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.

Dexamethasone inhibits small intestinal growth via increased protein catabolism in neonatal pigs

1999 ◽  
Vol 276 (2) ◽  
pp. E269-E277 ◽  
Author(s):  
Douglas G. Burrin ◽  
Timothy J. Wester ◽  
Teresa A. Davis ◽  
Marta L. Fiorotto ◽  
Xiaoyan Chang
Keyword(s):  
Protein Synthesis ◽  
Specific Activity ◽  
Synthesis Rate ◽  
Saline Control ◽  
Protein Synthesis Rate ◽  
Control Group ◽  
Intestinal Growth ◽  
Neonatal Pigs ◽  
Igf I ◽  
Small Intestinal

Our objective was to determine how dexamethasone (Dex) affects gastrointestinal protein metabolism and growth in neonatal pigs. Two-day-old pigs were given daily subcutaneous injections of either Dex (1 mg/kg body wt, n = 7) or saline (control, n = 6) for 7 days. In vivo protein synthesis was measured after 7 days with a bolus of [3H]phenylalanine. Tissue protein contents were measured in an initial control group of 2-day-old pigs and in control and Dex pigs after 7 days to estimate protein accretion and degradation. In control pigs, the protein accretion in the ileum was nearly sixfold greater than in the jejunum during the 7-day period. Dex nominally altered stomach growth but completely blocked the accretion of protein and DNA in the jejunum and ileum, with reduced villus height in the ileum. Dex increased the fractional protein degradation rate in the ileum (28%) and decreased the absolute protein synthesis rate in the jejunum and ileum by 17 and 21%, respectively. Dex resulted in a 40% lower total intestinal lactase activity compared with controls via reductions in both specific activity and tissue mass, especially in the ileum. Dex significantly decreased the circulating concentrations of insulin-like growth factor (IGF) I and IGF-binding protein (IGFBP)-1, -2, and -3. However, the tissue abundance of the IGF-I receptor in the stomach and ileum was greater in Dex pigs than controls. Our results suggest that Dex significantly inhibits small intestinal growth via both increased degradation and decreased synthesis of protein. Furthermore, the inhibition of intestinal growth resulted in significantly decreased lactose digestive capacity.

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.

Simulation of IGF-I pharmacokinetics after infusion of recombinant IGF-I in human subjects

1997 ◽  
Vol 273 (2) ◽  
pp. E438-E447 ◽  
Author(s):  
M. A. Boroujerdi ◽  
R. H. Jones ◽  
P. H. Sonksen ◽  
D. L. Russell-Jones
Keyword(s):  
Compartmental Model ◽  
Human Subjects ◽  
Metabolic Clearance ◽  
Recombinant Human Insulin ◽  
Metabolic Clearance Rate ◽  
Igf Binding Proteins ◽  
Igf I ◽  
Igf Binding ◽  
Vascular Compartment ◽  
Igfbp 3

The pharmacokinetics of recombinant human insulin-like growth factor I (IGF-I) were studied in four healthy volunteers by a 3-h infusion at a rate of 20 micrograms.kg-1.h-1. A compartmental model was used to simulate the plasma “free” IGF-I and IGF-I associated with the 50- and 150-kDa plasma protein fractions. The model is based on the concept that free IGF-I and IGF binding proteins (IGFBPs) are the substrates for their own degradation and that they act as reservoirs for retention of IGF-I in the vascular compartment or inhibiting IGF-I action. The metabolic clearance rate (MCR) of free IGF-I is estimated as 2.62 +/- 0.94 ml.min-1.min-1 with a production rate of 4.75 +/- 1.74 mg/day (621.0 +/- 227.34 nmol/day). The simulation shows that higher concentrations of IGFBP-3 would increase the estimate of MCR for free IGF-I by reducing free IGF-I concentration. The model will be of value for simulation of dynamic profiles of free IGF-I and receptor-bound IGF-I in a variety of pathophysiological conditions.

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.

Stimulation of proximal small intestinal mucosal growth by luminal polyamines

1991 ◽  
Vol 261 (3) ◽  
pp. G504-G511 ◽  
Author(s):  
J. Y. Wang ◽  
S. A. McCormack ◽  
M. J. Viar ◽  
L. R. Johnson
Keyword(s):  
Drinking Water ◽  
Oral Administration ◽  
Thymidine Incorporation ◽  
Growth Parameters ◽  
Jejunal Mucosa ◽  
Surrounding Environment ◽  
Small Intestinal ◽  
Mucosal Growth ◽  
Stimulation Of

The purpose of this study was to determine whether luminal polyamines stimulate intestinal mucosal growth in vivo. Rats received 2% alpha-difluoromethylornithine (DFMO) added to their drinking water throughout the experiment. The polyamines spermidine and spermine (3 mg each/100 g body wt) were given intragastrically in combined doses once at 9:30 A.M. and again at 5:30 P.M. Duodenal and jejunal mucosal ornithine decarboxylase (ODC) activity in the DFMO-treated rats was inhibited significantly for the duration of the study. DFMO also markedly decreased the rate of [3H]thymidine incorporation into DNA of duodenal and jejunal mucosa. The decrease in [3H]thymidine incorporation was significant 4 days and maximal 6 and 8 days after beginning treatment with DFMO. Decreased ODC activity and DNA synthesis were paralleled by decreases in total mucosal DNA, RNA, and protein content. Administration of the polyamines significantly reversed the effects of DFMO except the inhibition of ODC. In fact, there were no significant differences in mucosal growth parameters between the controls (without DFMO) and those treated with DFMO plus polyamines. Oral administration of spermidine and spermine at a dose of 4.5 mg each/100 g body wt for 6 days to rats not treated with DFMO increased the normal rate of mucosal growth in the duodenum and jejunum as well. Polyamine accumulation in IEC-6 cells was measured to determine whether it was altered by DFMO. IEC-6 cells took up [3H]putrescine and [3H]spermidine from their surrounding environment and the uptake was stimulated by serum. DFMO (5 mM) totally inhibited the increase in ODC activity but had no effect on the cellular uptake of polyamines in the presence of putrescine.(ABSTRACT TRUNCATED AT 250 WORDS)

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.

Exogenous growth hormone stimulates somatotropic axis function and growth in neonatal pigs

1998 ◽  
Vol 274 (1) ◽  
pp. E29-E37 ◽  
Author(s):  
Timothy J. Wester ◽  
Teresa A. Davis ◽  
Marta L. Fiorotto ◽  
Douglas G. Burrin
Keyword(s):  
Growth Hormone ◽  
Protein Synthesis ◽  
Body Weight Gain ◽  
Tissue Growth ◽  
Synthesis Rate ◽  
Protein Synthesis Rate ◽  
Igf Binding Proteins ◽  
Neonatal Pigs ◽  
Igf I ◽  
Igfbp 3

We studied the effects of exogenous porcine growth hormone (pGH) administration on circulating insulin-like growth factor I (IGF-I) concentration, IGF-binding proteins (IGFBP), tissue growth, and protein synthesis in neonatal pigs. One-day-old pigs were given daily intramuscular injections of either pGH (1 mg/kg body wt) ( n = 6) or saline ( n = 5) for 7 days, after which time we measured in vivo protein synthesis using a bolus of [3H]-phenylalanine. Mean plasma pGH concentration in pGH-treated pigs measured on day 7was 22-fold higher than in controls. The plasma IGF-I concentration in pGH-treated pigs was significantly greater than in controls after 1 day of treatment and plateaued at 285% of control values after 4 days. After 7 days of treatment, plasma IGFBP-3 concentrations and the plasma glucose response to a meal were also greater in pGH-treated than control pigs. pGH treatment significantly increased body weight gain and food conversion efficiency and the protein synthesis rate in several visceral organs. Our results demonstrate that exogenous pGH increases circulating IGF-I and IGFBP-3 concentrations and visceral organ growth in neonatal pigs, suggesting that the somatotrophic axis is functional in the neonate.

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