shows that cytotrophoblast, the progenitor of the syncytiotrophoblast, begins
to express GLUT1, prior to cell fusion, although the
major site of GLUT1 expression is the syncytiotrophoblast (Jansson et al., 1994).
Positive staining for GLUT1 was reported in the
endothelial cells in the core of the villi (Hahn et al.,
1995; Takata et al., 1992a). The endothelial cells are of
the continuous type in the human placenta (Heinrich et
al., 1976). Tight junctions connecting endothelial cells,
however, are discontinuous (Leach and Firth, 1992),
suggesting the paracellular clefts between endothelial
cells may contribute to the entry of glucose into the
capillary. The permeability of the fetal capillaries in the
term human placenta resembles that of continuous
non-brain capillaries found in skeletal muscle, where
restriction of the transfer of high molecular weight
substances are seen (Eaton et al., 1993). The transporter there may contribute to the uptake of glucose by
the endothelial cells, as well as facilitate the transfer of
glucose into and out of the fetal bloodstream.
A possible major glucose transfer mechanism in the
human placental villi may be depicted as follows (Fig.
1): Glucose in the maternal bloodstream passes the
apical microvillous plasma membrane with the help of
GLUT1; glucose moves through the cytoplasm of the
syncytiotrophoblast by simple diffusion; glucose leaves
the cytoplasm via GLUT1 in the basal plasma membrane (Takata, 1994; Takata et al., 1992a, 1993b).
Glucose then enters the blood vessels in the villous core.
GLUT1 in the endothelial cell may help glucose to enter
the fetal circulation. In addition to placenta, the presence of GLUT1 and GLUT3 in the fetal membranes was
reported (Wolf and Desoye, 1993), which does not seem
to be responsible for the glucose transfer from maternal
to fetal circulation.
After entry into the cytoplasm, glucose may be phosphorylated by hexokinases or glucokinases, which leads
to the glycolytic pathway. Since glucose is certainly
transported trans-epithelially in organs such as the
small intestine, kidney, and placenta, there must be a
mechanism to avoid such phosphorylation in the cytoplasm, and/or to dephosphorylate glucose phosphate
prior to the exit from the cytoplasm, which remains to
be investigated. The glucose transfer mechanism in the
human placental barrier seems to be basically similar
to that proposed for other blood–tissue barriers (Takata
et al., 1990, 1993a). The concentration of glucose in the
umbilical artery is about 80%, compared with that in
the maternal vein in the human placenta (Economides
and Nicolaides, 1989). This glucose concentration gradient drives the glucose transfer from the maternal blood
to the fetal blood in the placental villi. Under the
condition where glucose concentration in the fetal blood
is higher than that in the maternal blood, the backtransfer of glucose to the trophoblasts or to the maternal circulation may occur in the placentae of human
(Bozzetti et al., 1988) and other species (Anad et al.,
1979; Thomas et al., 1990). The perfusion experiment
showed that the bidirectional transfer of glucose could
occur. However, the transfer efficiency from mother to
fetus is much higher than that from fetus to mother,
suggesting the existence of a possible protective mechanism against glucose loss of the fetus under conditions
of maternal hypoglycemia (Reiber et al., 1991).
GLUCOSE TRANSPORT IN THE RAT
PLACENTA
The rat has a hemochorial placenta as is found in
humans. However, a labyrinth, a complex of maternal
and fetal blood flow routes, is formed instead of villi
(Benirschke and Kaufmann, 1995) (Fig. 1). The maternal blood and fetal capillaries are separated by a single
cytotrophoblast and two syncytiotrophoblastic layers
(termed from the cytotrophoblastic side as syncytiotrophoblasts I and II). Injection of a tracer into the
maternal circulation showed that the cytotrophoblastic
layer is highly permeable, due to the numerous pores
crossing its cytoplasm. The second layer, syncytiotrophoblast I, has well-developed invaginations toward the
cytotrophoblast. Tracers such as lanthanum chloride
and horseradish peroxidase are blocked by this syncytial layer, which thereby forms a barrier from the
maternal circulation (Metz et al., 1978). The third layer,
syncytiotrophoblast II, is a thin continuous layer next
to the fetal capillaries. Tracers administered into the
umbilical artery were blocked by this syncytium (Aoki
et al., 1978). Therefore, syncytiotrophoblast II constitutes the barrier from the fetal side. These observations
show that both syncytiotrophoblasts I and II serve as
the structural basis of the placental barrier in the rat.
Zhou and Bondy (1993) demonstrated by in situ
hybridization that both GLUT1 and GLUT3 are expressed in the rat placental labyrinth, and suggested
that GLUT3 is important for glucose transfer to the
embryo, whereas GLUT1 is responsible for supplying
glucose for use as a placental fuel. Abundant GLUT1
Fig. 3 Immunolocalization of glucose transporter GLUT1 in the rat
placenta. (a) A survey view of a 16-day placenta by immunoperoxidase
staining. Note that GLUT1 is abundant in the labyrinth (L). Bar: 1
µm. (b, c, d). Immunofluorescence localization of GLUT1 in the
labyrinthine wall. A semithin frozen section was triple-stained, for
GLUT1 by the rhodamine-labeling method (red), for F-actin with
fluorescein-phalloidin (green), and for nuclear DNA with DAPI (blue)
(Takata and Hirano, 1990). Double-exposure images for GLUT1 and
for nuclei (c) and for F-actin and nuclei (d) are shown. Nomarski-
differential interference contrast image of the same specimen is also
shown (b). Two GLUT1-positive lines (arrowheads and double arrowheads) are seen between maternal blood space (M) and the fetal
capillary (F). Cytotrophoblast (*), which directly faces the maternal
blood space, does not stain for GLUT1. Endothelial cells lining the
fetal capillary do not immunoreact for GLUT1 either (arrows). Note
that fluorescein-phalloidin staining of F-actin greatly facilitates identification of the GLUT1-positive sites. Bar: 10 µm.
150
K. TAKATA AND H. HIRANO
Fig. 4. Ultrastructural localization of GLUT1 in a 16-day rat
placenta. GLUT1 is seen along the invaginated plasma membrane of
syncytiotrophoblast I (arrowheads in Syn I). The basal plasma membrane of syncytiotrophoblast II is also positive for GLUT1 (arrowheads
in Syn II). Little labeling is seen in the cytotrophoblast (Cyt) or the
endothelial cell (End). M: maternal blood space; F: fetal blood space.
Immunogold staining of an LR White-embedded specimen. Bar: 0.1
µm. Reproduced from Takata et al. (1994) with permission from the
publisher. r Springer-Verlag GmbH & Co. KG.
protein was detected by immunoblotting (Takata et al.,
1990, 1994).
Immunohistochemically, the placental labyrinth is
rich in GLUT1 (Fig. 3). Immunofluorescence staining of
semithin frozen sections and immunogold labeling of
the ultrathin LR White sections of rat placenta showed
that GLUT1 is present at the plasma membranes of
syncytiotrophoblasts I and II (Takata et al., 1990, 1994)
(Figs. 3 and 4). In syncytiotrophoblast I, GLUT1 was
found to be abundant at the invaginated plasma mem-
Fig. 5. A freeze-fracture replica of day 20 rat placenta. Numerous
gap junctions connecting syncytiotrophoblasts I and II are seen (e.g.,
arrowheads). Bar: 0.5 µm.
brane facing the cytotrophoblasts. In syncytiotrophoblast II, the infolded basal plasma membrane was rich
in GLUT1. The apposing plasma membranes of syncytiotrophoblasts I and II exhibited a rather straight
contour and only a small amount of GLUT1 was found
there. Cytotrophoblast and endothelial cells, both of
which have numerous fenestrae in their thin cytoplasm, did not stain for GLUT1. These observations are
in line with the concept that GLUT1 is a glucose
transporter in the blood–tissue barriers (Takata et al.,
1990, 1993a).
Numerous gap junctions are formed between syncytiotrophoblasts I and II (Fig. 5) (Forssmann et al., 1975;
Metz et al., 1976a, 1976b). The gap junction is an
intercellular hydrophilic channel for relatively small
151
GLUCOSE TRANSPORT IN PLACENTA
molecules. Spherical molecules as large as 900–1000
daltons can pass through the gap junction (Pitts and
Finbow, 1986; Spray and Bennett, 1985). In fact, fluorescein-labeled glucose has been shown to pass through
the gap junction (Loewenstein, 1979). The possible role
of these gap junctions in placental transfer in general
was suggested many years ago (Forssmann et al., 1975;
Metz et al., 1976a, 1976b).
High-level expression of the gap junction protein
connexin 26 was observed (Risek and Gilula, 1991).
Immunofluorescence examination showed that connexin 26 is localized between syncytiotrophoblasts I
and II (Takata et al., unpublished observation). Immunoelectron microscopy confirmed that connexin 26 is
present in the gap junction between these syncytial
layers (Takata et al., unpublished observation).
Taking into account the labyrinthine structure and
the localization of GLUT1, we suggested a possible
major route of glucose transport across the placental
barrier in the rat as follows (Takata 1994; Takata et al.,
1994) (Fig. 1): 1) glucose in the maternal blood passes
across the cytotrophoblast via numerous pores; 2) the
sugar is transported into the cytoplasm of syncytiotrophoblast I via GLUT1 at the plasma membrane of the
cytotrophoblastic side; 3) glucose enters the cytoplasm
of syncytiotrophoblast II by the gap junctions connecting syncytiotrophoblasts I and II; 4) it is then transported from the cytoplasm of syncytiotrophoblast II to
the extracellular space via GLUT1 at its basal plasma
membrane; 5) glucose enters the fetal circulation by
passing through fenestrae of the endothelial cells covering the fetal capillary wall. In this context, a double
layer of syncytiotrophoblasts connected by gap junctions is functionally equivalent to the human placenta
made of a single syncytiotrophoblast layer. This model
is similar to that for glucose transport across the
blood–aqueous barrier of the eye, where glucose passes
a double-epithelial-cell barrier layer by the combination of GLUT1 and the gap junction (Takata et al.,
1991b, 1993a). We suggest that, in addition to glucose
transfer, a similar mechanism, a combination of specific
transporter and gap junction, may work for the transfer
of other small molecules across the rat placenta, where
specificity of the transport is determined by the specific
transporters at both sides of the barrier membrane.
CONCLUSION
Facilitated-diffusion glucose transporter GLUT1 is a
major isoform present in the placental barrier in human placental villi and rat placental labyrinth. GLUT1
is localized at both the maternal and fetal sides of the
plasma membranes of syncytiotrophoblasts. Abundant
GLUT1 in such critical plasma membranes of the
barrier may be crucial to the transplacental transfer of
glucose in human and rat placentae. In the rat placental labyrinth, numerous gap junctions are present
between a double-layered syncytiotrophoblast. These
gap junctions, in concert with GLUT1, seem to be a
major route of glucose transfer in the rat placental
barrier.
ACKNOWLEDGMENTS
We wish to thank Ms. S. Tsukui for secretarial
assistance. This work was supported in part by Grants-
in-Aid from the Ministry of Education, Science, Sports,
and Culture of Japan.
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