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-cell mass in fetuses of rats deprived of
protein and/or energy in last trimester of pregnancy
1 Laboratoire de Physiopathologie de la Nutrition, Centre National de la Recherche Scientifique-UMR 7059, Université Paris 7/D. DIDEROT, 75251 Paris Cedex 05; 2 Laboratoire de Biochimie, Hôpital Robert Debré, 51092 Reims Cedex; and 3 Centre de Recherche Merck-Lipha, 91385 Chilly-Mazarin Cedex, France
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Fetal malnutrition is now
proposed as a risk factor of later obesity and type II diabetes. We
previously analyzed the long-term impact of reduced protein and/or
energy intake strictly limited to the last week of pregnancy in Wistar
rats. Three protocols of gestational malnutrition were used:
1) low-protein isocaloric diet (5 instead of 15%) with pair
feeding to the mothers receiving the control diet, 2)
restricted diet (50% of control diet), and 3) low
protein-restricted diet (50% of low-protein diet). Only isolated
protein restriction induced a long-term 
-cell mass decrease. In the
present study, we used the same protocols of food restriction to
analyze their short-term impact (on day 21.5 of pregnancy) on -cell mass development. A 50% -cell mass decrease was present in the three restricted groups, but low-protein diet, either associated or not to energy restriction, increased fetal -cell insulin content. Among all the parameters analyzed to further explain our results, we
found that the fetal plasma level of taurine was lowered by low-protein
diet and was the main predictor of the fetal plasma insulin level
(r = 0.63, P < 0.01). In conclusion,
rat fetuses exposed to protein and/or energy restriction during the
third part of pregnancy have a similar dramatic decrease in -cell
mass, and their ability to recover -cell mass development
retardation depends on the type of malnutrition used. Moreover, our
results support the hypothesis that taurine might play an important
role in fetal -cell mass function.
endocrine pancreas
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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EPIDEMIOLOGICAL DATA IN VARIOUS human populations show that low birth weight and especially thinness at birth are associated with susceptibility to the development of impaired glucose tolerance/type II diabetes in adult life (16, 23, 26, 28, 31, 32). This association has been interpreted as reflecting long-term effects of nutritional factors that reduce fetal growth and impair the development of tissues regulating glucose metabolism (14, 29, 36).
Among these tissues, the endocrine pancreas, and especially -cells,
could suffer from fetal malnutrition. Babies with intrauterine growth
retardation have a marked reduction in the size of their endocrine
pancreas (41). Animal studies also report that fetal malnutrition is associated with persistently impaired pancreatic -cell function and development (11, 13). With the use
of a low-protein diet during whole rat pregnancy, reduced proliferation rate, size, and insulin content of pancreas islets were observed in
fetuses at the end of pregnancy (11, 38).
However, human data did not highlight a clear relationship between body
weight or ponderal index (weight/height3) at birth and
-cell function in adult age (8), and human fetal
malnutrition was reported to be more strongly related to insulin
resistance (5, 9, 10, 23, 26, 31, 40). Some experimental
data obtained in adult rats whose mothers were submitted to
malnutrition support this hypothesis, revealing an impact on insulin
action and fat mass development (17-19). Actually, various patterns of fetal malnutrition were shown to differentially affect adult -cell mass and then could explain the heterogeneity in
the above data. Indeed, 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-old male offspring (35). However, when such food restriction was applied in the last week of the
rat pregnancy, it did significantly affect the pancreatic insulin
stores and the -cell mass in the fetuses or the offspring neonates
(1, 13). Moreover, in a previous study, we demonstrated that pancreatic insulin content and -cell mass in adult age were influenced by the type of malnutrition (energy and/or protein restriction) during the fetal stage of pancreas development, with a
particularly deleterious impact of protein deficiency (3).
To explain the differential impact of the type of fetal malnutrition on
adult -cell mass, one may envisage the following options:
1) various adaptative responses of mothers and/or various specific nutrient needs for -cell mass development independently of
whole fetal growth. For example, amino acids, especially taurine, were
suggested to be essential to insulin secretion during fetal life
(6, 12, 39); 2) a differential recovery of
-cell mass deficiency after birth (34).
The present study was therefore designed to allow a separate analysis
of the immediate impact of protein deficiency per se from that of
energy deficiency in the last trimester of gestation on pancreatic
insulin content and -cell mass. More specifically, we analyzed at
the end of gestation (day 21.5) the impact of three different patterns of fetal malnutrition strictly limited to the last
week of pregnancy: 1) energy restriction to 50% of control diet, 2) low-protein diet with pair feeding on control diet,
or 3) energy restriction to 50% of control diet but using a
low-protein diet. Numerous other parameters (various anthropometric
data, plasma levels of glucose, insulin, amino acids pool, and taurine) were also measured to further document and interpret the short-term impact of malnutrition on -cell development retardation.
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MATERIALS AND METHODS |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Diets
The powdered semisynthetic 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 semisynthetic 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 in Picarel-Blanchot et al. (33).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 to 260 g, they were mated for 1 night (from 1700 to 0900). 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 cages. Pregnant females were fed a standard diet ad libitum during the first 2 wk of pregnancy and then assigned to one of the following four experimental conditions during the last week of pregnancy from day 14.5 to day 21.5 (1 day before delivery) where fetuses were analyzed. 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 with the low-protein diet. Control rats (the fourth group) were given access to standard diet ad libitum throughout pregnancy. Fetuses in the four groups will subsequently be referred to as standard diet restricted (CER), low-protein diet restricted (PER), low-protein pair fed (PR), and control (C) groups, respectively. In each group, four pregnant rats, with litters from 9 to 13 fetuses, were analyzed.Body weight was measured weekly in pregnant mothers. On day 21.5 of pregnancy, rats were fasted from 0800 and anesthetized with pentobarbital sodium (4 mg/100 g body wt ip; Sanofi Santé Animale, Sanofi, France) between 0930 and 1030. Blood samples (350 µl) were collected from the tail vein after 15-min anesthesia. After 20-min anesthesia, pregnant rats underwent a laparotomy for fetuses' analysis.
It is important to mention that no major alteration of the feeding pattern took place in the restricted groups, because we verified that rats had an excess of food available most of the time (e.g., at least for 11 h) during the nocturnal feeding period and that the restricted rats never consumed their daily food ration in one short meal. One may therefore consider that the duration of subsequent fasting was comparable in the four groups when blood samples were collected.
Fetal Sampling
Fetuses maintained connected to the mother by their placenta and umbilical cord were successively exteriorized from the uterus, and blood samples were collected after section of the axillary vessels. Blood was taken from fetuses on both uterine horns in parallel, following exactly the same procedure in each pregnant rat. The duration of blood sampling for all the fetuses in one litter never exceeded 15 min. During the whole experiment, the body temperature of the pregnant rat was maintained at 37°C with heating lamps. After the blood from all fetuses was collected, an additional blood sample was obtained from the tail of a pregnant rat to assess the variation of the plasma glucose level.The fetuses with their placenta were then removed from the uterus and
weighed. Fetus size was determined by measuring the anonasal length to
calculate the Lee index (body weight in g/size3 in dm) and
obtain an assessment of fetus thickness (22). For each
litter in each group, four pancreases were dissected and weighed. Two
pancreases were kept for measurement of pancreatic insulin content, and
two pancreases were kept for -cell mass measurement (from the
latter, only one pancreas was analyzed, and the other one was just kept
in paraplast as a security to avoid loss of information in case a
technical problem happened when sectioning and immunostaining the first
one). The weights of liver and kidneys were also obtained in the same
conditions in, respectively, two and four fetuses per litter to detect
a differential impact of protein and/or energy restriction on the development of these organs compared with pancreas development.
In fetuses, the plasma levels of glucose, 20 classical amino acids, taurine, insulin, glucagon, and corticosterone were measured. Amino acids and glucose are indeed the major stimuli of insulin secretion in fetal life (20, 37). Glucagon and corticosterone measurements were aimed to assess in fetuses the potential metabolic stress due to malnutrition (2, 25). Blood nutrient levels (glucose, free fatty acids, 20 classical amino acids pool and taurine) and plasma albumin were also determined in the pregnant rats.
-Cell Immunohistochemistry and Morphometry
-cell relative volume was obtained by calculating the ratio between
the area occupied by immunoreactive cells and the area occupied by
total pancreatic cells according to stereological methods. The total
-cell mass per pancreas was derived by multiplying the -cell
relative volume by the total pancreatic weight.
Samples and Analytic Techniques
Blood samples in pregnant rats (200 µl for serum and 150 µl for plasma measurements) and in fetuses (whole body blood content for plasma measurements) were immediately put into ice-chilled vials. They were then centrifuged and the plasma or the serum was separated. Plasma glucose concentration was immediately determined in a 10-µl aliquot, and the other plasma or serum aliquots were kept at
20°C until
other measurements determination. For glucagon and corticosterone,
plasma from three and five fetuses per litter was pooled. The plasma
sample for glucagon measurement was mixed with a kallikrein inhibitor
(Iniprol, Sanofi, Libourne, France) before freezing.
Plasma glucose level was determined with a glucose analyzer (Beckman, Palo Alto, CA).
Plasma amino acids and taurine concentrations were measured by ionic exchange chromatography on an automatic equipment using ninhydrine as a reactive agent (Liquimat 4HP, Labotron, France). Serum levels of free fatty acids were obtained by an enzymatic method (NEFA C Wako, Unipath SA, France). Albuminemia was measured with a classical technique using Green of Bromocresol. Immunoreactive insulin in the plasma and fetus pancreases was estimated with purified rat insulin as standard (Novo, Copenhagen, Denmark), and porcine monoiodinated 125I-labeled insulin (32). 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%. Commercial kits for determination of plasma glucagon and corticosterone concentrations were, respectively, from Pharmacia, St-Quentin, France and ICN.
Statistical Analysis
Results are given as means ± SE. ANOVA (Fischer's test) was used for comparison of unpaired data between groups. A P value <0.05 was considered significant.Pearson's correlation coefficient was also used, and stepwise multiple regression models permit to identify the variables independently related to the fetuses' parameters considered (Statview SE, Abacus Concepts, Berkeley, CA).
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Body Weight, Plasma Albumin, and Nutrient Concentrations in Pregnant Rats
On day 14.5 of pregnancy, body weight did not significantly differ among the four groups of mothers (which had similar numbers of fetuses per litter).In the three experimental groups of rats submitted to a 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 the CER and PR groups and a body weight stagnation
in the PER group (Table 1). In the four
groups, the whole daily food supply was fully ingested.
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Biological data related to pregnant rats on day 21.5 of
pregnancy are presented in Table 2.
Briefly, the plasma albumin level was decreased in the three restricted
groups but quite more in the protein-restricted PR and PER groups.
However, total amino acidemia was not significantly different among the
four groups. Free fatty acid concentrations were not significantly
different between the restricted groups and the C group. The basal
plasma glucose level was similarly decreased in the PR and PER groups without reaching significance compared with the C group. The CER group
had values similar to the C group.
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Characteristics of the Fetuses on Day 21.5 of Pregnancy
Fetal growth. The average number of fetuses per mother was similar in all groups studied. Fetuses differed in their body weight value according to the diet changes in the last week of pregnancy (Table 1). The fetuses from the CER, PR, and PER groups had a significantly lower birth weight compared with the C group. No relationship between offspring and mother body weights could be detected. The fetal anonasal length was significantly reduced in the three restricted groups compared with the C group. As the impact of food restriction on fetal size was more marked in the CER group, the fetuses' thickness as described by the Lee index was higher in the CER group than in the other groups.
The three different types of food restriction altered placenta development with a more marked effect in the PR and PER groups than in the CER group. Accordingly, the fetus-to-placenta weight ratio was significantly increased in the PR and PER groups, but not modified in the CER group, compared with the C group. Concerning the other organ-to-fetal weight ratios in fetuses, no significant difference was seen for kidneys and pancreas among the four groups. The liver-to-fetal weight ratio was significantly reduced in the three restricted groups, but the liver-to-placenta weight ratio did not significantly differ among the four groups.Plasma levels of glucose, amino acids, insulin, glucagon, and corticosterone. The plasma glucose level in pregnant rats was increased when collecting blood samples from fetuses, but this increment was moderate and not significantly different among the four groups (CER: +15%; PR: +17%; PER: +18%; C: +11%). This observation suggests that our sampling methodology is acceptable and allows a reliable comparison of plasma glucose and insulin levels among the different fetuses' groups.
Data are presented in Table 3. Glycemia was lower in the PR group than in the other groups (difference was only significant vs. the C and PER groups, respectively; P < 0.05 and 0.03). Concerning the insulinemia-to-glycemia ratio in fetuses, it was significantly decreased in the PER group with about half the value found in the CER and C groups (respectively, P < 0.03 and 0.05). No differences between fetuses from food-restricted and C dams were detected for plasma glucagon and corticosterone.
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Pancreatic Insulin Content and Total -Cell Mass of the Fetuses
on Day 21.5 of Pregnancy
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The pancreatic -cell mass (expressed as absolute value or relatively
to fetal body weight) was significantly decreased (P < 0.001) to a level similar in the CER, PR, and PER fetuses compared with
the C fetuses.
When calculating the mean insulin content-to--cell mass ratio, we
found that this parameter was significantly higher in the low
protein-restricted groups (PR and PER groups) than in the C group.
Interestingly, an inverse correlation was present between this ratio
and fetal insulinemia or insulinemia-to-glycemia ratio (respectively,
r = 0.73, P < 0.001 and
r = 0.65, P < 0.007) when analyzing
the litters of the four groups as a whole.
Blood Taurine Level in Dams and Fetuses on Day 21.5 of Pregnancy
Postabsorptive blood levels of taurine were similar in the four groups of pregnant rats (Table 5). In fetuses, a significant decrease was present in the PR and PER groups compared with the C and CER groups, arguing for a specific impact of protein restriction on this parameter.
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When pooling the data from the four groups, the fetal blood taurine level did appear as the only predictor of fetal insulinemia or insulinemia/glycemia (respectively, r = 0.63, P < 0.009 and r = 0.52, P < 0.04).
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Our present data indicate that low energy and/or protein diet in the third part of gestation do not significantly affect basal plasma nutrient levels (glucose, free fatty acids, and pool of amino acids) in pregnant rats when measured in the postabsorptive state. Plasma albumin level was decreased mainly in response to protein restriction. One may retain as important for the interpretation of our data that the CER group exhibits mainly energy deficiency with limited associated protein malnutrition, whereas the PR and PER groups were clearly protein deficient. Our data are therefore consistent with the report by Wade et al. (42) who demonstrated that a 50% reduction in food consumption during 6 wk in nonpregnant rats did not affect serum albumin level, whereas protein restriction (4% protein in the food) added to energy restriction significantly decreased serum concentration of albumin.
As previously reported by our group, the association of protein and energy restriction was more deleterious on body weight growth in pregnant rats (3). Our data suggest that hormonal compensatory changes occur in PER pregnant rats to maintain glycemia and nutrient flux despite the severity of the undernutrition as attested by maternal weight stagnation. This is also illustrated by the lack of additional decrease in the weight of PER fetuses compared with that of PR fetuses, whereas their mothers' body weight was significantly lower.
In the third part of gestation, placenta development was also found to be mainly dependent on protein supply, thus confirming previous reports in rat and other species (4, 15, 27). A strong positive relationship was detected between plasma albumin level in pregnant rats and placenta weight when pooling the four groups studied as a whole (r = 0.82, P < 0.0001). Liver development was also mainly significantly altered by protein restriction (Table 1). However, fetal growth of the pancreas and kidneys was not specifically altered by protein and/or energy restriction as assessed by the organ-to-body weight ratio measurements. To explain this result, we assume that the liver, which is first and directly connected to the placenta blood flow, could attenuate the deleterious impact of protein restriction. However, the highest value in the fetal body weight-to-placenta weight ratio was found in the PR group, suggesting that compensatory adaptations in nutrient flux through the placenta were probably induced by protein restriction, because no significant changes could be detected in the blood nutrient levels of PR pregnant rats compared with the C rats (see the results in Table 2).
In fetuses, the pool of free amino acids was maintained normal whatever the food-restriction protocol. The same conclusion could be drawn for the pool of essential amino acids (data not shown), whose blood level was similar among the four groups, whereas plasma glucagon or corticosterone levels were not significantly changed by food restriction. Taking into account a possible confounding effect of physiological variations in the 24 to 30 h preceding labor on the above parameters, we may reasonably assume that placenta is able to ensure sufficient nutrient supplies to fetuses even in unfavorable environmental conditions, at least during the third part of gestation.
Despite an unchanged pancreas-to-total body weight ratio in
food-restricted fetuses, -cell mass was highly reduced by both protein and energy restriction at a similar level (~48% of control data) when adjusting the results on total body weight. However, the
relative pancreatic insulin content (insulin content per mg of body
weight) was significantly changed (32% decrease) only in CER rats
compared with C rats. An increase of the pancreatic insulin
content-to--cell mass ratio was therefore present in PR and PER
fetuses. Moreover, no significant relationship between -cell mass
and pancreatic insulin content could be detected, and fetal insulinemia
and insulinemia/glycemia were inversely related to the pancreatic
insulin content-to--cell mass ratio (r = 0.73,
P < 0.001 and r = 0.65,
P < 0.007, respectively). Taken together,
these data suggest that insulin secretion might be impaired in fetuses
submitted to protein restriction, and this alteration would be located
at the exocytosis step in the insulin secretion cascade and not in the
insulin pool of the -cell. Although this is a speculative
assumption, recent experimental data from Cherif et al.
(7) support this hypothesis.
A few years ago, the -amino acid taurine was proposed as an
essential amino acid for fetal -cell function (6). In
their study, Cherif et al. (7) found an in vitro insulin
secretion defect by islets from low protein-fed rat fetuses, and these
defects were corrected when taurine was added to the low-protein diet of dams. Therefore, in the present study, we measured the
concentration of taurine in maternal and fetal blood at the end of the
malnutrition period. In the pregnant rats, blood taurine level was not
significantly changed by the different patterns of food restriction.
These results are in opposition with those of Cherif et al. who found a
decrease of taurine concentration in the low protein-fed pregnant rats, but at variance with us, they applied their protocol of protein restriction to the whole gestation. However, we also detected a
decrease of the taurine level in fetuses whose mothers were submitted
to a low-protein diet (PR and PER rats), and this decrease was present
independently of energy supply. We also found that the blood taurine
level was the main independent predictor of insulinemia or
insulinemia/glycemia in fetuses. At the opposite, maternal glycemia did
not appear as an independent predictor of fetal insulinemia in our
study. These results support the hypothesis that taurine could play a
role in fetal -cell function.
Concerning the impact on -cell mass, a previous report by Garofano
et al. (13), using a 50% energy-restriction protocol in
the same period, also showed a significant decrease of -cell mass
and of pancreatic insulin content. Fetal growth retardation was
assessed to be ~18% in their study vs. 15% in the present study. In
Garofano's work, however, analysis was performed at birth and only
pups with the lowest weights were selected and kept for further
analysis. A 40% decrease in total insulin content of CER pups compared
with C was found at birth. This result is very similar to the result of
32% decrease reported in our study for the CER group at day
21.5 of pregnancy. Concerning the absolute -cell mass, a 35%
decrease was reported by Garofano vs. 55% decrease in the present
study. This difference could be explained by the difference in the
stage of analysis and in the methodology (only 5 to 7 sections were
analyzed per pancreas in Garofano's study).
In previous work, we analyzed the long-term impact in the young adult
female offsprings of our different patterns of food restriction in the
same experimental conditions. Briefly, weight retardation was rapidly
(<15 days) reversed and no significant difference in body weight was
therefore detectable among the four groups at the age of 8 wk. The
female offspring of mothers who had been malnourished according to
different patterns in their third part of pregnancy get limited
impairment of their glucose metabolism in adult life without change in
insulin action. 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 micrograms per milligram of pancreas or micrograms per
gram of body weight (respectively, +23 and 29%). These data on the pancreatic insulin content are opposite to those found in the present
study at the fetal stage, at least for PR and CER rats. In PER rats,
the plasticity of the pancreas seems therefore more important as they
can totally correct the abnormalities detected during fetal stage. The
significant decrease of the -cell mass (~50%) present in fetuses
of the three restricted groups still persists at the age of 8 wk only
in the PR group (28%).
These data demonstrate that strong defects of -cell mass growth can
be partially recovered after birth when the food restriction is not
prolonged after a period of fetal malnutrition. However, this relative
recovery depends on the pattern of maternal food restriction. In the
present study, we did not detect any relevant differences between PR
and PER fetuses concerning biological parameters analyzed or fetal
growth for whole body or organs. When protein restriction was present,
-cell mass on day 21.5 of pregnancy was not influenced by
the level of energy supply. As a matter of fact, the Lee index was
increased in CER fetuses compared with the other groups, whereas a
stronger relationship was detected in humans between risk of diabetes
in adulthood and thinness at birth than with isolated low birth weight
(31). We thus may assume that energy restriction during
the third part of gestation represents a favorable situation to the
recovery of -cell mass during postnatal growth even when a protein
restriction is superimposed. But the determinants of the recovery of
-cell mass and function are presently unknown. A direct modulation
of differentiation and/or replication of -cells could be involved.
Persistent alterations of the autonomous nervous system may also be
supposed. Some studies indeed demonstrated a long-term impact of
protein malnutrition on the reactivity of the sympathetic system
(21, 24).
In conclusion, the present study is the first one to investigate the
immediate impact 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 and/or 50% energy restriction induced a
marked impairment of -cell mass development (50%) after adjusting
the results on fetal growth retardation. Moreover, our results support
the hypothesis that the amino acid taurine has an important role for
fetal -cell function, which could explain a differential impact of
protein and energy restriction on pancreatic insulin content. Compared
with our previous study analyzing the long-term impact of the same
patterns of malnutrition, the present results demonstrate that the
recovery of the -cell mass development retardation depends on the
type of fetal malnutrition.
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ACKNOWLEDGEMENTS |
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This work was partly supported by a grant from the Ministère de l'Education Nationale, de l'Enseignement Supérieur et de la Recherche (#95-G-0103; programme interministériel "Aliment Demain").
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FOOTNOTES |
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Address for reprint requests and other correspondence: E. Bertin, Laboratoire de Physiopathologie de la Nutrition, Centre National de la Recherche Scientifique-UMR 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).
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. Section 1734 solely to indicate this fact.
May 16, 2002;10.1152/ajpregu.00037.2002
Received 22 January 2002; accepted in final form 13 May 2002.
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REFERENCES |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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