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Department of Animal Science and Animal Health, Division of Animal Nutrition, Royal Veterinary and Agricultural University, DK-1870 Frederiksberg, Denmark;
* Department of Medical Physiology, University of Copenhagen, DK-2200 Copenhagen, Denmark; and
Unité Mixte de Recherches sur le Veau et le Porc, INRA, 35042 Rennes Cedex, France
2To whom correspondence should be addressed. E-mail: psa{at}kvl.dk.
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ABSTRACT |
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 TOP ABSTRACT MATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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KEY WORDS: • milk • fetus • newborn • weaning • enteral • parenteral nutrition • piglets
The pig small intestine grows more than the body as a whole during the weeks before parturition, and its weight relative to body weight increases 70–80% over the last 3 wk of gestation (1,2). Immediately after birth, relative small intestinal weight undergoes a further marked increase (60–100%) in response to the ingestion of milk nutrients (1–3). Luminal nutrients may exert their profound trophic effects on the small intestine both directly and indirectly via locally produced gastrointestinal peptides and growth factors (1,4,5). Large decreases in luminal feed intake, as in the case of newly weaned pigs, are associated with dramatic reductions in intestinal villous heights and deeper crypts (6,7). The villous height to crypt depth ratio is restored after the resumption of food intake, as a result of the trophic effects of luminal contents on the small intestine (6,7).
Glucagon-like peptide 2 (GLP-2) is a highly conserved 33 amino acid peptide released from the post-translational processing of proglucagon in the enteroendocrine L-cells of the ileum and colon. GLP-2 is released in response to enteral nutrient ingestion and is thought to mediate in part the response of the small intestine to luminal nutrients (5,8). We showed previously that GLP-2 administration reverses the atrophic effects of total parenteral nutrition (TPN) and stimulates small intestinal growth to the same extent as enteral nutrition in neonatal pigs (5). Despite this demonstrated responsiveness of the neonatal pig small intestine to exogenous GLP-2, it is not clear whether endogenous GLP-2 plays a physiologic role in gut development in the pig. To date, the sole documented physiologic role of GLP-2 has been as regulator of small intestinal development in a rat model of hyperphagia (9).
GLP-2 also mediates a variety of actions that collectively act to improve nutrient digestion and absorption and gut permeability (10–13). The actions of GLP-2 are mediated via a specific receptor that has been localized on the enteric neurons in rats and on the gastric and small intestinal endocrine cells in humans (14,15). Using relative reverse transcription polymerase chain reaction (RT-PCR), we have detected glucagon-like peptide 2 receptor (GLP-2R) mRNA in the gastrointestinal tract of fetal and neonatal pigs (16). To date, no studies have examined GLP-2R mRNA levels during development or in response to enteral nutrition. The first goal of this study was to measure plasma GLP-2 concentrations and GLP-2R mRNA levels over the course of development pre- and postnatally. The second goal was to determine the relationship among plasma GLP-2 concentrations, small intestinal GLP-2R mRNA abundance and small intestine growth in response to either the enteral intake of milk nutrients or the parenteral administration of elemental nutrients. To investigate the extent to which the responses to enteral nutrition were dependent on birth and gestational age at delivery, fetal, premature newborn and term newborn pigs were used in the study.
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MATERIALS AND METHODS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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Large White x Landrace pigs were used in all of the studies. The following groups of pigs were used to study plasma GLP-2 concentrations during development: fetal pigs (n = 23, delivered by cesarean section at 98 ± 1 d or 106 ± 2 d gestation, term = 115 ± 2 d); newborn pigs (n = 12, vaginally delivered at term); suckling pigs aged 1 d (n = 13), 2 d (n = 6), 3 d (n = 9), 7 d (n = 9), 18 d (n = 9), 21 d (n = 13) and 23 d (n = 6); and pigs weaned on d 21 and aged 23 d (n = 8) and 25 d (n = 9). The weaning diet was a commercial dry starter diet composed of (g/kg feed): wheat meal, 276; corn, 280; barley, 145; soybean meal, 250; calcium carbonate, 17; calcium phosphate, 18; vitamin/mineral premix, 5; lysine, 3; methionine, 1.2; threonine, 1.1; tryptophan, 0.1; and salt 3.5). Plasma was isolated from blood collected from the umbilical artery of the fetal cord or from the jugular vein of the suckling and weaned pigs. The following groups of pigs were used to study the small intestinal GLP-2R mRNA abundance during development: fetal pigs (n = 4, delivered by cesarean section at 106 ± 2 d gestation); newborn pigs (n = 4); suckling pigs aged 2 d (n = 4), 6 d (n = 4) and 18 d (n = 4); and weaned pigs aged 25 d (n = 4). The suckling pigs were housed in stalls with lactating sows, and the weaned piglets were housed in individual cages and consumed the dry starter diet ad libitum.
A total of 13 pigs, delivered prematurely by caesarean section at d 106, were used to study the effect of enteral administration of a milk diet vs. parenteral infusion of elemental nutrients on plasma GLP-2 concentrations and GLP-2R mRNA abundance. The piglets received either TPN (n = 7) or enteral nutrition (n = 6) during the first 6 postnatal days. Another 13 pigs, were delivered at term by caesarean section at 115 d, and received either TPN (n = 7) or enteral nutrition (n = 6) during the first 6 postnatal days. Piglets assigned to the TPN groups were fitted with a vascular catheter inserted into the dorsal aorta via the umbilical artery (infant feeding tube 4F, Portex, Kent, UK) while the pigs were still anesthetized. After the cord was ligated with a soft cotton thread close to the skin to prevent bleeding, sutures to the cord and skin were performed to secure the catheters. The pigs that were to be fed enterally were fitted with a dorsal aorta catheter as above, and an orogastric feeding tube (6F, Portex), which was passed through the cheek and secured to prevent damage by chewing. Finally, an elastic body suit (Danagrib, Copenhagen, Denmark) was fitted onto all pigs to protect the catheters.
The parenteral nutrition solution used for the TPN pigs was prepared aseptically and consisted of a series of commercial products mixed into 3-L TPN bags (Nutrimix, Braun, Melsungen, Germany) (4). The nutrient solution contained free amino acids (45.5 g amino acids/L; Vamin 18F), glucose (72.5 g/L), lipid (30.7 g/L; Intralipid) all supplied by KABI Pharmacia, Copenhagen, Denmark. The products, nutrient composition and concentrations of macrominerals in the TPN solution were listed previously and were slightly modified from those used and validated earlier for 3- to 10-d-old term pigs (4,17). Modifications included reductions in the concentrations of protein and macrominerals because preliminary results showed that the growth rate and the maximum energy and protein intakes tolerated by premature TPN-fed pigs were considerably less than those tolerated by term TPN-fed pigs, as assessed by blood urea and glucose levels (4,5). In the preliminary studies, excessive nutrient intakes were associated with urea levels of 8–12 mmol/L and glucose levels of 6–8 mmol/L (normal ranges, 3–6 mmol/L for both metabolites).
The TPN solution was infused continuously via the arterial catheter and the milk via the orogastric tube, using automatic infusion pumps (Infusomat Secura, Braun). The parenterally and enterally fed pigs received isoenergetic and isoproteinous amounts of nutrients daily by continuous infusion. The feeding protocols for all parenterally and enterally fed pigs have been described extensively (4). Feeding began 10 h after birth, and the piglets were weighed daily to adjust their nutrient infusion rates. The premature TPN pigs received 580 kJ/(kg body · d), 8.1 g amino acid/(kg body · d) and a fluid intake of 180 mL/(kg body · d) during the 2- to 6-d period. During the initial 2 d of the experiment, the pigs were fed at only 50% of this rate. For term pigs, the rate of TPN fluid input was equivalent to 730 kJ/(kg body · d), 10.3 g amino acid/(kg body · d) and a fluid intake of 230 mL/(kg body · d) with an initial adaptation period as above.
Enterally-fed piglets were administered sow’s colostrum (for 1 d) or the modified sow’s milk (for 5 d) at an hourly rate identical to that of the TPN solution. Sow’s colostrum was collected from a number of different sows within 6 h of parturition and sow’s milk was collected 4–10 d after parturition. The pooled sow’s milk, containing 4950 kJ/L and 51 g protein/L, was mixed (50:50, v/v) with skimmed cow’s milk, to make the energy and protein concentrations match those of the TPN fluid, resulting in 3350 kJ/L and 44 g protein/L for the final modified sow’s milk solution. The nutritional goal was to provide the pigs with sufficient energy and protein to allow for a slightly positive energy balance (e.g., growth rate) that was similar between parenterally and enterally fed pigs. All piglets were weighed daily and arterial blood samples (1.5 mL) were collected at 0800 h on d 2, 4 and 6 for later determination of plasma GLP-2 concentrations.
Four pregnant sows (gestational age 106 ± 2 d) were used to study the effect of enteral nutrition on plasma GLP-2 concentrations and GLP-2R mRNA levels in fetuses in utero. Surgery conditions were described previously (18). After exteriorizing the fetus, a small incision was made in the esophagus and a silastic catheter (vinyl tube, i.d. 0.86 mm, o.d. 1.52 mm, Dural Plastics and Engineering, Auburn, Australia) was passed down the esophagus of the fetus such that the tip entered the fetal stomach. The esophagus was ligated, and amniotic fluid swallowed by the fetus was returned to the amniotic cavity via a catheter inserted into the esophagus via the pharynx. After catheterization, the fetal skin incision, fetal membranes and uterine incision were closed. Two fetuses were randomly selected and catheterized in each sow. While in utero, fetal pigs were manually infused with a bolus of colostrum (15 mL) every 3 h for a period of 24 h. The colostrum fed was taken from a pool of colostrum collected from different sows within 6 h of delivery. Pig colostrum consists of (g/100 g colostrum) total protein, 15.0; fat, 5.9; and lactose, 3.4 (19). After 24 h, the fetuses were delivered by cesarean section and a 2-mL arterial blood sample was taken from the umbilical artery for later determination of plasma GLP-2 concentrations.
Tissue collection.
All of the pigs were killed with an intravenous overdose of sodium pentobarbitone (200 mg/kg body). The pigs were weighed, the abdomen was opened and the entire small intestine distal to the ligament of Treitz was removed and immediately flushed with ice-cold physiologic saline. The small intestine was divided into two segments of equal length (jejunum and ileum), and mid-section samples of each were snap-frozen individually in liquid nitrogen and stored at -70°C for mRNA analysis.
The weight of the small intestine was determined and a small intestinal sample was collected from the mid-jejunum of 18-d-old suckled and 25-d-old weaned, colostrum-fed and untreated control fetuses and parenterally and enterally fed premature and term-delivered neonates; the sample was fixed in 4% paraformaldehyde for 24 h and then stored in 75% ethanol at 4°C, for analysis of villous height. All of the animal experiments were approved by the National Committee on Animal Experimentation, Denmark.
Plasma GLP-2 analysis.
All blood samples were drawn into ice-cold tubes containing EDTA (3.9 mmol/L) for later determination of plasma GLP-2 concentrations. Blood samples were gently shaken and immediately centrifuged at 2000 x g at 4°C for 5 min to obtain plasma, which was stored at -20°C until analysis. Plasma GLP-2 concentrations were quantified as described previously (9). Approximately 300 µL of extracted samples and human GLP-2 (1–33) standards were incubated with 100 µL of rabbit GLP-2 antiserum (final dilution 1:25000) raised against an N-terminal fragment of human GLP-2; this antiserum specifically recognizes the N-terminal region of both human and porcine GLP-2. The experimental detection limit of this assay was <5 pmol/L and the intra-assay CV was 5% at a concentration of 40 pmol/L.
Reverse transcription polymerase chain reaction (RT-PCR).
RNA extraction, RT and PCR experimental procedures were described previously (16). Primers designed to identify GLP-2R mRNA sense (5'-ACCTTGCAGCTGATGTACAC-3') and antisense (5'GTGTTCTCCAGGTGTGCACG-3') were used. The relative abundance of the enzyme PCR products on the gels was quantified by an optical densitometry reading (Image Pro Plus 4.1 software) of PCR bands on digitalized pictures (BioCapt 97 software, Vilber Lourmat, Cedex, France) of gels. The density of each cDNA band was expressed relative to the density of its corresponding 18S rRNA band and expressed as arbitrary units (AU). To confirm the identity of each PCR product, the cDNA was extracted from the gel (QIAquick gel extraction kit, West Sussex, England), sequenced (TAGC, Copenhagen) and entered in BLAST (National Centre for Biotechnology Information). The partial pig GLP-2R cDNA sequenced showed 86 and 84% similarity to human and rat GLP-2R, respectively (16).
Morphometry.
Paraformaldehyde-fixed samples were embedded in paraffin, sectioned (5 µm) and stained with hematoxylin and eosin. Mean villous height was measured in 15 vertically well-oriented villus-crypt and averaged by an observer who was unaware of treatment using an Axiophot microscope (Carl Zeiss, Germany) and NIH image software version 1.60 (U.S. National Institutes of Health, Bethesda, MD).
Data analyses.
Data are expressed as means ± SEM, with n as the number of pigs. The developmental age data were analyzed by Duncan’s Multiple Range test using a general linear model within SAS (version 6.03, SAS Institute, Cary, NC). Plasma GLP-2 concentrations during development are expressed as means ± SEM. GLP-2R mRNA abundance was determined across the small intestine by including intestinal region (jejunum and ileum) as a main effect in the statistical analysis; the data were presented as least-square means ± SEM. The effects of enteral vs. parenteral nutrition in newborn and fetal pigs were tested by Student’s t test. Significance was assigned at P < 0.05 for all statistical evaluations.
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RESULTS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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Plasma GLP-2 concentrations in fetuses (98 d) were 
4 pmol/L (shown with the dotted line, below the 5 pmol/L detection limit of the assay), increased significantly before birth (18–30 pmol/L) and peaked on the first postnatal day (87 ± 14 pmol/L, P < 0.05, Fig. 1). Thereafter, plasma GLP-2 concentrations decreased and did not change throughout the suckling period. Intake of the weaning diet was very limited during the first days after weaning (10 ± 1 g/d) but increased thereafter to reach 239 ± 21 g/d on d 4 after weaning. Plasma GLP-2 concentrations decreased just after weaning (34 ± 5 pmol/L), in association with decreased food intake, but returned to preweaning levels in association with an increase in nutrient intake (81 ± 10 pmol/L, P < 0.05, Fig. 1). Plasma GLP-2 concentrations in 23-d-old weaned pigs were also decreased compared with age-matched suckling pigs (34 ± 5 vs. 63 ± 19 pmol/L, P < 0.05). GLP-2R mRNA abundance across the small intestine was lowest in association with the initiation of food intake after birth and weaning (P < 0.05, Fig. 1). Preliminary analyses of a limited number of amniotic fluid, milk and colostrum samples (n = 2) from three different species (pig, cow and sheep) showed that GLP-2 concentrations were relatively low in all of these fluids (0–20 pmol/L).
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Enteral nutrition before birth.
In fetuses, plasma GLP-2 concentrations were significantly increased by colostrum feeding (P < 0.05, Fig. 2). GLP-2R mRNA abundance, across the small intestine was markedly decreased by enteral colostrum feeding in fetuses (P < 0.05, Fig. 2). Villous heights were not different in the colostrum-fed and control fetuses (801 ± 71 vs. 806 ± 29 µm), despite a significant increase in the relative small intestinal weight of the enterally fed fetuses compared with untreated controls (34 ± 3 vs. 21 ± 2 g/kg body, P < 0.05). Fetal surgery and catheterization in pigs have previously been shown not to change circulating GLP-2 levels in fetal pigs compared with untreated controls (14 ± 1 vs. 16 ± 5 pmol/L) (16).
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All pigs gained weight (mean values 30–60 g/d) during the 6-d feeding protocol, and daily weight gain was not different between preterm and term pigs and parenterally and enterally fed pigs (4).
In premature pigs, symptoms indicative of feed intolerance and intestinal dysmotility (distended bowel and no feces after 2–3 d of feeding) were observed in 60% of the enterally fed group (4). In the prematurely delivered pigs, plasma GLP-2 concentrations were significantly lower in enterally vs. parenterally fed pigs on d 2 but on d 6, plasma GLP-2 concentrations were higher in the enterally fed pigs (Fig. 3a). On d 6, GLP-2R mRNA abundance across the small intestine was markedly decreased by enteral nutrition (P < 0.05, Fig. 3a). In premature pigs, villous heights were higher in the enterally vs. parenterally fed pigs (642 ± 12 vs. 478 ± 14 µm) (5). Relative small intestinal weight was also significantly higher in enterally compared with parenterally fed pigs (30 ± 2 vs. 20 ± 1 g/kg body, P < 0.05).
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DISCUSSION |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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Circulating GLP-2 concentrations decreased shortly after weaning; this may be explained by the marked decline in the pigs’ nutrient intakes because plasma GLP-2 concentrations were significantly higher in suckling pigs of the same age. The weaning transition period in pigs is frequently associated with adverse changes in intestinal morphology, such as reduced villous height, increased villous width, increased crypt depth, reduced absorptive capacity and altered disaccharidase activities that are thought to result in part from the decrease in enteral nutrient intake associated with the initiation of weaning (weaning anorexia) (6,7,22). Normal small intestinal growth and function are restored in association with increased feed intake and at this time, circulating GLP-2 concentrations increased markedly in this study (22). This result supports the hypothesis that GLP-2 plays a role in the response of the small intestine to enteral nutrients around the time of weaning. On the other hand, we were unable to demonstrate effects on intestinal growth and brush border enzyme activities when GLP-2 was given in pharmacologic doses to pigs before and during the weaning transition (7). This was surprising because exogenous GLP-2 has been shown to enhance intestinal adaptation in animal models of small bowel resection, inflammatory bowel disease, TPN-induced intestinal atrophy, enteritis and colitis and is considered to be a potentially therapeutic agent for the treatment of human intestinal disease (23).
Gestational age at delivery influenced the GLP-2 release in response to parenteral and enteral nutrition. In term pigs, enteral feeding of a milk diet induced an increase in circulating GLP-2 concentrations at 2 d of age, whereas in premature pigs, this response was delayed until 6 d after feeding. This may be explained by the fact that the premature newborn pigs were partly intolerant to enteral feeding (distended abdomen, intestinal dysmotility) during the first 2–3 d after birth (4). Metabolic and neuroendocrine disturbances related to premature birth may also explain the temporary increase in plasma GLP-2 in 2-d-old parenterally fed premature pigs, and a transient increase in plasma GLP-2 concentrations has also been reported in TPN-fed rats subjected to intestinal resection (24). The maximal GLP-2 levels in both groups of caesarean-delivered pigs fed continuous enteral milk by stomach tube were also lower than the values observed in vaginally delivered suckling pigs of the same age. This may be explained by the differences in the modes of delivery (caesarean vs. spontaneous vaginal) and enteral food administration (continuous enteral infusion vs. natural suckling). In addition, the total amount of milk administered via stomach tube daily to the premature and term pigs (170–220 mL/kg body) was less than the amount normally consumed daily by suckling newborn pigs (300–400 mL/kg body) (19). Low nutrient intakes are also common for premature or sick newborn infants and when these are administered enterally, rather than parenterally, elevated levels of GLP-2 in the plasma may play a role in maintaining normal mucosal structure and function.
We have shown that plasma GLP-2 concentrations are low in pig fetuses compared with both newborn and suckling pigs. Others have reported that circulating GLP-2 concentrations are high in neonatal rats compared with adult rats (25). In our study, plasma GLP-2 was significantly increased in response to enteral feeding in utero, indicating that the responsiveness of the enteroendocrine L-cells to luminal nutrition is already functional before birth. Despite this demonstrated ability of the fetal small intestine to secrete GLP-2, we showed previously that exogenous GLP-2 has no effect on small intestinal growth in the pig fetus although it stimulates aminopeptidase N enzyme mRNA abundance and activity (16).
Our results suggest that the introduction of enteral nutrients to fetal and newborn pigs, as well as, the resumption of feeding after weaning stimulates an increase in GLP-2 release. The observation that this acute increase in circulating plasma GLP-2 is not maintained but decreases to basal levels despite the continuation of feeding suggests that nutrients alone are not sufficient to elevate GLP-2 levels in pigs and that other factors may be involved. A possible regulatory factor is the stress hormone, cortisol, which is significantly increased in newborn and newly weaned pigs and stimulates small intestinal maturation (26–29). Endogenous plasma GLP-2 rises gradually in the late fetal period when fetal cortisol concentrations are very high (27). Nevertheless, plasma GLP-2 concentrations are increased in response to the resumption of feeding several days after weaning, whereas plasma cortisol levels are increased more acutely in response to the "weaning anorexia" (29). Furthermore, plasma GLP-2 concentrations are highest in 1-d-old suckling pigs at a time when cortisol concentrations have already decreased markedly (26). On the basis of these observations, we suggest that cortisol may play only a minor role in the regulation of GLP-2 release during pig development and that the introduction of enteral nutrients overshadows the possible effect of cortisol.
GLP-2 acts via a specific G-protein–coupled receptor localized in the endocrine cells of the stomach and small intestine in humans and in the enteric neurons in rats (14,15). The GLP-2R mRNA transcript has been detected specifically in the small and large intestine of both rodents and pigs (15,16,25). We have shown that the abundance of the GLP-2R mRNA was relatively high in fetal and newborn pigs, compared with suckling and weaned pigs. The increased abundance of GLP-2R mRNA at the time of birth, when circulating GLP-2 concentrations were relatively low, indicates that GLP-2 receptor mRNA abundance is related to circulating GLP-2 concentrations. This hypothesis is in agreement with the demonstration that GLP-2R mRNA abundance was lowered in enterally fed fetal pigs, at the initiation of suckling just after birth, in enterally vs. parenterally fed premature and term pigs, and in weaned pigs that had resumed feed intake. Receptor down-regulation after exposure to the receptor ligand is a common phenomenon, as is the case with epidermal growth factor receptors, somatostatin receptors and opioid receptors (30–32). Nonetheless, we recently infused GLP-2 into TPN-fed neonatal pigs and found that exogenous GLP-2 had no effect on receptor mRNA abundance (unpublished observations). Therefore the reductions in GLP-2R mRNA levels in response to the intake of enteral nutrients in fetal, newborn and weaned pigs are unlikely to be explained entirely by the associated increase in GLP-2 release. Possibly the rapid increase in mucosal growth that occurs with the intake of enteral nutrients in all of these situations is associated with a degree of unspecific "dilution" of intestinal functional proteins and their expression, including that of GLP-2R.
Finally we have shown that the intake of enteral nutrients is associated with considerable intestinal growth in fetal and newborn pigs. In both premature and term newborns, the increase in intestinal weight was associated with an increase in villous height. Results from our earlier studies indicate that GLP-2 may mediate the trophic effects of enteral nutrition on small intestinal growth by suppressing epithelial cell apoptosis in newborn pigs (5). Interestingly, we did not observe any changes in villous heights in colostrum-fed fetuses despite high circulating concentrations of GLP-2 (16). We showed previously that exogenous GLP-2 administration to pig fetuses does not stimulate villous height, and we suggest that the growth response of the fetal small intestine to enteral nutrition may be mediated by trophic effects that are independent of GLP-2. In addition, at the time of weaning, the mucosal growth after the resumption of food intake seems partly independent of the surge in endogenous GLP-2 because exogenous GLP-2 was unable to stimulate mucosal growth and function at this time (7). The developing intestine may therefore be particularly sensitive to the trophic actions of both enteral nutrients and GLP-2 during the immediate postnatal period.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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3 Abbreviations used: AU, arbitrary units; GLP-2, glucagon-like peptide 2; GLP-2R, glucagon-like peptide 2 receptor; RT-PCR, reverse transcription polymerase chain reaction; TPN, total parenteral nutrition.
Manuscript received 24 October 2002. Initial review completed 24 January 2003. Revision accepted 19 February 2003.
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LITERATURE CITED |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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