scholarly journals Enteral nutrients potentiate the intestinotrophic action of glucagon-like peptide-2 in association with increased insulin-like growth factor-I responses in rats

2008 ◽  
Vol 295 (6) ◽  
pp. R1794-R1802 ◽  
Author(s):  
Xiaowen Liu ◽  
Sangita G. Murali ◽  
Jens J. Holst ◽  
Denise M. Ney
Keyword(s):  
Specific Activity ◽  
Physiological Model ◽  
Intestinal Growth ◽  
Treatment Groups ◽  
Dpp Iv ◽  
Energy Needs ◽  
Igf I ◽  
Igf Binding ◽  
Glucagon Like Peptide ◽  
Mucosal Growth

Glucagon-like peptide-2 (GLP-2) is a nutrient-dependent, intestinotrophic hormone derived from posttranslational processing of proglucagon in the distal bowel. GLP-2 is thought to act through indirect mediators, such as IGF-I. We investigated whether intestinal expression of GLP-2 and IGF-I system components are increased with the mucosal growth induced by enteral nutrient (EN) and/or a low dose of GLP-2 in parenterally fed rats. Rats were randomized to four treatment groups using a 2×2 design and maintained with parenteral nutrition (PN) for 7 days: PN alone, EN, GLP-2, and EN+GLP-2; n = 7–9. The two main treatment effects are ±GLP-2 (100 μg·kg body wt−1·day−1) and ±EN (43% of energy needs, days 4–6). Combination treatment with EN+GLP-2 induced synergistic intestinal growth in ileum, resulting in greater mucosal cellularity, sucrase segmental activity, and gain of body weight (EN×GLP-2, P < 0.04). In addition, EN+GLP-2 induced a significant 28% increase in plasma concentration of bioactive GLP-2, a significant 102% increase in ileal proglucagon mRNA with no change in ileal dipeptidyl peptidase-IV (DPP-IV) specific activity, and significantly reduced plasma DPP-IV activity compared with GLP-2. This indicates that EN potentiates the intestinotrophic action of GLP-2. Proliferation of enterocytes due to GLP-2 infusion was associated with greater expression of ileal proglucagon, GLP-2 receptor, IGF-I, IGF binding protein-3 mRNAs, and greater IGF-I peptide concentration in ileum ( P < 0.032). Ileal IGF-I mRNA was positively correlated with expression of proglucagon, GLP-2R, and IGFBP-5 mRNAs ( R2 = 0.43–0.56, P < 0.0001). Our findings support the hypothesis that IGF-I is one of the downstream mediators of GLP-2 action in a physiological model of intestinal growth.

scholarly journals Effects of decreased estradiol-17β on the serum and anterior pituitary IGF-I system in pigs

2005 ◽  
Vol 187 (3) ◽  
pp. 369-378 ◽  
Author(s):  
C K Hilleson-Gayne ◽  
J A Clapper
Keyword(s):  
Anterior Pituitary ◽  
Percentage Increase ◽  
Serum Concentrations ◽  
Blood Samples ◽  
Treatment Groups ◽  
Igf System ◽  
Igf I ◽  
Igf Binding ◽  
Igf Binding Protein ◽  
Estradiol 17Β

To further delineate the role of estradiol in the IGF system an experiment was conducted to determine the dosage of the aromatase inhibitor, anastrozole, needed to decreases serum concentrations of estradiol-17β (E2) in maturing boars. A second experiment was conducted to determine if administration of anastrozole to growing boars decreased serum concentrations of E2 and affected components of the serum and anterior pituitary gland (AP) IGF system vs untreated boars and barrows. In Experiment 1, 12 crossbred boars (292 days, 158 kg) were administered either 0, 1 or 10 mg/day anastrozole (n=4/group) beginning on day 1. Blood samples were collected every 7–14 days. Mean serum concentrations of E2 were decreased (P < 0·05) in the 10 mg group vs the 0 and 1 mg groups by day 36; however, no difference (P > 0·05) existed between the 0 and 1 mg groups. In Experiment 2, 24 crossbred boars and 12 barrows (101 days, 44 kg) were stratified by litter to one of three treatment groups (n=12): boars administered 10 mg/day anastrozole, boars administered 0 mg/day, and barrows administered 0 mg/day. Blood samples were collected and pigs were weighed on day 0 and every 14 days thereafter, then killed on day 84 when blood and APs were collected. The 10 mg/day pigs were fed the anastrozole-amended diet beginning on day 1. Mean serum concentrations of E2 did not differ (P > 0·05) between the 10 mg/day pigs and 0 mg/day pigs on day 0; however, on day 15 through to 84 mean serum concentrations of E2 were greater (P < 0·05) in 0 mg/day pigs than in the 10 mg/day pigs. Mean percentage increase in serum concentrations of IGF-I was greater (P < 0·05) in untreated boars than anastrozole-treated boars and barrows from day 58 through to 84. Mean percentage of basal IGF-I increased (P < 0·05) from day 29 through to 84 in untreated boars. Mean relative amounts of AP IGF-binding protein (IGFBP)-2 and -5 were less (P < 0·01) in 10 mg/day pigs than in the 0 mg/day pigs, but each was greater (P < 0·01) than in barrows administered 0 mg/day. These results indicate anastrozole administered at a dosage of 10 mg/day suppresses serum concentrations of E2 in pigs. Administration of anastrozole to boars reduced the percentage increase in serum concentrations of IGF-I and relative amounts of AP IGFBP-2 and -5. These data further support a role for E2 in regulating components of the IGF system in pigs.

GH elevates serum IGF-I levels but does not alter mucosal atrophy in parenterally fed rats

1997 ◽  
Vol 272 (5) ◽  
pp. G1100-G1108 ◽  
Author(s):  
C. A. Peterson ◽  
H. V. Carey ◽  
P. L. Hinton ◽  
H. C. Lo ◽  
D. M. Ney
Keyword(s):  
Specific Activity ◽  
Growth Parameters ◽  
Villus Height ◽  
Intestinal Growth ◽  
Factor I ◽  
Ion Secretion ◽  
Igf I ◽  
Mucosal Mass ◽  
And Function ◽  
Induced Changes

Growth hormone (GH) action is primarily mediated by insulin-like growth factor I (IGF-I), although both growth factors show tissue-selective effects. We investigated the effects of GH, IGF-I, and GH plus IGF-I on jejunal growth and function in rats maintained with total parenteral nutrition (TPN) and given recombinant human GH (rhGH) (400 micrograms/day sc, twice daily) and/or rhIGF-I (800 micrograms/day in TPN solution) for 5 days. Administration of GH or IGF-I alone produced similar increases in serum IGF-I levels and body weight; GH plus IGF-I further increased these parameters. TPN reduced mucosal mass, protein and DNA content, villus height, crypt depth, and enterocyte migration rate. IGF-I or GH plus IGF-I produced equivalent increases in all intestinal growth parameters; GH alone had no effect. GH, IGF-I, or GH plus IGF-I reduced TPN-induced increases in sucrase-specific activity. IGF-I, but not GH, attenuated TPN-induced increases in tissue conductance and carbachol-stimulated ion secretion. In contrast to IGF-I, GH does not stimulate intestinal growth during TPN and has less effect on normalizing TPN-induced changes in epithelial function.

scholarly journals Exogenous GLP-2 and IGF-I induce a differential intestinal response in IGF binding protein-3 and -5 double knockout mice

2012 ◽  
Vol 302 (8) ◽  
pp. G794-G804 ◽  
Author(s):  
Sangita G. Murali ◽  
Adam S. Brinkman ◽  
Patrick Solverson ◽  
Wing Pun ◽  
John E. Pintar ◽  
...  
Keyword(s):  
Relative Mass ◽  
Jejunal Mucosa ◽  
Double Knockout ◽  
Igf Binding Proteins ◽  
Male Adult ◽  
Adult Mice ◽  
Igf I ◽  
Igf Binding ◽  
Mucosal Growth ◽  
Igfbp 3

Glucagon-like peptide-2 (GLP-2) action is dependent on intestinal expression of IGF-I, and IGF-I action is modulated by IGF binding proteins (IGFBP). Our objective was to evaluate whether the intestinal response to GLP-2 or IGF-I is dependent on expression of IGFBP-3 and -5. Male, adult mice in six treatment groups, three wild-type (WT) and three double IGFBP-3/-5 knockout (KO), received twice daily intraperitoneal injections of GLP-2 (0.5 μg/g body wt), IGF-I (4 μg/g body wt), or PBS (vehicle) for 7 days. IGFBP-3/-5 KO mice showed a phenotype of lower plasma IGF-I concentration, but greater body weight and relative mass of visceral organs, compared with WT mice ( P < 0.001). WT mice showed jejunal growth with either IGF-I or GLP-2 treatment. In KO mice, IGF-I did not stimulate jejunal growth, crypt mitosis, sucrase activity, and IGF-I receptor (IGF-IR) expression, suggesting that the intestinotrophic actions of IGF-I are dependent on expression of IGFBP-3 and -5. In KO mice, GLP-2 induced significant increases in jejunal mucosal cellularity, crypt mitosis, villus height, and crypt depth that was associated with increased expression of the ErbB ligand epiregulin and decreased expression of IGF-I and IGF-IR. This suggests that in KO mice, GLP-2 action in jejunal mucosa is independent of the IGF-I system and linked with ErbB ligands. In summary, the intestinotrophic actions of IGF-I, but not GLP-2, in mucosa are dependent on IGFBP-3 and -5. These findings support the role of multiple downstream mediators for the mucosal growth induced by GLP-2.

Orally administered IGF-I increases intestinal mucosal growth in formula-fed neonatal pigs

1996 ◽  
Vol 270 (5) ◽  
pp. R1085-R1091 ◽  
Author(s):  
D. G. Burrin ◽  
T. J. Wester ◽  
T. A. Davis ◽  
S. Amick ◽  
J. P. Heath
Keyword(s):  
Oral Administration ◽  
Peripheral Circulation ◽  
Intestinal Lumen ◽  
Recombinant Human Insulin ◽  
Igf Binding Proteins ◽  
Intestinal Growth ◽  
Neonatal Pigs ◽  
Igf I ◽  
Small Intestinal ◽  
Mucosal Growth

Our objective was to determine the potentially anabolic effects of orally administered recombinant human insulin-link growth factor I (rhIGF-I)on small intestinal growth in formula-fed neonatal pigs. Unsuckled neonatal pigs received formula or formula containing added rhIGF-I (3.5 mg.kg-1.day-1) from birth to 4 days of age. Pigs in both groups were fed 30 ml/kg formula every 2 h on day 1 and then every 4 h on days 2-4, and blood was sampled daily. Oral administration of rhIGF-I to formula-fed neonatal pigs increased small intestinal weight, protein, and DNA content,but not length. Jejunal and ileal villus height, but not crypt depth or muscularis thickness, also were increased by oral rhIGF-I administration. Neither the circulating concentration of IGF-I nor the IGF-binding proteins differed between control and oral rhIGF-treated pigs, suggesting that the absorption of orally administered rhIGF-I from the intestinal lumen into the peripheral circulation was limited. Our results demonstrate that oral administration of rhIGF-I during the first 4 days after birth significantly increased small intestinal mucosal growth in formula-fed neonatal pigs. These results suggest that oral administration of rhIGF-I may be a viable therapeutic approach to enhance intestinal growth in neonates.

Insulin-like growth factor I and glucagon-like peptide-2 responses to fasting followed by controlled or ad libitum refeeding in rats

2008 ◽  
Vol 294 (4) ◽  
pp. R1175-R1184 ◽  
Author(s):  
David W. Nelson ◽  
Sangita G. Murali ◽  
Xiaowen Liu ◽  
Matthew C. Koopmann ◽  
Jens J. Holst ◽  
...  
Keyword(s):  
Growth Factor ◽  
Plasma Concentrations ◽  
Insulin Like Growth Factor ◽  
Glucose Transporter 1 ◽  
Factor I ◽  
Igf I ◽  
Ad Libitum ◽  
Glucagon Like Peptide ◽  
Growth Factor I ◽  
Mucosal Growth

Luminal nutrients stimulate structural and functional regeneration in the intestine through mechanisms thought to involve insulin-like growth factor I (IGF-I) and glucagon-like peptide-2 (GLP-2). We investigated the relationship between IGF-I and GLP-2 responses and mucosal growth in rats fasted for 48 h and then refed for 2 or 4 days by continuous intravenous or intragastric infusion or ad libitum feeding. Fasting induced significant decreases in body weight, plasma concentrations of IGF-I and bioactive GLP-2, jejunal mucosal cellularity (mass, protein, DNA, and villus height), IGF-I mRNA, and ileal proglucagon mRNA. Plasma IGF-I concentration was restored to fed levels with 2 days of ad libitum refeeding but not with 4 days of intravenous or intragastric refeeding. Administration of an inhibitor of endogenous GLP-2 (rat GLP-23–33) during ad libitum refeeding partially attenuated mucosal growth and prevented the increase in plasma IGF-I to fed levels; however, plasma GLP-2 and jejunal IGF-I mRNA were restored to fed levels. Intragastric refeeding restored intestinal cellularity and functional capacity (sucrase activity and sodium-glucose transporter-1 expression) to fed levels, whereas intravenous refeeding had no effect. Intestinal regeneration after 4 days of intragastric or 2 days of ad libitum refeeding was positively associated with increases in plasma concentrations of GLP-2 and jejunal IGF-I mRNA. These data suggest that luminal nutrients stimulate intestinal growth, in part, by increased expression of both GLP-2 and IGF-I.

scholarly journals Mesenchymal IGF-I overexpression: paracrine effects in the intestine, distinct from endocrine actions

2002 ◽  
Vol 283 (4) ◽  
pp. G875-G885 ◽  
Author(s):  
Kristen L. Williams ◽  
C. Randall Fuller ◽  
James Fagin ◽  
P. Kay Lund
Keyword(s):  
Smooth Muscle Actin ◽  
Paracrine Effects ◽  
Igf I ◽  
Igf Binding ◽  
Actin Promoter ◽  
Mucosal Growth ◽  
Igf Binding Protein ◽  
Epithelial Growth ◽  
Igfbp 3

Local IGF-I expression is frequently increased in intestinal mesenchyme during adaptive growth of intestinal epithelium, but paracrine growth effects of IGF-I in vivo are not defined. We tested whether overexpression of IGF-I in intestinal mesenchyme increases epithelial growth and if effects are distinct from known effects of circulating IGF-I. SMP8-IGF-I-transgenic (TG) mice overexpress IGF-I driven by an α-smooth muscle actin promoter. Mucosal and muscularis growth were assessed in the jejunum, ileum, and colon of SMP8-IGF-I-TG mice and wild-type littermates. Abundance of the SMP8-IGF-I transgene and IGF binding protein (IGFBP)-3 and -5 mRNAs was determined. Mucosal growth was increased in SMP8-IGF-I-TG ileum but not jejunum or colon; muscularis growth was increased throughout the bowel. IGFBP-5 mRNA was increased in SMP8-IGF-I-TG jejunum and ileum and was specifically upregulated in ileal lamina propria. Overexpression of IGF-I in intestinal mesenchymal cells has preferential paracrine effects on the ileal mucosal epithelium and autocrine effects on the muscularis throughout the bowel. Locally expressed IGF-I has distinct actions on IGFBP expression compared with circulating IGF-I.

Intestinotrophic effects of exogenous IGF-I are not diminished in IGF binding protein-5 knockout mice

2007 ◽  
Vol 292 (6) ◽  
pp. R2144-R2150 ◽  
Author(s):  
Sangita G. Murali ◽  
Xiaowen Liu ◽  
David W. Nelson ◽  
Angela K. Hull ◽  
Michael Grahn ◽  
...  
Keyword(s):  
Body Weight ◽  
Binding Protein ◽  
Wild Type ◽  
Intestinal Growth ◽  
Male And Female ◽  
Igf I ◽  
Igf Binding ◽  
Igf Binding Protein ◽  
Stimulation Of ◽  
Igfbp 3

IGF binding protein-5 (IGFBP-5) modulates the availability of IGF-I to its receptor and potentiates the intestinotrophic action of IGF-I. Our aim was to test the hypothesis that stimulation of intestinal growth due to coinfusion of IGF-I with total parenteral nutrition (TPN) solution is dependent on increased expression of IGFBP-5 through conducting our studies in IGFBP-5 knockout (KO) mice. IGFBP-5 KO, heterozygote (HT) and wild type (WT) male and female mice were maintained with TPN or TPN plus coinfusion of IGF-I [recombinant human (rh)IGF-I; 2.5 mg·kg−1·day−1] for 5 days. The concentration of IGF-I in serum was 73% greater ( P < 0.0001) in mice given TPN + IGF-I infusion compared with TPN alone. IGF-I attenuated the 2–3 g loss of body weight associated with TPN in WT mice, whereas KO and HT mice did not show improvement in body weight with IGF-I treatment. KO and HT mice had significantly greater levels of circulating IGF-I binding proteins (IGFBPs) compared with WT mice. Intestinal growth due to IGF-I was observed in all groups treated with IGF-I based on greater concentrations of protein and DNA in small intestine and colon and significantly greater crypt depth and muscularis thickness in jejunum. Jejunal expression of IGFBP-5 mRNA was greater in WT mice, whereas IGFBP-3 mRNA was greater in KO mice treated with IGF-I. In summary, the absence of the IGFBP-5 gene did not block the ability of IGF-I to stimulate intestinal growth, possibly because greater jejunal expression of IGFBP-3 compensates for the absence of IGFBP-5.

Transfer of insulin-like growth factor (IGF)-I from blood to intestine: comparison with IGFs that bind poorly to IGF-binding proteins

1994 ◽  
Vol 141 (3) ◽  
pp. 505-515 ◽  
Author(s):  
A P D Lord ◽  
A A Martin ◽  
F J Ballard ◽  
L C Read
Keyword(s):  
Binding Proteins ◽  
Specific Activity ◽  
Intestinal Segment ◽  
Intestinal Tissue ◽  
Igf Binding Proteins ◽  
Free Peptide ◽  
Igf I ◽  
Igf Binding ◽  
Specific Activities ◽  
Venous Plasma

Abstract The net transfer of 125I-labelled insulin-like growth factor (IGF)-I from the blood to the distal small intestine was measured in anaesthetized lambs using a non-recirculating vascular-perfused intestine. To determine whether IGF-binding proteins (IGFBPs) reduce net IGF transfer, radio-labelled IGF-I was compared with two analogues, des(1–3)IGF-I and LR3IGF-I, which show reduced affinity for IGFBPs. Radiolabelled IGF-I, des(1–3)IGF-I or LR3IGF-I (1 ng/ml plasma) was infused for 45 min into the arterial supply of a 10 cm intestinal segment, either in the absence of added unlabelled peptide (high specific activity) or in the presence of a 100-fold excess of unlabelled homologous peptide (low specific activity) to achieve different proportions of free and complexed peptide. Very little degradation of radiolabelled peptides was detected in plasma, with 3–10% degradation in the intestinal tissue. Less than 5% of radiolabelled IGF-I remained as free peptide in the efferent venous plasma of the perfused segment at both specific activities. Bound radio-labelled IGF-I was found by size-exclusion chromatography mainly in the 30–50 kDa region, with a smaller proportion in the 150 kDa peak. The net intestinal transfer of IGF-I, calculated as the sum of the proportions of infused tracer recovered from intestinal tissue, luminal contents and lymph, was 3·46 ± 0·22% (s.e.m.) and 3·49 ± 0·93% when infused at high and low specific activities respectively. The analogues differed from IGF-I with up to ninefold higher concentrations of free radio-labelled peptide in venous plasma of the perfused intestinal segment, and corresponding decreases in binding to the 30–50 kDa binding proteins. Notwithstanding these marked differences in the plasma levels of free peptide, net intestinal transfer was very similar for the three peptides, as was the extent of degradation in the intestinal tissue. The lack of correlation between binding to 30–50 kDa binding proteins and net intestinal transfer suggests that association with 30–50 kDa plasma binding proteins is not a rate-limiting determinant of net IGF transfer to intestinal tissue. Journal of Endocrinology (1994) 141, 505–515

scholarly journals IGF Binding Protein-4 is Required for the Growth Effects of Glucagon-Like Peptide-2 in Murine Intestine

Endocrinology ◽  
2014 ◽  
Vol 156 (2) ◽  
pp. 429-436 ◽  
Author(s):  
Kaori Austin ◽  
Nuvair A. Imam ◽  
John E. Pintar ◽  
Patricia L. Brubaker
Keyword(s):  
Protein A ◽  
Jejunal Mucosa ◽  
Igf Binding Proteins ◽  
Intestinal Growth ◽  
Fetal Rat ◽  
Negative Effect ◽  
Igf Binding ◽  
Glucagon Like Peptide ◽  
Small Intestinal ◽  
Intestinal Weight

Glucagon-like peptide-2 (GLP-2) is an enteroendocrine hormone that stimulates the growth of the intestinal epithelium. We have previously demonstrated that GLP-2 exerts its intestinotropic effect through an indirect mechanism that requires both IGF-1 and the intestinal epithelial IGF-1 receptor. However, the biological activity of IGF-1 is modulated by IGF binding proteins (IGFBPs), including IGFBP-4, which is highly expressed in the intestine. To determine the role of IGFBP-4 in the tropic effects of GLP-2, IGFBP-4 knockout (KO) and control mice were treated with degradation-resistant GLP-2 or vehicle for 10 days. Comparable levels of IGFBP-1–3/5–7 mRNAs were observed in the intestinal mucosa of all animals. IGFBP-4 KO mice had greater small intestinal weight and length, and deeper crypts (P &lt; .05) as compared with controls, suggesting that IGFBP-4 has an inhibitory role in basal intestinal growth. However, small intestinal weight, crypt-villus height and crypt cell proliferation increased in response to GLP-2 in control mice (P &lt; .05), and these changes were abrogated with IGFBP-4 KO. In contrast, pregnancy-associated plasma protein-A KO mice, which have increased levels of circulating IGFBP-4, demonstrated a normal intestinotropic response to GLP-2. Finally, GLP-2 treatment of control mice significantly increased IGFBP-4 mRNA expression in the jejunal mucosa (P &lt; .05), a finding that was recapitulated by GLP-2 treatment of fetal rat intestinal cells in culture (10−8M for 2 h; P &lt; .05). Collectively, these results indicate that the IGF-I-modulating protein, IGFBP-4, exerts a negative effect on basal intestinal growth but plays a positive regulatory role in the intestinotropic actions of GLP-2.

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