Laboratoire de Physiopathologie de la Nutrition, Centre National de la Recherche Scientifique-ESA 7059, Université Paris 7/D. Diderot, 75251 Paris, France
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ABSTRACT |
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An association between
low birth weight and later impaired glucose tolerance was recently
demonstrated in several human populations. Although fetal malnutrition
is probably involved, the biological bases of such a relationship are
not yet clear, and animal studies on the matter are scarce. The present
study was aimed to identify, in adult (8-wk) female offspring, the
effects of reduced protein and/or energy intake strictly limited to the
last week of pregnancy. Thus we have tested three protocols of
gestational malnutrition: a low-protein isocaloric diet (5 instead of
15%), with pair feeding to the mothers receiving the control diet; a
restricted diet (50% of the control diet); and a low-protein
restricted diet (50% of low-protein diet). Only the low-protein diet
protocols, independent of total energy intake, led to a lower birth
weight. The adult offspring female rats in the three deprived groups
exhibited no decrease in body weight and no major impairment in glucose
tolerance, glucose utilization, or glucose production (basal state and
hyperinsulinemic clamp studies). However, pancreatic insulin content
and -cell mass were significantly decreased in the low-protein
isocaloric diet group compared with the two energy-restricted groups.
Such impairment of
-cell mass development induced by protein
deficiency limited to the last part of intrauterine life could
represent a situation predisposing to impaired glucose tolerance.
fetal malnutrition; endocrine pancreas
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INTRODUCTION |
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EPIDEMIOLOGICAL DATA have shown in different human
populations that low birth weight, and especially thinness at birth, is associated with susceptibility to the development of impaired glucose
tolerance or type 2 diabetes in adult life (10, 17, 19, 21, 24, 25).
This association has been interpreted as long-term effects of
nutritional factors that reduce fetal growth and impair the development
of tissues regulating glucose metabolism (9, 22, 29). Some authors have
suggested that it could be mediated through insulin resistance (17, 19,
24). However, reduced -cell function has also been described (4), and it is known that babies with intrauterine growth retardation have
marked reductions in the size of the endocrine pancreas (31). Animal
studies have also reported that fetal malnutrition is associated with
persistently impaired pancreatic
-cell function and development (5,
8). When a low-protein diet was used during the entire rat pregnancy,
reduced proliferation rate, size, and insulin content of pancreatic
islets were observed in fetuses at 21 days of pregnancy (5, 30). In
fact, a 50% reduction in the mother's intake during the first 2 wk of
gestation did not exert adverse effects on insulin secretion and action
in 4-mo male offspring (28). When such food restriction was applied in
the last week of the rat pregnancy, it did affect significantly the
pancreatic insulin stores and the
-cell mass in the fetuses or the
offspring neonates (1, 8). These data suggest that the impact of fetal
malnutrition on
-cell mass development could be influenced by the
type of malnutrition (energy and/or protein restriction) and/or the
time course of malnutrition. To our knowledge, none of the studies so
far published have undertaken to dissect the long-term impact of
undernutrition 1) limited to the
fetal stage of pancreas development, i.e., the 3rd wk of gestation (11,
27), or 2) designed to allow a
separate analysis of the effect of protein deficiency per se from that
of energy deficiency.
In the present study, we have therefore determined to what extent the
glucose homeostasis, the insulin action and secretion, and the total
pancreatic -cell mass are modified in adult female offspring of rats
undernourished during the last trimester of their pregnancy. More
specifically, we have analyzed on the adult progeny the impact of three
different patterns of fetal malnutrition, strictly limited to the last
week of pregnancy: energy restriction to 50% of the control diet, a
low-protein diet with pair feeding to a control diet, or energy
restriction to 50% of a control diet that was also a low-protein diet.
Because undernourished mothers exhibit compensatory hyperphagia after
the period of energy restriction (28), and to eliminate the possibility
that their hyperphagia after delivery is responsible for the subsequent
effects observed in their offspring, the pups were given as soon as
delivered to foster mothers fed ad libitum with the standard diet.
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MATERIALS AND METHODS |
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Diets. The powdered semi-synthetic standard diet contained by weight (g/100 g) 68% starch, 4% cellulose, 5% lipid (corn oil), and 15% protein (casein), and by calories 72% carbohydrate, 12% lipid, and 15% protein. The powdered semi-synthetic low-protein diet contained by weight (g/100 g) 78% starch, 4% cellulose, 5% lipid (corn oil), and 5% protein (casein) and by calories 83% carbohydrate, 12% lipid, and 5% protein. Energy content per 100 g diet was the same (375 cal) in both diets. Both diets contained 2 g/100 g yeast, a salt mixture (3.5 g/100 g), and a vitamin mixture (2.2 g/100 g) as described in Picarel-Blanchot et al. (26).
Animals.
Female Wistar rats bred in our colony were housed in a
temperature-controlled room with a 12:12-h light-dark cycle (lights on
0700). Weighing 230-260 g, they were mated for one night (from 1700 to 900). On the next morning, the presence of sperm in the vaginal
smear was confirmed, and this was taken as day
0.5 of pregnancy. After impregnation, females were
transferred to individual plastic maternity cages. Pregnant females
were fed standard diet ad libitum during the first 2 wk of pregnancy
and then were assigned to one of the following four experimental
conditions during the last week of pregnancy, from day
14.5 to delivery (day
22.5). Rats in the first group had their energy
restricted to 50% of their pregnancy standard diet intake. Rats in the
second group were energy restricted to 50% of their pregnancy intake
but were fed a low-protein diet. Rats in the third group were pair fed to control rats and were fed the low-protein diet. Control rats (the
fourth group) were given access to standard diet ad libitum throughout
pregnancy and lactation. Subsequently in this article, offspring of
mothers in the four groups will be referred to by their mother's diet
group: standard diet restricted (CER), low-protein diet restricted
(PER), low-protein pair fed (PR), and control (C), respectively.
Offspring of mothers in the four groups were nursed by foster mothers
fed with standard diet during their own pregnancy. Litters were culled
at birth to 10 pups each. On day 28 after birth, all of the offspring were weaned on the standard diet.
Females only were studied subsequently. Body weight measurements were
taken weekly in pregnant mothers and every 2 wk in the female offspring
from birth to the end of the experiment (at 8 wk of age). After feeding
on the standard diet for 8 wk, randomly selected animals from each
group underwent a glucose tolerance test or the measurement of in vivo
insulin action with the glucose-insulin clamp technique. The pancreatic
insulin content and the -cell mass were also measured in some
animals in each group.
In vivo glucose-induced insulin secretion tests.
Intravenous glucose tolerance tests (IVGTT) were performed under
pentobarbital sodium anesthesia (4 mg/100 g body wt ip) at 1400 in 8-wk-old CER, PR, PER, and C rats that had been fasted from
0900. A single injection of glucose (0.5 g glucose/kg body wt) was
administered via a saphenous vein. Blood samples (200 µl) were
collected sequentially from the tail vein before (time 0) and 5 (t5), 10 (t10), 20 (t20), and 30 (t30) min after the injection of
glucose. They were then centrifuged, and the plasma was separated.
Plasma glucose concentration was immediately determined on a 10-µl
aliquot, and the remaining plasma was kept at 20°C until
radioimmunoassayed for insulin.
Euglycemic-hyperinsulinemic clamp studies. Studies were performed at 1400 in rats fasted from 0900 according to a previously detailed procedure (3, 16). Rats were considered to be in the postabsorptive period, and the rate of glucose production was a measure of endogenous glucose production. Rats were anesthetized with pentobarbital. Body temperature was maintained at 37-38°C with heating lamps. One carotid artery was catheterized for blood sampling, and a tracheotomy was systematically performed to avoid respiratory problems during anesthesia.
Blood samples of 150 µl were collected 20 min after the end of the surgery for the determination of basal blood glucose and plasma insulin concentrations. Then insulin was infused at a constant rate in a saphenous vein, and blood glucose level was clamped at the level measured in the basal state by a variable infusion of glucose through the other saphenous vein with a Precidor pump (Infors, Basel, Switzerland). Insulin [a porcine monocomponent insulin (Actrapid), Novo, Copenhagen, Denmark] was dissolved in 0.9% NaCl containing 0.2% bovine serum albumin (Sigma). Infusion of exogenous glucose (7.5% solution) was started 5 min after insulin infusion. Then 25 µl of blood were sampled from the carotid artery every 5 min, and plasma glucose concentrations were determined within 60 s. Steady-state plasma insulin levels were reached 30 min after start of the insulin infusion, and steady-state blood glucose levels were reached after 40-45 min. Blood samples (200 µl) were collected at 45, 50, and 55 min to determine blood glucose specific activity and plasma insulin concentrations. Coefficients of variation in plasma glucose and insulin concentrations during the clamp were 5 and 15%, respectively.Endogenous glucose production.
Endogenous glucose production in the basal state and during
hyperinsulinemic clamp studies was assessed by a primed-continuous infusion of
[3-3H]glucose (New
England Nuclear, Dreiech, Germany). Labeled glucose was administered as
an initial intravenous priming dose (4 µCi) followed immediately by a
continuous intravenous infusion at a rate of 0.2 µCi/min.
Steady-state glucose specific activity was established by 40 min in
both the basal state and the clamp studies. The rate of glucose
appearance (Ra) was then equal
to the rate of glucose disappearance (Rd), and
these two parameters were calculated by dividing the
[3-3H]glucose infusion
rate (dpm/min) by the steady-state value of glucose specific activity
(dpm/g). In the basal state, the rate of endogenous glucose production
is equal to Ra. In clamp studies, the rate of endogenous glucose production was calculated by subtracting the exogenous steady-state glucose infusion rate (SSGIR) from Ra. The rate of glucose
utilization by the whole body mass (GUR) was calculated as GUR = Rd, and the glucose production rate (GPR) in the liver was
calculated as GPR = Ra SSGIR.
-Cell immunohistochemistry and morphometry.
After excision, whole pancreases (three in each restricted and control
group) were immediately weighed, fixed in aqueous Bouin's solution
overnight, and embedded in paraplast. Each pancreas was subsequently
sectioned (7 µm thick) throughout its length, and 10 sections taken
at regular intervals (1 every 35 sections) were immunostained for
insulin with a technique adapted from the peroxidase indirect labeling
method, as previously described (23). The anti-insulin serum was
purchased from ICN (65-104-1, ICN Pharmaceutical, Orsay,
France); it was raised in the guinea pig against porcine insulin.
Labeling was performed using a peroxidase-conjugated rabbit anti-guinea
pig IgG (PO141, Dako, Trappes, France). The activity was revealed with
a peroxidase substrate kit (Vector SG, Biosys-Vector, Compiègne,
France). After staining, sections were mounted in Eukitt. Quantitative
evaluation was performed using a computer-assisted image analysis based
on an Olympus microscope connected via a color video camera to a
Siemens PC computer and using the software Imagenia 2000 (Biocom, les
Ulis, France). The area of the insulin-positive cells and the total
area of the pancreatic cells were evaluated in each
stained section. The
-cell relative volume was obtained according to
stereological methods by calculating the ratio of the area occupied by
immunoreactive cells to that occupied by all pancreatic
cells. The total
-cell mass per pancreas was derived by
multiplying the
-cell relative volume by the total pancreatic weight.
Samples, analytic techniques, and calculations. Plasma glucose was determined with a glucose analyzer (Beckman, Palo Alto, CA). Blood samples for measuring glucose specific activity were deproteinized with Ba(OH)2-ZnSO4 and immediately centrifuged. An aliquot of the supernatant was used for determination of glucose by use of a glucose oxidase method. Another aliquot of the supernatant was evaporated to dryness at 60°C to remove tritiated water. The dry residue was dissolved in 0.1 ml of distilled water and counted with 3 ml ReadySolv-MP scintillation solution (Beckman). Immunoreactive insulin in the plasma and pancreases was estimated with purified rat insulin as standard (Novo, Copenhagen, Denmark) and with porcine monoiodinated 125I-labeled insulin (26). Charcoal was used to separate free from bound hormone. The method allows the determination of 2 µU/ml (0.08 ng/ml or 14 pmol/l) with a coefficient of variation within and between assays of 10%.
The insulin and glucose responses during the IVGTT were calculated as the incremental plasma insulin values integrated over the 30-min period after the glucose injection (Statistical analysis. Results are given as means ± SE. Statistical analysis was performed using ANOVA (Fisher's test) for comparison of unpaired data between groups. A P value of 0.05 was considered significant.
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RESULTS |
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Evolution of maternal body weight and plasma glucose and insulin
during pregnancy.
At day 14.5 of pregnancy, body weight
and plasma glucose and insulin did not significantly differ among the
four groups of mothers that gave birth to similar numbers of pups. In
the three experimental groups of rats submitted to food restriction
during the last week of pregnancy, the relative variation for body
weight was quite different compared with the C group, with a lower
weight gain in CER and PR groups, and even a decrease in body weight in
the PER group (Table 1). One may note that
in the PR group, the whole daily food supply was ingested.
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Characteristics of the offspring. As shown in Table 1, pups differed in their body weight value according to the diet changes in the last week of pregnancy. The pups from the PR and PER groups had a lower birth weight compared with the C group. The average number of pups per mother was similar in all groups studied. No relationship between offspring and mother body weights could be detected. Nursing the offspring of food-restricted mothers by non-food-restricted mothers immediately after birth corrected the decrease in birth weight within 2 wk. Thus final weights of dams at 8 wk of age did not significantly differ among the four groups.
The characteristics of the female offspring at the age of 8 wk are given in Table 2. Basal plasma glucose measured in the postabsorptive state was not significantly different among the four groups. However, plasma insulin level was found significantly lower in the CER group compared with the other groups.
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Glucose tolerance and insulin secretory response to glucose in the
offspring.
In response to intravenous glucose load, the mean incremental glucose
areas (G) in the CER, PR, and PER rats were not significantly different from those in C rats (Fig. 1 and
Table 2). However, a significant difference in
G was detected
between CER and PR rats (P < 0.02).
Rd was higher in CER than in PR and C rats
(P < 0.02 and
P < 0.01, respectively). Values of
the mean incremental insulin areas (
I) were increased in PER rats
and decreased in CER rats, whereas PR rats exhibited intermediary value
and did not differ significantly from C rats. The
I-to-
G ratio
was similar in PR and PER groups; it was significantly increased in PR
and PER rats and significantly decreased in CER rats compared with C
rats.
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In vivo insulin action in the offspring.
The basal GPR per rat was significantly lower in the PR group than in
the other groups (Table 3). This difference
was still significant when the data were expressed per kilogram body
weight. These data have to be interpreted in the presence of basal
steady-state plasma insulin (SSPI) levels, which were not significantly
different among the three restricted groups but were moderately and
significantly elevated in the PR and PER rats, respectively, compared
with the C levels. After a similar submaximal hyperinsulinemia, GPR was suppressed to the same extent in all groups. When the values were expressed per kilogram body weight, they were higher in PER than in PR
rats (P < 0.05), whereas SSPI was
lower, although not significantly, in PER than in PR rats. After
submaximal hyperinsulinemia, GUR did not differ among groups. The same
data could be observed whenever the results were expressed per kilogram
body weight. However, one should note that higher and lower insulin
infusion rates were needed in CER and PER groups, respectively, to
obtain SSPI levels similar in these groups to those in the C group.
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Pancreatic insulin content and total -cell mass in
the offspring.
The 8-wk-old female PER rats exhibited a pancreas weight significantly
higher than that of CER, PR, or C rats
(P < 0.001), and the difference
still persisted when the values were expressed per kilogram body
weight. The insulin content per pancreas was significantly lower in the
PR group and higher in the CER and PER groups compared with the C
group. Analysis of pancreatic insulin content per gram of body weight
showed the same tendency (Table 4).
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DISCUSSION |
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Our present data indicate that a low-energy and/or a low-protein diet
in the third part of gestation does affect basal plasma glucose and
insulin levels in pregnant rats, especially when expressed as relative
variation during the restriction period [(day
21.5 day
14.5)/day
14.5]. Compared with the C group, the relative variation of plasma glucose level was decreased in the CER and PR
groups but not in the PER group, whereas the relative variation of the
insulin level was increased in the CER group and decreased in the PR
and PER groups. At day 21.5, the basal
plasma insulin-to-glucose ratio was therefore increased only in the CER
group and decreased to a similar extent in the PR and PER groups
compared with the C group. This observation suggests that protein
deprivation has a specific effect on the adaptive changes in insulin
action and/or secretion in the last part of pregnancy. These data also
suggest that hormonal compensatory changes occur in PER mother rats to maintain glycemia and nutrient flux despite the severity of the undernutrition attested by maternal weight stagnation. This is also
illustrated by the lack of additional decrease in the birth weight of
PER pups compared with that of PR pups, whereas the body weights of the
mothers were significantly lower.
PR and PER, but not CER, pups had a significant decrease in their birth weight compared with C pups. This argues for a predominant effect of protein restriction over energy restriction on fetal growth retardation. One may retain as important for the interpretation of our data that the CER group exhibits mainly calorie deficiency, with limited associated protein malnutrition, whereas the PR group and the PER group were clearly protein deficient. Wade et al. (32), using diet compositions close to ours, indeed demonstrated that serum albumin level was not significantly affected by a reduction in food consumption as important as 50% after 6 wk (18% protein diet), whereas a 50% food restriction combined with 4% protein in the food significantly decreased serum concentration of albumin.
After birth, the pups of the four groups were submitted to a similar
environment, and weight retardation was rapidly (<15 days) remedied
in the protein-deprived groups; consequently no significant difference
in body weight was detectable among groups at the age of 8 wk. The female offspring of mothers who had been malnourished according to different patterns in the third part of
pregnancy acquired limited impairment of their glucose metabolism in
adult life. Whatever the adult experimental group, there was no clear
impairment of glucose tolerance compared with the C group after an
intravenous charge of glucose. A similar conclusion was previously
reported when a 65% reduction of daily energy intake was used during
the same period of gestation (20). However, the I-to-
G ratio was
significantly decreased in CER rats and significantly increased to a
similar extent in PR and PER rats compared with C rats. This decrease
in the CER group could be partly related to the lower basal plasma
insulin level observed in this group. Apart from long-term metabolic
changes induced by malnutrition, the difference in the
I-to-
G
ratio of PR and PER rats compared with C rats could also result from
differential response to the anesthetic procedure. The basal plasma
insulin-to-glucose ratio was enhanced by the anesthesia in the three
experimental groups but not in the C group (with 1.86-, 1.97-, 1.57-, and 0.97-fold increases, respectively, in CER, PR, PER, and C rats),
whereas no difference in its value could be detected between PR and PER rats vs. C rats in the awake state. Therefore, the aforementioned increase in the
I-to-
G ratio could be explained by a greater reactivity to anesthesia in the protein-restricted groups compared with
the C group. As a matter of fact, enhanced reaction to stressful situations and increased basal plasma levels of epinephrine and norepinephrine have been reported in protein undernutrition rat models
(15, 18).
In our study, insulin action was not dramatically altered whatever the model of malnutrition used. Comparison of the data related to GUR and GPR in the basal state in the restricted groups suggests that isolated protein restriction could contribute to a moderate but significant decrease in basal GPR and basal GUR. A previous study using protein restriction during gestation and lactation reported similar results in rats studied in the awake state (13). However, in our clamp studies under hyperinsulinemic and euglycemic conditions, analysis of GPR did not highlight any difference in the restricted groups compared with the C group, and no difference in GUR was detectable among the four groups. It is noticeable that a greater insulin infusion rate was needed during the clamp study in the CER group to get a SSPI value similar to that in the other groups. Therefore, an increased clearance of insulin would characterize the CER group. Our data show that the same SSPI as obtained during the clamp studies exerted the same efficiency on whole body GUR in the four groups and that restricted rats had no decrease in glucose utilization. Despite the possible enhanced reactivity of the rats to the anesthetized situation, we believe that extrapolating our data to the unanesthetized situation is nevertheless valid when the three restricted groups of rats are considered, because the three groups exhibited a similar relative change in their plasma insulin-to-glucose ratio from the awake to the anesthetized situation. A previous study based on 50% energy restriction during the entire pregnancy led to the same conclusion and did not show any effect on peripheral glucose utilization in adult female offspring (12).
The whole pancreas development was not dramatically changed despite an
increase of the pancreas weight in PER rats (1.25-fold increase), with
no impact on -cell mass or insulin content per milligram of
pancreas. On the other hand, the CER rats got an increase, whereas PR
rats got a decrease, in the insulin content expressed in microgram per
milligram of pancreas or microgram per gram of body weight. In the
absence of obvious change in insulin sensitivity, these data suggest
that protein restriction exerts a deleterious effect on
-cell
development during a critical period such as the end of pregnancy. This
was further confirmed by the decrease (28%) in
-cell mass only in
the PR group. The relatively higher insulin content found in the CER
group without change in
-cell mass could be explained by a lower
-cell stimulation, as suggested by a lower basal insulinemia and a
lower
I-to-
G ratio. Therefore, energy restriction (CER group) did
not appear to induce negative effects on
-cell development, at least
under our experimental conditions. Previous reports, using more severe energy restriction (65% reduction of daily intake) in the same period,
did not show any decrease of
-cell mass or of pancreatic insulin
content at 21 days of pregnancy and in adult life (1, 20). However, a
significant and persistent decrease of
-cell mass and of pancreatic
insulin content was found in another study in which the same conditions
and 50% energy restriction were used (8). In this work, only pups with
the lowest weights were selected and kept for further analysis. This
point could explain such discrepancy, because a vasculoplacental defect
would have been potentially associated with the effect of maternal
malnutrition on its own (7). Other studies have highlighted a
persistent decrease in
-cell mass in the adult offspring of
protein-restricted mothers (5), with a lower replication rate of
-cells and a lower islet vascularization in the fetuses (30) when
protein malnutrition was maintained during the entire pregnancy. The
decrease in
-cell mass reported in the aforementioned reference (5)
was very similar to what we found in the PR group. This reinforces the previous suggestion (27), that maternal malnutrition exerts long-term
adverse effects on insulin secretion only when it is applied during the
third part of gestation. Because amino acids are the main stimulus of
insulin secretion and
-cell growth during fetal life, this could
explain why protein malnutrition appeared particularly deleterious
during this period of development (6). It could imply a defect in
differentiation (neogenesis) and/or replication of
-cells, but the
targets of these detrimental effects of malnutrition are presently unknown.
Finally, we would like to point out that some of the minor disturbances here discussed could be aggravated during aging or other physiopathological conditions leading to insulin action impairment (2, 14).
In conclusion, the present study is the first one to investigate in the
rat the long-term effects of various fetal malnutrition protocols
strictly limited to the third part of pregnancy, which corresponds to
the crucial period for fetal rat pancreas development. Under these
conditions, protein deficiency, but not energy restriction, induced
persistent impairment of the development of the pancreas and especially
of -cell mass (
28%). On the other hand, glucose utilization
and production were only marginally affected in these models of
malnutrition. These changes did not induce alterations of glucose
tolerance in the adult under standard physiological conditions.
However, their implication as diabetes-predisposing situations acting
synergistically with other deleterious environmental and/or genetic
conditions cannot be excluded.
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ACKNOWLEDGEMENTS |
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This work was partly supported by a grant from the Ministre de l'Education Nationale, de l'Enseignement Suprieur et de la Recherche (95-G-0103; programme interministériel "Aliment Demain").
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FOOTNOTES |
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The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.
Address for reprint requests and other correspondence: E. Bertin, Laboratoire de Physiopathologie de la Nutrition, CNRS-ESA 7059, Université Paris 7/D. DIDEROT, Tour 33-43, 1er étage, 2 place Jussieu; 75251 Paris Cedex 05, France (E-mail: ebertin{at}chu_reims.fr).
Received 12 August 1998; accepted in final form 15 March 1999.
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