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Sikiric P, Skrtic A, Gojkovic S, Krezic I, Zizek H, Lovric E, Sikiric S, Knezevic M, Strbe S, Milavic M, Kokot A, Blagaic AB, Seiwerth S. Cytoprotective gastric pentadecapeptide BPC 157 resolves major vessel occlusion disturbances, ischemia-reperfusion injury following Pringle maneuver, and Budd-Chiari syndrome. World J Gastroenterol 2022; 28:23-46. [PMID: 35125818 PMCID: PMC8793015 DOI: 10.3748/wjg.v28.i1.23] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/21/2021] [Revised: 05/14/2021] [Accepted: 12/21/2021] [Indexed: 02/06/2023] Open
Abstract
The stable gastric pentadecapeptide BPC 157 counteracts various venous occlusion-induced syndromes. Summarized are all these arguments, in the Robert's cytoprotection concept, to substantiate the resolution of different major vessel occlusion disturbances, in particular ischemia-reperfusion injury following the Pringle maneuver and Budd-Chiari syndrome, which was obtained by BPC 157 therapy. Conceptually, there is a new point, namely, endothelium maintenance to epithelium maintenance (the recruitment of collateral blood vessels to compensate for vessel occlusion and reestablish blood flow or bypass the occluded or ruptured vessel). In this paper, we summarize the evidence of the native cytoprotective gastric pentadecapeptide BPC 157, which is stable in the human gastric juice, is a membrane stabilizer and counteracts gut-leaky syndrome. As a particular target, it is distinctive from the standard peptide growth factors, involving particular molecular pathways and controlling VEGF and NO pathways. In the early 1990s, BPC 157 appeared as a late outbreak of the Robert's and Szabo's cytoprotection-organoprotection concept, like the previous theoretical/practical breakthrough in the 1980s and the brain-gut axis and gut-brain axis. As the time went on, with its reported effects, it is likely most useful theory practical implementation and justification. Meantime, several reviews suggest that BPC 157, which does not have a lethal dose, has profound cytoprotective activity, used to be demonstrated in ulcerative colitis and multiple sclerosis trials. Likely, it may bring the theory to practical application, starting with the initial argument, no degradation in human gastric juice for more than 24 h, and thereby, the therapeutic effectiveness (including via a therapeutic per-oral regimen) and pleiotropic beneficial effects.
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Affiliation(s)
- Predrag Sikiric
- Department of Pharmacology, School of Medicine, University of Zagreb, Zagreb 10000, Croatia
| | - Anita Skrtic
- Department of Pathology, School of Medicine, University of Zagreb, Zagreb 10000, Croatia
| | - Slaven Gojkovic
- Department of Pharmacology, School of Medicine, University of Zagreb, Zagreb 10000, Croatia
| | - Ivan Krezic
- Department of Pharmacology, School of Medicine, University of Zagreb, Zagreb 10000, Croatia
| | - Helena Zizek
- Department of Pharmacology, School of Medicine, University of Zagreb, Zagreb 10000, Croatia
| | - Eva Lovric
- Department of Pathology, School of Medicine, University of Zagreb, Zagreb 10000, Croatia
| | - Suncana Sikiric
- Department of Pathology, School of Medicine, University of Zagreb, Zagreb 10000, Croatia
| | - Mario Knezevic
- Department of Pharmacology, School of Medicine, University of Zagreb, Zagreb 10000, Croatia
| | - Sanja Strbe
- Department of Pharmacology, School of Medicine, University of Zagreb, Zagreb 10000, Croatia
| | - Marija Milavic
- Department of Pathology, School of Medicine, University of Zagreb, Zagreb 10000, Croatia
| | - Antonio Kokot
- Department of Anatomy and Neuroscience, Faculty of Medicine Osijek, J.J.Strossmayer University of Osijek, Osijek 31000, Croatia
| | - Alenka Boban Blagaic
- Department of Pharmacology, School of Medicine, University of Zagreb, Zagreb 10000, Croatia
| | - Sven Seiwerth
- Department of Pathology, School of Medicine, University of Zagreb, Zagreb 10000, Croatia
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Mayo BJ, Stringer AM, Bowen JM, Bateman EH, Keefe DM. Irinotecan-induced mucositis: the interactions and potential role of GLP-2 analogues. Cancer Chemother Pharmacol 2016; 79:233-249. [PMID: 27770239 DOI: 10.1007/s00280-016-3165-9] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2016] [Accepted: 10/06/2016] [Indexed: 12/11/2022]
Abstract
PURPOSE A common side effect of irinotecan administration is gastrointestinal mucositis, often manifesting as severe diarrhoea. The damage to the structure and function of the gastrointestinal tract caused by this cytotoxic agent is debilitating and often leads to alterations in patients' regimens, hospitalisation or stoppage of treatment. The purpose of this review is to identify mechanisms of irinotecan-induced intestinal damage and a potential role for GLP-2 analogues for intervention. METHODS This is a review of current literature on irinotecan-induced mucositis and GLP-2 analogues mechanisms of action. RESULTS Recent studies have found alterations that appear to be crucial in the development of severe intestinal mucositis, including early apoptosis, alterations in proliferation and cell survival pathways, as well as induction of inflammatory cascades. Several studies have indicated a possible role for glucagon-like peptide-2 analogues in treating this toxicity, due to its proven intestinotrophic, anti-apoptotic and anti-inflammatory effects in other models of gastrointestinal disease. CONCLUSION This review provides evidence as to why and how this treatment may improve mucositis through the possible molecular crosstalk that may be occurring in models of severe intestinal mucositis.
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Affiliation(s)
- Bronwen J Mayo
- School of Medicine, University of Adelaide, Adelaide, South Australia, Australia. .,School of Pharmacy and Medical Sciences, Sansom Institute for Health Sciences, University of South Australia, Adelaide, South Australia, Australia.
| | - Andrea M Stringer
- School of Medicine, University of Adelaide, Adelaide, South Australia, Australia.,School of Pharmacy and Medical Sciences, Sansom Institute for Health Sciences, University of South Australia, Adelaide, South Australia, Australia
| | - Joanne M Bowen
- School of Medicine, University of Adelaide, Adelaide, South Australia, Australia
| | - Emma H Bateman
- School of Medicine, University of Adelaide, Adelaide, South Australia, Australia
| | - Dorothy M Keefe
- School of Medicine, University of Adelaide, Adelaide, South Australia, Australia
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Aunsholt L, Jeppesen PB, Lund P, Sangild PT, Ifaoui IBR, Qvist N, Husby S. Bovine colostrum to children with short bowel syndrome: a randomized, double-blind, crossover pilot study. JPEN J Parenter Enteral Nutr 2014; 38:99-106. [PMID: 23264167 DOI: 10.1177/0148607112469630] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Abstract
BACKGROUND Management of short bowel syndrome (SBS) aims to achieve intestinal autonomy to prevent fluid, electrolyte, and nutrient deficiencies and maintain adequate development. Remnant intestinal adaptation is required to obtain autonomy. In the newborn pig, colostrum has been shown to support intestinal development and hence adaptive processes. AIM The efficacy of bovine colostrum to improve intestinal function in children with SBS was evaluated by metabolic balance studies. MATERIALS AND METHODS Nine children with SBS were included in a randomized, double-blind, crossover study. Twenty percent of enteral fluid intake was replaced with bovine colostrum or a mixed milk diet for 4 weeks, separated by a 4-week washout period. Intestinal absorption of energy and wet weight was used to assess intestinal function and the efficacy of colostrum. RESULTS Colostrum did not improve energy or wet weight absorption compared with the mixed milk diet (P = 1.00 and P = .93, respectively). Growth as measured by weight and knemometry did not differ between diets (P = .93 and P = .28). In these patients, <150% enteral energy absorption of basal metabolic rate and 50% enteral fluid absorption of basal fluid requirement suggested intestinal failure and a need for parenteral nutrition (PN). CONCLUSION Inclusion of bovine colostrum to the diet did not improve intestinal function. Metabolic nutrient and wet weight balance studies successfully assessed intestinal function, and this method may distinguish between intestinal insufficiency (non-PN-dependent) and intestinal failure (PN-dependent) patients.
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Affiliation(s)
- Lise Aunsholt
- Hans Christian Andersen Children's Hospital, Odense University Hospital, Denmark
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Vipperla K, O'Keefe SJ. Teduglutide for the treatment of short bowel syndrome. Expert Rev Gastroenterol Hepatol 2011; 5:665-78. [PMID: 22017694 DOI: 10.1586/egh.11.82] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
Extensive resection of the intestine impairs its absorptive capacity and results in short bowel syndrome when the nutritional equilibrium is compromised. The remnant intestine adapts structurally to compensate, but nutritional autonomy cannot be achieved in patients with intestinal failure, requiring intravenous fluids and parenteral nutrition (PN) for sustenance of life. PN is expensive and associated with serious complications. Efforts to minimize or eliminate the need for PN heralded research focusing on the therapeutic utility of intrinsic gut factors involved in the postresection adaptation process. With the breakthrough recognition of the intestinotrophic properties of glucagon-like peptide-2, teduglutide, a recombinant analogue of glucagon-like peptide-2, is being investigated as a promising hope to mitigate the requirement of PN. Clinical studies to date have demonstrated a desirable benefit-to-risk profile in regards to its safety and efficacy. If approved for marketing, it will be the first of its class in short bowel syndrome management, offering an innovative therapeutic modality for this debilitating condition.
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Affiliation(s)
- Kishore Vipperla
- Division of General Internal Medicine, University of Pittsburgh Medical Center, 200 Lothrop Street, 933W MUH, Pittsburgh, PA 15213, USA
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Dicken BJ, Sergi C, Rescorla FJ, Breckler F, Sigalet D. Medical management of motility disorders in patients with intestinal failure: a focus on necrotizing enterocolitis, gastroschisis, and intestinal atresia. J Pediatr Surg 2011; 46:1618-1630. [PMID: 21843732 DOI: 10.1016/j.jpedsurg.2011.04.002] [Citation(s) in RCA: 49] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/04/2011] [Revised: 03/31/2011] [Accepted: 04/05/2011] [Indexed: 02/03/2023]
Abstract
BACKGROUND Intestinal failure (IF) is the dependence upon parenteral nutrition to maintain minimal energy requirements for growth and development. It may occur secondary to a loss of bowel length, disorders of motility, or both. Short bowel syndrome (SBS) is a malabsorptive state resulting from surgical resection, congenital defect, or diseases associated with loss of absorptive surface area. A particularly vexing problem is associated with whole bowel and/or segmental intestinal dysmotility. Motility disorders within the context of SBS and IF may relate to rapid intestinal transit secondary to loss of intestinal length, dysmotility associated with loss or poor antegrade peristalsis, or gastroparesis. Therapy may be classified into medical (prokinetic and antidiarrheal agents) and surgical to deal with the overdistended poorly motile bowel. METHODS We performed a systematic review of the literature pertaining to IF, SBS, and dysmotility in the pediatric population with gastroschisis, necrotizing enterocolitis, and intestinal atresia. In addition to the available treatment options, we have provided a review of the literature and a summary of the available evidence. CONCLUSION Despite relatively poor level of evidence regarding the application of promotility and antidiarrheal medications in patients with SBS and IF, these agents continue to be used. Herein, we provide a review of the physiology and pathophysiology of intestinal motility/dysmotility and available strategies for the use of promotility and antidiarrheal agents in patients with IF/SBS.
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Affiliation(s)
- Bryan J Dicken
- Division of Pediatric Surgery, Stollery Children's Hospital, University of Alberta Hospital, Edmonton, Alberta, Canada.
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Dominguez JA, Coopersmith CM. Can we protect the gut in critical illness? The role of growth factors and other novel approaches. Crit Care Clin 2010; 26:549-65, x. [PMID: 20643306 PMCID: PMC2908596 DOI: 10.1016/j.ccc.2010.04.005] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Abstract
The intestine plays a central role in the pathophysiology of critical illness and is frequently called the "motor" of the systemic inflammatory response. Perturbations to the intestinal barrier can lead to distant organ damage and multiple organ failure. Therefore, identifying ways to preserve intestinal integrity may be of paramount importance. Growth factors and other peptides have emerged as potential tools for modulation of intestinal inflammation and repair due to their roles in cellular proliferation, differentiation, migration, and survival. This review examines the involvement of growth factors and other peptides in intestinal epithelial repair during critical illness and their potential use as therapeutic targets.
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Affiliation(s)
- Jessica A Dominguez
- Department of Anesthesiology, University of Colorado Denver School of Medicine, 12700 East 19th Avenue, Campus Box 8602, Aurora, CO 80045, USA.
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Sigalet DL, Lam V, Boctor D. The assessment, and glucagon-like peptide-2 modulation, of intestinal absorption and function. Semin Pediatr Surg 2010; 19:44-9. [PMID: 20123273 DOI: 10.1053/j.sempedsurg.2009.11.005] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
The treatment of patients with short bowel syndrome is hampered by a lack of treatment and measurement methods. This article reviews our evolving understanding of the role of glucagon-like peptide 2 (GLP-2) in controlling the adaptive process. The ability of the remnant intestine to produce GLP-2 appears to be predictive of the adaptive process; exogenous GLP-2 may be a therapy to augment adaptation. Strategies for monitoring patients, including conventional means, such as anthropomorphic measurements, plasma levels of specific nutrients, and vitamins and radiological contrast studies are reviewed. Investigational methods, such as nutrient balance studies, plasma citrulline levels, and the absorption of inert sugars (3-0 methyl glucose, mannitol, and lactulose) are discussed with the evidence to support their use.
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Affiliation(s)
- David L Sigalet
- Alberta Children's Hospital Intestinal Rehabilitation Program, Alberta Children's Hospital and University of Calgary, Calgary, Alberta, Canada.
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Ersoy B, Ozbilgin K, Kasirga E, Inan S, Coskun S, Tuglu I. Effect of growth hormone on small intestinal homeostasis relation to cellular mediators IGF-I and IGFBP-3. World J Gastroenterol 2009; 15:5418-24. [PMID: 19916171 PMCID: PMC2778097 DOI: 10.3748/wjg.15.5418] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/21/2009] [Revised: 09/16/2009] [Accepted: 09/23/2009] [Indexed: 02/06/2023] Open
Abstract
AIM To evaluate the effects of growth hormone (GH) on the histology of small intestines which might be related to the role of insulin like growth factor (IGF)-I, IGF-binding protein 3 (IGFBP-3) and its receptors. METHODS Twelve week-old adult male Wistar albino rats were divided into two groups. The study group (n = 10), received recombinant human growth hormone (rGH) at a dose of 2 mg/kg per day subcutaneously for 14 d and the control group (n = 10) received physiologic serum. Paraffin sections of jejunum were stained with periodic acid shift (PAS) and hematoxylin and eosin (HE) for light microscopy. They were also examined for IGF-I, IGFBP-3 and IGF-receptor immunoreactivities. Staining intensity was graded semi-quantitatively using the HSCORE. RESULTS Goblet cells and the cells in crypt epithelia were significantly increased in the study group compared to that of the control group. We have demonstrated an increase of IGF-I and IGFBP-3 immunoreactivities in surface epithelium of the small intestine by GH application. IGF-I receptor immunoreactivities of crypt, villous columnar cells, enteroendocrine cells and muscularis mucosae were also more strongly positive in the study group compared to those of in the control group. CONCLUSION These findings confirm the important trophic and protective role of GH in the homeostasis of the small intestine. The trophic effect is mediated by an increase in IGF-I synthesis in the small intestine, but the protective effect is not related to IGF-I.
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Sever M, Klicek R, Radic B, Brcic L, Zoricic I, Drmic D, Ivica M, Barisic I, Ilic S, Berkopic L, Blagaic AB, Coric M, Kolenc D, Vrcic H, Anic T, Seiwerth S, Sikiric P. Gastric pentadecapeptide BPC 157 and short bowel syndrome in rats. Dig Dis Sci 2009; 54:2070-2083. [PMID: 19093208 DOI: 10.1007/s10620-008-0598-y] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/03/2008] [Accepted: 10/17/2008] [Indexed: 12/11/2022]
Abstract
The gastric pentadecapeptide BPC 157, which was shown to be safe as an antiulcer peptide in trials for inflammatory bowel disease (PL14736, Pliva), successfully healed intestinal anastomosis and fistula in rat. Therefore, we studied for 4 weeks rats with escalating short bowel syndrome and progressive weight loss after small bowel resection from fourth ileal artery cranially of ileocecal valve to 5 cm beneath pylorus. BPC 157 (10 microg/kg or 10 ng/kg) was given perorally, in drinking water (12 ml/rat/day) or intraperitoneally (once daily, first application 30 min following surgery, last 24 h before sacrifice). Postoperatively, features of increasingly exhausted presentation were: weight loss appearing immediately regardless of villus height, twofold increase in crypt depth and fourfold increase in muscle thickness within the first week, jejunal and ileal overdilation, and disturbed jejunum/ileum relation. In contrast, constant weight gain above preoperative values was observed immediately with BPC 157 therapy, both perorally and parenterally, and villus height, crypt depth, and muscle thickness [inner (circular) muscular layer] also increased, at 7, 14, 21, and 28 days. Moreover, rats treated with pentadecapeptide BPC 157 showed not different jejunal and ileal diameters, constant jejunum-to-ileum ratio, and increased anastomosis breaking strength. In conclusion, pentadecapeptide BPC 157 could be helpful to cure short bowel syndrome.
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Affiliation(s)
- Marko Sever
- Department of Pharmacology, Medical School, University of Zagreb, Salata 11, 10000, Zagreb, Croatia
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Temporal Changes in the Intestinal Growth Promoting Effects of Glucagon-Like Peptide 2 Following Intestinal Resection. J Surg Res 2009; 152:271-80. [DOI: 10.1016/j.jss.2008.05.007] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2007] [Revised: 04/15/2008] [Accepted: 05/18/2008] [Indexed: 12/19/2022]
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Gu GS, Ren JA, Li N, Li JS. Effects of recombinant human growth hormone on enterocutaneous fistula patients. World J Gastroenterol 2008; 14:6858-62. [PMID: 19058314 PMCID: PMC2773883 DOI: 10.3748/wjg.14.6858] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To explore the effects of recombinant human growth hormone (rhGH) on intestinal mucosal epithelial cell proliferation and nutritional status in patients with enterocutaneous fistula.
METHODS: Eight patients with enterocutaneous fistulas received recombinant human growth hormone (10 μg/d) for 7 d. Image analysis and immunohisto-chemical techniques were used to analyse the expression of proliferating cell nuclear antigen (PCNA) in intestinal mucosal epithelial cells in biopsy samples from the patients who had undergone an endoscopic biopsy through the fistula at day 0, 4 and 7. Body weights, nitrogen excretion, serum levels of total proteins, albumin, prealbumin, transferrin and fibronectin were measured at day 0, 4 and 7.
RESULTS: Significant improvements occurred in the expression of PCNA in the intestinal mucosal epithelial cells at day 4 and 7 compared to day 0 (24.93 ± 3.41%, 30.46 ± 5.24% vs 12.92 ± 4.20%, P < 0.01). These changes were accompanied by the significant improvement of villus height (500.54 ± 53.79 μm, 459.03 ± 88.98 μm vs 210.94 ± 49.16 μm, P < 0.01), serum levels of total proteins (70.52 ± 5.13 g/L, 74.89 ± 5.16 g/L vs 63.51 ± 2.47 g/L, P < 0.01), albumin (39.44 ± 1.18 g/L, 42.39 ± 1.68 g/L vs 35.74 ± 1.75 g/L, P < 0.01) and fibronectin (236.3 ± 16.5 mg/L, 275.8 ± 16.9 mg/L vs 172.5 ± 21.4 mg/L, P < 0.01) at day 4 and 7, and prealbumin (286.38 ± 65.61 mg/L vs 180.88 ± 48.28 mg/L, P < 0.05), transferrin (2.61 ± 0.12 g/L vs 2.41 ± 0.14 g/L, P < 0.05) at day 7. Nitrogen excretion was significantly decreased at day 7 (3.40 ± 1.65 g/d vs 7.25 ± 3.92 g/d, P < 0.05). No change was observed in the body weight.
CONCLUSION: Recombinant human growth hormone could promote intestinal mucosal epithelial cell proliferation and protein synthesis in patients with enterocutaneous fistula.
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Rowland KJ, Brubaker PL. Life in the crypt: a role for glucagon-like peptide-2? Mol Cell Endocrinol 2008; 288:63-70. [PMID: 18403107 DOI: 10.1016/j.mce.2008.02.014] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/03/2007] [Revised: 01/31/2008] [Accepted: 02/25/2008] [Indexed: 12/27/2022]
Abstract
The epithelial layer of the intestinal tract serves as a model to study the mechanisms regulating tissue renewal. Central to this process is the intestinal stem cell and, thus, both the intrinsic and extrinsic factors that modulate the function of these cells must be understood. Amongst the intrinsic regulators, both the canonical wnt and bone morphogenic protein (bmp) signaling pathways have been shown to be essential determinants of stem cell dynamics and intestinal homeostasis. The intestinotrophic hormone, glucagon-like peptide-2 (GLP-2), has also recently been demonstrated to exert a variety of effects on the intestinal crypt cells, including enhancement of the putative stem cell marker, musashi-1, as well as stimulating intestinal proliferation. As the GLP-2 receptor is not expressed by the crypt cells, these actions have been hypothesized to be mediated indirectly, through other gut peptides and/or growth factors. Of these, recent studies have demonstrated a requirement for insulin-like growth factor-1 in the proliferative effects of GLP-2, through a pathway that involves activation of the canonical wnt signaling pathway. This extrinsic pathway represents a novel mechanism by which intestinal stem cell dynamics may be regulated.
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Amin H, Holst JJ, Hartmann B, Wallace L, Wright J, Sigalet DL. Functional ontogeny of the proglucagon-derived peptide axis in the premature human neonate. Pediatrics 2008; 121:e180-6. [PMID: 18166537 DOI: 10.1542/peds.2007-1461] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
BACKGROUND The regulation of intestinal growth and development in human neonates is incompletely understood, which hinders the provision of nutrients enterally. The "hindgut" hormones glucagon-like peptides 1 and 2 have been shown to play an important role in the regulation of nutrient assimilation, intestinal growth, and function. OBJECTIVE Our goal was to investigate the production of glucagon-like peptides 1 and 2 in premature human infants and examine the effects of prematurity and feeding on hormone release. PATIENTS AND METHODS With informed consent, premature infants who were admitted to a tertiary neonatal intensive care nursery (gestational age: 28-32 weeks) were monitored with weekly determinations of postprandial glucagon-like peptide 1 and 2 levels. Comparison studies with groups of normal infants and adults were performed. Hormone levels were obtained by using specific radioimmunoassay for glucagon-like peptide 1 (1-36) and glucagon-like peptide 2 (1-33), modified for small sample volumes; accurate monitoring of enteral intake was performed at all of the sampling time points. RESULTS Forty-five infants with a mean gestational age of 29.6 +/- 1.9 weeks were studied; fasting levels of both glucagon-like peptides 1 and 2 were elevated. There was no correlation between gestational age and glucagon-like peptide 2 output. However, both glucagon-like peptide 1 and 2 levels were correlated with the caloric value of feeds. CONCLUSIONS The premature human neonate has significantly higher fasting levels of glucagon-like peptides 1 and 2 compared with adults; feeding increases these levels further. These findings suggest that the proglucagon-derived peptides may have a role in normal intestinal development and nutrient handling.
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Affiliation(s)
- Harish Amin
- Department of Neonatology, Foothills Hospital, Calgary, Alberta, Canada
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Martin GR, Beck PL, Sigalet DL. Gut hormones, and short bowel syndrome: The enigmatic role of glucagon-like peptide-2 in the regulation of intestinal adaptation. World J Gastroenterol 2006; 12:4117-29. [PMID: 16830359 PMCID: PMC4087358 DOI: 10.3748/wjg.v12.i26.4117] [Citation(s) in RCA: 56] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Short bowel syndrome (SBS) refers to the malabsorption of nutrients, water, and essential vitamins as a result of disease or surgical removal of parts of the small intestine. The most common reasons for removing part of the small intestine are due to surgical intervention for the treatment of either Crohn's disease or necrotizing enterocolitis. Intestinal adaptation following resection may take weeks to months to be achieved, thus nutritional support requires a variety of therapeutic measures, which include parenteral nutrition. Improper nutrition management can leave the SBS patient malnourished and/or dehydrated, which can be life threatening. The development of therapeutic strategies that reduce both the complications and medical costs associated with SBS/long-term parenteral nutrition while enhancing the intestinal adaptive response would be valuable.
Currently, therapeutic options available for the treatment of SBS are limited. There are many potential stimulators of intestinal adaptation including peptide hormones, growth factors, and neuronally-derived components. Glucagon-like peptide-2 (GLP-2) is one potential treatment for gastrointestinal disorders associated with insufficient mucosal function. A significant body of evidence demonstrates that GLP-2 is a trophic hormone that plays an important role in controlling intestinal adaptation. Recent data from clinical trials demonstrate that GLP-2 is safe, well-tolerated, and promotes intestinal growth in SBS patients. However, the mechanism of action and the localization of the glucagon-like peptide-2 receptor (GLP-2R) remains an enigma. This review summarizes the role of a number of mucosal-derived factors that might be involved with intestinal adaptation processes; however, this discussion primarily examines the physiology, mechanism of action, and utility of GLP-2 in the regulation of intestinal mucosal growth.
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Affiliation(s)
- G-R Martin
- Department of Gastrointestinal Sciences, Faculty of Medicine, University of Calgary, 3330 Hospital Drive NW., Calgary, Alberta T2N 4N1, Canada.
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Abbott CA, Yazbeck R, Geier MS, Demuth HU, Howarth GS. Dipeptidyl peptidases and inflammatory bowel disease. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2006; 575:155-62. [PMID: 16700518 DOI: 10.1007/0-387-32824-6_16] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Affiliation(s)
- Catherine A Abbott
- School of Biological Sciences, Flinders University, Adelaide, SA, Australia
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Abstract
Short bowel syndrome occurs when there is insufficient length of the small intestine to maintain adequate nutrition and/or hydration status without supplemental support. This syndrome most frequently occurs following extensive surgical resection of the intestine, and the extent of adaptation depends on the anatomy of the resected bowel and the amount of bowel remaining. Following resection, the intestinal tissue undergoes morphologic and functional changes to compensate for the lost function of the resected bowel. These changes are mediated by multiple interactive factors, including intraluminal and parenteral nutrients, gastrointestinal secretions, hormones, cytokines, and growth factors, many of which have been well characterized in animal models. The amount of small bowel remaining is the most important predictor of adaptive potential; neither structural nor functional adaptative changes have been demonstrated in humans or animal models with more extreme resections resulting in an end-jejunostomy. The current understanding of these processes has led to the recent use of supplemental hormones, such as growth hormone and glucagon-like peptide 2, in intestinal rehabilitation programs and may lead to the development of pharmacologic agents designed to augment the innate adaptive response.
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Affiliation(s)
- Jason J Cisler
- Division of Gastroenterology, Feinburg School of Medicine, Northwestern University, Chicago, IL, USA
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Iskit SH, Tugtepe H, Ayyildiz SH, Kotiloglu E, Dagli TE, Yeğen BC. Epidermal growth factor and bombesin act synergistically to support intestinal adaptation in rats with massive small bowel resection. Pediatr Surg Int 2005; 21:436-40. [PMID: 15891892 DOI: 10.1007/s00383-005-1430-9] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 03/15/2005] [Indexed: 11/28/2022]
Abstract
Intestinal adaptation is the most important event in short bowel syndrome following a massive small bowel resection. Effects of various growth factors and their synergism have been well documented in intestinal adaptation. This study aimed to compare the effect of two different trophic agents, epidermal growth factor (EGF) and bombesin (BBS), on intestinal adaptation following massive intestinal resection. Sprague-Dawley male rats were assigned to one of four groups after a 75% small bowel resection. Either EGF (90 microg/kg), BBS (10 microg/kg), EGF+BBS, or bovine serum albumin (BSA) were injected subcutaneously three times a day. The animals were killed 10 days after the operation. Weight loss and morphologic parameters such as mucosal thickness, villus height, crypt depth, villus-to-crypt ratio, and muscularis propria height were measured. In the EGF+BBS group, mucosal thickness was found to be significantly increased compared with the other study groups (p<0.05). Similarly, villus height was significantly increased only in the EGF+BBS group (p<0.05). In the BBS group, both villus height and mucosal thickness showed a slight increase, but the values were not statistically significant compared with the vehicle-treated group. There were no significant differences in any of the remaining parameters between the groups. The results of this study indicate that the gut hormones EGF and BBS act synergistically in facilitating the adaptive response of the remnant ileum to massive intestinal resection.
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Affiliation(s)
- Serdar H Iskit
- Department of Pediatric Surgery, Marmara University School of Medicine, Mazharbey Evsan Sok., Aytac Ap. No: 20/6, Goztepe, 34724 Istanbul, Turkey
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Washizawa N, Gu LH, Gu L, Openo KP, Jones DP, Ziegler TR. Comparative effects of glucagon-like peptide-2 (GLP-2), growth hormone (GH), and keratinocyte growth factor (KGF) on markers of gut adaptation after massive small bowel resection in rats. JPEN J Parenter Enteral Nutr 2005; 28:399-409. [PMID: 15568286 DOI: 10.1177/0148607104028006399] [Citation(s) in RCA: 47] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
BACKGROUND Administration of specific growth factors exert gut-trophic effects in animal models of massive small bowel resection (SBR); however, little comparative data are available. Our aim was to compare effects of a human glucagon-like peptide-2 (GLP-2) analog, recombinant growth hormone (GH) and recombinant keratinocyte growth factor (KGF) on jejunal, ileal, and colonic growth and functional indices after 80% SBR in rats. METHODS Thirty-seven male rats underwent small bowel transection (sham operation) with s.c. saline administration (control; Tx-S; n = 7) or 80% midjejuno-ileal resection (Rx) and treatment with either s.c. saline (Rx-S, n = 7), GLP-2 at 0.2 mg/kg/d (Rx-GLP-2; n = 8), GH at 3.0 mg/kg/d (Rx-GH; n = 8), or KGF at 3.0 mg/kg/d (Rx-KGF; n = 7) for 7 days. All groups were pair-fed to intake of Rx-S rats. Gut mucosal cell growth indices (wet weight, DNA and protein content, villus height, crypt depth, and total mucosal height) were measured. Expression of the cytoprotective trefoil peptide TFF3 was determined by Western blot. Gut mucosal concentrations of the tripeptide glutathione (L-glutamyl-L-cysteinyl-glycine) and glutathione disulfide (GSSG) were measured by high-performance liquid chromatography and the glutathione/GSSG ratio calculated. RESULTS SBR increased adaptive growth indices in jejunal, ileal, and colonic mucosa. GLP-2 treatment increased jejunal villus height and jejunal total mucosal height compared with effects of resection alone or resection with GH or KGF treatment. Both GH and KGF modestly increased colonic crypt depth after SBR. SBR did not affect small bowel or colonic goblet cell number or TFF3 expression; however, goblet cell number and TFF3 expression in both small bowel and colon were markedly up-regulated by KGF treatment and unaffected by GLP-2 and GH. SBR oxidized the ileal and colonic mucosal glutathione/GSSG redox pools. GLP-2 treatment after SBR increased the glutathione/GSSG ratio in jejunum, whereas KGF had an intermediate effect. In addition, GLP-2 (but not GH or KGF) prevented the SBR-induced oxidation of the glutathione/GSSG pools in both ileum and colon. CONCLUSIONS GLP-2 exerts superior trophic effects on jejunal growth and also improves mucosal glutathione redox status throughout the bowel after massive SBR in rats. Both GH and KGF increase colonic mucosal growth in this model. KGF alone potently increases gut mucosal goblet cell number and expression of the cytoprotective trefoil peptide TFF3. The differential effects of GLP-2, GH and KGF administration in this model of short bowel syndrome suggest that individual therapy with these growth factors may not be an adequate strategy to maximally improve adaptive gut mucosal growth and cytoprotection after massive small intestinal resection. Future research should address the use of these agents in combination in short bowel syndrome.
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Affiliation(s)
- Naohiro Washizawa
- Department of Surgery, Toho University School of Medicine, Tokyo, Japan
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Martin GR, Wallace LE, Hartmann B, Holst JJ, Demchyshyn L, Toney K, Sigalet DL. Nutrient-stimulated GLP-2 release and crypt cell proliferation in experimental short bowel syndrome. Am J Physiol Gastrointest Liver Physiol 2005; 288:G431-8. [PMID: 15388486 DOI: 10.1152/ajpgi.00242.2004] [Citation(s) in RCA: 99] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Glucagon-like peptide-2 (GLP-2) is an enteroendocrine peptide that is released in response to luminal nutrients and has unique trophic actions in the gastrointestinal tract. These features suggest GLP-2 may be important in controlling intestinal adaptation. We examined the relationship over time of GLP-2 production and adaptation to intestinal resection, the effects of resection-induced malabsorption on GLP-2 production, and the correlation of endogenous serum GLP-2 levels with adaptation as measured by crypt-cell proliferation (CCP). We initially examined the effect of nutrient malabsorption, induced by a 90% resection of the proximal intestine studied on day 4, on the time course and levels of GLP-2 release. Secondly, the degree of malabsorption was varied by performing intestinal transection or 50, 75, or 90% resection of proximal small intestine. Finally, the relationship of GLP-2 levels over time with adaptation to a 90% resection was examined by determining GLP-2 levels on days 7, 14, and 28, and correlating this with intestinal adaptation, as assessed by morphology and CCP rate. A 90% resection significantly increased basal and postprandial GLP-2 levels, with a net increase in nutrient-stimulated exposure over 90 min; GLP-2 exposure (integrated levels vs. time) increased 12.7-fold in resected animals (P < 0.001). Basal and postprandial GLP-2 levels significantly correlated with the magnitude of intestinal resection (r(2) = 0.71; P < 0.001), CCP (r(2) = 0.48; P < 0.005), and nutrient malabsorption (protein, P < 0.001; fat, P < 0.005). The increase in CCP was maintained to 28 days after small bowel resection and was associated with an ongoing elevation in GLP-2 release. These findings suggest that GLP-2 is important in initiating and maintaining the small intestinal adaptive response to resection.
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Affiliation(s)
- G R Martin
- University of Calgary, Gastrointestinal Research Group, Health Sciences Bldg, Rm. 1746, 3330 Hospital Dr. NW, Calgary, AB, Canada T2N 4N1.
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20
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21
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Ray EC, Avissar NE, Salloum R, Sax HC. Growth hormone and epidermal growth factor upregulate specific sodium-dependent glutamine uptake systems in human intestinal C2BBe1 cells. J Nutr 2005; 135:14-8. [PMID: 15623826 DOI: 10.1093/jn/135.1.14] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
Glutamine (Gln) is one of the major oxidative fuels of the enterocyte and enters from the lumen via Na(+)-dependent transport mechanisms. When given parenterally, growth hormone (GH) + epidermal growth factor (EGF) increase apical Gln uptake after massive enterectomy in rabbits. Although both receptors are basolateral, GH and EGF are present in luminal contents. We hypothesized that short-term luminal growth factor exposure to enterocytes increases apical Gln uptake by selective upregulation of systems A, B(0,+), or ASC+B(0). A monolayer of C2(BBe)1 cells was exposed for 10 or 60 min to GH (500 microg/L), EGF (100 microg/L), both, or neither. Initial uptake of [(3)H]Gln (50 micromol/L) was measured in the presence of Na(+) or choline. The contributions of systems A, B(0,+), and ASC+B(0) were determined by competitive inhibition with arginine and/or alpha-(methylamino)butyric acid. Gln uptake was linear for up to 8 min. Na(+)-independent transport was negligible. Under control conditions the relative contributions of systems A, B(0,+), and ASC+B(0) were 0, 19 +/- 6, and 80 +/- 4%, respectively. GH alone had no effect on Gln transport. After 10 min of EGF exposure, Na(+)-dependent Gln uptake increased by 50% (P < 0.001) with no change in individual transport systems. Combined EGF and GH for 60 min increased Gln transport by system B(0,+) nearly 250% (P < 0.001) and system A from undetectable levels to 16% of total transport (P < 0.01). Thus, short-term luminal exposure to EGF+GH increases Na(+)-dependent Gln transport mainly by upregulating system B(0+).
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Affiliation(s)
- Edward C Ray
- Department of Surgery, University of Rochester, School of Medicine and Dentistry, Rochester, NY 14642, USA
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Fairbanks TJ, Kanard RC, De Langhe SP, Sala FG, Del Moral PM, Warburton D, Anderson KD, Bellusci S, Burns RC. A genetic mechanism for cecal atresia: the role of the Fgf10 signaling pathway. J Surg Res 2004; 120:201-9. [PMID: 15234214 DOI: 10.1016/j.jss.2003.12.017] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2003] [Indexed: 12/18/2022]
Abstract
BACKGROUND Intestinal atresia represents a significant surgically correctable cause of intestinal obstruction in neonates. Intestinal development proceeds as a tube-like structure with differentiation along its axis. As the intestine differentiates, the cecum develops at the transition from small to large intestine. Fgf10 is known to serve a key role in budding morphogenesis; however, little is known about its role in the development of this transitional structure. Here we evaluate the effect of Fgf10/Fgfr2b invalidation on the developing cecum. MATERIALS AND METHODS Wild-type C57Bl/6, Fgf10(-/-), and Fgfr2b(-/-) embryos harvested from timed pregnant mothers were analyzed for cecal phenotype, Fgf10 expression, and differentiation of smooth muscle actin. RESULTS Wt cecal development is first evident at E11.5. FGF10 is discreetly expressed in the area of the developing cecum at early stages of development. One hundred percent of Fgf10(-/-) and Fgfr2b(-/-) mutant embryos demonstrate cecal atresia with absence of epithelial and muscular layers. The development of neighboring anatomical structures such as the ileocecal valve is not affected by Fgf10/Fgfr2b invalidation. CONCLUSIONS FGF10 expression is localized to the cecum early in the normal development of the cecum. Fgf10(-/-) and Fgfr2b(-/-) mutant embryos demonstrate cecal atresia with complete penetrance. Epithelial and muscular layers of the cecum are not present in the atretic cecum. The Fgf10(-/-) and Fgfr2b(-/-) mutants represent a genetically reproducible animal model of autosomal recessive intestinal atresia.
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Affiliation(s)
- T J Fairbanks
- Developmental Biology Program, Children's Hospital Los Angeles, 4650 Sunset Boulevard, Smith Research Tower 804, Mail Stop #100, Los Angeles, CA 90027, USA
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Martin GR, Wallace LE, Sigalet DL. Glucagon-like peptide-2 induces intestinal adaptation in parenterally fed rats with short bowel syndrome. Am J Physiol Gastrointest Liver Physiol 2004; 286:G964-72. [PMID: 14962847 DOI: 10.1152/ajpgi.00509.2003] [Citation(s) in RCA: 111] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Glucagon-like peptide-2 (GLP-2) is an intestinal trophic enteroendocrine peptide that is associated with intestinal adaptation following resection. Herein, we investigate the effects of GLP-2 in a total parenteral nutrition (TPN)-supported model of experimental short bowel syndrome. Juvenile Sprague-Dawley rats underwent a 90% small intestinal resection and jugular catheter insertion. Rats were randomized to three groups: enteral diet and intravenous saline infusion, TPN only, or TPN + 10 microg.kg(-1).h(-1) GLP-2. Nutritional maintenance was isocaloric and isonitrogenous. After 7 days, intestinal permeability was assessed by quantifying the urinary recovery of gavaged carbohydrate probes. The following day, animals were euthanized, and intestinal tissue was processed for morphological and crypt cell proliferation (CCP) analysis, apoptosis (caspase-3), and expression of SGLT-1 and GLUT-5 transport proteins. TPN plus GLP-2 treatment resulted in increased bowel and body weight, villus height, intestinal mucosal surface area, CCP, and reduced intestinal permeability compared with the TPN alone animals (P < 0.05). GLP-2 treatment induced increases in serum GLP-2 levels and intestinal SGLT-1 expression (P < 0.01) compared with either TPN or enteral groups. No differences were seen in the villus apoptotic index between resection groups. Enterally fed resected animals had a significant decrease in crypt apoptotic indexes compared with nontreated animals. This study demonstrates that GLP-2 alone, without enteral feeding, stimulates indexes of intestinal adaptation. Secondly, villus hypertrophy associated with adaptation was predominantly due to an increase in CCP and not to changes in apoptotic rates. Further studies are warranted to establish the mechanisms of action and therapeutic potential of GLP-2.
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Affiliation(s)
- Gary R Martin
- University of Calgary, Gastrointestinal Research Group, Calgary, Alberta, Canada, T2T 5C7
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Su ZD, Qin HL. Effects of growth hormone on intestinal adaptation of rat with short bowel syndrome. Shijie Huaren Xiaohua Zazhi 2004; 12:646-649. [DOI: 10.11569/wcjd.v12.i3.646] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To evaluate the effects of growth hormone (GH) on the residual small intestine of rats with short bowel syndrome (SBS), including adaptive hyperplasia and absorption of glucose and amino acids.
METHODS: Forty Sprague-Dawley (SD) male rats with more than 85% small intestine resected were equally divided into five groups randomly: H-GH group (high dose at 7.5 IU/kg per day), M-GH group (moderate dose at 3.75 IU/kg per day), L-GH group (low dose at 1.88 IU/kg per day), SBS group and sham operation group. From the second to the 15th day after operation, all the GH-managed groups were treated by sc injection twice a day, while SBS group and sham group were managed with same volume normal saline for injection. All samples were gained by laparotomy under anesthesia at the 16th day after operation.
RESULTS: Weight loss of rats in H-GH group (36±4.4 g), which was the least among the four groups except sham group, was significantly less than that in SBS group (94±10.0 g) (P < 0.05). But preoperative body weight of rats in the four groups except sham group was not retrieved. Among all groups there was no significant difference in the length of jejunum and ileum, as well as no significant difference in the morphological variables of colon. Mucosal height of jejunum and ileum was greater in H-GH group and M-GH group (997±65.9 m, 752±79.3 m and 974±67.6 m, 788±75.1 m respectively) than those in SBS group (776±61.0 m, 664±64.0 m) (P < 0.05). Similarly, intestinal wall width of jejunum and ileum was also thicker in H-GH group and M-GH group (1142±65.4 m, 884±91.2 m and 1 145±78.7 m, 895±95.6 m respectively) than those in SBS group (848±194.7 m, 776±57.5 m) (P < 0.05). But mucosal height and intestinal wall width of jejunum and ileum in H-GH group were not significantly greater than those in M-GH group. Blood insulinlike growth factor 1 (IGF-1) concentration and PCNA index of liver did not differ among the five groups. No significant differences of blood glucose and amino acids concentrations were detected after nutritional administration among the five groups.
CONCLUSION: Treatment of SBS with GH only slows body weight decrease rather than promotes body weight gain by the support of enteral nutrition. GH enhances adaptive mucosal hyperplasia after massive resection of small intestine, while its enhanced effect does not parallel its dose increase. Because of GH resistance resulted from the SBS-induced malnutrition,elevation of blood IGF-1 is impaired and absorpton of glucose and amino acids is not enhanced.
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Giardino R, Torricelli P, Giavaresi G, Fini M, Aldini NN, Ruggeri G, Lima M, Carpi A. Histomorphometric bone modifications induced by growth hormone treatment in a rabbit model of short bowel syndrome. Biomed Pharmacother 2004; 58:116-22. [PMID: 14992793 DOI: 10.1016/j.biopha.2003.09.011] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2003] [Accepted: 09/16/2003] [Indexed: 11/21/2022] Open
Abstract
The effects of recombinant human growth hormone (rhGH) on cancellous and cortical bone were investigated in an experimental rabbit model of short bowel syndrome (SBS). Eighteen young male New Zealand rabbits, 2.0 +/- 0.2 kg b.w., were divided into three groups: an SBS Group submitted to a 70% midjejunoileal enterectomy and reanastomosis; an SBS-GH Group undergoing the same surgery and receiving 0.4 mg/kg/day rhGH for 28 days; a Control Group which was sham-operated. Thirty-five days after surgery, all the animals were pharmacologically euthanised and their femurs and L5 vertebrae were used for densitometric and histomorphometric studies. Vertebral and femoral densitometric results showed that the SBS Group presented significantly (P<0.01) lower values (10-25%) than the Control and SBS-GH Groups. Significant differences in the cancellous histomorphometric parameters, namely the trabecular bone area (-7% to 46%), trabecular thickness (-21% to 34%) and trabecular separation (17-32%), were observed between the SBS Group and the other groups. Both the SBS and SBS-GH Groups showed significantly (P<0.05) higher values than the Control Group in terms of cross-sectional area (approximately 24%), cortical area (approximately 20%), and periosteal perimeter (approximately 9%), while medullary area (41%) and endocortical perimeter (18%) were significantly higher (P<0.05) in SBS Group than those of Control Group. The current findings are encouraging and suggest that GH administration in SBS animal model used may improve skeletal tissue remodelling.
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Affiliation(s)
- R Giardino
- Department of Experimental Surgery, Istituti Ortopedici Rizzoli, Via di Barbiano, 1/10, 40136 Bologna, Italy.
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Abstract
Glucagon-like peptide 2 (GLP-2) is a member of family of peptides derived from the proglucagon gene expressed in the intestines, pancreas and brain. Tissue-specific posttranslational processing of proglucagon leads to GLP-2 and GLP-1 secretion from the intestine and glucagon secretion from the pancreas. GLP-2 and GLP-1 are co-secreted from the enteroendocrine L-cells located in distal intestine in response to enteral nutrient ingestion, especially carbohydrate and fat. GLP-2 secretion is mediated by direct nutrient stimulation of the L-cells and indirect action from enteroendocrine and neural inputs, including GIP, gastrin-releasing peptide (GRP) and the vagus nerve. GLP-2 is secreted as a 33-amino acid peptide and is rapidly cleaved by dipeptidylpeptidase IV (DPP-IV) to a truncated peptide which acts as a weak agonist with competitive antagonistic properties. GLP-2 acts to enhance nutrient absorption by inhibiting gastric motility and secretion and stimulating nutrient transport. GLP-2 also suppresses food intake when infused centrally. The trophic actions of GLP-2 are specific for the intestine and occur via stimulation of crypt cell proliferation and suppression of apoptosis in mucosal epithelial cells. GLP-2 reduces gut permeability, bacterial translocation and proinflammatory cytokine expression under conditions of intestinal inflammation and injury. The effects of GLP-2 are mediated by a G-protein-linked receptor that is localized to the intestinal mucosa and hypothalamus. The intestinal localization of the GLP-2R to neural and endocrine cells, but not enterocytes, suggests that its actions are mediated indirectly via a secondary signaling mechanism. The implications of GLP-2 in domestic animal production are largely unexplored. However, GLP-2 may have therapeutic application in treatment of gastrointestinal injury and diarrheal diseases that occur in developing neonatal and weanling animals.
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Affiliation(s)
- D G Burrin
- USDA/ARS Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, 1100 Bates Street, Houston, TX 77030, USA.
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Drucker DJ. Glucagon-like peptides: regulators of cell proliferation, differentiation, and apoptosis. Mol Endocrinol 2003; 17:161-71. [PMID: 12554744 DOI: 10.1210/me.2002-0306] [Citation(s) in RCA: 343] [Impact Index Per Article: 15.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023] Open
Abstract
Peptide hormones are secreted from endocrine cells and neurons and exert their actions through activation of G protein-coupled receptors to regulate a diverse number of physiological systems including control of energy homeostasis, gastrointestinal motility, neuroendocrine circuits, and hormone secretion. The glucagon-like peptides, GLP-1 and GLP-2 are prototype peptide hormones released from gut endocrine cells in response to nutrient ingestion that regulate not only energy absorption and disposal, but also cell proliferation and survival. GLP-1 expands islet mass by stimulating pancreatic beta-cell proliferation and induction of islet neogenesis. GLP-1 also promotes cell differentiation, from exocrine cells or immature islet progenitors, toward a more differentiated beta-cell phenotype. GLP-2 stimulates cell proliferation in the gastrointestinal mucosa, leading to expansion of the normal mucosal epithelium, or attenuation of intestinal injury in experimental models of intestinal disease. Both GLP-1 and GLP-2 exert antiapoptotic actions in vivo, resulting in preservation of beta-cell mass and gut epithelium, respectively. Furthermore, GLP-1 and GLP-2 promote direct resistance to apoptosis in cells expressing GLP-1 or GLP-2 receptors. Moreover, an increasing number of structurally related peptide hormones and neuropeptides exert cytoprotective effects through G protein-coupled receptor activation in diverse cell types. Hence, peptide hormones, as exemplified by GLP-1 and GLP-2, may prove to be useful adjunctive tools for enhancement of cell differentiation, tissue regeneration, and cytoprotection for the treatment of human disease.
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Affiliation(s)
- Daniel J Drucker
- Department of Medicine, Toronto General Hospital, University Health Network, Banting and Best Diabetes Centre, University of Toronto, Toronto, Canada M5G 2C4.
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Abstract
UNLABELLED Intestinal failure (IF) refers to the condition in which certain causes lead to derangements in nutrient absorption capacity. Gut adaptation occurs in response to IF and it is both morphologic and physiologic in nature and can be mediated by growth factors and nutrients. Our paper reviews certain trophic growth factors that have important interactions relevant for intestinal growth, function and adaptation. DATA SOURCE The literature was reviewed (data from both animal and human studies) and certain trophic factors that modulate intestinal adaptation are summarized. The factors reviewed are: epidermal growth factor, insulin-like growth factor I and II, transforming growth factor alpha and beta, neurotensin, interleukin-11, glucagon-like peptide-2, keratinocyte growth factor, human growth hormone, short-chain fatty acids, and glutamine. CONCLUSIONS Growth factors augment intestinal proliferation, diminish programmed apoptosis, and modulate the adaptive process. They also have the potential to improve nutrient absorption in some bowel disease. The enhancement of gut adaptation may allow patients to transition of parenteral/enteral to normal nutrition, in a shorter period of time, which reduce the rate of adverse effects caused by artificial nutrition and improve quality of life.
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Affiliation(s)
- D S Botsios
- 4th Surgical Clinic, Aristotle University of Thessaloniki, Thessaloniki, Greece.
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Fant ME, Weisoly D. Insulin and insulin-like growth factors in human development: implications for the perinatal period. Semin Perinatol 2001; 25:426-35. [PMID: 11778913 DOI: 10.1053/sper.2001.29036] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
The physiologic and cellular mechanisms regulating fetal growth cannot be adequately described by regulatory mechanisms important postnatally. This review summarizes recent advances in clinical medicine, cell and molecular biology, and physiology showing the central and essential roles of insulin and the insulin-like growth factor family of peptides in regulating fetal growth. Moreover, the importance of insulin-like growth factors in tissue-specific growth regulation during critical periods of development suggest that these mechanisms may also be relevant to the pathogenesis of tissue injury in the preterm infant, and may offer therapeutic strategies aimed at reducing morbidity associated with prematurity. Illustrations of how the insulin-like growth factor axis may represent potential therapeutic targets for specific clinical problems facing the newborn are briefly discussed.
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Affiliation(s)
- M E Fant
- Deportment of Pediatrics, University of Texas, Houston Medical School, 77030, USA
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Yamaguchi M, Asakawa K, Kuzume M, Nemoto H, Sanada Y, Kumada K. Effects of insulin-like growth factor-1 on Short bowel syndrome without ileocecal valve in rats. Eur Surg Res 2001; 33:291-6. [PMID: 11684836 DOI: 10.1159/000049720] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
Insulin-like growth factor-1 (IGF-1) can promote enterocyte proliferation which may be beneficial to postoperative conditions after massive small bowel resection (SBR) including the ileocecal valve (ICV). Wistar rats were subjected to SBR including or preserving ICV and continuously received IGF-1 or saline alone. Nutritional status, enterocyte proliferation, liver damage and hepatic IGF-1 mRNA levels were analyzed. Body weights, serum levels of total protein and transferrin, and enterocyte proliferation were significantly lower after SBR including ICV than preserving it. IGF-1 mRNA levels in the liver were decreased after SBR, especially after SBR including ICV. However, IGF-1 therapy significantly attenuated those decreased levels after SBR including ICV. Furthermore, IGF-1 significantly decreased serum liver transaminase levels which were increased after SBR including ICV. Continuous administration of IGF-1 may be available as a supplemented therapy for short bowel syndrome without ICV.
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Affiliation(s)
- M Yamaguchi
- Department of Surgery, Showa University Fujigaoka Hospital, Yokohama, Japan.
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Ito T, Igarashi H, Pradhan TK, Hou W, Mantey SA, Taylor JE, Murphy WA, Coy DH, Jensen RT. GI side-effects of a possible therapeutic GRF analogue in monkeys are likely due to VIP receptor agonist activity. Peptides 2001; 22:1139-1151. [PMID: 11445245 DOI: 10.1016/s0196-9781(01)00436-3] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Abstract
Growth hormone (GH) is used or is being evaluated for efficacy in treatment of short stature, aspects of aging, cardiac disorders, Crohn's disease, and short bowel syndrome. Therefore, we synthesized several stable growth hormone-releasing factor (GRF) analogues that could be therapeutically useful. One potent analog, [D-Ala(2),Aib(8, 18,)Ala(9, 15, 16, 22, 24-26,)Gab(27)]hGRF(1-27)NH(2) (GRF-6), with prolonged infusion caused severe diarrhea in monkeys; however, it had no side-effects in rats. Because GRF has similarity to VIP/PACAP and VIPomas cause diarrhea, this study investigated the ability of this and other GRF analogues to interact with the VIP/PACAP receptors. Rat VPAC(1)-R (rVPAC(1)-R), human VPAC(1)-R (hVPAC(1)-R), rVPAC(2)-R and hVPAC(2)-R stably transfected CHO and PANC 1 cells were made and T47D breast cancer cells containing native human VPAC(1)-R and AR4-2J cells containing PAC(1)-R were used. hGRF(1-29)NH(2) had low affinity for both rVPAC(1)-R and rVPAC(2)-R while VIP had a high affinity for both receptors. GRF-6 had a low affinity for both rVPAC(1)-R and rVPAC(2)-R and very low affinity for the rPAC(1)-R. VIP had a high affinity, whereas hGRF(1-29)NH(2) had a low affinity for both hVPAC(1)-R and hVPAC(2)-R. In contrast GRF-6, while having a low affinity for hVPAC(2)-R, had relatively higher affinity for the hVPAC(1)-R. In guinea pig pancreatic acini, all GRF analogues were full agonists at the VPAC(1)-R causing enzyme secretion. These results demonstrate that in contrast to native hGRF(1-29)NH(2,) GRF-6 has a relatively high affinity for the human VPAC(1)-R but not for the human VPAC(2)-R, rat VPAC(1)-R, rat VPAC(2)-R or rat PAC(1)-R. These results suggest that the substituted GRF analog, GRF-6, likely causes the diarrheal side-effects in monkeys by interacting with the VPAC(1)-R. Furthermore, they demonstrate significant species differences can exist for possible therapeutic peptide agonists of the VIP/PACAP/GRF receptor family and that it is essential that receptor affinity assessments be performed in human cells or from a closely related species.
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Affiliation(s)
- T Ito
- Digestive Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892-1804, USA
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Abstract
Short bowel syndrome is a spectrum of malnutrition resulting from inadequate bowel length. In infant and pediatric patients, the most common causes are necrotizing enterocolitis, abdominal wall defects, jejunal ileal atresia, and mid gut volvulus. There appear to be regional variations in etiology. Since the publication of Wilmore's classic monograph in 1972, there have been significant improvements in monitoring and nutritional support. In the modern era, survival rate ranges from 80% to 94%, and the presence or absence the ileal cecal valve appears to not impact on mortality rate, but does significantly affect the length of time on total parenteral nutrition TPN. The most common morbidities remain sepsis, both central line related and bacterial overgrowth, and TPN cholestasis. Long-term recovery of these children often is remarkably normal, but there is a 10% to 15% incidence of neurologic and developmental defects. The clinical and ethical considerations around the care of infants with 20 to 40 cm of residual bowel remains controversial, as does the place of intestinal transplantation, especially in patients developing gut failure in infancy. Perioperative surgical decision making plays a critical role in the long-term outcome of these patients. This chapter presents an overview of the current status of care and outcome in this difficult population; these topics are further expanded in subsequent chapters.
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Affiliation(s)
- D L Sigalet
- The Alberta Children's Hospital, Calgary, Alberta, Canada
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Abstract
Glucagon-like peptide-2 (GLP-2) is a newly discovered growth factor that has been demonstrated to enhance intestinal growth and function in normal rodents and to prevent damage and facilitate intestinal repair in various animal models of intestinal insufficiency. A recent study has demonstrated that GLP-2 also acts as an intestinotropin in humans with short-bowel syndrome. The high degree of specificity of GLP-2 for induction of intestinal growth, without affecting growth of other peripheral tissues, is determined by the highly localized expression of the GLP-2 receptor in the intestinal epithelium. In this article, we review the regulation of GLP-2 in physiology, from synthesis to metabolism, with a particular emphasis on potential targets in this pathway for therapeutic manipulation of GLP-2 actions. We also discuss the various animal models of intestinal insufficiency that have been used to demonstrate the therapeutic potential of this intestinotropic hormone, including short bowel, intestinal atrophy, enteritis and colitis. The results of these studies indicate that GLP-2 is a promising therapeutic agent for the treatment of various forms of intestinal insufficiency in humans.
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Affiliation(s)
- M C L'Heureux
- Department of Physiology, University of Toronto, Ontario, Canada
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Topstad D, Martin G, Sigalet D. Systemic GLP-2 levels do not limit adaptation after distal intestinal resection. J Pediatr Surg 2001; 36:750-4. [PMID: 11329581 DOI: 10.1053/jpsu.2001.22952] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
BACKGROUND/PURPOSE Glucagonlike peptide 2 (GLP-2) is trophic for the small bowel; it is produced by L cells in the distal intestine in response to luminal nutrients. This study tests the hypothesis that distal small bowel and cecal resection would decrease GLP-2 levels and reduce adaptation. METHODS Male Sprague-Dawley rats (200 to 300 g) underwent either ileal transection (controls) or resection of the ileum and cecum, leaving 10 or 20 cm jejunal remnant anastomosed to the ascending colon. Animals were followed up for up to 21 days. Endpoints were daily weights, intestinal histology, in vivo absorption of 3-0 methylglucose (a measurement of active nutrient absorptive capacity), and serum GLP-2 levels. RESULTS The control group had a maximum 6% weight loss around day 2, and then recovered with a steady weight gain. The 10-cm jejunal remnant group lost weight continuously and never recovered postsurgery. The 20-cm jejunal remnant group of animals had a maximum of 12% weight loss by day 4 and then slowly gained weight. The average villus height increased significantly (P <.01) in the 10-cm and 20-cm jejunal remnant groups compared with controls. Absorption of 3-0 methylglucose was significantly decreased (P <.01) in both resected groups. Serum GLP-2 levels were increased significantly (P <.05) when compared with controls in both resection groups. CONCLUSIONS Increased serum GLP-2 levels were found in the ileocecal resection rat model, and these levels correlated with morphologic adaptation. However, this morphologic adaptation was not sufficient to restore nutrient absorption as shown by weight changes and 3-0 methylglucose absorption. Thus, the original hypothesis of this study is incorrect: systemic GLP-2 levels do not limit adaptation following distal ileocecal resection.
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Affiliation(s)
- D Topstad
- Division of Pediatric General Surgery and GI Research Group, University of Calgary, Calgary, Alberta, Canada
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