Department of Comparative Biosciences, School of Veterinary Medicine, University of Wisconsin, Madison, Wisconsin 53706
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ABSTRACT |
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The effect of
orally administered insulin-like growth factor-I (IGF-I) on small
intestinal structure and function was studied in 5-day-old
colostrum-deprived piglets. Human recombinant IGF-I (3.5 mg · kg1 · day
1)
or control vehicle was given orogastrically for 4 days. Body weights,
jejunal and ileal mucosa wet and dry weights, and serum IGF-I levels
were similar in the two groups. Small intestinal villus height and
crypt depth and jejunal enterocyte microvillar dimensions were also
similar between groups. Oral IGF-I produced higher rates of jejunal ion
transport because of increased basal Na+ absorption. Short-circuit
current responses to mucosal addition of
D-glucose and
L-alanine and net
transepithelial absorption of
3-O-methylglucose were increased by
IGF-I. Carrier-mediated uptake of
D-glucose per milligram in
everted jejunal sleeves was greater in IGF-I-treated piglets because of
a significantly greater maximal rate of uptake. We conclude that rates
of net Na+ and
Na+-dependent nutrient absorption
are enhanced in piglets treated with oral IGF-I, and this effect is
independent of changes in mucosal mass or surface area.
growth factors; ion transport; insulin-like growth factor-I
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INTRODUCTION |
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MATURATION OF THE SMALL intestine shortly after birth is thought to be due, at least in part, to one or more growth factors present in breast milk and colostrum (13, 41, 42). Interest has been focused primarily on two of these: epidermal growth factor (EGF) and insulin-like growth factor-I (IGF-I). Both peptides have been shown to stimulate gastrointestinal mucosal growth and brush-border enzyme activity when given exogenously to suckling animals (1, 4, 18, 28, 44, 47). Far fewer studies have examined the effects of these molecules on epithelial transport function in neonates. Luminal or systemic administration of EGF was shown to stimulate nutrient and electrolyte transport in adult animals (2, 17), and there is both supportive (28) and inconclusive (15) evidence for its role in nutrient absorption in suckling animals. In contrast, the ability of IGF-I to influence intestinal absorptive function in neonates is poorly understood.
IGF-I is a 70-amino-acid-long polypeptide whose structure is highly conserved among species and shares 100% homology among human, porcine, and bovine IGF-I (38). The liver is the major site for synthesis of IGF-I in serum, but IGF-I is also synthesized locally in other tissues, including the gastrointestinal tract (20, 46). IGF-I is the mediator of most of the anabolic effects of growth hormone, particularly through its effects on protein and carbohydrate metabolism (36). IGF-I has a wide range of biological actions, including stimulation of proliferation and differentiation in many tissues (20). Physiologically, IGF-I has been shown to have both acute and chronic effects on tissues, depending on route and duration of administration. In vitro, IGF-I can stimulate a number of cellular transport processes, including facilitated glucose uptake (32), Na+/H+ exchange (19), Na+-K+-ATPase activity (37), and Na+-dependent phosphate absorption (11, 35). In vivo experiments have further characterized the effects of IGF-I at the whole animal level. Chronic infusion of recombinant human IGF-I into human volunteers stimulated Na+ reabsorption from the kidney via the Na+/H+ exchanger on the brush border of proximal tubule cells (16).
It is well established that IGF-I can influence gastrointestinal growth
in adults when the peptide is given systemically. Intravenous or
subcutaneous administration of IGF-I in adults increases intestinal
mucosal weight, protein and DNA content, villus height, and epithelial
proliferation (22, 29, 30, 34, 49). There are also reports that
systemic IGF-I can influence intestinal epithelial function. Peterson
et al. (30) showed that adult rats maintained on total parenteral
nutrition (TPN) solutions coinfused with recombinant human IGF-I
(rhIGF-I) had significantly less jejunal atrophy as well as partial to
complete reversal of the enhanced tissue permeability and
hypersecretion of Cl that
is induced by TPN alone. Subcutaneous IGF-I treatment has been shown to
ameliorate the diminished intestinal absorptive function observed in a
rat model of liver cirrhosis (10).
In contrast to these effects of IGF-I when given systemically, it appears to have little effect on the adult gastrointestinal tract after enteral administration. In neonates, however, oral administration of the peptide stimulates intestinal mucosal growth and brush-border enzyme activity (18), perhaps because of its protection from proteolytic degradation by casein in breast milk (43). Burrin et al. (4) demonstrated greater intestinal weight, protein and DNA content, and villus heights of the jejunum and ileum in neonatal piglets administered rhIGF-I via orogastric gavage. Oral IGF-I also stimulated enterocyte proliferation and disaccharidase activity in neonatal pig ileum (18). Although these studies provide compelling evidence that oral IGF-I can enhance intestinal growth and enzyme activity in neonates, its effect on epithelial transport is less well understood. Thus the aim of our study was to determine whether orally administered IGF-I influences intestinal nutrient and electrolyte transport in neonatal piglets. We focused our functional studies on the jejunum, which is the major site of nutrient absorption in the small intestine. To complement the functional studies, we determined the effect of oral IGF-I on jejunal mucosal morphology at light and electron microscope levels. We also carried out limited measurements on ileal structure because others have reported that orally administered IGF-I may selectively enhance ileal mucosal growth (4, 18).
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MATERIALS AND METHODS |
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Experimental animals and diets.
The University of Wisconsin Institutional Animal Care and Use Committee
approved the protocol used in this study. Colostrum-deprived neonatal
crossbred pigs (1-2 kg body wt) were obtained through the
University of Wisconsin Swine Teaching and Research herd. To ensure
that piglets did not consume mammary gland-derived IGF-I, they were
removed from the sow immediately postpartum. All piglets were provided
free access to porcine milk replacer (Milk Specialties, Dundee, IL)
throughout the study. At birth, piglets were randomly assigned to one
of two groups. Group 1 received
rhIGF-I (Genentech, South San Francisco, CA) dissolved in 2 ml of milk
replacer delivered by orogastric gavage, and group
2 received the same volume of milk replacer given
orogastrically with no IGF-I added. The dose of IGF-I administered was
3.5 mg · kg1 · day
1
for 4 days. We chose this dose of oral IGF-I because Burrin et al. (4)
showed previously that it stimulated intestinal growth in neonatal
piglets. The total daily dose of IGF-I was divided into three equal
aliquots administered every 8 h. The final IGF-I dose was given 5 h
before euthanasia.
Intestinal dimensions. Mucosa was scraped from jejunal and ileal segments of known length and was weighed before and after drying at 70°C overnight. Adjacent 1-cm sections of intestine were pinned flat in Sylgard dishes, fixed in Histochoice (Amresco, Solon, OH), blocked in paraffin, sectioned at 6 µm, and stained with hematoxylin and eosin. Morphological measurements from 5 crypt-villus units per animal were used to determine the mean villus height and crypt depth.
Enterocyte brush-border surface area. Jejunal tissues were sliced into ~1- to 3-mm-thick sections and immersion fixed in 2.5% glutaraldehyde-2.0% paraformaldehyde in 0.1 M phosphate buffer (pH 7.4) overnight at 4°C. After rinsing in phosphate buffer, tissues were treated with 1% OSO4 for 2 h at room temperature. After washing, dehydration, and embedding in Polybed 812 resin (Epon, Polysciences), ultrathin sections (100-150 nm) were stained with 2% uranyl acetate, poststained with lead citrate, and examined with an electron microscope. At least three enterocytes per animal from the upper third of the villus but below the villus tip were examined to obtain cells that lie in the absorptive zone. Photomicrographs were used for microvillus measurements with appropriate scaling factors. For each enterocyte, the mean microvillus height of the 10 longest microvilli was determined. Microvillar density was estimated from three enterocytes per piglet by counting the number of microvilli in a standardized apical surface length. Morphological measurements were performed with SigmaScan image measurement software (Jandel Scientific Software).
Basal electrical parameters.
Flat sheets of proximal jejunum were stripped of outer muscle layers
and mounted in Ussing chambers with an aperture of 1.13 cm2. The Krebs solution that
bathed mucosal and serosal sides of tissues contained (in mM) 148.5 Na+, 6.3 K+, 139.7 Cl, 0.3 H2PO
4, 1.3 HPO2
4, 19.6 HCO
3, 3.0 Ca2+, and 0.7 Mg2+.
D-Glucose (11.5 mmol/l) or
mannitol (11.5 mmol/l) was present in serosal and mucosal solutions,
respectively. Tissues were bathed with 10 ml of solution by
recirculation from a reservoir maintained at 39°C (porcine core
temperature). Solutions were bubbled with a 95%
O2-5%
CO2 mixture, and solution pH was
~7.4. A short-circuit current
(Isc) was
delivered by a voltage-clamp apparatus; the magnitude of the
Isc reflected
active ion transport. Transepithelial potential difference (PD) was
recorded under open circuit conditions every 10 min. Tissue conductance
(Gt)
was calculated from
Isc and PD values
using Ohm's law. For transepithelial flux studies, tissues from the
same animal having
Gt
values within 25% of each other were paired to determine net fluxes.
Transepithelial fluxes of
Na+ and
Cl.
Methods for measuring unidirectional and net
Na+ and
Cl
fluxes in piglet jejunum
were similar to those described previously (8). Briefly, unidirectional
Na+ and
Cl
fluxes were measured by
adding 3 µCi of
22Na+ and 7 µCi of
36Cl
to mucosal
or serosal bathing solutions. After 20 min to achieve isotopic steady
state, five fluid samples (0.5 ml) separated by 10 min were withdrawn
and replaced with nonradioactive aliquots of similar composition and
volume. At the completion of the experiment, 0.5 ml of fluid was
withdrawn from the "hot" side, diluted into 50 ml of
H2O, and used as a baseline
sample. The samples were assayed with a gamma counter (for
Na+ flux), and then 4 ml of
scintillation fluid were added to each vial and mixed. The samples were
then counted on a liquid scintillation counter (for
Cl
flux). The
Na+ activity was subtracted from
the combined activity of the two isotopes to yield
Cl
activity. The four flux
values obtained for each tissue were averaged to yield one
unidirectional flux value for each ion. Unidirectional
Na+ and
Cl
flux values were paired
based on
Gt
to obtain net fluxes. Residual ion flux
(J Rnet), i.e., that portion of
the Isc not accounted for by Na+ and
Cl
fluxes, was calculated as
JRnet = Isc
(JNanet + JClnet).
Mucosal addition of D-glucose and L-alanine. Methods and solution compositions were similar to those described for measurement of basal electrical parameters. Twenty minutes after they were mounted, jejunal tissues were exposed to D-glucose (10 mM) or L-alanine (10 mM) added to the mucosal solution, and the maximal change in Isc was recorded.
Transepithelial nutrient absorption. Methods were similar to those reported previously (5, 7). Briefly, transepithelial glucose fluxes were determined with the nonmetabolizable glucose analog 3-O-methylglucose (3-OMG) to avoid metabolism of D-glucose in enterocytes during the flux experiments. For these experiments the Krebs buffer contained nonradioactive 3-OMG (10 mM) in the mucosal and serosal solutions. After the tissues were mounted, 20 µCi of 3-O-methyl-D-[1-3H]glucose (Amersham) was added to either mucosal or serosal solutions. After isotopic equilibration (25-30 min), five flux samples separated by 10 min were taken from the unlabeled side to obtain four fluxes that were averaged for each tissue. For each piglet, 3-6 tissues were used to determine unidirectional and net fluxes.
Kinetics of active D-glucose transport in intact jejunal tissues. Methods were similar to those previously described (9, 33, 39, 48). After harvest from the animal, jejunal tissues were bathed continually in ice-cold Krebs solution and bubbled with 95% O2-5% CO2 during tissue preparation. Tissues were everted, and 1-cm sleeves were mounted on grooved metal rods (7 mm diameter) suspended in a warmed (39°C) oxygenated Krebs solution over a stir bar rotating at 1,200 rotations/min. Sleeves were preincubated in isotope-free solution for 5 min and then transferred to incubation solutions containing varying concentrations of unlabeled D-glucose and radiolabeled probes. Incubation solutions containing unlabeled D-glucose were prepared by isosmotic replacement of mannitol to obtain a solution osmolality of ~290 mosmol/kgH2O. Uptake studies used 4 µCi of D-[3H]glucose (American Radiolabeled Chemical, St. Louis, MO) added to each incubation solution of cold D-glucose. After incubation, sleeves were rinsed in Krebs solution for 20 s, blotted on filter paper, placed into tared vials, and weighed. Tissue solubilizer (500 µl, Solvable, Packard) was added, and 24 h later 4 ml of aqueous counting scintillant (Ultima Gold, Packard) were added to each vial. Radiotracer counting procedures and data analyses were performed as previously described (21). Uptake rates were corrected for solute present in adherent fluid by addition of tracer amounts of [14C]polyethyline glycol. Passive permeability coefficients (P*) were calculated from uptake rates of tracer quantities of L-glucose, which is not transported by the Na+-glucose transporter (SGLT1), with the use of methods described by Karasov and Diamond (21). Carrier-mediated D-glucose uptake was computed by subtracting passive uptake (P*[S]) from the total glucose uptake rate at each D-glucose concentration. Kinetic data were analyzed with regression models outlined by Carey and Sills (9). The method of Motulsky and Ransnas (26) was used to fit data to linear or nonlinear regression models. Significance of differences between control and IGF-I-treated pigs were determined by methods previously described (24).
Statistics. Values are reported as means ± SE. Student's t-tests were used to determine significance of differences between means. A probability level of P < 0.05 was considered statistically significant.
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RESULTS |
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There were no differences in overall animal demeanor or fecal consistency between IGF-I-treated and control piglets. However, a small percentage (<10%) of the piglets that included animals from both treatment groups failed to thrive and were removed from the study.
Piglet body weights and serum IGF-I levels. Control and IGF-I-treated piglets had similar rates of weight gain (177.0 ± 35.2 g/day and 172.5 ± 38.2 g/day, respectively). Mean body weights on day 5 in IGF-I-treated and control piglets were similar (2.1 ± 0.1 kg vs. 1.9 ± 0.1 kg, respectively; P = 0.20). Serum IGF-I levels determined by radioimmunoassay were similar in IGF-I-treated and control piglets (66.3 ± 11.0 µg/l, n = 6, vs. 58.5 ± 6.3 µg/l, n = 10, respectively; P = 0.55).
Intestinal mucosa and brush-border morphology.
Oral administration of IGF-I had no significant effect on mucosal wet
or dry weight per centimeter, villus height, or crypt depth in the
jejunum and ileum compared with control piglets (Table 1). Ultrastructural analysis was carried
out on three jejunal enterocytes from each of five piglets per
treatment group. There were no significant differences in jejunal
microvillus length (6.9 ± 0.3 µm in IGF-I-treated and 5.9 ± 0.3 µm in control piglets; P = 0.45)
or density (5.2 ± 0.04 microvilli/µm for 5 IGF-I-treated pigs vs.
5.0 ± 0.14 microvilli/µm for controls;
P = 0.10) between the two groups.
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Ion transport.
Because jejunal morphology and brush-border parameters were similar
between groups, electrical parameters and flux data were normalized to
the area (1.13 cm2) of tissue
mounted in Ussing chambers. Basal
Isc and PD of
jejunal tissues from piglets receiving oral IGF-I were significantly
greater than in control piglets, but
Gt
was similar between the two groups (Table
2).
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Nutrient absorption. We compared jejunal nutrient absorption in control and IGF-I-treated piglets in three ways: the change in Isc after mucosal addition of either D-glucose or L-alanine, the transepithelial flux of 3-OMG, and brush-border uptake of D-glucose into everted sleeves.
Changes in Isc stimulated by addition of 10 mM D-glucose or 10 mM L-alanine to the mucosal bathing solution were greater in tissues from piglets treated with oral IGF-I (Fig. 1). Net transepithelial absorption of the nonmetabolizable glucose analog 3-OMG was also enhanced in jejunal tissues from IGF-I-treated animals compared with controls (170 ± 20 nmol · cm
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DISCUSSION |
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The goal of this study was to investigate the effect of orally
administered IGF-I on intestinal ion and nutrient transport in neonatal
piglets. The concentration of IGF-I we used (3.5 mg · kg1 · day
1)
was shown by others (4) to stimulate intestinal mucosal growth in
newborn piglets. We used the same dosing regime to determine whether
this pharmacological concentration also influenced intestinal function
in a similar animal model. We administered IGF-I orally to mimic the
natural presence of the peptide in the neonatal gut lumen. There is
evidence for apically located IGF-I receptors on jejunal enterocytes
during the suckling period (25) that could potentially mediate effects
of luminal IGF-I on epithelial function. Furthermore, IGF-I is thought
to retain bioactivity in the neonatal intestinal lumen, possibly
because of the lower pH of gastric contents in neonates and protection
of the peptide from luminal proteolysis by high concentrations of
casein in milk and milk replacers (13, 43).
In our study, oral administration of IGF-I had no effect on serum IGF-I levels, which is consistent with the findings of Burrin et al. (4). However, other studies suggest that luminal IGF-I may cross the intestinal mucosa in neonates and accumulate within the gastrointestinal wall and/or in the systemic circulation (31, 45). The contrasting findings in these studies may reflect differences in the detection methods used to measure IGF-I in serum. Our study and that of Burrin et al. (4) used radioimmunoassay, whereas those studies that documented an elevation in serum IGF-I administered radiolabeled IGF-I and subsequently detected the radiolabel in serum and tissues (31). The half-life of IGF-I in serum ranges from minutes for free IGF-I to hours for IGF-I bound to IGF-I-binding proteins (40). Serum levels of IGF-I-binding proteins were not measured in our study, and thus their influence on serum IGF-I levels is unknown.
Oral IGF-I had no effect on piglet body weight nor did it affect the
mass or mucosal architecture of either the jejunum or ileum. The study
of Burrin et al. (4), which used the same oral IGF-I concentration,
reported no effect of the peptide on piglet body weight; however, oral
IGF-I significantly increased intestinal weight as well as jejunal and
ileal villus heights. Recently, the same investigators reported minimal
effects of IGF-I on intestinal growth of mouse pups suckling from dams
that overexpressed IGF-I in mammary secretions (3). Houle et al. (18)
administered oral IGF-I to 14-day-old piglets at a concentration
similar to that found in sow colostrum (200 µg · kg1 · day
1)
for 14 days and reported no effect of the peptide on body weight, but
it significantly increased ileal (but not jejunal) villus height. In
our study, oral IGF-I also had no effect on enterocyte microvillus
dimensions, including microvillus height and density. In the only other
study that examined IGF-I effects on enterocyte microvillus structure,
parenteral IGF-I (0.2 µg · kg
1 · day
1)
normalized the increased microvillus length induced by cirrhotic liver
disease in rats (10). Together, our results and those of others suggest
that the small intestine of healthy neonates with adequate nutrition
may already be achieving maximal growth rates and that IGF-I
supplementation is unable to stimulate additional growth.
Although oral IGF-I did not alter intestinal growth or structure, the peptide had significant effects on epithelial transport. Basal Isc and PD of jejunal tissues were greater in piglets treated with oral IGF-I, suggesting that the peptide resulted in a higher level of active ion transport in the basal state (as indicated by the higher Isc) and produced a steeper electrical gradient across the epithelium (as indicated by the elevated PD). Oral IGF-I did not alter ionic permeability of the jejunum because Gt was similar in both groups. Changes in Gt in a leaky epithelium like the jejunum are largely due to changes in paracellular permeability, and the absence of an effect of IGF-I on this transport route suggests the peptide did not compromise the barrier function of the intestinal mucosa.
The effects of oral IGF-I on basal electrical parameters were mirrored
by its effects on transepithelial ion fluxes. The higher basal
Isc of
IGF-I-treated piglets was due primarily to increased net absorption of
Na+, due to an increase in
mucosal-to-serosal fluxes of the cation. Although mucosal-to-serosal
Cl flux was increased by
the peptide, the effect on net
Cl
movement was not
significant. Similarly,
JR, which most
likely reflects bicarbonate secretion, was reduced by IGF-I, but the
effect was not significant. These trends for reduced secretion of both
anions, which tend to reduce
Isc values, likely accounted for the disparity between the increase in
Isc induced by
the peptide (about twofold) and the larger increase in net
Na+ flux (about threefold).
In addition to its effect on net Na+ absorption, oral IGF-I also increased the absorptive capacity for two different Na+-coupled nutrients, D-glucose and L-alanine. This was supported by three separate experiments. First, the increase in Isc induced by mucosal addition of either nutrient was greater in IGF-I-treated piglets. Because both nutrients are cotransported with Na+, the D-glucose- and L-alanine-stimulated changes in Isc are indirect measures of each nutrient's absorption rate. These electrical findings were confirmed by the enhanced rates of net transepithelial absorption of 3-OMG observed in IGF-I-treated piglets. An effect of IGF-I on stimulating Na+-coupled solute transport has been demonstrated in other cell types, including kidney epithelial cells (11) and osteoblasts (35), in which it stimulates Na+-dependent phosphate absorption.
Studies with everted jejunal sleeves provided a third measure of the peptide's effects on nutrient absorption by focusing on changes in sugar uptake across the brush-border membrane into enterocytes. Piglets receiving oral IGF-I had significantly greater total and carrier-mediated D-glucose uptake rates when normalized to tissue mass. Total uptake represents the rate of solute transport through both the nonselective paracellular pathway and the brush-border Na+-glucose transporter (SGLT1). We calculated P* using L-glucose fluxes, and we used these to derive carrier-mediated uptake rates in the two groups of piglets. The observation that P* values were similar in control and IGF-I-treated piglets lends further support to the idea that oral IGF-I does not alter paracellular permeability of the jejunal epithelium.
Kinetic analysis of carrier-mediated D-glucose uptake indicated that jejunal tissues from animals given IGF-I had significantly greater Jmax, but the affinity of the sugar for SGLT1 (Km) was unchanged. Several mechanisms could account for a greater Jmax in IGF-I-treated piglets. One is an increase in SGLT1 expression secondary to increased proliferation of enterocytes in IGF-I-treated piglets. This mechanism is unlikely to account for our results because we found no differences in jejunal tissue weight, villus height, crypt depth, or microvillar surface morphology as the result of IGF-I treatment. Second, there could be an increase in density of SGLT1 molecules in brush-border membranes of individual enterocytes after IGF-I treatment. Recently, Cheeseman et al. (12) demonstrated an increase in SGLT1 abundance in brush-border membranes in rats perfused in vivo with glucagon-like peptide 2; thus there is precedent for hormonal regulation of this transporter. Furthermore, EGF, another peptide growth factor present in high concentrations in porcine colostrum, has been reported to increase SGLT1 abundance in intestinal tissues after massive small bowl resection in adult rats (14).
Another mechanism to explain the ability of IGF-I to increase the Jmax for D-glucose in piglet jejunum is an increase in the electrochemical driving force for Na+-coupled nutrient transport. This possibility is supported by the enhanced rates of net Na+ absorption as well as the greater change in Isc induced by L-alanine in IGF-I-treated piglets. Both of these processes would also be favored by a change in the Na+ electrochemical gradient across the brush-border membrane. Because the Na+ electrochemical gradient is dependent on basolateral Na+-K+-ATPase activity, an increase in the number and/or activity of Na+-K+-ATPase pumps could be involved in the upregulation of nutrient absorption in IGF-I-treated piglets. Treatment of rat arterial smooth muscle cells in vitro with IGF-I was reported to stimulate Na+-K+-ATPase activity (37), and in preliminary studies we observed greater Na+-K+-ATPase activity in enterocytes from IGF-I-treated piglets compared with control animals (unpublished observations).
In summary, our results provide evidence that oral administration of IGF-I to neonatal piglets can enhance intestinal epithelial Na+ and Na+-coupled nutrient absorption in the absence of changes in enterocyte mass or architecture. Because orogastric administration of IGF-I did not alter serum IGF-I levels, we speculate that luminal IGF-I exerted its effects via stimulation of brush-border IGF-I receptors (23, 25, 47) and/or transepithelial transport of IGF-I and subsequent activation of IGF-I receptors located on basolateral membranes. Future studies should focus on elucidating the cellular mechanisms of IGF-I action in the neonatal intestine.
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ACKNOWLEDGEMENTS |
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We thank Nancy Sills and Yanira Oneill-Naumann for technical assistance and Dr. Tom Crenshaw for advice and assistance in piglet management.
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FOOTNOTES |
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This study was supported by United States Department of Agriculture Grant 93-37206-9222 (H. V. Carey), National Institute of Diabetes and Digestive and Kidney Diseases Grant F32-DK-09629 (A. N. Alexander), and grants from the University of Wisconsin-Madison Graduate School and the University of Wisconsin-Madison School of Veterinary Medicine.
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: H. V. Carey, Department of Comparative Biosciences, Univ. of Wisconsin, 2015 Linden Drive West, Madison, WI 53706 (E-mail: careyh{at}svm.vetmed.wisc.edu).
Received 25 February 1999; accepted in final form 16 June 1999.
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REFERENCES |
---|
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---|
1.
Baumrucker, C. R.,
D. L. Hadsell,
and
J. W. Blum.
Effects of dietary insulin-like growth factor I on growth and insulin-like growth factor receptors in neonatal calf intestine.
J. Anim. Sci.
72:
428-433,
1994
2.
Bird, A. R.,
W. J. Croom, Jr.,
Y. K. Fan,
B. L. Black,
B. W. McBride,
and
I. L. Taylor.
Peptide regulation of intestinal glucose absorption.
J. Anim. Sci.
74:
2523-2540,
1996
3.
Burrin, D. G.,
M. L. Fiorott,
and
D. L. Hadsell.
Transgenic hypersecretion of des(13) human insulin-like growth factor 1 in mouse milk has limited effects on the gastrointestinal tract in suckling pups.
J. Nutr.
129:
51-56,
1999
4.
Burrin, D. G.,
T. J. Wester,
T. A. Davis,
S. Amick,
and
J. P. Heath.
Orally administered IGF-I increases intestinal mucosal growth in formula-fed neonatal pigs.
Am. J. Physiol.
270 (Regulatory Integrative Comp. Physiol. 39):
R1085-R1091,
1996
5.
Carey, H. V.
Seasonal changes in mucosal structure and function in ground squirrel intestine.
Am. J. Physiol.
259 (Regulatory Integrative Comp. Physiol. 28):
R385-R392,
1990
7.
Carey, H. V.,
H. J. Cooke,
W. T. Gerthoffer,
and
L. W. Welling.
Intestinal transport in megacolonic mice: alterations in sugar absorption.
Dig. Dis. Sci.
34:
185-192,
1989[Medline].
8.
Carey, H. V.,
U. L. Hayden,
and
K. E. Tucker.
Fasting alters basal and stimulated ion transport in piglet jejunum.
Am. J. Physiol.
267 (Regulatory Integrative Comp. Physiol. 36):
R156-R163,
1994
9.
Carey, H. V.,
and
N. S. Sills.
Maintenance of intestinal nutrient transport during hibernation.
Am. J. Physiol.
263 (Regulatory Integrative Comp. Physiol. 32):
R517-R523,
1992
10.
Castilla-Cortazar, I.,
J. Prieto,
E. Urdaneta,
M. Pascual,
M. Nuñez,
E. Zudaire,
M. Garcia,
J. Quiroga,
and
S. Santidrian.
Impaired intestinal sugar transport in cirrhotic rats: correction by low doses of insulin-like growth factor I.
Gastroenterology
113:
1180-1187,
1997[Medline].
11.
Caverzasio, J.,
and
J.-P. Bonjour.
Insulin-like growth factor I stimulates Na-dependent Pi transport in cultured kidney cells.
Am. J. Physiol.
257 (Renal Fluid Electrolyte Physiol. 26):
F712-F717,
1989
12.
Cheeseman, C. I.
Upregulation of SGLT-I transport activity in rat jejunum induced by GLP-2 infusion in vivo.
Am. J. Physiol.
273 (Regulatory Integrative Comp. Physiol. 42):
R1965-R1971,
1997
13.
Donovan, S. M.,
V. M. Houle,
M. H. Monaco,
E. A. Schroeder,
Y. Park,
and
J. Odle.
The neonatal piglet as a model to study insulin like growth factor mediated intestinal growth and function.
In: Advances in Swine in Biomedical Research, edited by L. B. Schook,
and M. Tumbleson. New York: Plenum, 1996, p. 733-743.
14.
Dunn, J. C. Y.,
C. P. Parungo,
E. W. Fonkalsrud,
D. W. McFadden,
and
S. W. Ashley.
Epidermal growth factor selectively enhances functional enterocyte adaptation after massive bowel resection.
J. Surg. Res.
67:
90-93,
1997[Medline].
15.
Greene, H. L.,
M. C. Moore,
H. M. Said,
F. K. Ghishan,
and
D. N. Orth.
Intestinal glucose transport in suckling rats fed artificial milk with and without added epidermal growth factor.
Pediatr. Res.
21:
404-408,
1987[Abstract].
16.
Guler, H. P.,
K. U. Eckardt,
J. Zapf,
C. Bauer,
and
E. R. Froesch.
Insulin-like growth factor I increases glomerular filtration rate and renal plasma flow in man.
Acta Endocrinol.
121:
101-106,
1989[Medline].
17.
Hardin, J. A.,
J. K. Wong,
C. I. Cheeseman,
and
D. G. Gall.
Effect of luminal epidermal growth factor on enterocyte glucose and proline transport.
Am. J. Physiol.
271 (Gastrointest. Liver Physiol. 34):
G509-G515,
1996
18.
Houle, V. M.,
E. A. Schroeder,
J. Odle,
and
S. M. Donovan.
Small intestinal disaccharidase activity and ileal villus height are increased in piglets consuming formula containing recombinant human insulin-like growth factor-I.
Pediatr. Res.
42:
78-86,
1997[Abstract].
19.
Johnson, D. W.,
B. K. Brew,
P. Poronnik,
D. I. Cook,
M. J. Field,
A. Z. Györy,
and
C. A. Pollock.
Insulin-like growth factor I stimulates apical sodium/hydrogen exchange in human proximal tubule cells.
Am. J. Physiol.
272 (Renal Physiol. 41):
F484-F490,
1997
20.
Jones, J. I.,
and
D. R. Clemmons.
Insulin-like growth factors and their binding proteins: biological actions.
Endocr. Rev.
16:
3-34,
1995[Medline].
21.
Karasov, W. H.,
and
J. M. Diamond.
A simple method for measuring intestinal solute uptake in vitro.
J. Comp. Physiol. [B]
152:
105-116,
1983.
22.
Lemmey, A. B.,
A. A. Martin,
L. C. Read,
F. M. Tomas,
P. C. Owens,
and
F. J. Ballard.
IGF-I and the truncated analogue des-(13)IGF-I enhance growth in rats after gut resection.
Am. J. Physiol.
260 (Endocrinol. Metab. 23):
E213-E219,
1991
23.
Louveau, I.,
S. Combes,
A. Cochard,
and
M. Bonneau.
Developmental changes in insulin-like growth factor-I (IGF- I) receptor levels and plasma IGF-I concentrations in Large White and Meishan pigs.
Gen. Comp. Endocrinol.
104:
29-36,
1996[Medline].
24.
Meddings, J. B.,
R. B. Scott,
and
G. H. Fick.
Analysis and comparison of sigmoidal curves: application to dose-response data.
Am. J. Physiol.
257 (Gastrointest. Liver Physiol. 20):
G982-G989,
1989
25.
Morgan, C. J.,
A. G. P. Coutts,
M. C. McFadyen,
T. P. King,
and
D. Kelly.
Characterization of IGF-I receptors in the porcine small intestine during postnatal development.
J. Nutr. Biochem.
7:
339-347,
1996.
26.
Motulsky, H. J.,
and
L. A. Ransnas.
Fitting curves to data using nonlinear regression: a practical and nonmathematical review.
FASEB J.
1:
365-374,
1987
27.
Ney, D. M.,
H. Yang,
S. M. Smith,
and
T. G. Unterman.
High-calorie total parenteral nutrition reduces hepatic insulin-like growth factor-I mRNA and alters serum levels of insulin-like growth factor-binding proteins-1, -3, -5 and -6 in the rat.
Metabolism
44:
152-160,
1995[Medline].
28.
Opleta-Madsen, K.,
J. B. Meddings,
and
D. G. Gall.
Epidermal growth factor and postnatal development of intestinal transport and membrane structure.
Pediatr. Res.
30:
342-350,
1991[Abstract].
29.
Peterson, C. A.,
H. V. Carey,
P. S. Hinton,
H.-C. Lo,
and
D. M. Ney.
GH elevates serum IGF-I levels but does not alter mucosal atrophy in parenterally-fed rats.
Am. J. Physiol.
272 (Gastrointest. Liver Physiol. 35):
G1100-G1108,
1997
30.
Peterson, C. A.,
D. M. Ney,
P. S. Hinton,
and
H. V. Carey.
Beneficial effects of insulin-like growth factor-I on epithelial structure and function in parenterally-fed rat jejunum.
Gastroenterology
111:
1501-1508,
1996[Medline].
31.
Philipps, A. F.,
R. Rao,
G. G. Anderson,
D. M. McCracken,
M. Lake,
and
O. Koldovsky.
Fate of insulin-like growth factors I and II administered orogastrically to suckling rats.
Pediatr. Res.
37:
586-592,
1995[Abstract].
32.
Prosser, C. G.,
L. Sankaran,
L. Henninghausen,
and
Y. J. Topper.
Comparison of the roles of insulin and insulin-like growth factor-I in casein gene expression and in the development of alpha-lactalbumin and glucose transport in the mouse mammary epithelial cell.
Endocrinology
120:
1411-1416,
1987[Abstract].
33.
Puchal, A. A.,
and
R. K. Buddington.
Postnatal development of monosaccharide transport in pig intestine.
Am. J. Physiol.
262 (Gastrointest. Liver Physiol. 25):
G895-G902,
1992
34.
Read, L. C.,
F. M. Tomas,
G. S. Howarth,
A. A. Martin,
K. J. Edson,
C. M. Gillespie,
P. C. Owens,
and
F. J. Ballard.
Insulin-like growth factor-I and its N-terminal modified analogues induce marked gut growth in dexamethasone-treated rats.
J. Endocrinol.
133:
421-431,
1992[Abstract].
35.
Schmid, C.,
C. Keller,
I. Schlapfer,
C. Veldman,
and
J. Zapf.
Calcium and insulin-like growth factor I stimulation of sodium-dependent phosphate transport and proliferation of cultured rat osteoblasts.
Biochem. Biophys. Res. Commun.
245:
220-225,
1998[Medline].
36.
Schober, D. A.,
F. A. Simmen,
D. L. Hadsell,
and
C. R. Baumrucker.
Perinatal expression of type I IGF receptors in porcine small intestine.
Endocrinology
126:
1125-1132,
1990[Abstract].
37.
Standley, P. R.,
F. Zhang,
R. M. Zayas,
R. Muniyappa,
M. F. Walsh,
E. Cragoe,
and
J. R. Sowers.
IGF-I regulation of Na+-K+-ATPase in rat arterial smooth muscle.
Am. J. Physiol.
273 (Endocrinol. Metab. 36):
E113-E121,
1997
38.
Tavakkol, A.,
F. A. Simmen,
and
R. C. M. Simmen.
Porcine insulin-like growth factor-I (pIGF-I): complementary deoxyribonucleic acid cloning and uterine expression of messenger ribonucleic acid encoding evolutionarily conserved IGF-I peptides.
Mol. Endocrinol.
2:
674-681,
1988[Abstract].
39.
Vega, Y. M.,
A. A. Puchal,
and
R. K. Buddington.
Intestinal amino acid and monosaccharide transport in suckling pigs fed milk replacers with different sources of carbohydrates.
J. Nutr.
122:
2430-2439,
1992[Medline].
40.
Walton, P. E.,
R. Gopinath,
B. D. Burleigh,
and
T. Etherton.
Administration of recombinant human insulin-like growth factor I to pigs: determination of circulating half-lives and chromatographic profiles.
Horm. Res.
31:
138-142,
1989[Medline].
41.
Wang, T.,
and
R. J. Xu.
Effects of colostrum feeding on intestinal development in newborn pigs.
Biol. Neonate
70:
339-348,
1996[Medline].
42.
Widdowson, E. M.,
V. E. Colombo,
and
C. A. Artavanis.
Changes in the organs of pigs in response to feeding for the first 24 h after birth. II. The digestive tract.
Biol. Neonate
28:
272-281,
1976.
43.
Xian, C. J.,
C. A. Shoubridge,
and
L. C. Read.
Degradation of IGF-I in the adult rat gastrointestinal tract is limited by a specific antiserum or the dietary protein casein.
J. Endocrinol.
146:
215-225,
1995[Abstract].
44.
Xu, R.-J.,
D. J. Mellor,
M. J. Birtles,
G. W. Reynolds,
H. V. Simpson,
B. H. Breier,
and
P. D. Gluckman.
Morphological changes in the oesophagus of newborn pigs: effects of age, diet and oral insulin-like growth factor I (IGF-I) or IGF-II.
Reprod. Fertil. Dev.
8:
903-909,
1996[Medline].
45.
Xu, R.-J.,
and
T. Wang.
Gastrointestinal absorption of insulinlike growth factor-I in neonatal pigs.
J. Pediatr. Gastroenterol. Nutr.
23:
430-437,
1996[Medline].
46.
Yang, H.,
and
D. M. Ney.
Insulin-like growth factor-I (IGF-I) responses in rats maintained with intravenous or intragastric infusion of total parenteral nutrition solutions containing medium- or long-chain triglyceride emulsions.
Am. J. Clin. Nutr.
59:
1403-1408,
1994[Abstract].
47.
Young, G. P.,
T. M. Taranto,
H. A. Jonas,
A. J. Cox,
A. Hogg,
and
G. A. Werther.
Insulin-like growth factors and the developing and mature rat small intestine: receptors and biological actions.
Digestion
46, Suppl. 2:
240-252,
1990[Medline].
48.
Zhang, H.,
C. Malo,
and
R. K. Buddington.
Suckling induces rapid intestinal growth and changes in brush border digestive functions of newborn piglets.
J. Nutr.
127:
418-426,
1997
49.
Zhang, W.,
W. L. Frankel,
W. T. Adamson,
J. A. Roth,
M. P. Mantell,
A. Bain,
T. R. Ziegler,
R. J. Smith,
and
J. L. Rombeau.
Insulin-like growth factor-I improves mucosal structure and function in transplanted rat small intestine.
Transplantation
59:
755-761,
1995[Medline].