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Original Studies |
Department of Obstetrics and Gynecology, University of Medicine and Dentistry of New Jersey- New Jersey Medical School, Newark, New Jersey 07103
Address all correspondence and requests for reprints to: Nicholas P. Illsley, D.Phil., Department of Obstetrics and Gynecology, Medical Sciences Building, E506, University of Medicine and Dentistry-New Jersey Medical School, 185 South Orange Avenue, Newark, New Jersey 07103-2714. E-mail: illsleni{at}umdnj.edu
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Poorly controlled maternal diabetes results in fetal hyperglycemia and hyperinsulinemia, which frequently cause increased fetal growth, especially in those tissues that are insulin sensitive. As a consequence, there is an increase in birth weight in a substantial proportion of the fetuses born to diabetic women (7, 8, 9). However, macrosomic babies are also delivered to women whose diabetes is well controlled, and normal birth weight infants are born to overt diabetics (10, 11). These events suggest that the regulation of fetal growth in diabetic pregnancies is not simply a case of nutrient oversupply.
Prior studies have demonstrated that transplacental glucose transport is mediated by GLUT1, one of the family of facilitative (GLUT) glucose transporters, embedded in the microvillous and basal membranes of the placental syncytiotrophoblast (12, 13). Alterations in GLUT1 expression have been shown to result from changes in plasma glucose or insulin in a variety of cells (14, 15, 16, 17). In diabetic pregnancies the major effect of maternal hyperglycemia on the fetus is to increase plasma glucose levels. Beyond fetal hyperglycemia and hyperinsulinemia, very little is known of the fetal response to maternal diabetes or of the role of the placenta.
Placental glucose transporters are responsible for transmitting the effects of maternal diabetes to the fetus, and it is possible that this function is modulated through changes in glucose transporter expression and activity. Investigations in vitro have demonstrated that the expression of syncytiotrophoblast GLUT1 is suppressed by hyperglycemia (18, 19), although glucose alone may not produce these effects in the physiological range (20). A stimulatory role for insulin on GLUT1 expression in trophoblast cells has also been demonstrated (19). From these data, it was hypothesized that maternal diabetes would cause suppression of placental GLUT1 expression via hyperglycemia and hypoinsulinemia. The aims of this initial study were to compare the expression and transport activity of the GLUT1 glucose transporter in microvillous and basal membranes obtained from normal and diabetic pregnancies.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Placental tissue from control and diabetic pregnancies was obtained under procedures approved by the New Jersey Medical School institutional review board. Criteria for inclusion were 1) diagnosis of White class A or B diabetes (see below), 2) maternal age between 18–38 yr, 3) absence of medical or obstetric complications other than diabetes, 4) term delivery (37+ weeks gestation), and 5) singleton pregnancy. Exclusion criteria included the existence of nephropathy, retinopathy, hypertension (essential or pregnancy-induced), and conditions that might indicate altered uteroplacental blood flow or substrate delivery. Normal, age-matched control placental tissue was obtained and processed in a manner identical to the diabetic tissue.
Patient classification
All patients were managed under the same protocol at University of Medicine and Dentistry of New Jersey-University Hospital (Newark, NJ) by the Department of Obstetrics and Gynecology. Diabetes was diagnosed by history or presence of two abnormal values during a 3-h oral glucose tolerance test at 24–28 weeks gestation (e.g. fasting, >100; 1 h, >195; 2 h, >165; 3 h, >145 mg/dL). For the gestational diabetics, demonstration of abnormal values led to treatment with a standard American Diabetes Association dietary regimen for a minimum of 24 h. Persistent abnormal glucose levels after dietary restriction (fasting, >100; 2 h postprandial, >140 mg/dL) were the signal for initiation of insulin therapy. Pregestational diabetics using oral antihyperglycemic agents were switched to regulation via diet and insulin during pregnancy. Diabetics in this study were stratified by the White classification, based on their diagnostic categories as White class A, gestational diabetics controlled by diet alone (GDM A1) or by diet and insulin (GDM A2), and White class B, maturity-onset pregestational diabetics (duration, <10 yr) without vascular lesions. Classes C through T and those class A or class B diabetics with signs of cardiovascular, metabolic, or other abnormalities likely to affect placental function were excluded.
Vesicle preparation
Placental tissue was obtained at delivery and placed on ice before preparation. Microvillous and basal membrane vesicles were prepared according to methods described previously (12). The only modification was the inclusion of protease inhibitory components (0.5 mmol/L ethylenediamine tetraacetate, 0.5 µg/mL aprotinin, and 0.5 µg/mL leupeptin) in the standard preparative buffer (250 mmol/L sucrose and 10 mmol/L HEPES/Tris, pH 7.0). Microvillous membrane (MVM) and basal membrane (BM) fractions were stored at -70 C until use.
Adult brain tissue
Adult human brain tissue, used as a positive control for measurement of GLUT3, was obtained postmortem using a protocol approved by the institutional review board. A membrane preparation was obtained by homogenization and centrifugation as described previously (12).
Immunoblotting
Analysis of the expression of GLUT1 protein was performed by slot blotting. Western blotting demonstrated the existence of a single broad immunoreactive band for GLUT1 (20); optimization of the blotting conditions eliminated background contributions to the blotting signal. Vesicle samples were extracted in 1% (wt/vol) SDS in Tris-buffered saline (TBS; 150 mmol/L NaCl and 100 mmol/L Tris-HCl, pH 7.5) diluted 20-fold in TBS to minimize the SDS concentration, and samples (100 µL) containing 3 µg membrane protein were blotted on to nitrocellulose membranes using a Minifold II slot blot apparatus (Schleicher & Schuell, Inc., Keene, NH). The nitrocellulose membrane was blocked with 5% casein in TBS (60 min at room temperature) followed by washing in TBS (once for 15 min and twice for 5 min each time at room temperature). The membrane was then incubated with the primary antibody, a polyclonal anti-GLUT1 diluted 1:10,000 in TBS containing 0.5% BSA for 60 min at room temperature. After washing in TBS containing 0.05% Tween (once for 15 min and twice for 5 min each time at room temperature), the membrane was incubated for 60 min at room temperature in a 1:20,000 dilution of the secondary antibody, a goat anti-rabbit IgG coupled to horseradish peroxidase, in TBS-BSA. Detection was performed using a chemiluminescent detection system after a final wash in TBS containing 0.05% Tween (once for 15 min and twice for 5 min each time at room temperature). Blots were visualized on x-ray film and quantified by two-dimensional scanning densitometry (Silverscanner II, La Cie, Beaverton, OR). Blot density was measured using Image software (version 1.49, NIH, Bethesda, MD). A series of control samples containing a range of protein concentrations was included on each membrane to construct a standard curve, which was subsequently used to correct experimental values for nonlinearity in the blotting, film, and scanner responses. GLUT3 immunoblotting was performed as described previously (12).
Transport measurements
Rates of glucose transport into MVM and BM were determined by a
recent method that measures the changes in light scattering that result
from the alterations in vesicle volume after glucose entry (21).
Vesicles were mixed in a 1:1 ratio with a challenge solution in a
stopped flow spectrometer (SF50, Hi-Tech, Salisbury, UK). Vesicles
containing 100 mmol/L raffinose and 10 mmol/L HEPES-Tris, pH 7.4, were
mixed with 80 mmol/L glucose, 20 mmol/L raffinose, and 10 mmol/L
HEPES-Tris, pH 7.4, resulting in the formation of an inwardly directed
gradient of 40 mmol/L glucose. Light scattered by the vesicles
(excitation, 500 ± 5 nm) was measured in a flow cell at a 90°
angle to the incident beam using a photomultiplier. All experiments
were performed at room temperature, and a minimum of six curves were
obtained for each separate placental sample under each condition.
Transport experiments were analyzed by fitting the light scattering
data to a double exponential function, the two exponentials
representing transporter-mediated and diffusional components. Fitting
was performed using a nonlinear least squares method, minimizing the
sum of the residuals. Exponential time constants (
1,
2) and amplitudes (A1, A2) were
obtained for each component. The fraction of total glucose transport
mediated by the transporter (F) was calculated as the ratio of the
amplitude of the transporter-mediated component of the curve
(A1) to the total amplitude of the light scattering data
(A1 + A2). The transporter-mediated glucose
flux, Jglc (nmol/s·mg) was determined from the
expression, Jglc = (1/1) x V x 
C
x F, where 1 is the exponential time constant
for the transporter-mediated component (in seconds), V is the mean
vesicular volume (µL/mg protein), C is the initial concentration
gradient (mmol/L), and F is the fraction of transport mediated by the
transporter. Diffusional flux, Dglc (nmol/s·mg), was
calculated from the equation, Dglc = (1/2)
x V x C x (1 - F), where 2 is the
time constant for the diffusional component.
Other assays
Alkaline phosphatase, adenylate cyclase, and protein were assayed by previously described methods (22, 23, 24). Maternal hemoglobin A1c (HbA1c) was assayed by the Clinical Laboratories at University of Medicine and Dentistry of New Jersey-University Hospital. Vesicular volume was determined by measuring the uptake of 2-deoxyglucose after equilibration at room temperature for 120 min in Hanks’ Balanced Salt Solution containing 1.5 µCi/mL [3H]2-deoxyglucose. After equilibration, vesicles were separated from the free [3H]2-deoxyglucose using 0.45-µm pore size, mixed ester filters on a vacuum filtration manifold (1225 Sampling Manifold, Millipore Corp., Bedford, MA). The filters were washed with cold Hanks’ Solution and solubilized with 2-ethoxyethanol, and the trapped [3H]2-deoxyglucose was counted in a scintillation counter.
Data analysis
All data are given as the mean ± SEM. Comparisons between nondiabetic controls and the three diabetic groups were performed by ANOVA using Dunnett’s test. Pairwise comparisons were performed using Student’s t test.
Materials
Anti-GLUT1 antibody was obtained from Biodesign International (Kennebunk, ME), and horseradish peroxidase-coupled anti-rabbit IgG was obtained from Sigma Chemical Co. (St. Louis, MO). Anti-GLUT3 antibody was a gift from Dr. Gywn Gould (University of Glasgow, Glasgow, U.K.). Hyperbond ECL nitrocellulose and Hyperfilm ECL x-ray film were obtained from Amersham Life Science (Arlington Heights, IL); Renaissance chemiluminescence detection kits were obtained from New England Nuclear Life Science Products (Boston, MA). [3H]2-Deoxyglucose was purchased from American Radiolabeled Chemicals, Inc. (St. Louis, MO), mixed ester HAWP 0.45-µm pore size filters were obtained from Millipore Corp. (Bedford, MA), and other chemicals, including enzyme assay components and electrophoresis materials, were obtained from Sigma Chemical Co. and Bio-Rad Laboratories, Inc. (Hercules, CA).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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To avoid vascular and other complications associated with chronic
diabetes, subjects for this study were confined to White class B
pregestational diabetics (onset <10 yr) and to White class A
gestational diabetics. For the same reason, diabetic subjects who
showed symptoms of hypertensive disease were also excluded. The type
and severity of diabetes were evaluated by the criteria described
above, and subjects were assigned to experimental groups based on this
classification. All diabetics were treated under the same protocol,
eliminating potential differences in diagnostic and treatment criteria.
Placental tissue was obtained from 7 control and 25 diabetic
pregnancies, comprising 6 pregestational (White class B), 14
gestational diet-controlled (White class A1, GDM A1), and 5 gestational
insulin-controlled (White class A2, GDM A2) diabetics. Population data
for these subjects are presented in Table 1
. The gestational ages at delivery in
the groups were similar, although the gestational age of the
pregestational group was lower than that of the control group
(38.2 ± 0.3 vs. 39.7 ± 0.3 weeks;
P < 0.05). The diabetic groups did not differ from
control with respect to birth weights or placental weights.
Nevertheless, analysis of the birth weights showed that 8 of 25
neonates from diabetic pregnancies were macrosomic, defined as greater
than the 90th percentile, using the birth weight data of Amini et
al. (25). Of the macrosomics, 3 were in the pregestational group,
4 were in the GDM A1 group, and 1 was in the GDM A2 group.
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Measurements of maternal HbA1c at or immediately before delivery were available for 18 of the 25 diabetics. Compared to the normal range of 4.8–7.8%, the value for the pregestational diabetics was 5.6 ± 0.4% (n = 5), the value for the GDM A1 group was 5.9 ± 0.3% (n = 10), and the value for the GDM A2 group was 6.2 ± 1.0% (n = 3). None of the diabetic (or control) subjects displayed HbA1c levels outside the normal range at term. These data indicate that maternal diabetes, as judged by HbA1c, appeared to be adequately controlled at term. Of the 7 subjects for whom HbA1c values were not available, none showed values for the experimental parameters (e.g. GLUT1 expression) different from others in the same group, suggesting that the changes observed in the experimental parameters of the diabetics (see below) were not caused by inclusion of those subjects for whom HbA1c results were not available.
Vesicle characterization
The MVM and BM prepared from the diabetic groups were compared to
those from the control pregnancies in terms of vesicle enrichment,
cross-contamination, and vesicle volume. MVM enrichment and BM
cross-contamination by MVM were assessed using alkaline phosphatase
activity as a marker for the microvillous surface. Alkaline phosphatase
activities in homogenates from control and diabetic groups were not
significantly different and were therefore pooled. Compared to the
pooled homogenate value (0.081 ± 0.07 µmol/min·mg; n =
21), all MVM samples were enriched 20-fold or more. MVM from diabetic
pregnancies displayed alkaline phosphatase activities not significantly
different from those of control MVM (Table 2). BM from both control and diabetic
groups showed similar levels of alkaline phosphatase activity, which
were the same as those for the homogenates, indicating a lack of
cross-contamination of the BM fractions by MVM. BM enrichment and MVM
cross-contamination by BM were determined through measurements of
adenylate cyclase activity, a basal membrane marker (26). Adenylate
cyclase activity in homogenates did not differ between groups, and
homogenate values were therefore pooled. By comparison with the pooled
homogenate (17 ± 4 pmol/min·mg; n = 20), all BM samples
were also enriched 20-fold or more. Adenylate cyclase activity in BM
from the diabetic groups was not different from that in the control
group (Table 2). Adenylate cyclase activity in the MVM was similar to
that in homogenates, demonstrating minimal contamination of the MVM
fraction by BM. Vesicle volumes, determined by measuring the
[3H]2-deoxyglucose space, are shown in Table 3. Neither MVM nor BM from the
diabetic groups was different from the respective control value.
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Preliminary Western blotting experiments demonstrated that under
the appropriate conditions, a single broad band (
50–60 kDa) could
be obtained for both MVM and BM GLUT1 in the absence of background
signals (data not shown). This was confirmed by demonstrating complete
loss of signal after omission of the primary antibody. GLUT3 protein
was not apparent in either MVM or BM samples from controls or
diabetics, although it was present in control adult human brain tissue
(data not shown). To measure MVM and BM GLUT1 expression, vesicles were
extracted; slot blotted, enabling not only the comparison of all
control and diabetic samples on a single membrane but also the blotting
of a standard curve composed of membrane protein from the control
samples (Fig. 1); and centered around the
concentration of membrane protein loaded into each slot (3 µg). The
equation describing the best fit to the standard curve was used to
correct experimental points for nonlinear responses.
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). In examining the relationship between
GLUT1 content and other parameters reflecting fetoplacental response to
maternal diabetes, an inverse correlation was noted between birth
weight and MVM GLUT1 content (Fig. 3;
r = -0.43; P < 0.01), showing that those infants
with higher birth weights tended to have a decreased density of
microvillous GLUT1. No correlation was observed between MVM GLUT1
content and placental weight or maternal HbA1c at term.
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. This shows that there was an increase
in GLUT1 expression in BM from all of the diabetic groups compared to
that in controls (P < 0.05). The increase in
expression of GLUT1 was approximately 2-fold for all diabetic groups.
In contrast to that in the MVM, there was no correlation between BM
GLUT1 content and birth weight, or between BM GLUT1 content and
placental weight or maternal HbA1c. The diabetic subjects
delivering macrosomic infants had mean a BM GLUT1 level not
significantly different from that in the diabetics delivering normal
weight infants.
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Glucose flux into MVM and BM was measured using a 40 mmol/L
glucose gradient and was composed of two components, a
transporter-mediated flux and a lipid diffusional flux. The
transporter-mediated influx rates (Jglc) and the fraction
of glucose crossing the membrane via the transporter (F) are shown in
Table 4. The Jglc for control
BM was not significantly different from control MVM (19.5 ± 1.9
vs. 17.2 ± 1.2 nmol/s·mg; n = 6; significance
determined by t test). The Jglc for BM from each
of the diabetic groups was increased compared to the control value
(P < 0.05). This increase in Jglc for the
BM was the result in part of an increase in the fraction of glucose
traversing the membrane via the transporter-mediated pathway; F for
the BM was increased in all diabetic groups (P <
0.05). In the MVM, diabetics from the GDM A2 group showed an increase
in Jglc compared to the control value (P <
0.05), but Jglc for MVM from the other diabetic groups was
not increased. No changes in F were observed for the MVM. The
diffusional components (Dglc) for BM and MVM (Table 5) were not affected by diabetes, except
for a small increase (17%) in the GDM A1 group for MVM
(P < 0.05).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The expression of GLUT1, although unaltered in MVM, was increased approximately 2-fold in BM from pregestational, gestational class A1, and gestational class A2 diabetics. Measurements of glucose transporter activity complemented the changes observed in GLUT1 expression; increases noted in BM GLUT1 expression occurred in parallel with increases in BM transport activity, which, in turn, appear to have been based primarily on the increase in F, the fraction of glucose transport taking place via the transporter. The changes in glucose transport rates might have taken place as a result of an increase in the membrane content of the transporter (increase in Vmax) and/or an increase in the affinity of the transporter for glucose (decrease in Km). A distinction cannot be made between these alternatives using these measurements; however, the increase in BM GLUT1 expression favors the former.
In normal term pregnancy, the surface area of the MVM is 5 times or more that of the BM (27, 28). Given this difference and the transporter activities reported here, a model can be envisaged in which the microvillous face of the syncytiotrophoblast cell has a transport capacity 4- to 5-fold greater than that of the basal surface. It is reasonable to assume that under these conditions the BM forms the rate-limiting step to transsyncytial glucose transfer. It is probable therefore that the increase in GLUT1 activity observed in diabetes will have the effect of increasing glucose flux across not only the BM, but also the entire syncytiotrophoblast epithelial layer. The placental response to maternal diabetes is therefore likely to be an increased maternal-fetal flux of glucose, contrary to the change originally postulated.
Animal studies have demonstrated the presence in the placenta of GLUT3 (29, 30, 31, 32, 33), an isoform that changes with gestational age and, in the rat, in response to diabetes (34). In the human, however, although GLUT3 messenger ribonucleic acid (mRNA) has been observed throughout the placenta (35, 36), GLUT3 protein has been observed only in homogenates and endothelial cells (35, 37). Numerous investigators have reported the absence of GLUT3 protein from cyto- and syncytiotrophoblast cells (12, 13, 35, 38). GLUT3 protein was not detected in the MVM or BM samples used here and is unlikely to play a role in the fetoplacental response to diabetes.
In view of the asymmetric distribution of GLUT1 between MVM and BM, it is probable that changes in BM GLUT1 expression on the order described here would not have been apparent had the quantitation been performed on a crude, unfractioned placental membrane preparation, as the changes in BM GLUT1 content would have been small compared to the total syncytial GLUT1 content. It is also possible that changes such as those found in the present study might not have been observed had this question been investigated through measurements of mRNA, as an alteration in GLUT1 mRNA sufficient to create a significant difference in BM protein expression would, in all probability, be small compared to the total quantity of syncytial GLUT1 mRNA. Should the increased BM GLUT1 be ascribed to an increased rate of synthesis of GLUT1 protein or to redistribution of the existing synthesis between MVM and BM? Although no significant changes were observed in MVM GLUT1 expression, the decrement in MVM GLUT1 density required to achieve the increases observed in BM GLUT1 density would be relatively small, on the order of 10–20%, and thus difficult to confirm experimentally. The inverse correlation between MVM GLUT1 content and birth weight might be a reflection of GLUT1 redistribution from the MVM to BM in diabetics; i.e. increased redistribution from the MVM to the BM, associated with increased birth weight. However the absence of a positive correlation between BM GLUT1 content and birth weight suggests that there is another, as yet unknown, component that accounts for the correlation between MVM GLUT1 content and birth weight.
Maternal glycemic status was assessed, where possible, by determination of maternal HbA1c, because this parameter provides a time-averaged measurement of maternal glycemia over several weeks preceding delivery. The values obtained at term indicated that glycemic control, as judged by HbA1c, was apparently within normal limits during the latter part of the third trimester of pregnancy. These measurements do not exclude the occurrence of hyperglycemic events but, rather, point to the absence of extended or recurring hyperglycemia. One possibility is that hyperglycemia earlier in gestation, at or before diagnosis, may have been a factor in producing the changes in GLUT1 expression and activity observed at term in the syncytiotrophoblast. Alternatively, a very mild hyperglycemia in the third trimester, difficult to measure in any systematic fashion, might lead to elevated GLUT1 and macrosomia.
The apparent absence of a maternal hyperglycemic stimulus at or close to term raises the question of the means by which the elevated levels of placental GLUT1 expression and activity might have been achieved and maintained in the diabetics. It is possible to hypothesize that fetal hyperglycemia earlier in gestation acts as a stimulus to fetoplacental growth, including the increased synthesis of BM GLUT1. This could occur through the increased fetal secretion of factors such as insulin and the insulin-like growth factors, events that have been observed both in diabetic pregnancies (39, 40, 41, 42) and in response to fetal hyperglycemia (43, 44, 45). The increased transplacental glucose flux resulting from this increase in BM GLUT1 would prolong the increased rate of fetoplacental growth (including BM GLUT1 expression) through continued elevation of growth factors and despite normalization of maternal plasma glucose. In this way, it may be possible to account for elevated BM GLUT1 levels and macrosomic growth in the absence of continuing maternal hyperglycemia, although there is no evidence to date to demonstrate sustained growth factor levels after removal of a hyperglycemic stimulus. It is possible that GLUT1 plays a relatively minor role in maternal-fetal glucose transport, and therefore, that the changes observed here are not particularly relevant to the fetal response to diabetes. However, the absence of other recognized glucose transporters (12, 13, 36, 46, 47) and the limited pathway for paracellular glucose transport (48) make this improbable.
It is important to understand that the hypothesis described above extends beyond systems transporting glucose, and that glucose transport in diabetics may be modulated by a variety of other effects. For example, it has been recognized for some time that the synthesis of amino acid transporters such as the system A transporter is stimulated by insulin-like growth factor I (49). Thus, fetoplacental growth, stimulated initially by fetal hyperglycemia, may be sustained in part by increased amino acid transport and amino acid stimulation of growth factor release (50, 51, 52). Moreover, it is likely that the effects of glucose will be subject to other influences, such as gestational age, frequency and extent of hyperglycemic episodes, and effects of therapeutic intervention. Nevertheless, the observations reported here provide the basis for a hypothesis that may hold the key to some of the fetal consequences of diabetic pregnancy.
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Acknowledgments |
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Footnotes |
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Received July 24, 1998.
Revised September 8, 1998.
Accepted October 20, 1998.
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