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The Journal of Clinical Endocrinology & Metabolism Vol. 83, No. 11 4097-4101
Copyright © 1998 by The Endocrine Society

Original Studies

Unexpected Expression of Glucose Transporter 4 in Villous Stromal Cells of Human Placenta1

A. Y. Xing2, J. C. Challier, J. Lepercq, M. Caüzac, M. J. Charron, J. Girard and S. Hauguel-de Mouzon

CNRS-UPR 1524 (A.Y.X., M.C., J.G., S.H.M.), 92190 Meudon-Bellevue, France; Université Pierre et Marie Curie (J.C.C.), Physiopathologie de l’Implantation et du Developpement, UPRESA 2396, 75005 Paris, France; Hôpital Saint-Vincent-de-Paul (J.L.), Service de Gynécologie Obstétrique, 75014 Paris, France; and Department of Biochemistry (M.J.C.), Albert Einstein College of Medicine, Bronx, New York 10461

Address all correspondence and requests for reprints to: S. Hauguel-de Mouzon, CNRS-UPR 1524, 9 rue Jules Hetzel, Meudon-Bellevue, France. E-mail: shm{at}infobiogen.fr


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Glucose transporter 4 (GLUT4) protein expression was characterized in human and rodent term placentas. A 50-kDa protein was detected, by immunoblotting, in term human placenta at levels averaging 25% of those found in white adipose tissue. It was also present, albeit at lower levels, in mouse and rat placentas. The specificity of the 50-kDa signal was established by using skeletal muscle and placental tissues obtained from GLUT4-null mice as controls. Indirect immunohistochemistry, performed in human placentas, showed that intravillous stromal cells were conspicuously labeled by GLUT4 and revealed colocalization of GLUT4 transporters with insulin receptors. This study provides the first evidence that the insulin-responsive GLUT4 glucose transporter is present in human and rodent hemochorial placentas. Placental GLUT4 gene and protein levels were not modified in human pregnancy complicated by insulin-dependent diabetes mellitus. The significance of the high level of GLUT4 protein in human placenta remains to be elucidated, because, so far, this organ was not considered to be insulin-sensitive, with regard to glucose transport.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
IN MAMMALIAN pregnancy, the placenta plays a prominent role in the transfer of glucose from the maternal circulation to the conceptus. Glucose transport across the cell membrane is carried out by stereospecific, sodium-independent facilitated diffusion, a process in which a family of specific integral membrane proteins passively transport glucose down a concentration gradient. To date, five members of this supergene family have been described (reviewed in Refs. 1, 2). Two of these glucose transporters, GLUT1 and GLUT3, are considered as the major isoforms of mammalian placentas (reviewed in Ref. 3). GLUT1 shows a homogeneous distribution in mammalian tissues (4), with highest expression in hemochorial placenta (5, 6). GLUT3 is the neuronal isoform, characteristic of organs with a high glucose requirement, such as brain, testis, and placenta (6, 7, 8, 9). The differential cellular localization of GLUT1 and GLUT3, in both human (6) and rat (9, 10) placentas, has raised the concept of a functional specificity of these isoforms.

GLUT4 is the major insulin-responsive glucose transporter isoform, expressed primarily in tissues in which glucose transport is rapidly stimulated in response to insulin. The placenta is richly endowed with insulin receptors (11, 12), but this organ is not considered a classical insulin target, with regard to glucose transport and metabolism (13, 14, 15, 16). So far, several studies have failed to detect GLUT4 in mammalian placentas (10, 17, 18, 19), although a faint GLUT4 protein signal was recently identified in human placenta (20). The present study was aimed at characterizing the expression of GLUT4 in the hemochorial placentas of human and rodents and to investigate its regulation under situations of insulin resistance.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Patients, animals, and tissue sampling

Freshly delivered human term placentas (38- to 40-weeks pregnancy) were obtained after cesarean section or vaginal delivery from diabetic or uncomplicated term pregnancies. Samples from pyramidalis muscle and abdominal sc white adipose tissue were obtained at the end of the cesarean sections. None of the patients received glucose during delivery. Insulin-dependent diabetes mellitus (IDDM) was diagnosed with a standard 75-g oral glucose tolerance test, according to World Health Organization (WHO) criteria (21). After removing the chorionic and basal plates, tissue samples (50 x 50 mm) were excised within an intact placental lobule, frozen in liquid nitrogen, and stored at -80 C. Samples for immunohistochemistry were processed as described in the relevant section. Rat placentas were sampled after maternal laparotomy, performed on days 19–20 of gestation, immediately frozen in liquid nitrogen, and stored at -80 C. Placenta and skeletal muscle from transgenic GLUT4-null and control mice (22) were sampled on days 18–19 of pregnancy and were processed as described above. Tissues were sampled and processed according to protocols approved by the board of Cochin Faculty-Hôpital Saint Vincent-de-Paul and, after consent was obtained, from the patients.

Membrane preparations

Postnuclear placental membranes were prepared as previously described (9). Crude muscle membranes were prepared according to the following procedure: All steps were performed at 4 C. Muscle samples (300–600 mg, wet weight) were homogenized in 3 mL buffer containing 20 mmol/L HEPES, 250 mmol/L sucrose, 1 mmol/L EDTA, 10 mmol/L phenylmethylsulfonylfluoride, 2% aprotinine (10 mg/mL) (pH 7.4) with 20 strokes of ultra-turrax (Janke & Kunkei KG, Staufen, Breisgau, Germany). The homogenate was centrifuged for 20 min at 15,000 x g; the supernatant was incubated with 0.8 mol/L potassium chloride for 30 min and centrifuged 90 min at 160,000 x g. The membrane pellet was resuspended in 100 µL phosphate-buffered saline (PBS) and stored at -80 C. White adipose tissue (100 mg, wet weight) was homogenized with an ultraturrax in 1 mL TES buffer (2 mol/L Trisbase, 100 mmol/L EDTA, 250 mmol/L sucrose, pH 7.4), clarified for 10 min at 2,500 x g, and centrifuged for 10 min at 25,000 x g. The resultant pellet was resuspended in PBS. Protein concentrations were determined by the standard Bio-Rad assay (Bio-Rad, Munich, Germany) using human BSA as standard.

Immunoblotting

Equal amounts of proteins were solubilized, without heating, in Laemmli sample buffer containing 100 mmol/L dithiothreitol (23) and were subjected to 10% SDS-PAGE. The proteins were transferred to nitrocellulose membranes and reacted as described previously (9). Anti-GLUT4 antibody was used at 1:500 dilution. The secondary antibody was a horseradish peroxidase-conjugated antirabbit IgG, diluted 1:2000 (Pierce, Inc., Rockford, IL). The immunoreactive signals were visualized by addition of ECL chemiluminescence reagent (Amersham International, Les Ulis, France) according to the manufacturer’s instructions.

Immunohistochemistry

Fresh human term placental samples were snap frozen in isopentane chilled to -70 C with liquid nitrogen. Frozen cryostat sections (5 µm) were laid on glass slides, fixed in 2% paraformaldehyde for 20 min, washed in PBS, and incubated with PBS containing 5% nonfat dried milk for 1 h to reduce nonspecific binding. After washing in PBS and drying, the sections were incubated overnight at 4 C with anti-GLUT4 antibody at 1:100 dilution in PBS containing 1% normal swine serum. Sections were washed twice for 10 min with PBS. Incubation with the secondary antibody, fluorescein isothiocyanate-conjugated swine antirabbit IgG (Dako Corp. A/S Glostrup, Denmark) at 1:40 dilution, was carried out in the dark for 1 h at room temperature. The slides were washed twice for 10 min with PBS and mounted in mowiol (Polysciences, Inc, Warrington, PA). Antihuman insulin receptor ß-subunit (rabbit polyclonal antisera to the last C-terminal amino acid residues of the human insulin receptor ß chain) at 1:100 dilution was used as primary antibody for detection of insulin receptors, and all subsequent steps were carried out as described above. Counterstaining was performed with Evans blue 0.5% (Sigma) before incubation with the secondary antibody. Controls were performed by omitting primary antibody. Sections were examined and photographed using a Dialux 22 microscope (Leitz, Inc., Wetzlar, Germany) equipped with an epifluorescence light source.

RNA analysis

Total RNA was extracted from placentas, according to Chirgwin’s procedure (24), and from striated muscle and adipose tissue, according to Chomczynski’s procedure (25). RNA concentration was determined by absorbance at 260 nm. All samples had a 260/280 absorbance ratio close to 2.0. Total RNA (20 µg/lane) was analyzed by Northern blot, as described (9), and sequentially hybridized with GLUT4 and ß-actin-labeled complementary DNA (cDNA) probes. Quantitation of the specific signals was performed by scanning densitometry of four autoradiograms (GS-300 Scanning densitometer; Hoefer Scientific Instruments, Inc., San Francisco, CA).

Biochemical assays

Maternal and cord plasma glucose were measured using the glucose oxidase method (Peridochrom, Boehringer-Mannheim, Mannheim, Germany). Free insulin levels were measured, in control and diabetic women, on deproteinized serum samples, by RIA, using reagents provided by CIS-Bio International (Gif-sur-Yvette, France).

Antibody and cDNA probes

The rabbit polyclonal affinity-purified anti-GLUT4 antiserum, prepared against the C terminal portion of GLUT4 protein (26), was a generous gift of Dr. Y. Le Marchand-Brustel (INSERM U 145, Nice, France). GLUT4 cDNA probe was prepared from a 1.7-kb (kilobase) human cDNA fragment (provided by Prof. G. I. Bell, University of Chicago, Chicago, IL) subcloned into pBR327, and from a 2.1-kb rat GLUT4 cDNA fragment provided by Dr. D. James (27) subcloned into pBSK+. Rat ß-actin cDNA probe was obtained as a 3.75-kb fragment subcloned into pBR322. Probes were labeled with [{alpha}-32P] deoxy-ATP using the multiprime labeling system (Amersham).

Statistical analysis

Results are expressed as means ± SE. Statistical analysis was performed by Student’s t test for unpaired data (Statworks Software, Calabasas, CA).


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
GLUT4 protein expression in human and rodent tissues

GLUT4 protein levels were compared in term placentas (mouse, rat, and human) and human insulin-sensitive tissues (striated muscle, white adipose tissue). A protein migrating at 50 kDa was detected in all tissues (Fig. 1AGo). Strong immunoreactivity, representing 25% of adipose tissue levels, was found in human placenta, whereas only a faint signal was detected in rat and mouse placentas. GLUT4 protein levels were similar in the junctional (maternal side) and labyrinthine (fetal side) zones of the rat placentas. The specificity of GLUT4 signal was further established using tissues from GLUT4-null mice as controls. A 50-kDa protein was detected, by immunoblotting, in placental and skeletal muscle membranes from control but not GLUT4-null mice (Fig. 1BGo). The expression of GLUT1 and GLUT3 proteins remained unchanged in placentas of GLUT4-null mice (results not shown).



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  		Figure 1. GLUT4 protein expression in human and rodent tissues. GLUT4 immunoblot of postnuclear membranes from placenta (100 µg protein), human muscle (20 µg protein), and white adipose tissue (20 µg protein). The autoradiogram is representative of three independent immunoblots. RaL, Rat placental labyrinthine zone (fetal side); RaJ, rat placental junctional zone (maternal side); Mo, mouse placenta; Hu, human placenta; WAT, human white adipose tissue; M, human striated muscle. The positions of molecular mass markers are indicated in kDa. Immunoblot of membranes from control and GLUT4-null mouse tissues. Samples from placenta (100 µg protein) and skeletal muscle (10 µg protein) were subjected to 10% SDS-PAGE, transferred to nitrocellulose filters, and reacted with anti-GLUT4 antibody. The autoradiogram is representative of three independent immunoblots. P, Placenta; M, skeletal muscle. The position of molecular mass markers (kDa) is shown on the right.

 
Immunofluorescent localization of GLUT4 in human placenta

GLUT4 localization was studied in placental sections obtained from normal pregnancy. GLUT4 immunoreactivity (green staining) was confined to intravillous stromal cells (Fig. 2Go, A and B). Neither the trophoblast layer nor the endothelium of fetal vessels was stained by GLUT4. The yellow staining detected in the trophoblast layer (Fig. 2AGo) appeared as a nonspecific reaction because of binding of the secondary antibody, because control sections showed the same coloration and a red label was observed after Evans blue counterstaining (Fig. 2BGo). To investigate a possible relationship between placental GLUT4 and insulin action, the localization of insulin receptors was studied in adjacent sections of the same placentas. Immunoreactivity (green staining) was detected in intravillous stromal, as well as in the endothelial and smooth muscle cells of fetal vessels (Fig. 2Go, C and D), suggesting a colocalization of GLUT4 and insulin receptors in some stromal cells. There was no real evidence of a trophoblast staining by antiinsulin receptor antibody (Fig. 2Go, C and D).



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  		Figure 2. Immunohistochemical localization of GLUT4 and insulin receptors in human term placenta. Indirect immunofluorescence of tissue sections showing stem and mature term placental villi. Staining with polyclonal antibody against the C-terminus of GLUT4 without (A) or with Evans blue counterstaining (B) shows that intravillous stromal cells were labeled in varying intensity (small arrows), with no reactivity in other cell types. Adjacent sections, incubated with antihuman insulin receptor antibody, showed specific green label (small arrows) in intravillous stromal cells (C, D) strong label in muscular media (m) of fetal vessels (C), and vascular endothelium (D). There was no evidence of a trophoblast staining with antiinsulin receptor antibody (C and D). Bar, 23 µm; star, trophoblast layer.

 
Placental GLUT4 expression in diabetic pregnancy

Concentrations of GLUT4 messenger RNA (mRNA) were compared in human placentas from control and diabetic (IDDM) pregnant women. At the time of delivery, all diabetic women (98 ± 7 vs. 86 ± 6 mg/dL in control) and infants (58 ± 6 vs. 64 ± 9 mg/dL in control) were normoglycemic. The insulin-treated IDDM women and their fetuses were hyperinsulinemic (13.1 ± 2.6 vs. 6.9 ± 1.1 µU/mL, P < 0.001; and 27.3 ± 7.8 vs. 5.3 ± 1.1 µU/mL, P < 0.001; respectively). GLUT4 mRNA abundance was slightly decreased in the diabetic (compared with control) group, but the difference did not reach statistical significance (Fig. 3Go, upper panel). Similarly, the level of GLUT4 protein was not modified in placentas from diabetic women (Fig. 3Go, lower panel).



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  		Figure 3. Placental GLUT4 expression in diabetic human pregnancies. Upper panel, Quantitation of human placental GLUT4 mRNA levels by scanning densitometry analysis of four individual Northern blots. The number of placental samples analyzed in each group is given in parentheses. Results are expressed as mean ± SE after normalization to ß-actin signals. Lower panel, Immunoblot of membranes from human placenta probed with anti-GLUT4 antibody. Proteins from placental (100 µg) and muscle (20 µg) membranes (M) were electrophoresed in each lane. The position of molecular mass markers is indicated in kDa.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
Based on extensive studies, mostly conducted during the last decade, GLUT1 and GLUT3 are now considered as the prominent placental glucose transporter isoforms. The present findings support this assumption in rodent placentas, in which we have found very low GLUT4 expression. However, this does not hold for the human placenta, in which GLUT4 is expressed at higher levels than in rodents (Fig. 1Go). This clearly indicates that the overall process of glucose transport is more sophisticated than previously thought for the human placenta. The specificity of GLUT4 label was clearly established, using a GLUT4 antibody, which gives similar immunoreactivity in striated muscle from human, rat, and mouse (Fig. 1Go). In all species, the placental signal migrated as a thiner band than in muscle and fat, possibly reflecting a difference in the glycosylation pattern of GLUT4 protein. The specific localization of GLUT4 in intravillous stromal cells (Fig. 2Go) could explain failure to identify the protein in the syncytiotrophoblast layer of human placentas (19). Alternatively, the lack of detectable GLUT4 label previously reported in human placental sections (20) could be caused by a low specificity of the antibody used for immunohistochemistry. GLUT4 and insulin receptors seem to colocalize in stromal cells. From their adventitial location and their shape, these stromal cells could be myofibroblasts or fibroblasts, favoring the previous suggestion that insulin might regulate part of glucose uptake into amnion and placental fibroblasts (28, 29). Placental fibroblasts show well-developed endoplasmic reticulum, polyribosomes, and cytoplasmic vesicles; and, although it has not been studied extensively, they may make an active contribution to intravillous placental metabolism (30). The colocalization of insulin receptors and GLUT4 transporters make possible the regulation of placental glucose transport by insulin, as suggested for amnion cells (29). Based on the shift of insulin receptors to the fetal-facing side of the placenta with the progression of pregnancy (11, 28) and the classical consensus that, under physiological conditions, maternal insulin does not cross the placental barrier (31, 32), the current findings suggest that fetal (rather than maternal) insulin would be implicated in the regulation of placental GLUT4. So far, only one study has reported an effect of fetal insulin on placental glucose uptake and metabolism in the sheep (33), whereas maternal insulin does not regulate these processes in human term placenta (13, 34).

Regulation of GLUT4 expression by insulin is largely documented in white adipose tissue. In rodents, hyperinsulinemia increases GLUT4 expression during the development of obesity (26) and in clamp studies (35), whereas insulinopenia is responsible for GLUT4 decrease in diabetic rats (36). In human adipose cells, the decrease in GLUT4 levels observed in NIDDM, obesity, or gestational diabetes (37, 38) is related to the degree of insulin resistance, rather than to changes in circulating insulin. Placental GLUT4 mRNA and protein expression were not significantly modified in human pregnancies complicated by impaired glucose homeostasis (Fig. 3Go) associated with patent hyperinsulinemia in mother and fetuses. This finding does not necessarily rule out an effect of insulin on placental GLUT4 but could reflect either a weak insulin resistance in these diabetic pregnant women or a tissue-specific response, as observed in classical insulin-sensitive tissues. Indeed, changes in GLUT4 protein expression occur later, and are less pronounced, in skeletal muscle than in adipose cells under situations of insulin resistance (36, 39, 40), indicating that GLUT4 is subjected to tissue-specific regulation mechanisms. Changes in the function and subcellular distribution (translocation) of GLUT4 occur in skeletal muscle (41) and could also be relevant in tissues in which insulin-resistant glucose transport cannot be explained on the basis of impaired GLUT4 expression. However, placental GLUT4 translocation was not addressed in the present studies.

One fundamental action of insulin in target cells is to stimulate uptake of glucose, which eventually enters the glycolytic or glycogenic pathways. Placental glucose transfer and utilization are increased in diabetic rats (42, 43). Glycogen concentrations are elevated in diabetic human (44, 45), mouse (18), and rat (9, 46) placentas, indicating enhanced glucose use and storage. Despite controversial reports (47), glycogen synthesis was found to be increased by insulin in human placental tissue (48). The observation that neither insulin nor glucose were capable of modifying the glycogen content of isolated cultured trophoblast cells in vitro (16) suggests that glycogen is stored in cell types other than syncytiotrophoblasts. Indeed, glycogen accumulation has been found in placental fibroblasts (49) and around fetal vessels, likely in pericytes and myocytes (11). Altogether, these data are in keeping with a possible role of GLUT4 to mediate placental glucose uptake for further intravillous metabolic needs.

In human term placenta, GLUT1 is found in syncytiotrophoblast and endothelial cells (6, 17, 50) and GLUT3 is predominantly localized in endothelial cells of fetal vessels (6), whereas GLUT4 is present in intravillous stromal cells (present study). The defined cellular localization of the three glucose transporters suggests that these isoforms have to fulfill different functions within the placenta. We have postulated earlier that GLUT1 would be essential for glucose transfer from maternal circulation to the placenta, whereas GLUT3 would ensure delivery of glucose from the placental pool to the fetal blood (6). The present study suggests that GLUT4 serves additional functions contributing to villous placental glucose metabolic needs. Further investigations should help to elucidate the link between the high amount of stromal GLUT4 protein and fetal insulin action in the human placenta.


   Acknowledgments
 
We thank Dr. A. Kacemi for help with immunofluorescence studies and Dr. A. Lahlou for performing RIA measurements on human samples. The skillful technical assistance of M. J. Espié and M. Galtier is acknowledged. We are grateful to Dr. J. Timsit for follow-up of diabetic pregnancies and his contribution to this work.


   Footnotes
 
1 This work was supported by Grant DK47425 from the National Institutes of Health (to M.J.C.). Back

2 Recipient of a fellowship from the Chinese government. Back

Received May 15, 1998.

Revised July 28, 1998.

Accepted August 11, 1998.


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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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