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 < .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 < .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 < .05), a finding that was recapitulated by GLP-2 treatment of fetal rat intestinal cells in culture (10−8M for 2 h; P < .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.

Intestinal growth is associated with elevated levels of glucagon-like peptide 2 in diabetic rats

1997 ◽  
Vol 273 (4) ◽  
pp. E815-E820 ◽  
Author(s):  
Kirk D. Fischer ◽  
Savita Dhanvantari ◽  
Daniel J. Drucker ◽  
Patricia L. Brubaker
Keyword(s):  
Experimental Diabetes ◽  
Plasma Concentrations ◽  
Diabetic Rats ◽  
Diabetic Rat ◽  
Villus Height ◽  
Intestinal Growth ◽  
Glucagon Like Peptide ◽  
Small Intestinal ◽  
The Relationship ◽  
Intestinal Weight

Glucagon-like peptide 2 (GLP-2) has recently been identified as a novel intestinal growth factor. Because experimental diabetes is associated with bowel growth, we examined the relationship between GLP-2 and intestinal growth in rats made diabetic by streptozotocin (STZ) injection and treated with or without insulin for 3 wk. Ileal concentrations of the intestinal proglucagon-derived peptides, i.e., glicentin + oxyntomodulin, and GLPs 1 and 2, were increased by 57 ± 20% above those of controls in untreated STZ diabetes ( P < 0.05–0.001). Similar increases in plasma concentrations of glicentin + oxyntomodulin (77 ± 15% above controls, P < 0.01) and GLP-2 (91 ± 32% above controls, P < 0.05) were seen in untreated STZ diabetes. Both wet and dry small intestinal weight increased by 74 ± 20% above controls ( P < 0.01) in STZ diabetes, and macromolecular analysis indicated parallel increases in both protein ( P < 0.001) and lipid ( P < 0.05) content. Villus height ( P < 0.001) and crypt depth ( P < 0.01) were also increased in untreated diabetic rat intestine. Insulin therapy prevented the changes in plasma GLP-2 and intestinal mass seen in untreated STZ diabetes. Thus STZ diabetes is associated with both increased production of GLP-2 and enhanced bowel weight, thereby suggesting a role for GLP-2 in diabetes-associated bowel growth.

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.

scholarly journals Selection of the Dominant Follicle and Insulin-Like Growth Factor (IGF)-Binding Proteins: Evidence that Pregnancy-Associated Plasma Protein A Contributes to Proteolysis of IGF-Binding Protein 5 in Bovine Follicular Fluid

Endocrinology ◽  
2003 ◽  
Vol 144 (2) ◽  
pp. 437-446 ◽  
Author(s):  
G. M. Rivera ◽  
J. E. Fortune
Keyword(s):  
Proteolytic Activity ◽  
Plasma Protein ◽  
Follicular Fluid ◽  
Binding Proteins ◽  
Protein A ◽  
Positive Control ◽  
Dominant Follicle ◽  
Igf Binding Proteins ◽  
Igf Binding ◽  
Igf Binding Protein

Development of a dominant follicle is associated with decreased intrafollicular low molecular weight IGF-binding proteins (namely IGFBP-2, -4, and -5) and increased proteolysis of IGFBP-4 by pregnancy-associated plasma protein A (PAPP-A). In addition to IGFBP-4 proteolytic activity, bovine follicular fluid contains strong proteolytic activity for IGFBP-5, but not for IGFBP-2. Here we show that the IGFBP-5 protease present in bovine follicular fluid is a neutral/basic pH-favoring, Zn2+ metalloprotease very similar to the previously described IGFBP-4 protease. We hypothesized that immunoneutralization and immunoprecipitation with anti-PAPP-A antibodies would result in abrogation of the IGFBP-4, but not the IGFBP-5, proteolytic activity in follicular fluid. As expected, anti-PAPP-A antibodies were able to neutralize and precipitate the IGFBP-4, but not the IGFBP-5, proteolytic activity of human pregnancy serum, which was used as a positive control for PAPP-A. Surprisingly, immunoneutralization and immunoprecipitation of follicular fluid from bovine preovulatory follicles with anti-PAPP-A antibodies abrogated both IGFBP-4 and IGFBP-5 proteolysis. Quantitative results derived from phosphorimaging revealed a complete inhibition of both IGFBP-4 and -5 proteolysis by follicular fluid incubated for 2 or 5 h in the presence of anti-PAPP-A antibodies. After 18 h of incubation, anti-PAPP-A antibodies still inhibited IGFBP-5 degradation, although with an efficiency lower than that for IGFBP-4 degradation. Both proteolytic activities have identical electrophoretic mobility, and a single band (∼400 kDa) was detected by Western immunoblotting of bovine follicular fluid with anti-PAPP-A antibodies. Proteolysis of IGFBP-5 was readily detectable in follicular fluid from dominant follicles and was negligible in subordinate follicles from the same cohort. These results suggest that an active intrafollicular IGFBP-4/-5 proteolytic system, in which PAPP-A is the major protease involved, is an important determinant of follicular fate.

scholarly journals Analysis of Pregnancy-Associated Plasma Protein A Production in Human Adult Cardiac Progenitor Cells

2013 ◽  
Vol 2013 ◽  
pp. 1-8 ◽  
Author(s):  
Piera D’Elia ◽  
Vittoria Ionta ◽  
Isotta Chimenti ◽  
Francesco Angelini ◽  
Fabio Miraldi ◽  
...  
Keyword(s):  
Progenitor Cells ◽  
Plasma Protein ◽  
Protein A ◽  
Therapeutic Effects ◽  
Cardiac Progenitor Cells ◽  
Cardiac Cell ◽  
Igf Binding Proteins ◽  
Human Adult ◽  
Igf Binding ◽  
Cardiac Cell Therapy

IGF-binding proteins (IGFBPs) and their proteases regulate IGFs bioavailability in multiple tissues. Pregnancy-associated plasma protein A (PAPP-A) is a protease acting by cleaving IGFBP2, 4, and 5, regulating local bioavailability of IGFs. We have previously shown that IGFs and IGFBPs are produced by human adult cardiac progenitor cells (haCPCs) and that IGF-1 exerts paracrine therapeutic effects in cardiac cell therapy with CPCs. Using immunofluorescence and enzyme immunoassays, we firstly report that PAPP-A is produced and secreted in surprisingly high amounts by haCPCs. In particular, the homodimeric, enzymatically active, PAPP-A is secreted in relevant concentrations in haCPC-conditioned media, while the enzymatically inactive PAPPA/proMBP complex is not detectable in the same media. Furthermore, we show that both homodimeric PAPP-A and proMBP can be detected as cell associated, suggesting that the previously described complex formation at the cell surface does not occur easily, thus positively affecting IGF signalling. Therefore, our results strongly support the importance of PAPP-A for the IGFs/IGFBPs/PAPP-A axis in CPCs biology.

scholarly journals Author Correction: A common variant of the pregnancy-associated plasma protein-A (PAPPA) gene encodes a protein with reduced proteolytic activity towards IGF-binding proteins

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
J. A. Bøtkjær ◽  
P. R. Noer ◽  
Claus Oxvig ◽  
Claus Yding Andersen
Keyword(s):  
Proteolytic Activity ◽  
Plasma Protein ◽  
Binding Proteins ◽  
Protein A ◽  
Common Variant ◽  
Igf Binding Proteins ◽  
Igf Binding

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

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.

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 The effect of trypsin inhibitor on the pancreas and small intestine of mice

1993 ◽  
Vol 70 (1) ◽  
pp. 333-345 ◽  
Author(s):  
Y. C. Ge ◽  
R. G. H. Morgan
Keyword(s):  
Small Intestine ◽  
Trypsin Inhibitor ◽  
Growth Rates ◽  
Intestinal Growth ◽  
Pancreatic Growth ◽  
Bovine Trypsin ◽  
Bean Flour ◽  
Mucosal Layer ◽  
Small Intestinal ◽  
Intestinal Weight

Pancreatic and intestinal growth rates were measured in mice fed on raw soya-bean flour (RSF) for up to 24 weeks. Control animals were fed on standard chow. The effects of RSF on the mouse pancreas resembled that seen in rats, showing hypertrophy with some hyperplasia. A marked increase in small intestinal weight was also found in mice fed on RSF but not in rats fed on this diet. Histological studies showed an increase in both villous and crypt thicknesses in the small intestine from these mice, and DNA, RNA and protein measurements indicated that the increase in intestinal weight was due to hypertrophy and hyperplasia of the mucosal layer. To determine whether the intestinal growth in mice fed on RSF was purely a response to the trypsin inhibitor (TI) component of the diet, pancreatic and intestinal growth rates were also determined in mice fed on the synthetic trypsin inhibitor camostate, at levels of 0·5 or 2 g/kg in rat chow, for periods of 1–8 weeks. Control animals were fed on standard chow. RSF and 0·5 g camostate/kg had similar trypsin inhibitor activities (measured against bovine trypsin), and both caused similar increases in pancreatic weight, DNA, RNA and protein content. However, 0·5 g camostate/kg did not affect small intestinal weight. Chow containing 2 g camostate/kg contained twice as much TI activity as the RSF diet but produced only a small increase in small intestinal weight at 2 and 8 weeks. This intestinal growth was significantly less than that seen with RSF. The present study shows that, in the mouse, RSF or a diet containing camostate in the appropriate dose produces pancreatic growth comparable to that seen in the rat. RSF also causes intestinal growth, but camostate-containing diets have little or no effect on the growth of the intestine.

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