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1
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Fu R, Chen J, Fang Y, Wu Q, Zhang X, Wang Z. Impact of dipeptidyl peptidase-4 inhibitors on incidence of colorectal cancer in patients with type 2 diabetes mellitus: a systematic review and meta-analysis. Ther Adv Drug Saf 2025; 16:20420986251318842. [PMID: 39974280 PMCID: PMC11837066 DOI: 10.1177/20420986251318842] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2024] [Accepted: 01/21/2025] [Indexed: 02/21/2025] Open
Abstract
Background The association between dipeptidyl peptidase-4 inhibitors (DPP-4i) exposure and the risk of colorectal cancer (CRC) in patients with type 2 diabetes mellitus (T2DM) is unclear. Objectives This meta-analysis aims to investigate the relationship between DPP-4i exposure and the incidence of CRC in patients with T2DM. Design A systematic review and meta-analysis. Methods A comprehensive search of electronic databases, including PubMed, Web of Science, EMBASE, and ScienceDirect, was conducted up to March 2024. The studies including randomized clinical trials (RCTs), cohort studies, and case-control studies were retrieved. The odds ratio (OR) was calculated using Stata 12.0 statistical software. The primary outcome assessed was the incidence of CRC. Results This meta-analysis incorporated six retrospective cohort studies and two case-control studies. The findings indicate that the incidence of CRC in the DPP-4i exposure group was significantly higher than that in the control group (OR = 1.11, 95% CI: 1.02-1.21, p = 0.013). Subgroup analysis revealed that both male (OR = 2.07, p < 0.001) and female participants (OR = 1.49, p = 0.05) in the DPP-4i exposure group exhibited a significantly higher incidence of CRC compared to the control group. Among participants younger than 65 years, the incidence of CRC was markedly elevated in the exposure group (OR = 2.81, p < 0.001). Furthermore, when the exposure duration was less than 1 year, the CRC incidence in the exposure group surpassed that of the control group (OR = 1.24, p = 0.005). When sulfonylureas (SU) were used as control drugs, the incidence of CRC was higher in the exposure group (OR = 1.10, p = 0.017). Conclusion There is a potential correlation between DPP-4i exposure and increased incidence of CRC in T2DM patients. This association appears to be influenced by gender, age, duration of exposure, and the choice of control medications. Therefore, attention should be paid to colorectal diseases when DPP-4i is employed in the clinic. Trial registration The meta-analysis has been registered with the International Prospective Register of Systematic Reviews (PROSPERO). The registration number is CRD42024535292.
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Affiliation(s)
- Rongrong Fu
- The First School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
| | - Jingqi Chen
- The First School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
| | - Yingying Fang
- The First School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
| | - Qingping Wu
- The First School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
| | - Xiaoming Zhang
- The First School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
| | - Zhiyan Wang
- Department of General Surgery, Ningbo Yinzhou No. 2 Hospital, 998 North Qianhe Road, Ningbo, Yinzhou District, Zhejiang 315100, China
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Ali A, Khan D, Dubey V, Tarasov AI, Flatt PR, Irwin N. Comparative Effects of GLP-1 and GLP-2 on Beta-Cell Function, Glucose Homeostasis and Appetite Regulation. Biomolecules 2024; 14:1520. [PMID: 39766228 PMCID: PMC11673903 DOI: 10.3390/biom14121520] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2024] [Revised: 11/21/2024] [Accepted: 11/26/2024] [Indexed: 01/11/2025] Open
Abstract
Glucagon-like peptide-1 (GLP-1) and glucagon-like peptide-2 (GLP-2) are related intestinal L-cell derived secretory products. GLP-1 has been extensively studied in terms of its influence on metabolism, but less attention has been devoted to GLP-2 in this regard. The current study compares the effects of these proglucagon-derived peptides on pancreatic beta-cell function, as well as on glucose tolerance and appetite. The insulin secretory effects of GLP-1 and GLP-2 (10-12-10-6 M) were investigated in BRIN-BD11 beta-cells as well as isolated mouse islets, with the impact of test peptides (10 nM) on real-time cytosolic cAMP levels further evaluated in mouse islets. The impact of both peptides (10-8-10-6 M) on beta-cell growth and survival was also studied in BRIN BD11 cells. Acute in vivo (peptides administered at 25 nmol/kg) glucose homeostatic and appetite suppressive actions were then examined in healthy mice. GLP-1, but not GLP-2, concentration dependently augmented insulin secretion from BRIN-BD11 cells, with similar observations made in isolated murine islets. In addition, GLP-1 substantially increased [cAMP]cyt in islet cells and was significantly more prominent than GLP-2 in this regard. Both GLP-1 and GLP-2 promoted beta-cell proliferation and protected against cytokine-induced apoptosis. In overnight fasted healthy mice, as well as mice trained to eat for 3 h per day, the administration of GLP-1 or GLP-2 suppressed appetite. When injected conjointly with glucose, both peptides improved glucose disposal, which was associated with enhanced glucose-stimulated insulin secretion by GLP-1, but not GLP-2. To conclude, the impact of GLP-1 and GLP-2 on insulin secretion is divergent, but the effects of beta-cell signaling and overall health are similar. Moreover, the peripheral administration of either hormone in rodents results in comparable positive effects on blood glucose levels and appetite.
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Affiliation(s)
| | | | | | | | | | - Nigel Irwin
- Centre for Diabetes, School of Biomedical Sciences, Ulster University, Cromore Road, Coleraine BT52 1SA, Northern Ireland, UK; (A.A.); (D.K.); (V.D.); (A.I.T.); (P.R.F.)
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3
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Beloqui A. Gut hormone stimulation as a therapeutic approach in oral peptide delivery. J Control Release 2024; 373:31-37. [PMID: 38971429 PMCID: PMC11413617 DOI: 10.1016/j.jconrel.2024.07.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2024] [Revised: 06/07/2024] [Accepted: 07/03/2024] [Indexed: 07/08/2024]
Abstract
In this contribution to the Orations - New Horizons of the Journal of Controlled Release, I discuss the research that we have conducted on gut hormone stimulation as a therapeutic strategy in oral peptide delivery. One of the greatest challenges in oral drug delivery involves the development of new drug delivery systems that enable the absorption of therapeutic peptides into the systemic circulation at therapeutically relevant concentrations. This scenario is especially challenging in the treatment of chronic diseases (such as type 2 diabetes mellitus), wherein daily injections are often needed. However, for certain peptides, there may be an alternative in drug delivery to meet the need for increased peptide bioavailability; this is the case for gut hormone mimetics (including glucagon-like peptide (GLP)-1 or GLP-2). One plausible alternative for improved oral delivery of these peptides is the co-stimulation of the endogenous secretion of the hormone to reach therapeutic levels of the peptide. This oration will be focused on studies conducted on the stimulation of gut hormones secreted from enteroendocrine L cells in the treatment of gastrointestinal disorders, including a critical discussion of the limitations and future perspectives of implementing this approach in the clinical setting.
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Affiliation(s)
- Ana Beloqui
- UCLouvain, Université catholique de Louvain, Louvain Drug Research Institute, Advanced Drug Delivery and Biomaterials, 1200 Brussels, Belgium; WEL Research Institute, Avenue Pasteur, 6, 1300 Wavre, Belgium.
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4
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Gondolesi GE, Pape UF, Mason JB, Allard JP, Pironi L, Casas MNV, Schwartz LK, Joly F, Gabriel A, Sabrdaran S, Zhang P, Kohl-Sobania M, Huang YW, Jeppesen PB. Baseline Characteristics of Adult Patients Treated and Never Treated with Teduglutide in a Multinational Short Bowel Syndrome and Intestinal Failure Registry. Nutrients 2024; 16:2513. [PMID: 39125394 PMCID: PMC11314329 DOI: 10.3390/nu16152513] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2024] [Revised: 07/24/2024] [Accepted: 07/25/2024] [Indexed: 08/12/2024] Open
Abstract
The Short Bowel Syndrome (SBS) Registry (NCT01990040) is a multinational real-world study evaluating the long-term safety of teduglutide in patients with SBS and intestinal failure (SBS-IF) in routine clinical practice. This paper describes the study methodology and baseline characteristics of adult patients who have (ever-treated) or have never (never-treated) received teduglutide. A total of 1411 adult patients (679 ever-treated; 732 never-treated) were enrolled at 124 sites across 17 countries. The mean (standard deviation [SD]) age at enrollment was 55.4 (15.46) years, and 60.2% of patients were women. Crohn's disease was the most common cause of major intestinal resection in both ever-treated (34.1%) and never-treated patients (20.4%). A similar proportion of ever-treated and never-treated patients had a prior history of colorectal polyps (2.7% vs. 3.6%), whereas proportionally fewer ever-treated patients reported a history of colorectal cancer (1.8% vs. 6.2%) or any malignancy (17.7% vs. 30.0%) than never-treated patients. Never-treated patients received a numerically greater mean (SD) volume of parenteral nutrition and/or intravenous fluids than ever-treated patients (12.4 [8.02] vs. 10.1 [6.64] L/week). Ever-treated patients received a mean teduglutide dosage of 0.05 mg/kg/day. This is the first report of patient baseline characteristics from the SBS Registry, and the largest cohort of patients with SBS-IF to date. Overall, ever-treated and never-treated patients had similar baseline characteristics. Differences between treatment groups may reflect variations in patient selection and degree of monitoring.
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Affiliation(s)
- Gabriel E. Gondolesi
- Intestinal Failure, Rehabilitation and Transplant Unit, Hospital Universitario Fundación Favaloro, Buenos Aires C1044AAA, Argentina
| | - Ulrich-Frank Pape
- Asklepios Klinik St. Georg, Asklepios Medical School, 20099 Hamburg, Germany
- Department of Hepatology and Gastroenterology, Charité University Medicine Berlin, 13353 Berlin, Germany
| | - Joel B. Mason
- Tufts Medical Center, Tufts University, Boston, MA 02111, USA
| | - Johane P. Allard
- Toronto General Hospital, University of Toronto, Toronto, ON M5G 2C4, Canada
| | - Loris Pironi
- Department of Medical and Surgical Sciences, University of Bologna, 40138 Bologna, Italy;
- Centre for Chronic Intestinal Failure, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy
| | | | | | - Francisca Joly
- Hôpital Beaujon, University of Paris Cité, 92110 Clichy, France
| | - André Gabriel
- Takeda Development Center Americas, Inc., Cambridge, MA 02142, USA
| | - Sasan Sabrdaran
- Takeda Development Center Americas, Inc., Cambridge, MA 02142, USA
| | - Pinggao Zhang
- Takeda Development Center Americas, Inc., Cambridge, MA 02142, USA
| | - Martina Kohl-Sobania
- Outpatient Clinic, Pediatric Emergency Department, University Hospital Schleswig-Holstein, 23538 Lübeck, Germany
| | - Yi-Wen Huang
- Takeda Development Center Americas, Inc., Cambridge, MA 02142, USA
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5
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Pálsson TG, Gilliam-Vigh H, Jensen BAH, Jeppesen PB, Lund AB, Knop FK, Nielsen CK. Targeting the GLP-2 receptor in the management of obesity. Peptides 2024; 177:171210. [PMID: 38579917 DOI: 10.1016/j.peptides.2024.171210] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/22/2023] [Revised: 03/27/2024] [Accepted: 04/01/2024] [Indexed: 04/07/2024]
Abstract
Recent advancements in understanding glucagon-like peptide 2 (GLP-2) biology and pharmacology have sparked interest in targeting the GLP-2 receptor (GLP-2R) in the treatment of obesity. GLP-2 is a proglucagon-derived 33-amino acid peptide co-secreted from enteroendocrine L cells along with glucagon-like peptide 1 (GLP-1) and has a range of actions via the GLP-2R, which is particularly expressed in the gastrointestinal tract, the liver, adipose tissue, and the central nervous system (CNS). In humans, GLP-2 evidently induces intestinotrophic effects (i.e., induction of intestinal mucosal proliferation and improved gut barrier function) and promotes mesenteric blood flow. However, GLP-2 does not seem to have appetite or food intake-reducing effects in humans, but its gut barrier-promoting effect may be of interest in the context of obesity. Obesity is associated with reduced gut barrier function, increasing the translocation of proinflammatory gut content to the circulation. This phenomenon constitutes a strong driver of obesity-associated systemic low-grade inflammation, which in turn plays a major role in the development of most obesity-associated complications. Thus, the intestinotrophic and gut barrier-improving effect of GLP-2, which in obese rodent models shows strong anti-inflammatory potential, may, in combination with food intake-reducing strategies, e.g., GLP-1 receptor (GLP-1) agonism, be able to rectify core pathophysiological mechanism of obesity. Here, we provide an overview of GLP-2 physiology in the context of obesity pathophysiology and review the pharmacological potential of GLP-2R activation in the management of obesity and related comorbidities.
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Affiliation(s)
- Thorir G Pálsson
- Center for Clinical Metabolic Research, Copenhagen University Hospital - Herlev and Gentofte, Hellerup, Denmark
| | - Hannah Gilliam-Vigh
- Center for Clinical Metabolic Research, Copenhagen University Hospital - Herlev and Gentofte, Hellerup, Denmark
| | - Benjamin A H Jensen
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Palle B Jeppesen
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Department of Intestinal Failure and Liver Diseases, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
| | - Asger B Lund
- Center for Clinical Metabolic Research, Copenhagen University Hospital - Herlev and Gentofte, Hellerup, Denmark; Steno Diabetes Center Copenhagen, Copenhagen University Hospital, Herlev, Denmark
| | - Filip K Knop
- Center for Clinical Metabolic Research, Copenhagen University Hospital - Herlev and Gentofte, Hellerup, Denmark; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Steno Diabetes Center Copenhagen, Copenhagen University Hospital, Herlev, Denmark
| | - Casper K Nielsen
- Center for Clinical Metabolic Research, Copenhagen University Hospital - Herlev and Gentofte, Hellerup, Denmark.
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6
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Marotti V, Xu Y, Bohns Michalowski C, Zhang W, Domingues I, Ameraoui H, Moreels TG, Baatsen P, Van Hul M, Muccioli GG, Cani PD, Alhouayek M, Malfanti A, Beloqui A. A nanoparticle platform for combined mucosal healing and immunomodulation in inflammatory bowel disease treatment. Bioact Mater 2024; 32:206-221. [PMID: 37859689 PMCID: PMC10582360 DOI: 10.1016/j.bioactmat.2023.09.014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2023] [Revised: 09/19/2023] [Accepted: 09/22/2023] [Indexed: 10/21/2023] Open
Abstract
Current treatments for inflammatory bowel disease (IBD) treatment consist of anti-inflammatory products. In this study, we sought to induce the physiological secretion of glucagon-like peptide 2, a peptide with intestinal growth-promoting activity, via nanoparticles while simultaneously providing with immunomodulation by tailoring the nanoparticle surface. To this end, we developed hybrid lipid hyaluronate-KPV conjugated nanoparticles loaded with teduglutide for combination therapy in IBD. The nanocarriers induced (or did not induce) immunosuppression depending on the presence (or absence) of a hyaluronan-KPV functionalization. This strategy holds promise as a nanoparticle platform for combined mucosal healing and immunomodulation in IBD treatment.
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Affiliation(s)
- Valentina Marotti
- UCLouvain, Université catholique de Louvain, Louvain Drug Research Institute, Advanced Drug Delivery and Biomaterials, 1200 Brussels, Belgium
| | - Yining Xu
- UCLouvain, Université catholique de Louvain, Louvain Drug Research Institute, Advanced Drug Delivery and Biomaterials, 1200 Brussels, Belgium
| | - Cécilia Bohns Michalowski
- UCLouvain, Université catholique de Louvain, Louvain Drug Research Institute, Advanced Drug Delivery and Biomaterials, 1200 Brussels, Belgium
| | - Wunan Zhang
- UCLouvain, Université catholique de Louvain, Louvain Drug Research Institute, Advanced Drug Delivery and Biomaterials, 1200 Brussels, Belgium
| | - Inês Domingues
- UCLouvain, Université catholique de Louvain, Louvain Drug Research Institute, Advanced Drug Delivery and Biomaterials, 1200 Brussels, Belgium
| | - Hafsa Ameraoui
- UCLouvain, Université catholique de Louvain, Louvain Drug Research Institute, Bioanalysis and Pharmacology of Bioactive Lipids, 1200 Brussels, Belgium
| | - Tom G. Moreels
- UCLouvain, Université catholique de Louvain, Institute of Experimental and Clinical Research, Laboratory of Hepato-Gastroenterology, 1200 Brussels, Belgium
- Cliniques universitaires Saint-Luc, Department of Hepato-Gastroenterology, Brussels, Belgium
| | - Pieter Baatsen
- EM-platform, VIB Bio Imaging Core, KU Leuven, Campus Gasthuisberg, Herestraat 49, 3000 Leuven, Belgium
| | - Matthias Van Hul
- UCLouvain, Université catholique de Louvain, Louvain Drug Research Institute, Metabolism and Nutrition Group, 1200 Brussels, Belgium
| | - Giulio G. Muccioli
- UCLouvain, Université catholique de Louvain, Louvain Drug Research Institute, Bioanalysis and Pharmacology of Bioactive Lipids, 1200 Brussels, Belgium
| | - Patrice D. Cani
- UCLouvain, Université catholique de Louvain, Louvain Drug Research Institute, Metabolism and Nutrition Group, 1200 Brussels, Belgium
- UCLouvain, Institute of Experimental and Clinical Research, 1200 Brussels, Belgium
- WEL Research Institute, Avenue Pasteur, 6, 1300 Wavre, Belgium
| | - Mireille Alhouayek
- UCLouvain, Université catholique de Louvain, Louvain Drug Research Institute, Bioanalysis and Pharmacology of Bioactive Lipids, 1200 Brussels, Belgium
| | - Alessio Malfanti
- UCLouvain, Université catholique de Louvain, Louvain Drug Research Institute, Advanced Drug Delivery and Biomaterials, 1200 Brussels, Belgium
| | - Ana Beloqui
- UCLouvain, Université catholique de Louvain, Louvain Drug Research Institute, Advanced Drug Delivery and Biomaterials, 1200 Brussels, Belgium
- WEL Research Institute, Avenue Pasteur, 6, 1300 Wavre, Belgium
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7
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Ramírez-Perdomo A, Márquez-Barrios G, Gutiérrez-Castañeda LD, Parra-Medina R. NEUROENDOCRINE PEPTIDES IN THE PATHOGENESIS OF COLORECTAL CARCINOMA. Exp Oncol 2023; 45:3-16. [PMID: 37417286 DOI: 10.15407/exp-oncology.2023.01.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2023] [Indexed: 07/08/2023]
Abstract
Colorectal carcinoma (CRC) is the third most frequent neoplasm worldwide and the second leading cause of mortality. Neuroendocrine peptides such as glucagon, bombesin, somatostatin, cholecystokinin, and gastrin as well as growth factors such as platelet-derived growth factor, epidermal growth factor, insulin-like growth factor, and fibroblast growth factor have been postulated as being involved in carcinogenesis. The fact that these neuroendocrine peptides are involved in the development of CRC through the activation of growth factors that stimulate a series of molecular pathways that activate oncogenic signaling mechanisms is emphasized in this review. Peptides such as CCK1, serotonin, and bombesin have been found to be over-expressed in human tumor tissues. Meanwhile, the expression of peptides such as GLP2 has been seen mainly in murine models. The information contained in this review provides a better understanding of the role these peptides play in the pathogenesis of CRC for basic and clinical science studies.
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Affiliation(s)
- A Ramírez-Perdomo
- Pathology, University Foundation of Health Sciences, Bogota Calle 10 #18-75, ColombiaPathology, University Foundation of Health Sciences, Bogota Calle 10 #18-75, Colombia
| | - G Márquez-Barrios
- Pathology, University Foundation of Health Sciences, Bogota Calle 10 #18-75, Colombia
| | - L D Gutiérrez-Castañeda
- Basic Health Sciences Group, University Foundation of Health Sciences, Bogota, Colombia
- Research Institute, University Foundation of Health Sciences (FUCS), Bogotá, Colombia
| | - R Parra-Medina
- Pathology Department, University Foundation of Health Sciences (FUCS), Bogota Calle 10 #18-75, Colombia
- Research Institute, University Foundation of Health Sciences, Bogota, Colombia
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8
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Fourati S, Dumay A, Roy M, Willemetz A, Ribeiro-Parenti L, Mauras A, Mayeur C, Thomas M, Kapel N, Joly F, Le Gall M, Bado A, Le Beyec J. Fecal microbiota transplantation in a rodent model of short bowel syndrome: A therapeutic approach? Front Cell Infect Microbiol 2023; 13:1023441. [PMID: 36936775 PMCID: PMC10020656 DOI: 10.3389/fcimb.2023.1023441] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2022] [Accepted: 02/03/2023] [Indexed: 03/06/2023] Open
Abstract
Extensive intestinal resection leads to Short Bowel Syndrome (SBS), the main cause of chronic intestinal failure. Colon preservation is crucial for spontaneous adaptation, to improve absorption and reduce parenteral nutrition dependence. Fecal microbiota transplantation (FMT), a promising approach in pathologies with dysbiosis as the one observed in SBS patients, was assessed in SBS rats with jejuno-colonic anastomosis. The evolution of weight and food intake, the lenght of intestinal villi and crypts and the composition of fecal microbiota of Sham and SBS rats, transplanted or not with high fat diet rat microbiota, were analyzed. All SBS rats lost weight, increased their food intake and exhibited jejunal and colonic hyperplasia. Microbiota composition of SBS rats, transplanted or not, was largely enriched with Lactobacillaceae, and α- and β-diversity were significantly different from Sham. The FMT altered microbiota composition and α- and β-diversity in Sham but not SBS rats. FMT from high fat diet rats was successfully engrafted in Sham, but failed to take hold in SBS rats, probably because of the specific luminal environment in colon of SBS subjects favoring aero-tolerant over anaerobic bacteria. Finally, the level of food intake in SBS rats was positively correlated with their Lactobacillaceae abundance. Microbiota transfer must be optimized and adapted to this specific SBS environment.
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Affiliation(s)
- Salma Fourati
- UMR-S1149, Centre de recherche sur l’inflammation, INSERM, Universite Paris Cite, Paris, France
- Sorbonne Université, AP-HP, Hôpital de la Pitié‐Salpêtrière‐Charles Foix, Service de Biochimie Endocrinienne et Oncologique, Paris, France
- Paris Center for Microbiome Medicine, Federation Hospitalo-Universitaire, Paris, France
| | - Anne Dumay
- UMR-S1149, Centre de recherche sur l’inflammation, INSERM, Universite Paris Cite, Paris, France
| | - Maryline Roy
- UMR-S1149, Centre de recherche sur l’inflammation, INSERM, Universite Paris Cite, Paris, France
| | - Alexandra Willemetz
- UMR-S1149, Centre de recherche sur l’inflammation, INSERM, Universite Paris Cite, Paris, France
| | - Lara Ribeiro-Parenti
- UMR-S1149, Centre de recherche sur l’inflammation, INSERM, Universite Paris Cite, Paris, France
- AP-HP, Hôpital Bichat -Claude Bernard, Service de chirurgie Générale OEsogastrique et Bariatrique, Paris, France
| | - Aurélie Mauras
- Paris Center for Microbiome Medicine, Federation Hospitalo-Universitaire, Paris, France
- UMR1319 - Micalis Institute, Institut National de Recherche pour l’Agriculture, l’alimentation et l’environnement (INRAE), AgroParisTech, Université Paris-Saclay, Jouy-en-Josas, France
| | - Camille Mayeur
- Paris Center for Microbiome Medicine, Federation Hospitalo-Universitaire, Paris, France
- UMR1319 - Micalis Institute, Institut National de Recherche pour l’Agriculture, l’alimentation et l’environnement (INRAE), AgroParisTech, Université Paris-Saclay, Jouy-en-Josas, France
| | - Muriel Thomas
- Paris Center for Microbiome Medicine, Federation Hospitalo-Universitaire, Paris, France
- UMR1319 - Micalis Institute, Institut National de Recherche pour l’Agriculture, l’alimentation et l’environnement (INRAE), AgroParisTech, Université Paris-Saclay, Jouy-en-Josas, France
| | - Nathalie Kapel
- Paris Center for Microbiome Medicine, Federation Hospitalo-Universitaire, Paris, France
- UMR-S 1139, INSERM, Universite Paris Cite, Paris, France
- AP-HP, Hôpital de la Pitié‐Salpêtrière‐Charles Foix, Service de Coprologie fonctionnelle, Paris, France
| | - Francisca Joly
- UMR-S1149, Centre de recherche sur l’inflammation, INSERM, Universite Paris Cite, Paris, France
- Department of gastroenterology, IBD and nutrition Support, AP‐HP, CRMR MarDi, Hôpital Beaujon, Clichy, France
| | - Maude Le Gall
- UMR-S1149, Centre de recherche sur l’inflammation, INSERM, Universite Paris Cite, Paris, France
| | - André Bado
- UMR-S1149, Centre de recherche sur l’inflammation, INSERM, Universite Paris Cite, Paris, France
| | - Johanne Le Beyec
- UMR-S1149, Centre de recherche sur l’inflammation, INSERM, Universite Paris Cite, Paris, France
- Sorbonne Université, AP-HP, Hôpital de la Pitié‐Salpêtrière‐Charles Foix, Service de Biochimie Endocrinienne et Oncologique, Paris, France
- Paris Center for Microbiome Medicine, Federation Hospitalo-Universitaire, Paris, France
- *Correspondence: Johanne Le Beyec, ;;
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9
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Pizzoferrato M, Puca P, Ennas S, Cammarota G, Guidi L. Glucagon-like peptide-2 analogues for Crohn’s disease patients with short bowel syndrome and intestinal failure. World J Gastroenterol 2022; 28:6258-6270. [PMID: 36504557 PMCID: PMC9730438 DOI: 10.3748/wjg.v28.i44.6258] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/10/2022] [Revised: 11/01/2022] [Accepted: 11/17/2022] [Indexed: 02/06/2023] Open
Abstract
Short bowel syndrome (SBS) with intestinal failure (IF) is a rare but severe complication of Crohn’s disease (CD), which is the most frequent benign condition that leads to SBS after repeated surgical resections, even in the era of biologics and small molecules. Glucagon-like peptide-2 analogues have been deeply studied recently for the treatment of SBS-IF. These drugs have a significant intestinotrophic effect and the potential to reduce the chronic dependence of SBS-IF patients on parenteral support or nutrition. Teduglutide has been approved for the treatment of SBS-IF, and apraglutide is currently in clinical development. The use of these drugs was examined with a focus on their use in CD patients.
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Affiliation(s)
- Marco Pizzoferrato
- UOC Gastroenterologia, Dipartimento di Scienze Mediche e Chirurgiche, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome 00168, Italy
| | - Pierluigi Puca
- UOC Gastroenterologia, Dipartimento di Scienze Mediche e Chirurgiche, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome 00168, Italy
- Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Rome 00168, Italy
| | - Sara Ennas
- UOC Gastroenterologia, Dipartimento di Scienze Mediche e Chirurgiche, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome 00168, Italy
| | - Giovanni Cammarota
- UOC Gastroenterologia, Dipartimento di Scienze Mediche e Chirurgiche, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome 00168, Italy
- Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Rome 00168, Italy
| | - Luisa Guidi
- UOC Gastroenterologia, Dipartimento di Scienze Mediche e Chirurgiche, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome 00168, Italy
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10
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Abdalqadir N, Adeli K. GLP-1 and GLP-2 Orchestrate Intestine Integrity, Gut Microbiota, and Immune System Crosstalk. Microorganisms 2022; 10:2061. [PMID: 36296337 PMCID: PMC9610230 DOI: 10.3390/microorganisms10102061] [Citation(s) in RCA: 43] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2022] [Revised: 10/11/2022] [Accepted: 10/13/2022] [Indexed: 12/15/2022] Open
Abstract
The intestine represents the body's largest interface between internal organs and external environments except for its nutrient and fluid absorption functions. It has the ability to sense numerous endogenous and exogenous signals from both apical and basolateral surfaces and respond through endocrine and neuronal signaling to maintain metabolic homeostasis and energy expenditure. The intestine also harbours the largest population of microbes that interact with the host to maintain human health and diseases. Furthermore, the gut is known as the largest endocrine gland, secreting over 100 peptides and other molecules that act as signaling molecules to regulate human nutrition and physiology. Among these gut-derived hormones, glucagon-like peptide 1 (GLP-1) and -2 have received the most attention due to their critical role in intestinal function and food absorption as well as their application as key drug targets. In this review, we highlight the current state of the literature that has brought into light the importance of GLP-1 and GLP-2 in orchestrating intestine-microbiota-immune system crosstalk to maintain intestinal barrier integrity, inflammation, and metabolic homeostasis.
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Affiliation(s)
- Nyan Abdalqadir
- Molecular Medicine, Research Institute, The Hospital for Sick Children, Toronto, ON M5G 1H3, Canada
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M5S 1A8, Canada
- Department of Biology, College of Science, University of Sulaimani, Sulaymaniyah 46001, Iraq
| | - Khosrow Adeli
- Molecular Medicine, Research Institute, The Hospital for Sick Children, Toronto, ON M5G 1H3, Canada
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M5S 1A8, Canada
- Department of Biochemistry, University of Toronto, Toronto, ON M5S 1A8, Canada
- Department of Physiology, University of Toronto, Toronto, ON M5S 1A8, Canada
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11
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Falco EC, Lezo A, Calvo P, Rigazio C, Opramolla A, Verdun L, Cenacchi G, Pellegrini M, Spada M, Canavese G. Case Report: Morphologic and Functional Characteristics of Intestinal Mucosa in a Child With Short Bowel Syndrome After Treatment With Teduglutide: Evidence in Favor of GLP-2 Analog Safety. Front Nutr 2022; 9:866048. [PMID: 35811959 PMCID: PMC9261410 DOI: 10.3389/fnut.2022.866048] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2022] [Accepted: 03/29/2022] [Indexed: 11/22/2022] Open
Abstract
Teduglutide is a glucagon-like peptide-2 (GLP-2) analog employed in patients with short bowel syndrome (SBS) to reduce the need of parenteral nutrition in these patients, by virtue of its effects on enteric function. The experimental studies reported that the stimulating action of GLP-2 on epithelial turnover implies the potential development of dysplastic and neoplastic lesion. However, the clinical trials could not detect preneoplastic lesions on histologic material, and in a recent pilot study the occurrence of polyps was similar before and after treatment and included only low-grade dysplastic lesions. Another clue in GLP-2 function in stimulating mucosal restore is its enhancement through cooperation with epidermal growth factor (EGF). In this study, we analyzed gastroscopy and colonoscopy samplings from a child successfully weaned off parenteral nutrition with teduglutide. Villous and crypt structure was regular both in duodenal and in colonic samplings; in properly oriented villi, villus/crypt ratio was regular. The absorptive epithelium demonstrated a regular morphology. No atypia was detected in enterocytes, along epithelial structures. At the ultrastructural analysis, only a few enterocytes with vacuolized cytoplasm were observed. An S-phase marker Ki67 stained nuclei in the transitional amplifying zone, while nuclei stained by the cell cycle regulatory proteins p21 and p27 were placed in the differentiated epithelium of the duodenal villi and colonic crypts, as in the control cases. The counts of enterocytes immunostained with the same antisera, evaluated with image analysis software, were in the range of control cases. The ratio of the number of epidermal growth factor receptor (EGFR) signals/the number of centromere probe of chromosome 7 (CEP7) signals was less than 2. The findings available from this single patient are consistent with good preservation of functional capability of intestinal epithelium after treatment with GLP-2, given the histologic and ultrastructural features of enterocytes. In addition, the findings from cell cycle regulatory proteins immunolocalization and quantitative analysis show that cell renewal machinery in our case is comparable to control cases. The gene of the receptor EGFR is regularly expressed in enteric epithelium of our case. Morphologic and functional data from our patient improve evidence in favor of the safety of GLP-2 employ in SBS.
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Affiliation(s)
| | - Antonella Lezo
- Dietetics and Clinical Nutrition Unit, Children’s Hospital Regina Margherita, AOU Città della Salute e della Scienza di Torino, Turin, Italy
| | - Pierluigi Calvo
- Department of Pediatric Gastroenterology, AOU Città della Salute e della Scienza di Torino, Turin, Italy
| | - Caterina Rigazio
- Department of Pediatric Gastroenterology, AOU Città della Salute e della Scienza di Torino, Turin, Italy
| | - Anna Opramolla
- Department of Pediatric Gastroenterology, AOU Città della Salute e della Scienza di Torino, Turin, Italy
| | - Ludovica Verdun
- Department of Pathology, AOU Città della Salute e della Scienza di Torino, Turin, Italy
| | - Giovanna Cenacchi
- Department of Biomedical and Neuromotor Sciences, Alma Mater Studiorum Universitá di Bologna, Bologna, Italy
| | - Marianna Pellegrini
- Dietetics and Clinical Nutrition Unit, Children’s Hospital Regina Margherita, AOU Città della Salute e della Scienza di Torino, Turin, Italy
| | - Marco Spada
- Department of Pediatric Gastroenterology, AOU Città della Salute e della Scienza di Torino, Turin, Italy
| | - Gabriella Canavese
- Department of Pathology, AOU Città della Salute e della Scienza di Torino, Turin, Italy
- *Correspondence: Gabriella Canavese,
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12
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The Regulatory Role of Neuropeptide Gene Glucagon in Colorectal Cancer: A Comprehensive Bioinformatic Analysis. DISEASE MARKERS 2022; 2022:4262600. [PMID: 35340411 PMCID: PMC8956438 DOI: 10.1155/2022/4262600] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/11/2021] [Revised: 01/05/2022] [Accepted: 01/08/2022] [Indexed: 11/26/2022]
Abstract
Background Colorectal cancer is highly prevalent and causes high global mortality, and glucagon axis has been implicated in colon cancer. The present study is aimed at investigating the regulating mechanisms of glucagon involvement in colorectal cancer. Methods Publicly available data from the TCGA database was utilized to explore the expression pattern and regulating role of glucagon (GCG) in colorectal cancer (COADREAD) including colon adenocarcinomas (COAD) and rectum adenocarcinomas (READ). Statistical analyses were performed using the R software packages and public web servers. The expression pattern and prognostic significance of GCG gene in pan-cancer and TCGA-COADREAD data were investigated by performing unpaired and paired sample analyses. The association of GCG expression with clinical characteristics was investigated using logistic regression analysis. Univariate cox regression analysis was performed to test the prognostic value of GCG expression for overall survival in COADREAD patients. GCG-significantly correlated genes were obtained. Biological functions and signaling pathways were identified by performing functional enrichment analysis and Gene Set Enrichment Analysis (GSEA). Additionally, the potential involvement of GCG in tumor immunity was researched by investigating the correlation between GCG expression and 24 tumor infiltrating immune cells. Results GCG was found to be significantly downregulated in COADREAD tumor samples compared with healthy control samples. GCG gene was shown to be associated with the prognostic outcomes of COADREAD, whereby its upregulation predicted improved survival outcomes. Functional enrichment analysis showed that the top 100 positively and top 100 negatively GCG-correlated genes were mainly enriched in three signaling pathways including ribosome, nitrogen metabolism, and proximal tubule bicarbonate reclamation. The GSEA showed that GCG-significantly correlated genes were mainly enriched in cell cycle-related pathways (reactome cell cycle, reactome cell cycle mitotic, reactome cell cycle checkpoints, reactome M phase, Reactome G2 M DNA damage checkpoint, and Reactome G2 M checkpoints), neuropeptide ligand receptor interaction, RHO GTPases signaling, WNT signaling, RUNX1 signaling, NOTCH signaling, ESR signaling, HCMV infection, and oxidative stress-related signaling. GCG was positively correlated with Th17 cells, pDC, macrophages, TFH cells, iDC, Tem, B cells, dendritic cells, neutrophils, mast cells, and eosinophils and was negatively associated with NK cells. Conclusions GCG dysregulation with high prognostic value in COADREAD was noted. Several tumor progression-related pathways and tumor immune-modulatory cells were linked to GCG expression in COADREAD. Therefore, GCG may be regarded as a potential therapeutic target for treating colorectal cancer.
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13
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Harpain F, Schlager L, Hütterer E, Dawoud C, Kirchnawy S, Stift J, Krotka P, Stift A. Teduglutide in short bowel syndrome patients: A way back to normal life? JPEN J Parenter Enteral Nutr 2021; 46:300-309. [PMID: 34614239 PMCID: PMC9298195 DOI: 10.1002/jpen.2272] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
Background The glucagon‐like peptide 2 analogue teduglutide is an effective drug for the treatment of short bowel syndrome patients with intestinal failure (SBS‐IF). This intestinotrophic peptide improves intestinal capacity for fluid and nutrient absorption through induction of mucosal growth and reduction of gastrointestinal motility. Clinical trials demonstrated the efficacy of teduglutide in reducing the need for parenteral support (PS). This study describes an SBS‐IF patient population receiving teduglutide therapy in a specialized medical care setting. Method A retrospective analysis was performed using data of patients experiencing nonmalignant SBS‐IF. They were treated with teduglutide in a multidisciplinary SBS‐IF program at a single university medical center between June 2016 and June 2020. Results Thirteen patients under teduglutide treatment were included in the final analysis. Mean small bowel length was 82 ± 31 cm, with 77% of patients having their colon in continuity. Over a median follow‐up of 107 weeks, all patients (13 of 13, 100%) responded to the therapy with a clinically significant reduction of PS volume. Mean PS reduction increased with therapy duration and ranged from −82.5% at week 24 (n = 13) to −100% in patients (n = 5) who were treated for 144 weeks. Enteral autonomy was achieved in 12 of 13 (92%) patients. Teduglutide therapy improved stool frequency and consistency, changed dietary habits, and reduced disease‐associated sleep disruptions. Conclusion Integrating SBS‐IF patients treated with teduglutide in a proactive and tight‐meshed patient care program significantly improves the clinical outcome, leading to an increased proportion of patients reaching enteral autonomy.
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Affiliation(s)
- Felix Harpain
- Department of General Surgery, Division of Visceral Surgery, Medical University of Vienna, Vienna, Austria
| | - Lukas Schlager
- Department of General Surgery, Division of Visceral Surgery, Medical University of Vienna, Vienna, Austria
| | - Elisabeth Hütterer
- Department of Internal Medicine I, Division of Oncology, Medical University of Vienna, Vienna, Austria
| | - Christopher Dawoud
- Department of General Surgery, Division of Visceral Surgery, Medical University of Vienna, Vienna, Austria
| | - Sabine Kirchnawy
- Department of General Surgery, Division of Visceral Surgery, Medical University of Vienna, Vienna, Austria
| | - Judith Stift
- Department of Pathology, Medical University of Vienna, Vienna, Austria
| | - Pavla Krotka
- Center for Medical Statistics, Informatics, and Intelligent Systems, Medical University of Vienna, Vienna, Austria
| | - Anton Stift
- Department of General Surgery, Division of Visceral Surgery, Medical University of Vienna, Vienna, Austria
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14
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Shah PA, Park CJ, Shaughnessy MP, Cowles RA. Serotonin as a Mitogen in the Gastrointestinal Tract: Revisiting a Familiar Molecule in a New Role. Cell Mol Gastroenterol Hepatol 2021; 12:1093-1104. [PMID: 34022423 PMCID: PMC8350061 DOI: 10.1016/j.jcmgh.2021.05.008] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/12/2020] [Revised: 05/11/2021] [Accepted: 05/12/2021] [Indexed: 02/02/2023]
Abstract
Serotonin signaling is ubiquitous in the gastrointestinal (GI) system, where it acts as a neurotransmitter in the enteric nervous system (ENS) and influences intestinal motility and inflammation. Since its discovery, serotonin has been linked to cellular proliferation in several types of tissues, including vascular smooth muscle, neurons, and hepatocytes. Activation of serotonin receptors on distinct cell types has been shown to induce well-known intracellular proliferation pathways. In the GI tract, potentiation of serotonin signaling results in enhanced intestinal epithelial proliferation, and decreased injury from intestinal inflammation. Furthermore, activation of the type 4 serotonin receptor on enteric neurons leads to neurogenesis and neuroprotection in the setting of intestinal injury. It is not surprising that the mitogenic properties of serotonin are pronounced within the GI tract, where enterochromaffin cells in the intestinal epithelium produce 90% of the body's serotonin; however, these proliferative effects are attributed to increased serotonin signaling within the ENS compartment as opposed to the intestinal mucosa, which are functionally and chemically separate by virtue of the distinct tryptophan hydroxylase enzyme isoforms involved in serotonin synthesis. The exact mechanism by which serotonergic neurons in the ENS lead to intestinal proliferation are not known, but the activation of muscarinic receptors on intestinal crypt cells indicate that cholinergic signaling is essential to this signaling pathway. Further understanding of serotonin's role in mucosal and enteric nervous system mitogenesis may aid in harnessing serotonin signaling for therapeutic benefit in many GI diseases, including inflammatory bowel disease, malabsorptive conditions, and cancer.
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Affiliation(s)
- Pooja A Shah
- Division of Pediatric Surgery, Department of Surgery, Yale School of Medicine, New Haven, Connecticut
| | - Christine J Park
- Division of Pediatric Surgery, Department of Surgery, Yale School of Medicine, New Haven, Connecticut
| | - Matthew P Shaughnessy
- Division of Pediatric Surgery, Department of Surgery, Yale School of Medicine, New Haven, Connecticut
| | - Robert A Cowles
- Division of Pediatric Surgery, Department of Surgery, Yale School of Medicine, New Haven, Connecticut.
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15
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Hunt JE, Yassin M, Olsen J, Hartmann B, Holst JJ, Kissow H. Intestinal Growth in Glucagon Receptor Knockout Mice Is Not Associated With the Formation of AOM/DSS-Induced Tumors. Front Endocrinol (Lausanne) 2021; 12:695145. [PMID: 34108943 PMCID: PMC8181411 DOI: 10.3389/fendo.2021.695145] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/14/2021] [Accepted: 05/03/2021] [Indexed: 12/22/2022] Open
Abstract
Treatment with exogenous GLP-2 has been shown to accelerate the growth of intestinal adenomas and adenocarcinomas in experimental models of colonic neoplasia, however, the role of endogenous GLP-2 in tumor promotion is less well known. Mice with a global deletion of the glucagon receptor (Gcgr-/-) display an increase in circulating GLP-1 and GLP-2. Due to the intestinotrophic nature of GLP-2, we hypothesized that Gcgr-/- mice would be more susceptible to colonic dysplasia in a model of inflammation-induced colonic carcinogenesis. Female Gcgr-/- mice were first characterized for GLP-2 secretion and in a subsequent study they were given a single injection with the carcinogen azoxymethane (7.5 mg/kg) and treated with dextran sodium sulfate (DSS) (3%) for six days (n=19 and 9). A cohort of animals (n=4) received a colonoscopy 12 days following DSS treatment and all animals were sacrificed after six weeks. Disruption of glucagon receptor signaling led to increased GLP-2 secretion (p<0.0001) and an increased concentration of GLP-2 in the pancreas of Gcgr-/- mice, coinciding with an increase in small intestinal (p<0.0001) and colonic (p<0.05) weight. Increased villus height was recorded in the duodenum (p<0.001) and crypt depth was increased in the duodenum and jejunum (p<0.05 and p<0.05). Disruption of glucagon receptor signaling did not affect body weight during AOM/DSS treatment, neither did it affect the inflammatory score assessed during colonoscopy or the number of large and small adenomas present at the end of the study period. In conclusion, despite the increased endogenous GLP-2 secretion Gcgr-/- mice were not more susceptible to AOM/DSS-induced tumors.
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Affiliation(s)
- Jenna Elizabeth Hunt
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Mohammad Yassin
- Department of Cellular and Molecular Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Jørgen Olsen
- Department of Cellular and Molecular Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Bolette Hartmann
- Department of Biomedical Sciences and Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Jens Juul Holst
- Department of Biomedical Sciences and Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Hannelouise Kissow
- Department of Biomedical Sciences and Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- *Correspondence: Hannelouise Kissow,
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16
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Hinchliffe T, Pauline ML, Wizzard PR, Nation PN, Brubaker P, Campbell JR, Kim Y, Dimitriadou V, Wales PW, Turner JM. Durability of Linear Small-Intestinal Growth Following Treatment Discontinuation of Long-Acting Glucagon-Like Peptide 2 (GLP-2) Analogues. JPEN J Parenter Enteral Nutr 2020; 45:1466-1474. [PMID: 33241564 DOI: 10.1002/jpen.2053] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2020] [Revised: 10/23/2020] [Accepted: 11/17/2020] [Indexed: 11/08/2022]
Abstract
BACKGROUND Short-bowel syndrome is the leading cause of pediatric intestinal failure, resulting in dependency on long-term parenteral nutrition (PN). To promote enteral autonomy in neonates, a key outcome may be intestinal growth in length. The purpose of this study was to determine if intestinal lengthening persists following discontinuation of treatment with 1 of 2 GLP-2 analogues with different pharmacokinetic profiles. METHODS Neonatal short-bowel piglets were assigned to saline control (S), 7-day treatment with teduglutide (T) (0.05 mg/kg twice daily), or 7-day treatment with apraglutide (A) (5 mg/kg twice weekly). Comparisons were made between day 7 and day 14 endpoints using analysis of variance. Data included small-intestine length, weight, histology, and quantitative polymerase chain reaction analysis of mucosal transcripts for peptide growth factors and their receptors, nutrient transporters, and tight-junction proteins. RESULTS Compared with control, 7 days of GLP-2 analogue treatment induced mucosal adaptation based on villus hyperplasia (P = .003), which was not durable 7 days after treatment cessation (day 14; P = .081). Treatment increased intestinal growth in length by day 7 (P = .005), which was maintained (by T) or further increased (by A) at day 14 (P < .001). No significant differences in mucosal transcripts were detected. CONCLUSION Unlike mucosal adaptation, intestinal growth appears to be a lasting outcome of treatment with long-acting GLP-2 analogues in a neonatal piglet short-bowel model. This has significant clinical implications for neonates, given their potential for intestinal growth. Intestinal lengthening varies between analogues with different half-lives; however, molecular mechanisms require further elucidation.
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Affiliation(s)
- Tierah Hinchliffe
- Department of Pediatrics, University of Alberta, Edmonton, Alberta, Canada
| | - Mirielle L Pauline
- Department of Pediatrics, University of Alberta, Edmonton, Alberta, Canada
| | - Pamela R Wizzard
- Department of Pediatrics, University of Alberta, Edmonton, Alberta, Canada
| | - Patrick N Nation
- Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, Alberta, Canada
| | - Patricia Brubaker
- Departments of Physiology and Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Jhenielle R Campbell
- Departments of Physiology and Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Yunji Kim
- Department of Pediatrics, University of Alberta, Edmonton, Alberta, Canada
| | | | - Paul W Wales
- Department of Surgery, Hospital for Sick Children and University of Toronto, Toronto, Ontario, Canada
| | - Justine M Turner
- Department of Pediatrics, University of Alberta, Edmonton, Alberta, Canada
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17
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George AT, Di Cocco P, Benedetti E, Boulay BR, Carroll RE. Teduglutide Therapy in 2 Patients With Short-Bowel Syndrome and Familial Adenomatous Polyposis. JPEN J Parenter Enteral Nutr 2020; 45:839-843. [PMID: 32829492 DOI: 10.1002/jpen.2001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2020] [Revised: 08/04/2020] [Accepted: 08/17/2020] [Indexed: 11/08/2022]
Affiliation(s)
- Alvin T George
- Division of Gastroenterology and Hepatology, University of Illinois at Chicago, Chicago, Illinois, USA
| | - Pierpaolo Di Cocco
- Department of Surgery, University of Illinois at Chicago, Chicago, Illinois, USA
| | - Enrico Benedetti
- Department of Surgery, University of Illinois at Chicago, Chicago, Illinois, USA
| | - Brian R Boulay
- Division of Gastroenterology and Hepatology, University of Illinois at Chicago, Chicago, Illinois, USA
| | - Robert E Carroll
- Division of Gastroenterology and Hepatology, University of Illinois at Chicago, Chicago, Illinois, USA
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18
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The Neuropeptide System and Colorectal Cancer Liver Metastases: Mechanisms and Management. Int J Mol Sci 2020; 21:ijms21103494. [PMID: 32429087 PMCID: PMC7279011 DOI: 10.3390/ijms21103494] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2020] [Revised: 05/05/2020] [Accepted: 05/11/2020] [Indexed: 12/24/2022] Open
Abstract
Colorectal cancer (CRC), classified as the third most prevalent cancer worldwide, remains to be a clinical and research challenge. It is estimated that ~50% of CRC patients die from distant metastases, with treatment of this complication still posing significant difficulties. While liver metastasis (LM) cascade is known in the literature, its mechanisms are still unclear and remain studied in different research models. A connection is suggested between nervous system dysfunctions and a range of Neurotransmitters (Nts) (including Neuropeptides, NPs), Neurotrophins (Ntt) and their receptors (Rs) in CRC liver metastasis development. Studies on the role of NP/NP-Rs in the progression and metastasis of CRC, show the complexity of brain–tumor interactions, caused by their different forms of release to the extracellular environment (endocrine, autocrine, paracrine and neurocrine). Many stages of LM are connected to the activity of pro-inflammatory, e.g., Corticotropin-releasing Hormone Receptor 1 (CRHR1), Neuropeptide Y (NPY) and Neurotensin (NT), anti-inflammatory, e.g., Calcitonin Gene-related Peptide (CGRP), CRHR2 and Vasoactive Intestinal Polypeptide (VIP) or dual role neuropeptides, e.g., Substance P (SP). The regulation of the local immunological profile (e.g., CRH/CRHRs), dysfunctions of enteroprotective role of NPs on epithelial cells (e.g., NT/NT-R), as well as structural-functional changes in enteric nervous system innervation of the tumor are also important. More research is needed to understand the exact mechanisms of communication between the neurons and tumor cells. The knowledge on the mechanisms regulating tumor growth and different stages of metastasis, as well as effects of the action of a numerous group of Nts/NPs/Ntt as growth factors, have implications for future therapeutic strategies. To obtain the best treatment outcomes, it is important to use signaling pathways common for many NPs, as well to develop a range of broad-spectrum antagonists. This review aims to summarize the current knowledge on the importance of neuroactive molecules in the promotion of the invasion-metastasis cascade in CRC, as well as the improvements of clinical management of CRC liver metastasis.
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19
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Abstract
The ultimate goal of treatment of short bowel syndrome/intestinal failure patients is to achieve enteral autonomy by eliminating parenteral nutrition (PN)/intravenous fluids (IV). After optimization of diet, oral hydration and anti-diarrheal medications, attempt should be made to eliminate PN/IV. Weaning from PN/IV should be individualized for each patient. Although teduglutide is the preferred agent for PN/IV volume reduction or successful weaning, optimal patient selection and long-term safety need further evaluation. Following PN/IV elimination, patients need long-term monitoring for nutritional deficiencies. This article will address clinical considerations before, during, and after PN/IV weaning to facilitate safe and successful PN/IV weaning process.
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Affiliation(s)
- Andrew Ukleja
- Division of Gastroenterology and Hepatology, Beth Israel Deaconess Medical Center/Beth Israel Lahey Health, 330 Brookline Ave., Boston, MA 02215, USA.
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20
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Bian Q, Chen J, Qiu W, Peng C, Song M, Sun X, Liu Y, Ding F, Chen J, Zhang L. Four targeted genes for predicting the prognosis of colorectal cancer: A bioinformatics analysis case. Oncol Lett 2019; 18:5043-5054. [PMID: 31612015 PMCID: PMC6781647 DOI: 10.3892/ol.2019.10866] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2019] [Accepted: 08/13/2019] [Indexed: 12/12/2022] Open
Abstract
The molecular mechanisms underlying the development and progression of colorectal cancer (CRC) have not been clarified. The purpose of the present study was to identify key genes that may serve as novel therapeutic targets or prognostic predictors in patients with CRC using bioinformatics analysis. Four gene expression datasets were downloaded from the Gene Expression Omnibus database, which revealed 19 upregulated and 34 downregulated differentially expressed genes (DEGs). The downregulated DEGs were significantly enriched in eight pathways according to Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis. A protein-protein interaction network was constructed with 52 DEGs and 458 edges. Ten key genes were identified according to the degree value, betweenness centrality and closeness centrality. Survival analysis revealed that low expression of four of the ten genes, carcinoembryonic antigen related cell adhesion molecule 7 (CEACAM7), solute carrier family 4 member 4 (SLC4A4), glucagon (GCG) and chloride channel accessory 1 (CLCA1) genes, were associated with unfavorable prognosis in CRC. Furthermore, gene set enrichment analysis revealed that two pathways were significantly enriched in the CEACAM7 low-expression group. Thus, CEACAM7, SLC4A4, GCG and CLCA1 may be prognostic markers or therapeutic targets of CRC. Low CEACAM7 expression may be associated with the activation of glycosaminoglycan biosynthesis-chondroitin sulfate and extracellular matrix receptor interaction pathways and may affect the prognosis of CRC.
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Affiliation(s)
- Qinglai Bian
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing 100029, P.R. China
| | - Jiaxu Chen
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing 100029, P.R. China.,Formula-Pattern Research Center, School of Traditional Chinese Medicine, Jinan University, Guangzhou, Guangdong 510632, P.R. China
| | - Wenqi Qiu
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing 100029, P.R. China
| | - Chenxi Peng
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing 100029, P.R. China
| | - Meifang Song
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing 100029, P.R. China
| | - Xuebin Sun
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing 100029, P.R. China
| | - Yueyun Liu
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing 100029, P.R. China
| | - Fengmin Ding
- School of Basic Medical Science, Hubei University of Chinese Medicine, Wuhan, Hubei 430065, P.R. China
| | - Jianbei Chen
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing 100029, P.R. China
| | - Liqing Zhang
- Department of Computer Science, Virginia Tech, Blacksburg, VA 24060, USA
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George AT, Leong M, Shokouh-Amiri M, Benedetti E, Carroll RE. Accelerated Colorectal Polyposis in an Immunosuppressed Patient With a Small Bowel Transplant Treated With Teduglutide: Case Report and Review of Literature. Clin Colorectal Cancer 2019; 18:e275-e279. [PMID: 31176580 DOI: 10.1016/j.clcc.2019.02.006] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2019] [Revised: 02/18/2019] [Accepted: 02/20/2019] [Indexed: 12/15/2022]
Affiliation(s)
- Alvin T George
- Intestinal Rehabilitation and Transplant Center, Departments of Medicine and Surgery, University of Illinois at Chicago, Chicago, IL
| | - Michelle Leong
- Intestinal Rehabilitation and Transplant Center, Departments of Medicine and Surgery, University of Illinois at Chicago, Chicago, IL
| | | | - Enrico Benedetti
- Intestinal Rehabilitation and Transplant Center, Departments of Medicine and Surgery, University of Illinois at Chicago, Chicago, IL
| | - Robert E Carroll
- Intestinal Rehabilitation and Transplant Center, Departments of Medicine and Surgery, University of Illinois at Chicago, Chicago, IL.
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Radiation-induced oxidative injury of the ileum and colon is alleviated by glucagon-like peptide-1 and -2. JOURNAL OF RADIATION RESEARCH AND APPLIED SCIENCES 2019. [DOI: 10.1016/j.jrras.2015.01.010] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
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23
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Sigalet DL. Advances in glucagon like peptide-2 therapy. physiology, current indications and future directions. Semin Pediatr Surg 2018; 27:237-241. [PMID: 30342598 DOI: 10.1053/j.sempedsurg.2018.07.008] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
The treatment paradigm for pediatric patients with short bowel syndrome (SBS) and intestinal failure (IF) has changed significantly over recent years; the development of dedicated IF teams, refinements in PN and surgical treatments have greatly improved survival. The majority of SBS patients undergo intestinal adaptation such that nutrient absorption from enteral feeds increases and the child can come off of PN. This "adaptation" or upregulation in nutrient absorptive capacity is still poorly understood; the enteric hormone Glucagon like peptide 2 (GLP-2) appears to be a key regulator in this process. The development of Teduglutide, a long acting GLP-2 ligand as a therapy to specifically enhance adaptation has been anticipated as a further shift in the paradigm. This article reviews the physiology of GLP-2 with an emphasis on the known or potential roles in infants and children with SBS and IF. The results and implications of the present studies and approved indications for GLP-2 and its ligands are discussed. Finally, the potential future uses of GLP-2 ligands in the pediatric population are considered.
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Affiliation(s)
- D L Sigalet
- Department of Pediatric Surgery, Sidra Medical and Research Center, Doha, Qatar; Professor of Surgery, Weill Cornell Medical College, Doha, Qatar.
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Orhan A, Gögenur I, Kissow H. The Intestinotrophic Effects of Glucagon-Like Peptide-2 in Relation to Intestinal Neoplasia. J Clin Endocrinol Metab 2018; 103:2827-2837. [PMID: 29741675 DOI: 10.1210/jc.2018-00655] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/24/2018] [Accepted: 05/01/2018] [Indexed: 02/07/2023]
Abstract
CONTEXT Glucagon-like peptide-2 (GLP-2) is a gastrointestinal hormone with intestinotrophic and antiapoptotic effects. The hormone's therapeutic potential in intestinal diseases and relation to intestinal neoplasia has raised great interest among researchers. This article reviews and discusses published experimental and clinical studies concerning the growth-stimulating and antiapoptotic effects of GLP-2 in relation to intestinal neoplasia. EVIDENCE ACQUISITION The data used in this narrative review were collected through literature research in PubMed using English keywords. All studies to date examining GLP-2's relation to intestinal neoplasms have been reviewed in this article, as the studies on the matter are sparse. EVIDENCE SYNTHESIS GLP-2 has been found to stimulate intestinal growth through secondary mediators and through the involvement of Akt phosphorylation. Studies on rodents have shown that exogenously administered GLP-2 increases the growth and incidence of adenomas in the colon, suggesting that GLP-2 may play an important role in the progression of intestinal tumors. Clinical studies have found that exogenous GLP-2 treatment is well tolerated for up to 30 months, but the tolerability for even longer periods of treatment has not been examined. CONCLUSION Exogenous GLP-2 is currently available as teduglutide for the treatment of short bowel syndrome. However, the association between exogenous GLP-2 treatment and intestinal neoplasia in humans has not been fully identified. This leads to a cause for concern regarding the later risk of the development or progression of intestinal tumors with long-term GLP-2 treatment. Therefore, further research regarding GLP-2's potential relation to intestinal cancers is needed.
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Affiliation(s)
- Adile Orhan
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen N, Denmark
| | - Ismail Gögenur
- Center for Surgical Science, Department of Surgery, Zealand University Hospital, Koege, Denmark
| | - Hannelouise Kissow
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen N, Denmark
- NNF Center of Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen N, Denmark
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Ring LL, Nerup N, Jeppesen PB, Svendsen LB, Achiam MP. Glucagon like peptide-2 and neoplasia; a systematic review. Expert Rev Gastroenterol Hepatol 2018; 12:257-264. [PMID: 29231791 DOI: 10.1080/17474124.2018.1417032] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Glucagon like peptide-2 is synthesized from enteroendocrine L cells primarily located in the ileum and large intestine. GLP-2 stimulates crypt cell proliferation, increases intestinal blood flow, enhances gut barrier function, induces mucosal healing, and exerts an anti-apoptotic effect. Due to these effects GLP-2 is used in the treatment of short bowel syndrome (SBS). Areas covered: The aim of this systematic review was to provide information on the potential risk of intestinal neoplasia in patients receiving treatment with GLP-2. The literature search was performed independently by two authors in the following databases; Pubmed, Embase, Scopus, Web of Science and Cochrane. Expert commentary: This systematic review indicated that treatment with GLP-2(1-33) up to 30 months in humans without any known pre-existing cancer did not confer an increased risk of intestinal neoplasia in patients or animals. However, due to the small amount of patients studied it is premature to reach any final conclusions about GLP-2 - induced neoplasia. GLP-2(1-33) treatment in animals with a pre-induced cancer showed that GLP-2(1-33) may promote growth of existing neoplasia.
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Affiliation(s)
- Linea Landgrebe Ring
- a Department of Surgical Gastroenterology , Rigshospitalet, Copenhagen University Hospital , Copenhagen , Denmark
| | - Nikolaj Nerup
- a Department of Surgical Gastroenterology , Rigshospitalet, Copenhagen University Hospital , Copenhagen , Denmark
| | - Palle Bekker Jeppesen
- b Department of Medical Gastroenterology , Rigshospitalet, Copenhagen University Hospital , Copenhagen , Denmark
| | - Lars Bo Svendsen
- a Department of Surgical Gastroenterology , Rigshospitalet, Copenhagen University Hospital , Copenhagen , Denmark
| | - Michael Patrick Achiam
- a Department of Surgical Gastroenterology , Rigshospitalet, Copenhagen University Hospital , Copenhagen , Denmark
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26
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Nunez DJ, D'Alessio D. Glucagon receptor as a drug target: A witches' brew of eye of newt (peptides) and toe of frog (receptors). Diabetes Obes Metab 2018; 20:233-237. [PMID: 28842950 DOI: 10.1111/dom.13102] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/21/2017] [Accepted: 08/22/2017] [Indexed: 12/16/2022]
MESH Headings
- Animals
- Antibodies, Monoclonal/adverse effects
- Antibodies, Monoclonal/pharmacology
- Antibodies, Monoclonal/therapeutic use
- Antibodies, Monoclonal, Humanized
- Diabetes Mellitus, Type 2/drug therapy
- Diabetes Mellitus, Type 2/metabolism
- Drugs, Investigational/adverse effects
- Drugs, Investigational/pharmacology
- Drugs, Investigational/therapeutic use
- Glucagon-Like Peptide-1 Receptor/agonists
- Glucagon-Like Peptide-1 Receptor/metabolism
- Humans
- Hypoglycemic Agents/adverse effects
- Hypoglycemic Agents/pharmacology
- Hypoglycemic Agents/therapeutic use
- Molecular Targeted Therapy
- Receptors, Glucagon/agonists
- Receptors, Glucagon/antagonists & inhibitors
- Receptors, Glucagon/metabolism
- Signal Transduction/drug effects
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Affiliation(s)
- Derek J Nunez
- Division of Endocrinology, Metabolism and Nutrition, Duke Molecular Physiology Institute, Duke University School of Medicine, Durham, North Carolina
| | - David D'Alessio
- Division of Endocrinology, Metabolism and Nutrition, Duke Molecular Physiology Institute, Duke University School of Medicine, Durham, North Carolina
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Lei Q, Bi J, Chen H, Tian F, Gao X, Li N, Wang X. Glucagon-like peptide-2 improves intestinal immune function and diminishes bacterial translocation in a mouse model of parenteral nutrition. Nutr Res 2018; 49:56-66. [DOI: 10.1016/j.nutres.2017.10.007] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2017] [Revised: 09/29/2017] [Accepted: 10/05/2017] [Indexed: 02/07/2023]
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28
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The role of enteric neurons in the development and progression of colorectal cancer. Biochim Biophys Acta Rev Cancer 2017; 1868:420-434. [PMID: 28847715 DOI: 10.1016/j.bbcan.2017.08.003] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2017] [Revised: 08/16/2017] [Accepted: 08/17/2017] [Indexed: 02/06/2023]
Abstract
The enteric nervous system (ENS) is the intrinsic neural network of the gastrointestinal tract, which is essential for regulating gut functions and intestinal homeostasis. The importance of the ENS is underscored by the existence of severe gastrointestinal diseases, such as Hirschsprung's disease and intestinal pseudo-obstruction, which arise when the ENS fails to develop normally or becomes dysregulated. Moreover, it is known that enteric neurons are involved in intestinal inflammation. However, the role of the ENS in colorectal cancer (CRC) carcinogenesis remains poorly understood, even though processes like perineural invasion and neoneurogenesis are important factors in CRC. Here we summarize how enteric neurons are affected during CRC and discuss the influence of enteric neurons, either direct or indirect, on the development and/or progression of CRC. Finally, we illustrate how the ENS could be targeted as a potential anti-cancer therapy, establishing the ENS as an integral part of the tumor microenvironment.
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Shawe-Taylor M, Kumar JD, Holden W, Dodd S, Varga A, Giger O, Varro A, Dockray GJ. Glucagon-like petide-2 acts on colon cancer myofibroblasts to stimulate proliferation, migration and invasion of both myofibroblasts and cancer cells via the IGF pathway. Peptides 2017; 91:49-57. [PMID: 28363795 DOI: 10.1016/j.peptides.2017.03.008] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/21/2016] [Revised: 03/21/2017] [Accepted: 03/27/2017] [Indexed: 01/17/2023]
Abstract
Glucagon-like peptide (GLP)-2 stimulates intestinal epithelial proliferation by acting, in part, via IGF release from sub-epithelial myofibroblasts. The response of myofibroblasts to GLP-2 remains incompletely understood. We studied the action of GLP-2 on myofibroblasts from colon cancer and adjacent tissue, and the effects of conditioned medium from these cells on epithelial cell proliferation, migration and invasion. GLP-2 stimulated proliferation, migration and invasion of myofibroblasts and the proliferative and invasive responses of cancer-associated myofibroblasts were greater than those of myofibroblasts from adjacent tissue. The responses were inhibited by an IGF receptor inhibitor, AG1024. Conditioned medium from GLP-2 treated myofibroblasts increased proliferation, migration and invasion of SW480, HT29, LoVo epithelial cells and these responses were inhibited by AG1024; GLP-2 alone had no effect on these cells. In addition, when myofibroblasts and epithelial cells were co-cultured in Ibidi chambers there was mutual stimulation of migration in response to GLP-2. The latter increased both IGF-1 and IGF-2 transcript abundance in myofibroblasts. Moreover, a number of IGF binding proteins (IGFBP-4, -5, -7) were identified in myofibroblast medium; in the presence of GLP-2 there was increased abundance of the cleavage products of IGBBP-4 and IGFBP-5 suggesting activation of a degradation mechanism that might increase IGF bioavailability. The data suggest that GLP-2 stimulates cancer myofibroblast proliferation, migration and invasion; GLP-2 acts indirectly on epithelial cells partly via increased IGF expression in myofibroblasts and partly, perhaps, by increased bioavailability through degradation of IGFBPs.
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Affiliation(s)
- Marianne Shawe-Taylor
- Department of Cellular and Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Liverpool, UK
| | - J Dinesh Kumar
- Department of Cellular and Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Liverpool, UK
| | - Whitney Holden
- Department of Cellular and Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Liverpool, UK
| | - Steven Dodd
- Department of Cellular and Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Liverpool, UK
| | - Akos Varga
- Department of Cellular and Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Liverpool, UK
| | - Olivier Giger
- Department of Cellular and Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Liverpool, UK
| | - Andrea Varro
- Department of Cellular and Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Liverpool, UK
| | - Graham J Dockray
- Department of Cellular and Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Liverpool, UK.
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30
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Increased GLP2R expression in gastric chief cells of patients with severe obesity regardless of diabetes status. Int J Obes (Lond) 2017; 41:1303-1305. [DOI: 10.1038/ijo.2017.77] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/09/2016] [Revised: 01/22/2017] [Accepted: 03/12/2017] [Indexed: 12/20/2022]
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Kitchen PA, Goodlad RA, FitzGerald AJ, Mandir N, Ghatei MA, Bloom SR, Berlanga-Acosta J, Playford RJ, Forbes A, Walters JRF. Intestinal Growth in Parenterally-Fed Rats Induced by the Combined Effects of Glucagon-like Peptide 2 and Epidermal Growth Factor. JPEN J Parenter Enteral Nutr 2017; 29:248-54. [PMID: 15961680 DOI: 10.1177/0148607105029004248] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
BACKGROUND Parenteral nutrition and the absence of luminal feeding result in impaired intestinal growth and differentiation of enterocytes. Glucagon-like peptide 2 (GLP-2) and epidermal growth factor (EGF) have each been shown to have trophic effects on the intestine, and thus have the potential to benefit patients fed parenterally, such as those with intestinal failure from short bowel syndrome. We report studies aimed to determine whether there may be synergistic effects of these 2 peptides. METHODS Rats were established on parenteral nutrition (PN) and infused for 6 days with GLP-2 (20 microg/d), EGF (20 microg/d), or GLP-2 + EGF (20 microg/d of each). These groups were compared with untreated PN-fed and orally-fed controls. Tissue was obtained from small intestine and colon to determine growth, proliferation, and representative gene expression. RESULTS Small intestinal weight was increased by 75%, 43%, and 116% in the GLP-2, EGF, and GLP-2 + EGF groups, respectively, compared with PN controls (all p < .001). Cell proliferation increased with GLP-2, EGF, and GLP-2 + EGF in proximal small intestine by factors of 2.3, 1.7, and 3.4 respectively (p < .001). A synergistic effect on villous and crypt area was observed in the proximal small intestine when GLP-2 and EGF were combined (p < .05). GLP-2 had no effect in the colon, unlike EGF. Further studies showed GLP-2 + EGF significantly increased expression in distal small intestine of transcripts for the bile acid transport protein IBABP (p < .05) and showed a significant correlation between the expression of IBABP and the transcription factor HNF-4. CONCLUSIONS Both GLP-2 and EGF upregulate growth of the small intestine, and this is augmented when GLP-2 and EGF are combined. These findings may lead to improved treatment of patients receiving PN.
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Affiliation(s)
- Paul A Kitchen
- St Mark's Hospital, Imperial College London, Harrow, United Kingdom
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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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Abstract
PURPOSE OF REVIEW Intestinal failure because of more or less extensive resection of parts of the small and large intestine (short bowel syndrome) results from the reduction of absorptive surface of the remaining intestine and frequently results in dependence on parenteral nutrition. Parenteral nutrition, although lifesaving, is associated with short and long-term complications as well as with reduced quality of life and overall survival. RECENT FINDINGS Pharmacological enhancement of the physiological intestinal adaptive response by subcutaneous application of the glucagon-like peptide 2 analogue teduglutide results in an improved, hyperadaptive response. This is reflected by decreased parenteral calorie and fluid requirements, decreased parenteral nutrition infusion days per week including complete weaning off parenteral nutrition with complete oral autonomy, improved quality of life, and metabolic and nutritional stability. SUMMARY The advent of teduglutide as an authority-approved specific medication for intestinal failure in parenteral nutrition-dependent short bowel syndrome offers an effective and beneficial treatment for these patients. As a result, patients are more stable whether for medical or further surgical management including intestinal transplantation. Long-term efficacy and safety still have to be proven.
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Carroll RE, Benedetti E, Schowalter JP, Buchman AL. Management and Complications of Short Bowel Syndrome: an Updated Review. Curr Gastroenterol Rep 2016; 18:40. [PMID: 27324885 DOI: 10.1007/s11894-016-0511-3] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/06/2023]
Abstract
Short bowel syndrome (SBS) is defined as loss of bowel mass from surgical resection, congenital defects, or disease. Intestinal failure (IF) includes the subset of SBS unable to meet nutrition needs with enteral supplements and requires parenteral nutrition (PN). The parenteral treatment of SBS is now a half-century old. Recent pharmacologic treatment (GLP-2 analogues) has begun to make a significant impact in the care and ultimate management of these patients such that the possibility of reducing PN requirements in formerly PN-dependent patients is a now a real possibility. Finally, newer understanding and possible treatment for some of the complications related to IF have more recently evolved and will be an emphasis of this report. This review will focus on developments over the last 10 years with the goal of updating the reader to new advances in our understanding of the care and feeding of the SBS patient.
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Affiliation(s)
- Robert E Carroll
- Intestinal Rehabilitation and Transplant Center, Departments of Medicine and Surgery, University of Illinois at Chicago and Chicago Veterans Administration Medical Center (West Side Division), 840 South Wood Street (M/C 787), Chicago, IL, 60612, USA.
| | - Enrico Benedetti
- Intestinal Rehabilitation and Transplant Center, Departments of Medicine and Surgery, University of Illinois at Chicago and Chicago Veterans Administration Medical Center (West Side Division), 840 South Wood Street (M/C 787), Chicago, IL, 60612, USA
| | - Joseph P Schowalter
- Intestinal Rehabilitation and Transplant Center, Departments of Medicine and Surgery, University of Illinois at Chicago and Chicago Veterans Administration Medical Center (West Side Division), 840 South Wood Street (M/C 787), Chicago, IL, 60612, USA
| | - Alan L Buchman
- Intestinal Rehabilitation and Transplant Center, Departments of Medicine and Surgery, University of Illinois at Chicago and Chicago Veterans Administration Medical Center (West Side Division), 840 South Wood Street (M/C 787), Chicago, IL, 60612, USA
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Abstract
Intestinal failure (IF) is a state in which the nutritional demands are not met by the gastrointestinal absorptive surface. A majority of IF cases are associated with short-bowel syndrome, which is a result of malabsorption after significant intestinal resection for numerous reasons, some of which include Crohn's disease, vascular thrombosis, and radiation enteritis. IF can also be caused by obstruction, dysmotility, and congenital defects. Recognition and management of IF can be challenging, given the complex nature of this condition. This review discusses the management of IF with a focus on intestinal rehabilitation, parenteral nutrition, and transplantation.
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Bankoglu EE, Seyfried F, Rotzinger L, Nordbeck A, Corteville C, Jurowich C, Germer CT, Otto C, Stopper H. Impact of weight loss induced by gastric bypass or caloric restriction on oxidative stress and genomic damage in obese Zucker rats. Free Radic Biol Med 2016; 94:208-17. [PMID: 26939878 DOI: 10.1016/j.freeradbiomed.2016.02.033] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/23/2015] [Revised: 02/26/2016] [Accepted: 02/27/2016] [Indexed: 12/19/2022]
Abstract
BACKGROUND Evidence on bariatric surgery induced weight loss and its possible impact on cancer risk is limited, but also controversial. We used obese Zucker(fa/fa) and lean Zucker(fa/+) to investigate the association between obesity, oxidative stress and genomic damage after weight loss induced either by Roux-en-Y gastric bypass surgery (RYGB) or caloric restriction. METHODS Male Zucker(fa/fa) rats underwent RYGB (n=15) or sham surgery (n=17). Five shams were food restricted and body weight matched (BWM) to RYGB. Twelve Zucker(fa/+) rats served as lean controls. Body weight and food intake were measured daily. An oral glucose tolerance test was performed on day 27. DHE staining and western blots of HSP70 and HO-1 were used to evaluate oxidative stress and anti-3-nitrotyrosine antibody staining for nitrative stress detection in colon and kidney. Lipid peroxidation products in urine were quantified by TBARS assay. LC/MS/MS was applied to measure urinary excretion of 8-oxoGua (oxidized DNA derived base), 8-oxodG (oxidized DNA derived nucleoside) and 8-oxoGuo (oxidized RNA derived nucleoside). DNA double strand breaks (DSBs) and cell proliferation (PCNA) were detected by immunohistochemistry. RESULTS Sham-operated rats showed impaired glucose tolerance, elevated plasma insulin levels as well as elevated oxidative stress and nitrative stress markers, which were less severe after weight loss by RYGB or caloric restriction. Cell proliferation showed similar trends but no significant alteration. DNA DSBs were more frequent in sham-operated compared to all other groups. DNA damage in Zucker(fa/fa) rats positively correlated with basal plasma insulin values (Spearman's correlation coefficient for colon, 0.634 and for kidney, 0.525). CONCLUSIONS RYGB and caloric restriction were sufficient to significantly reduce elevated oxidative/nitrative stress and genomic damage in obese Zucker(fa/fa) rats. Further investigations are needed to elucidate the underlying mechanism of these genome protective effects.
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Affiliation(s)
- Ezgi Eyluel Bankoglu
- Institute of Pharmacology and Toxicology, University of Wuerzburg, Versbacher Str. 9, 97078 Würzburg, Germany
| | - Florian Seyfried
- Department of General, Visceral, Vascular and Paediatric Surgery, University Hospital of Wuerzburg, Germany
| | - Laura Rotzinger
- Department of General, Visceral, Vascular and Paediatric Surgery, University Hospital of Wuerzburg, Germany
| | - Arno Nordbeck
- Department of General, Visceral, Vascular and Paediatric Surgery, University Hospital of Wuerzburg, Germany
| | - Caroline Corteville
- Department of General, Visceral, Vascular and Paediatric Surgery, University Hospital of Wuerzburg, Germany
| | - Christian Jurowich
- Department of General, Visceral, Vascular and Paediatric Surgery, University Hospital of Wuerzburg, Germany
| | - Christoph Thomas Germer
- Department of General, Visceral, Vascular and Paediatric Surgery, University Hospital of Wuerzburg, Germany
| | - Christoph Otto
- Department of General, Visceral, Vascular and Paediatric Surgery, University Hospital of Wuerzburg, Germany; Experimental Surgery, Department of General, Visceral, Vascular, and Pediatric Surgery, University Hospital of Wuerzburg, Germany
| | - Helga Stopper
- Institute of Pharmacology and Toxicology, University of Wuerzburg, Versbacher Str. 9, 97078 Würzburg, Germany.
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Pini A, Garella R, Idrizaj E, Calosi L, Baccari MC, Vannucchi MG. Glucagon-like peptide 2 counteracts the mucosal damage and the neuropathy induced by chronic treatment with cisplatin in the mouse gastric fundus. Neurogastroenterol Motil 2016; 28:206-16. [PMID: 26547262 DOI: 10.1111/nmo.12712] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/30/2015] [Accepted: 09/28/2015] [Indexed: 12/16/2022]
Abstract
BACKGROUND Glucagon-like peptide-2 (GLP-2) is a pleiotropic hormone synthesized and secreted by the enteroendocrine 'L' cells able to exert intestine-trophic and anti-inflammatory effects. The antineoplastic drug cisplatin causes gastrointestinal alterations with clinical symptoms (nausea and vomiting) that greatly affect the therapy compliance. Experimentally, it has been reported that chronic cisplatin treatment caused mucosal damage and enteric neuropathy in the rat colon. METHODS We investigated, through a combined immunohistochemical and functional approach, whether [Gly(2) ]GLP-2, a GLP-2 analog, was able to counteract the detrimental effects of long-term cisplatin administration in the mucosa and myenteric neurons of mouse gastric fundus. KEY RESULTS Morphological experiments showed a reduction in the epithelium thickness in cisplatin-treated mice, which was prevented by [Gly(2) ]GLP-2 co-treatment. Immunohistochemistry demonstrated that cisplatin caused a significant decrease in myenteric neurons, mainly those expressing neuronal nitric oxide synthase (nNOS), that was prevented by [Gly(2) ]GLP-2 co-treatment. In the functional experiments, [Gly(2) ]GLP-2 co-treatment counteracted the increase in amplitude of the neurally induced contractions observed in strips from cisplatin-treated animals. The NO synthesis inhibitor L-N(G) -nitro arginine caused an increase in amplitude of the contractile responses that was greater in preparations from cisplatin+[Gly(2) ]GLP-2 treated mice compared to the cisplatin-treated ones. CONCLUSIONS & INFERENCES The results demonstrate that in cisplatin long-term treated mice [Gly(2) ]GLP-2 is able to counteract both the mucosal gastric fundus damage, by preventing the epithelium thickness decrease, and the neuropathy, by protecting the nNOS neurons. Taken together, the present data suggest that [Gly(2) ]GLP-2 could represent an effective strategy to overcome the distressing gastrointestinal symptoms present during the anti-neoplastic therapy.
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Affiliation(s)
- A Pini
- Department of Experimental and Clinical Medicine, Histology and Embryology Research Unit, University of Florence, Florence, Italy
| | - R Garella
- Department of Experimental and Clinical Medicine, Section of Physiological Sciences, University of Florence, Florence, Italy
| | - E Idrizaj
- Department of Experimental and Clinical Medicine, Section of Physiological Sciences, University of Florence, Florence, Italy
| | - L Calosi
- Department of Experimental and Clinical Medicine, Histology and Embryology Research Unit, University of Florence, Florence, Italy
| | - M C Baccari
- Department of Experimental and Clinical Medicine, Section of Physiological Sciences, University of Florence, Florence, Italy
| | - M G Vannucchi
- Department of Experimental and Clinical Medicine, Histology and Embryology Research Unit, University of Florence, Florence, Italy
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Glucagon-like peptides 1 and 2: intestinal hormones implicated in the pathophysiology of mucositis. Curr Opin Support Palliat Care 2016; 9:196-202. [PMID: 25872118 DOI: 10.1097/spc.0000000000000132] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
PURPOSE OF REVIEW Chemotherapy often causes adverse effects, including pain, bloating, diarrhea, and inflammation and ulceration of the mucous membranes lining the digestive tract, which are collectively referred to as mucositis. Unfortunately, no remedy has been found yet to manage these side-effects. RECENT FINDINGS The intestinal glucagon-like peptide-2 (GLP-2) is secreted from the intestinal endocrine L cells after nutrient intake, but recent findings show that the peptide concentration in the plasma also rises after intestinal injury and that GLP-2 receptor activation is crucial for intestinal healing. The antidiabetic hormone GLP-1, cosecreted with GLP-2, diminished mucositis in an animal model of the condition. Therefore, both peptides could be involved in the pathophysiology of mucositis. SUMMARY The intestinal GLPs have shown beneficial effects in experimental trials and have potential for therapeutic use. In type 2 diabetic and obese patients, GLP secretion is impaired. Elucidating the role of these endogenous hormones could lead to the identification of mucositis risk factors and an alternative preventive therapy for these patients.
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Pedersen J, Pedersen NB, Brix SW, Grunddal KV, Rosenkilde MM, Hartmann B, Ørskov C, Poulsen SS, Holst JJ. The glucagon-like peptide 2 receptor is expressed in enteric neurons and not in the epithelium of the intestine. Peptides 2015; 67:20-8. [PMID: 25748021 DOI: 10.1016/j.peptides.2015.02.007] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/24/2015] [Accepted: 02/26/2015] [Indexed: 12/25/2022]
Abstract
Glucagon-like peptide 2 (GLP-2) is a potent intestinotrophic growth factor with therapeutic potential in the treatment of intestinal deficiencies. It has recently been approved for the treatment of short bowel syndrome. The effects of GLP-2 are mediated by specific binding of the hormone to the GLP-2 receptor (GLP-2R) which was cloned in 1999. However, consensus about the exact receptor localization in the intestine has never been established. By physical, chemical and enzymatic tissue fragmentation, we were able to divide rat jejunum into different compartments consisting of: (1) epithelium alone, (2) mucosa with lamina propria and epithelium, (3) the external muscle coat including myenteric plexus, (4) a compartment enriched for the myenteric plexus and (5) intestine without epithelium. Expression of Glp2r; chromogranin A; tubulin, beta 3; actin, gamma 2, smooth muscle, enteric and glial fibrillary acidic protein in these isolated tissue fractions was quantified with qRT-PCR. Expression of the Glp2r was confined to compartments containing enteric neurons and receptor expression was absent in the epithelium. Our findings provide evidence for the expression of the GLP-2R in intestinal compartments rich in enteric neurons and, importantly they exclude significant expression in the epithelium of rat jejunal mucosa.
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Affiliation(s)
- Jens Pedersen
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, DK-2200 Copenhagen, Denmark
| | - Nis B Pedersen
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, DK-2200 Copenhagen, Denmark
| | - Sophie W Brix
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, DK-2200 Copenhagen, Denmark
| | - Kaare Villum Grunddal
- Department of Neuroscience and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, DK-2200 Copenhagen, Denmark
| | - Mette M Rosenkilde
- Department of Neuroscience and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, DK-2200 Copenhagen, Denmark
| | - Bolette Hartmann
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, DK-2200 Copenhagen, Denmark
| | - Cathrine Ørskov
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, DK-2200 Copenhagen, Denmark
| | - Steen S Poulsen
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, DK-2200 Copenhagen, Denmark
| | - Jens J Holst
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, DK-2200 Copenhagen, Denmark.
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Zhao Y, Yang L, Zhou Z. Dipeptidyl peptidase-4 inhibitors: multitarget drugs, not only antidiabetes drugs. J Diabetes 2014; 6:21-9. [PMID: 23683065 DOI: 10.1111/1753-0407.12063] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/04/2012] [Revised: 04/25/2013] [Accepted: 05/10/2013] [Indexed: 12/19/2022] Open
Abstract
Dipeptidyl peptidase (DPP)-4 inhibitors are a new class of antidiabetic agents that reduce blood glucose by preventing the degradation of the endogenous incretin hormones glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide. Protection by DPP-4 inhibitors of β-cell function has been demonstrated in patients with type 2 diabetes. Because DPP-4 is an enzyme widely expressed in humans, DPP-4 inhibitors are speculated to be multitarget agents. However, other potential therapeutic benefits of DPP-4 inhibitors remain unknown. Recently, some therapeutic effects of DPP-4 inhibitors, such as immune regulation, cardiovascular protection, and anti-inflammatory effects, have been observed. This article provides a systematic and comprehensive review of current research into the newly found effects and mechanism of action of DPP-4 inhibitors in a therapeutic context.
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Affiliation(s)
- Yunjuan Zhao
- Diabetes Center, Institute of Metabolism and Endocrinology, The Second Xiangya Hospital and Key Laboratory of Diabetes Immunology, Ministry of Education, Central South University, Changsha, China
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Abstract
BACKGROUND Glucagon-like peptide-2 (GLP-2) has been suggested for the treatment of mucositis, but the peptide has also been shown to accentuate colonic dysplasia in carcinogen-treated mice. Recently, an effect on intestinal growth was discovered for glucagon-like peptide-1 (GLP-1), OBJECTIVE: To determine whether endogenous GLP-1 contributes to the healing processes and if exogenous GLP-1 has a potential role in treating mucositis. METHODS Mice were injected with 5-fluorouracil (5-FU) or saline to induce mucositis and were then treated with GLP-1, GLP-2, GLP-2 (3-33), exendin (9-39) or vehicle. The mice were sacrificed 48 or 96 h after the 5-FU injections. The end points were intestinal weight, villus height, proliferation and histological scoring of mucositis severity. Rats were injected with 5-FU or saline, and after 48 h, blood was drawn and analysed for GLP-1 and GLP-2 concentration. RESULTS GLP-1 and GLP-2 significantly prevented the loss of mucosal mass and villus height and significantly decreased the mucositis severity score in the duodenum and jejunum 48 h after chemotherapy. The effect was equivalent. Exendin (9-39) reduced the intestinal weight 96 h after chemotherapy. The GLP-1 levels in blood were increased more than 10-fold, and GLP-2 levels were increased sevenfold. CONCLUSIONS GLP-1 and GLP-2 were secreted after intestinal injury, and recovery was delayed after treatment with exendin (9-39), indicating an important role for the peptides in the protection of the intestine from injury. GLP-1 treatment ameliorated mucositis, which suggests that mucositis and other acute intestinal disorders might benefit from treatment with GLP-1 analogues.
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Affiliation(s)
- Hannelouise Kissow
- Department of Biomedical Sciences and the Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark
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Vipperla K, O'Keefe SJ. Study of teduglutide effectiveness in parenteral nutrition-dependent short-bowel syndrome subjects. Expert Rev Gastroenterol Hepatol 2013; 7:683-7. [PMID: 24134154 DOI: 10.1586/17474124.2013.842894] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
Loss of intestinal absorptive capacity from congenital defect, surgical resection or mucosal disease results in short bowel syndrome (SBS)-associated intestinal failure. In the past, few medical management options were available besides dietary modification, controlling diarrhea or high stomal output, and providing parenteral fluid, electrolyte and nutrient support (parenteral support). Recent research on strategies to enhance the intestinal absorptive capacity focused on glucagon-like peptide-2, an intestinotrophic hormone that has been shown to increase the villus height and crypt depth, and decrease gastric motility and intestinal secretory losses. STEPS is a Phase III randomized double-blinded controlled trial in which teduglutide, a recombinant analog of glucagon-like peptide-2, or placebo was given subcutaneously to SBS patients for 24 weeks. A clinically meaningful response, defined as a 20-100% reduction in parenteral support volume, was achieved in 63% of the treatment group compared with 30% in the placebo group (p = 0.002) without an increase in serious side effects. Teduglutide offers a new targeted approach to SBS-associated intestinal failure management. Its specific role in clinical practice remains to be evaluated.
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Affiliation(s)
- Kishore Vipperla
- Clinical Instructor of Medicine, Division of General Internal Medicine, University of Pittsburgh Medical Center, 200 Lothrop Street, 933W MUH, Pittsburgh, PA 15213, USA
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Drucker DJ, Yusta B. Physiology and pharmacology of the enteroendocrine hormone glucagon-like peptide-2. Annu Rev Physiol 2013; 76:561-83. [PMID: 24161075 DOI: 10.1146/annurev-physiol-021113-170317] [Citation(s) in RCA: 242] [Impact Index Per Article: 20.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Glucagon-like peptide-2 (GLP-2) is a 33-amino-acid proglucagon-derived peptide secreted from enteroendocrine L cells. GLP-2 circulates at low basal levels in the fasting period, and plasma levels rise rapidly after food ingestion. Renal clearance and enzymatic inactivation control the elimination of bioactive GLP-2. GLP-2 increases mesenteric blood flow and activates proabsorptive pathways in the gut, facilitating nutrient absorption. GLP-2 also enhances gut barrier function and induces proliferative and cytoprotective pathways in the small bowel. The actions of GLP-2 are transduced via a single G protein-coupled receptor (GLP-2R), expressed predominantly within the gastrointestinal tract. Disruption of GLP-2R signaling increases susceptibility to gut injury and impairs the adaptive mucosal response to refeeding. Sustained augmentation of GLP-2R signaling reduces the requirement for parenteral nutrition in human subjects with short-bowel syndrome. Hence GLP-2 integrates nutrient-derived signals to optimize mucosal integrity and energy absorption.
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Affiliation(s)
- Daniel J Drucker
- Department of Medicine, Mount Sinai Hospital, Lunenfeld Tanenbaum Research Institute, University of Toronto, Toronto, Ontario, Canada M5G 1X5; ,
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Teduglutide enhances structural adaptation of the small intestinal mucosa in patients with short bowel syndrome. J Clin Gastroenterol 2013; 47:602-7. [PMID: 23426461 DOI: 10.1097/mcg.0b013e3182828f57] [Citation(s) in RCA: 52] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
BACKGROUND Intestinotrophic therapies, such as glucagon-like peptide-2 (GLP-2) analogs, may enhance intestinal adaptation and reduce dependence on parenteral nutrition (PN) in patients with intestinal failure associated with short bowel syndrome (SBS-IF). However, because GLP-2 enhances cellular growth, there is concern that GLP-2 analogs may also encourage growth of malignant cells. AIMS To histologically examine the effects of teduglutide, a recombinant human GLP-2 analog, on the mucosa of the small and large intestine for indications of dysplastic transformation. METHODS In a multicenter, prospective, randomized, placebo-controlled study, 83 PN-dependent patients with SBS-IF were monitored for several weeks to ensure optimal and stable PN. Patients were then randomized to receive 24 weeks of placebo (n=16), teduglutide (0.5 mg/kg/d; n=35), or teduglutide (0.10 mg/kg/d; n=32). RESULTS Biopsies were obtained from 77 patients to yield 390 individual histologic interpretations. After 6 months of treatment, no features of dysplasia were found in any biopsy from the large or small intestine of patients receiving placebo or either dose of teduglutide. New secondary diagnoses, such as eosinophilic colitis or Crohn's disease, were found at a low frequency overall: teduglutide (0.05 mg/kg/d; range, 3.1% to 6.3%); teduglutide (0.10 mg/kg/d, 3.3%); placebo (range, 6.7% to 13.3%). CONCLUSIONS Although this histologic substudy of biopsy samples was not powered to detect differences in occurrence of dysplasia between teduglutide-treated patients and those randomized to placebo, it demonstrated that no dysplasia or other pathologic processes were evident within the intestinal mucosa in the placebo group or the 2 teduglutide groups after 6 months of treatment.
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45
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Glucagon-like peptide 2 in colon carcinogenesis: Possible target for anti-cancer therapy? Pharmacol Ther 2013; 139:87-94. [DOI: 10.1016/j.pharmthera.2013.04.007] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2013] [Accepted: 03/21/2013] [Indexed: 12/18/2022]
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Janssen P, Rotondo A, Mulé F, Tack J. Review article: a comparison of glucagon-like peptides 1 and 2. Aliment Pharmacol Ther 2013; 37:18-36. [PMID: 23121085 DOI: 10.1111/apt.12092] [Citation(s) in RCA: 87] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/12/2012] [Revised: 07/09/2012] [Accepted: 09/29/2012] [Indexed: 12/18/2022]
Abstract
BACKGROUND Recent advancements in understanding the roles and functions of glucagon-like peptide 1 (GLP-1) and 2 (GLP-2) have provided a basis for targeting these peptides in therapeutic strategies. AIM To summarise the preclinical and clinical research supporting the discovery of new therapeutic molecules targeting GLP-1 and GLP-2. METHODS This review is based on a comprehensive PubMed search, representing literature published during the past 30 years related to GLP-1 and GLP-2. RESULTS Although produced and secreted together primarily from L cells of the intestine in response to ingestion of nutrients, GLP-1 and GLP-2 exhibit distinctive biological functions that are governed by the expression of their respective receptors, GLP-1R and GLP-2R. Through widespread expression in the pancreas, intestine, nervous tissue, et cetera, GLP-1Rs facilitates an incretin effect along with effects on appetite and satiety. GLP-1 analogues resistant to degradation by dipeptidyl peptidase-IV and inhibitors of dipeptidyl peptidase-IV have been developed to aid treatment of diabetes and obesity. The GLP-2R is expressed almost exclusively in the stomach and bowel. The most apparent role for GLP-2 is its promotion of growth and function of intestinal mucosa, which has been targeted for therapies that promote repair and adaptive growth. These are used as treatments for intestinal failure and related conditions. CONCLUSIONS Our growing understanding of the biology and function of GLP-1, GLP-2 and corresponding receptors has fostered further discovery of fundamental biological function as well as new categories of potent therapeutic medicines.
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Affiliation(s)
- P Janssen
- Translational Research Center for Gastrointestinal Disorders, University of Leuven, Belgium
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47
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Jeppesen PB, Pertkiewicz M, Messing B, Iyer K, Seidner DL, O'keefe SJD, Forbes A, Heinze H, Joelsson B. Teduglutide reduces need for parenteral support among patients with short bowel syndrome with intestinal failure. Gastroenterology 2012; 143:1473-1481.e3. [PMID: 22982184 DOI: 10.1053/j.gastro.2012.09.007] [Citation(s) in RCA: 322] [Impact Index Per Article: 24.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2012] [Revised: 08/27/2012] [Accepted: 09/07/2012] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Teduglutide, a glucagon-like peptide 2 analogue, might restore intestinal structural and functional integrity by promoting growth of the mucosa and reducing gastric emptying and secretion. These factors could increase fluid and nutrient absorption in patients with short bowel syndrome with intestinal failure (SBS-IF). We performed a prospective study to determine whether teduglutide reduces parenteral support in patients with SBS-IF. METHODS We performed a 24-week study of patients with SBS-IF who were given subcutaneous teduglutide (0.05 mg/kg/d; n = 43) or placebo (n = 43) once daily. Parenteral support was reduced if 48-hour urine volumes exceeded baseline values by ≥ 10%. The primary efficacy end point was number of responders (patients with >20% reduction in parenteral support volume from baseline at weeks 20 and 24). RESULTS There were significantly more responders in the teduglutide group (27/43 [63%]) than the placebo group (13/43 [30%]; P = .002). At week 24, the mean reduction in parenteral support volume in the teduglutide group was 4.4 ± 3.8 L/wk (baseline 12.9 ± 7.8 L/wk) compared with 2.3 ± 2.7 L/wk (baseline 13.2 ± 7.4 L/wk) in the placebo group (P < .001). The percentage of patients with a 1-day or more reduction in the weekly need for parenteral support was greater in the teduglutide group (21/39 [54%]) than in the placebo group (9/39 [23%]; P = .005). Teduglutide increased plasma concentrations of citrulline, a biomarker of mucosal mass. The distribution of treatment-emergent adverse events that led to study discontinuation was similar between patients given teduglutide (n = 2) and placebo (n = 3). CONCLUSIONS Twenty-four weeks of teduglutide treatment was generally well tolerated in patients with SBS-IF. Treatment with teduglutide reduced volumes and numbers of days of parenteral support for patients with SBS-IF; ClinicalTrials.gov Number, NCT00798967.
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Affiliation(s)
- Palle B Jeppesen
- Department of Medical Gastroenterology, Rigshospitalet, Copenhagen, Denmark.
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Buchman AL. Teduglutide and short bowel syndrome: every night without parenteral fluids is a good night. Gastroenterology 2012; 143:1416-20. [PMID: 23089542 DOI: 10.1053/j.gastro.2012.10.022] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
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Körner M, Rehmann R, Reubi JC. GLP-2 receptors in human disease: high expression in gastrointestinal stromal tumors and Crohn's disease. Mol Cell Endocrinol 2012; 364:46-53. [PMID: 22951144 DOI: 10.1016/j.mce.2012.08.008] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/18/2012] [Revised: 08/13/2012] [Accepted: 08/13/2012] [Indexed: 12/22/2022]
Abstract
Peptide hormones of the glucagon-like peptide (GLP) family play an increasing clinical role, as reported for GLP-1 in diabetes therapy and insulinoma diagnostics. GLP-2, despite its known trophic and anti-inflammatory intestinal actions translated into preliminary clinical studies using the GLP-2 analogue teduglutide for treatment of short bowel syndrome and Crohn's disease, remains poorly characterized in terms of expression of its receptor in tissues of interest. Therefore, the GLP-2 receptor expression was assessed in 237 tumor and 148 non-neoplastic tissue samples with in vitro receptor autoradiography. A GLP-2 receptor expression was present in 68% of gastrointestinal stromal tumors (GIST). Furthermore, GLP-2 receptors were identified in the intestinal myenteric plexus, with significant up-regulation in active Crohn's disease. The GLP-2 receptors in GIST may be used for clinical applications like in vivo targeting with radiolabelled GLP-2 analogues for imaging and therapy. Moreover, the over-expressed GLP-2 receptor in the myenteric plexus may represent the morphological correlate of the clinical target of teduglutide in Crohn's disease.
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Affiliation(s)
- Meike Körner
- Division of Cell Biology and Experimental Cancer Research, Institute of Pathology, University of Berne, Berne, Switzerland.
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Ishizuka S, Shiwaku M, Hagio M, Suzuki T, Hira T, Hara H. Glycochenodeoxycholic acid promotes proliferation of intestinal epithelia via reduction of cyclic AMP and increase in H2AX phosphorylation after exposure to γ-rays. Biomed Res 2012; 33:159-65. [PMID: 22790215 DOI: 10.2220/biomedres.33.159] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
Bile acids (BAs) are considered to be promotive factors in colorectal carcinogenesis. We investigated whether BAs in the cellular environment influence proliferation of intestinal epithelial cell lines. Some BAs induced proliferation in several epithelial cell lines. In the proliferation assay, significant increases in IEC-6 cell proliferation were observed in response to glycodeoxycholic acid or glycochenodeoxycholic acid (GCDCA). Among the glycine-conjugated derivatives of BAs, especially GCDCA reduced cAMP production in IEC-6 cells. Pertussis toxin completely inhibited the GCDCA-induced increase in IEC-6 proliferation, suggesting GCDCA-induced proliferation required Gαi activation and cAMP reduction. Treatment with 3-isobutyl-1-methylxanthine, a phosphodiesterase inhibitor, also suppressed GCDCA-induced IEC-6 proliferation. We confirmed an increase in MEK1/2 phosphorylation in GCDCA-treated IEC-6 cells, and inhibition of MEK1/2 by U0126 clearly suppressed GCDCA-induced IEC-6 cell proliferation. A significant increase was observed in the phosphorylation of histone H2AX in GCDCA-treated IEC-6 cells after exposure to γ-rays. Cell cycle analysis revealed that GCDCA increased the proportion of cells in S phase only after γ-ray exposure. These results indicate that glycine-conjugated BAs in the cellular environment are potent inducers of cell proliferation accompanied by genomic instability in intestinal epithelia.
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Affiliation(s)
- Satoshi Ishizuka
- Division of Applied Bioscience, Research Faculty of Agriculture, Hokkaido University, Sapporo 060-8589, Japan.
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