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Goldschmidt ML, Oliveira S, Slaughter C, Kocoshis SA. Use of glucagon-like polypeptide 2 analogs for intestinal failure. Expert Opin Pharmacother 2024; 25:2341-2346. [PMID: 39588923 DOI: 10.1080/14656566.2024.2431291] [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: 09/18/2024] [Accepted: 11/14/2024] [Indexed: 11/27/2024]
Abstract
INTRODUCTION Over a half century ago, a component of glucagon was found to have potent gastrointestinal effects. Shortly after proglucagon was sequenced, its component peptides were characterized, and glucagon-like polypeptide-2 (GLP-2) was noted to have the most potent intestinotrophic properties improving fluid and electrolyte balance in experimental animals and humans. AREAS COVERED Glucagon-like polypeptide-1 (GLP-1) slows small intestinal motility more effectively, but its intestinotrophic properties are weaker. GLP-2's properties prompted study of its effects upon function of the surgically foreshortened small intestine, but its short half-life limited its usefulness, but the subsequent discovery that substitution of glycine for alanine at the second position of the molecule's N-terminus could lengthen its half-life to 2.5 hours, established efficacy in short bowel management with a single daily subcutaneous injection. Both adult and pediatric studies have shown reduced parenteral nutrition requirements and establishment of enteral autonomy for some patients. More recently, ultralong acting GLP-2 analogs with half-lives of 70-80 hours can improve gastrointestinal function in surgically foreshortened bowel with only one injection every three to seven days. EXPERT OPINION Future research is likely to focus upon the potential complementary role of GLP-1 and GLP-2 in treating short bowel syndrome.
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Affiliation(s)
- Monique L Goldschmidt
- Department of Pediatrics, Division of Gastroenterology, Hepatology, and Nutrition, University of Cincinnati College of Medicine, Cincinnati, OH, USA
- Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
| | - Stephanie Oliveira
- Department of Pediatrics, Division of Gastroenterology, Hepatology, and Nutrition, University of Cincinnati College of Medicine, Cincinnati, OH, USA
- Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
| | - Crystal Slaughter
- Department of Pediatrics, Division of Gastroenterology, Hepatology, and Nutrition, University of Cincinnati College of Medicine, Cincinnati, OH, USA
- Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
| | - Samuel A Kocoshis
- Department of Pediatrics, Division of Gastroenterology, Hepatology, and Nutrition, University of Cincinnati College of Medicine, Cincinnati, OH, USA
- Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
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Raghu VK, Rumbo C, Horslen SP. From intestinal failure to transplantation: Review on the current need for transplant indications under multidisciplinary transplant programs worldwide. Pediatr Transplant 2024; 28:e14756. [PMID: 38623905 PMCID: PMC11115375 DOI: 10.1111/petr.14756] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/06/2023] [Revised: 11/24/2023] [Accepted: 04/01/2024] [Indexed: 04/17/2024]
Abstract
INTRODUCTION Intestinal failure, defined as the loss of gastrointestinal function to the point where nutrition cannot be maintained by enteral intake alone, presents numerous challenges in children, not least the timing of consideration of intestine transplantation. OBJECTIVES To describe the evolution of care of infants and children with intestinal failure including parenteral nutrition, intestine transplantation, and contemporary intestinal failure care. METHODS The review is based on the authors' experience supported by an in-depth review of the published literature. RESULTS The history of parenteral nutrition, including out-patient (home) administration, and intestine transplantation are reviewed along with the complications of intestinal failure that may become indications for consideration of intestine transplantation. Current management strategies for children with intestinal failure are discussed along with changes in need for intestine transplantation, recognizing the difficulty in generalizing recommendations due to the high level of heterogeneity of intestinal pathology and residual bowel anatomy and function. DISCUSSION Advances in the medical and surgical care of children with intestinal failure have resulted in improved transplant-free survival and a significant fall in demand for transplantation. Despite these improvements a number of children continue to fail rehabilitative care and require intestine transplantation as life-saving therapy or when the burden on ongoing parenteral nutrition becomes too great to bear.
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Affiliation(s)
- Vikram K. Raghu
- Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15224
| | - Carolina Rumbo
- Unidad de Soporte Nutricional, Rehabilitación y Trasplante Intestinal Hospital Universitario Fundación Favaloro, Buenos Aires, Argentina
| | - Simon P. Horslen
- Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15224
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Kasajima A, Pfarr N, von Werder A, Schwamborn K, Gschwend J, Din NU, Esposito I, Weichert W, Pavel M, Agaimy A, Klöppel G. Renal neuroendocrine tumors: clinical and molecular pathology with an emphasis on frequent association with ectopic Cushing syndrome. Virchows Arch 2023; 483:465-476. [PMID: 37405461 PMCID: PMC10611615 DOI: 10.1007/s00428-023-03596-5] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2023] [Revised: 06/21/2023] [Accepted: 06/29/2023] [Indexed: 07/06/2023]
Abstract
Renal neuroendocrine tumors (RenNETs) are rare malignancies with largely unknown biology, hormone expression, and genetic abnormalities. This study aims to improve our understanding of the RenNETs with emphasis of functional, hormonal, and genetic features. Surgically resected RenNETs (N = 13) were retrieved, and immunohistochemistry and next-generation sequencing (NGS) were performed in all cases. In addition, all published RenNETs were systematically reviewed. Our cohort (4 men and 9 women, mean age 42, mean tumor size 7.6 cm) included 2 patients with Cushing syndrome (CS). WHO grade (23% G1, 54% G2, and 23% G3) and tumor progression did not correlate. CS-associated RenNETs (CS-RenNETs) showed a solid and eosinophilic histology and stained for ACTH, while the remaining non-functioning tumors had a trabecular pattern and expressed variably hormones somatostatin (91%), pancreatic polypeptide (63%), glucagon (54%), and serotonin (18%). The transcription factors ISL1 and SATB2 were expressed in all non-functioning, but not in CS-RenNETs. NGS revealed no pathogenic alterations or gene fusions. In the literature review (N = 194), 15 (8%) of the patients had hormonal syndromes, in which CS being the most frequent (7/15). Large tumor size and presence of metastasis were associated with shorter patients' survival (p < 0.01). RenNETs present as large tumors with metastases. CS-RenNETs differ through ACTH production and solid-eosinophilic histology from the non-functioning trabecular RenNETs that produce pancreas-related hormones and express ISL1 and SATB2. MEN1 or DAXX/ARTX abnormalities and fusion genes are not detected in RenNETs, indicating a distinct yet unknown molecular pathogenesis.
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Affiliation(s)
- Atsuko Kasajima
- Department of Pathology, Technical University Munich, Trogerstr. 18, 81675, Munich, Germany.
| | - Nicole Pfarr
- Department of Pathology, Technical University Munich, Trogerstr. 18, 81675, Munich, Germany
| | - Alexander von Werder
- Department of Internal Medicine II, Technical University Munich, Munich, Germany
| | - Kristina Schwamborn
- Department of Pathology, Technical University Munich, Trogerstr. 18, 81675, Munich, Germany
| | - Jürgen Gschwend
- Department of Urology, Technical University Munich, Munich, Germany
| | - Nasir Ud Din
- Section of Histopathology, Department of Pathology and Laboratory Medicine, Aga Khan University Hospital, Karachi, Pakistan
| | - Irene Esposito
- Institute of Pathology, Heinrich-Heine University and University Hospital Düsseldorf, Düsseldorf, Germany
| | - Wilko Weichert
- Department of Pathology, Technical University Munich, Trogerstr. 18, 81675, Munich, Germany
| | - Marianne Pavel
- Department of Internal Medicine, University Hospital Erlangen, Erlangen, Germany
| | - Abbas Agaimy
- Department of Pathology, University Hospital Erlangen, Erlangen, Germany
| | - Günter Klöppel
- Department of Pathology, Technical University Munich, Trogerstr. 18, 81675, Munich, Germany
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Kamal RS, Dean A, Dutt H, Rajeh A, Fernandes R. Hypoglycemia as first presentation of presumed immune checkpoint inhibitor-induced type 1 diabetes. Clin Case Rep 2023; 11:e7897. [PMID: 37692147 PMCID: PMC10485243 DOI: 10.1002/ccr3.7897] [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: 07/04/2023] [Revised: 08/17/2023] [Accepted: 08/23/2023] [Indexed: 09/12/2023] Open
Abstract
We present a case of a 60-year-old male diagnosed with metastatic clear cell renal cell carcinoma who developed hypoglycemia during induction ipilimumab and nivolumab treatment. This was diagnosed as presumed type 1 diabetes mellitus secondary to immunotherapy.
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Affiliation(s)
- Rayyan Syed Kamal
- Schulich School of Medicine and DentistryWestern UniversityLondonOntarioCanada
- Cancer Research Laboratory Program, Lawson Health Research InstituteLondon Health Sciences CentreLondonOntarioCanada
| | - Arleigh Dean
- Schulich School of Medicine and DentistryWestern UniversityLondonOntarioCanada
- Cancer Research Laboratory Program, Lawson Health Research InstituteLondon Health Sciences CentreLondonOntarioCanada
| | - Hanna Dutt
- Schulich School of Medicine and DentistryWestern UniversityLondonOntarioCanada
- Cancer Research Laboratory Program, Lawson Health Research InstituteLondon Health Sciences CentreLondonOntarioCanada
| | - Adnan Rajeh
- Schulich School of Medicine and DentistryWestern UniversityLondonOntarioCanada
- Department of Oncology, Division of Medical Oncology, Schulich School of Medicine & DentistryWestern UniversityLondonOntarioCanada
| | - Ricardo Fernandes
- Department of Oncology, Division of Medical Oncology, Schulich School of Medicine & DentistryWestern UniversityLondonOntarioCanada
- Cancer Research Laboratory ProgramLawson Health Research InstituteLondonOntarioCanada
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Oliveira SB, Kocoshis SA. Teduglutide for the treatment of short bowel syndrome: a double-edged sword? Am J Clin Nutr 2023; 117:1057-1058. [PMID: 37270286 DOI: 10.1016/j.ajcnut.2023.04.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2023] [Revised: 04/07/2023] [Accepted: 04/07/2023] [Indexed: 06/05/2023] Open
Affiliation(s)
- Stephanie B Oliveira
- Department of Pediatrics University of Cincinnati College of Medicine and Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
| | - Samuel A Kocoshis
- Department of Pediatrics University of Cincinnati College of Medicine and Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
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Conlon JM. The Enigmatic N-Terminal Domain of Proglucagon; A Historical Perspective. Front Endocrinol (Lausanne) 2021; 12:683089. [PMID: 34177808 PMCID: PMC8226317 DOI: 10.3389/fendo.2021.683089] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/19/2021] [Accepted: 04/26/2021] [Indexed: 11/16/2022] Open
Abstract
Enteroglucagon refers to the predominant peptide with glucagon-like immunoreactivity (GLI) that is released by the intestine into the circulation in response to nutrients. Development of a radioimmunoassay for glucagon revealed issues that were not apparent in applications of the insulin radioimmunoassay. The fact that some antisera raised against glucagon recognized glucagon-related peptides in extracts of both pancreas and gut whereas others recognized only components in the pancreas remained a mystery until it was realized that the "gut GLI cross-reactive" antisera were directed against an epitope in the N-terminal to central region of glucagon whereas the "pancreatic glucagon specific" antisera were directed against an epitope in the C-terminal region. Unlike the cross-reactive antisera, the glucagon specific antisera did not recognize components in which glucagon was extended from its C-terminus by additional amino acids. Initial attempts to purify enteroglucagon from porcine ileum led to the erroneous conclusion that enteroglucagon comprised 100 amino acids with an apparent molecular mass of 12,000 Da and was consequently given the name glicentin. Subsequent work established that the peptide constituted residues (1-69) of proglucagon (Mr 8128). In the 40 years since the structural characterization of glicentin, attempts to establish an unambiguous physiological function for enteroglucagon have not been successful. Unlike the oxyntomodulin domain at the C-terminus of enteroglucagon, the primary structure of the N-terminal domain (glicentin-related pancreatic peptide) has been poorly conserved among mammals. Consequently, most investigations of the bioactivity of porcine glicentin may have been carried out in inappropriate animal models. Enteroglucagon may simply represent an inactive peptide that ensures that the intestine does not release equimolar amounts of a hyperglycemic agent (glucagon) and a hypoglycemic agent (GLP-1) after ingestion of nutrients.
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Betella N, Smiroldo V, Baldelli R, Lania A. Treatment of NETs from Rare Origin. NEUROENDOCRINE NEOPLASIA MANAGEMENT 2021:211-229. [DOI: 10.1007/978-3-030-72830-4_16] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
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Abbasova DV, Polikarpova SB, Kozlov NA, Markova AS, Bogush EA, Kirsanov VY. Neuroendocrine tumors of the urinary system: literature review. CANCER UROLOGY 2019; 15:126-133. [DOI: 10.17650/1726-9776-2019-15-2-126-133] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
Abstract
Most often, neuroendocrine carcinoma (NEC) is found in the gastrointestinal tract, broncho-pulmonary system, but they can also occur in other organs, such as the kidney, bladder, which is of most interest because of the rarity of this pathology. Until recently, there was not even a proper morphological classification for kidney NEC, and among some histological types, such as large cell neuroendocrine carcinoma of the kidney, only about 7 cases were recorded, and independent bladder carcinoids, about 15 cases. Currently, there are no clinical and morphological features of the NEC of the kidney and bladder, fundamentally distinguishing them from other neuroendocrine tumors and “classic” cancer of the same localization. This article also provides the data of the N.N. Blokhin National Medical Research Centre of Oncology on the incidence of all malignant neoplasms of the urinary system.
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Affiliation(s)
- D. V. Abbasova
- Sechenov First Moscow State Medical University, Ministry of Health of Russia
| | - S. B. Polikarpova
- Sechenov First Moscow State Medical University, Ministry of Health of Russia
| | - N. A. Kozlov
- N.N. Blokhin National Medical Research Centre of Oncology, Ministry of Health of Russia
| | - A. S. Markova
- N.N. Blokhin National Medical Research Centre of Oncology, Ministry of Health of Russia
| | - E. A. Bogush
- N.N. Blokhin National Medical Research Centre of Oncology, Ministry of Health of Russia
| | - V. Yu. Kirsanov
- Sechenov First Moscow State Medical University, Ministry of Health of Russia
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Drucker DJ. The Discovery of GLP-2 and Development of Teduglutide for Short Bowel Syndrome. ACS Pharmacol Transl Sci 2019; 2:134-142. [PMID: 32219218 DOI: 10.1021/acsptsci.9b00016] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2019] [Indexed: 12/18/2022]
Abstract
The proglucagon gene encodes multiple structurally related peptides with overlapping actions promoting the absorption and assimilation of ingested energy. Notably, glucagon has been developed pharmaceutically to treat hypoglycemia, and glucagon-like peptide-1 (GLP-1) receptor agonists are used for the therapy of type 2 diabetes and obesity. Here I describe the discovery of glucagon-like peptide-2 (GLP-2), a 33 amino acid peptide cosecreted together with GLP-1 from gut endocrine cells. GLP-2 was found to exhibit robust intestinal growth-promoting activity, following serendipitous observations that proglucagon-producing tumors induced intestinal growth in mice. Key developments in the pharmaceutical development of GLP-2 included the cloning of the GLP-2 receptor, and the recognition of the importance of dipeptidyl peptidase-4 as a critical determinant of GLP-2 bioactivity. A therapeutic focus on short bowel syndrome, a serious medical disorder with compelling unmet medical need, enabled the pharmaceutical development of a simple GLP-2 analogue, teduglutide, suitable for once daily administration.
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Affiliation(s)
- Daniel J Drucker
- Department of Medicine, the Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, Ontario M5G 1X5, Canada
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Henry K. Paraneoplastic syndromes: Definitions, classification, pathophysiology and principles of treatment. Semin Diagn Pathol 2019; 36:204-210. [PMID: 30876820 DOI: 10.1053/j.semdp.2019.01.002] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Paraneoplastic syndromes (PNS) are rare clinical syndromes due to the systemic effects of tumours; they are unrelated to tumour size, invasiveness or metastases. Recent years have seen considerable advances leading to improved understanding of their pathophysiology and increased recognition of new PNS entities and PNS associated tumours. While of paramount importance, diagnosis is still frequently missed or delayed. Diverse organs and systems are affected by the associated tumours- which may be benign or malignant. PNS can occur concurrently with tumour diagnosis, before tumour is diagnosed and even after tumours have been resected. Also, there are autoimmune diseases later progressing to PNS when occult tumours are identified. Another confounding factor is that many PNS clinically resemble non-neoplastic diseases. PNS are largely due to two main causes: those due to tumour secretions of hormones, functionally active peptides, enzymes cytokines or to tumours operating through auto-immune/immunological mechanisms with cross-reacting antibodies between neoplastic and normal tissues. Remission of symptoms often follows resection of humoral secretory tumours but not always of tumours due to immunological mechanisms. Classifications schemes vary but most currently place PNS in one of five groups: endocrine, neurological, musculocutaneous, haematological and other. Due to advances both in diagnostic techniques in identifying tumours as well as in therapy, early diagnosis not only results in improved prognosis of both PNS and associated tumours but also enables monitoring response to treatment and early detection of recurrence. This article covers definition, general principals of classification, diagnosis, pathophysiology and treatment, with emphasis on tumour related PNS serving as an introduction to the following articles.
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Affiliation(s)
- Kristin Henry
- Imperial College London, Charing Cross Hospital Campus, Department of Histopathology, Fulham Place Road, London W6 8RF, United Kingdom.
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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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Ammendolia MG, Iosi F, Maranghi F, Tassinari R, Cubadda F, Aureli F, Raggi A, Superti F, Mantovani A, De Berardis B. Short-term oral exposure to low doses of nano-sized TiO 2 and potential modulatory effects on intestinal cells. Food Chem Toxicol 2017; 102:63-75. [DOI: 10.1016/j.fct.2017.01.031] [Citation(s) in RCA: 44] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2016] [Revised: 01/23/2017] [Accepted: 01/30/2017] [Indexed: 12/22/2022]
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Thomazini BF, Dolder MAH. Dose dependent treatment with isotretinoin induces more changes in the ileum than in the duodenum and jejunum in Wistar rats. Tissue Cell 2017; 49:203-208. [PMID: 28341060 DOI: 10.1016/j.tice.2017.03.003] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2016] [Revised: 03/01/2017] [Accepted: 03/07/2017] [Indexed: 01/06/2023]
Abstract
Acne is the most common skin disorder and can directly affect the patients' self-esteem. Systemic treatment has been indicated for nodular, cystic or persistent acne rather than another type of treatment, such as a topic one. Isotretinoin is an analogue of vitamin A and by suppressing the sebaceous glands the disease can be controlled. This study was designed to mimic the treatment performed in young patients using the dosage of 1mg/kg, and a higher one of 10mg/kg, for 60days in young male Wistar rats. 24 Wistar rats were divided into four groups: control(water), D0(soybean oil, control group), D1(1mg/kg of Isotretinoin solution), D10(10mg/kg of Isotretinoin solution). Using the morphometry tool and histochemical techniques we evaluated the villus, intestinal crypts, and goblet cells to find signs of possible alterations of the duodenum, jejunum and ileum segments of the small intestine. We found no signs of changes in the jejunum mucosa after 60 days of treatment with 1mg/kg and 10mg/kg. The duodenum is also less affected, whereas significant modifications were found in the ileum. The goblet cell frequency was altered, indicating a proliferative potential for the substance. Although some patients have described intestinal symptoms, no important alterations were found with this protocol, reaffirming the security involved in the treatment with this substance.
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Affiliation(s)
- B F Thomazini
- Department of Structural and Functional Biology, Biology Institute, State University of Campinas, Campinas, SP, Brazil.
| | - M A H Dolder
- Department of Structural and Functional Biology, Biology Institute, State University of Campinas, Campinas, SP, Brazil
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Abstract
Objective: To summarize the pharmacology, development, and clinical application of teduglutide (ALX-0600), a glucagon-like peptide-2 (GLP-2) analog for the treatment of short bowel syndrome (SBS). Data Sources: Clinical literature, including both primary sources and review articles, was accessed through a search of the MEDLINE databases (1980–March 2006). Key search terms included teduglutide, ALX-0600, glucagon-like peptide-2, short bowel syndrome, short gut, and intestinal adaptation. Clinical trial and drug data were supplied by the manufacturer, NPS Pharmaceuticals. Study Selection and Data Extraction: Review articles, abstracts, and clinical studies related to GLP-2 and its analog, teduglutide, were analyzed. An evaluation of the research exploring teduglutide for the management of SBS was conducted. Relevant information was then selected. Data Synthesis: Research has revealed that administration of GLP-2 to patients following major small bowel resection improves intestinal adaptation and nutrient absorption. Teduglutide is an enzyme-resistant GLP-2 analog that shows promise in preventing intestinal injury, restoring mucosal integrity, and enhancing intestinal absorptive function. Conclusions: Data from ongoing clinical trials indicate that teduglutide may have the ability to enhance intestinal absorptive capacity in patients with SBS. Further studies and the completion of Phase III trials are necessary to determine the appropriate dosage and length of treatment for patients with SBS to gain optimal therapeutic benefit from this drug.
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Affiliation(s)
- Marcus Ferrone
- Department of Pharmacy; Nutrition Mayo Clinic/St. Luke's Hospital, Jacksonville, FL 32216, USA.
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Primary Carcinoid Tumor of the Renal Pelvis Arising From Intestinal Metaplasia: An Unusual Histogenetic Pathway? Appl Immunohistochem Mol Morphol 2016; 25:e49-e57. [PMID: 27753663 DOI: 10.1097/pai.0000000000000445] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
OBJECTIVES Primary carcinoid tumor of the renal pelvis is a rare neoplasm with few cases reported in the literature. Here we present the clinical and histopathologic findings of a primary carcinoid tumor arising in the left renal pelvis of a horseshoe kidney in a 61-year-old female patient. MATERIALS AND METHODS Pathologic features were evaluated with standard hematoxylin and eosin sections and immunohistochemical studies. A literature review was performed to place our case in context to previous reports. RESULTS The tumor was associated with intestinal metaplasia with high-grade dysplasia and neuroendocrine hyperplasia. Molecular testing for microsatellite instability and loss of heterozygosity were negative. CONCLUSIONS This report portrays a unique presentation of carcinoid tumor arising from intestinal metaplasia of the pelvic urothelium, and supports its histogenesis from urothelial intestinal metaplasia and neuroendocrine hyperplasia.
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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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Wewer Albrechtsen NJ, Challis BG, Damjanov I, Holst JJ. Do glucagonomas always produce glucagon? Bosn J Basic Med Sci 2016; 16:1-7. [PMID: 26773171 PMCID: PMC4765933 DOI: 10.17305/bjbms.2015.794] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2015] [Accepted: 10/12/2015] [Indexed: 12/14/2022] Open
Abstract
Pancreatic islet α-cell tumours that overexpress proglucagon are typically associated with the glucagonoma syndrome, a rare disease entity characterised by necrolytic migratory erythema, impaired glucose tolerance, thromboembolic complications and psychiatric disturbances. Paraneoplastic phenomena associated with enteric overexpression of proglucagon-derived peptides are less well recognized and include gastrointestinal dysfunction and hyperinsulinaemic hypoglycaemia. The diverse clinical manifestations associated with glucagon-expressing tumours can be explained, in part, by the repertoire of tumorally secreted peptides liberated through differential post-translational processing of tumour-derived proglucagon. Proglucagon-expressing tumours may be divided into two broad biochemical subtypes defined by either secretion of glucagon or GLP-1, GLP-2 and the glucagon-containing peptides, glicentin and oxyntomodulin, due to an islet α-cell or enteroendocrine L-cell pattern of proglucagon processing, respectively. In the current review we provide an updated overview of the clinical presentation of proglucagon-expressing tumours in relation to known physiological actions of proglucagon-derived peptides and suggest that detailed biochemical characterisation of the peptide repertoire secreted from these tumours may provide new opportunities for diagnosis and clinical management.
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Affiliation(s)
- Nicolai Jacob Wewer Albrechtsen
- 1: Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark 2: Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark.
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Challis BG, Albrechtsen NJW, Bansiya V, Burling K, Barker P, Hartmann B, Gribble F, O'Rahilly S, Holst JJ, Simpson HL. Heterogeneity of glucagonomas due to differential processing of proglucagon-derived peptides. Endocrinol Diabetes Metab Case Rep 2015; 2015:150105. [PMID: 26693280 PMCID: PMC4685488 DOI: 10.1530/edm-15-0105] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2015] [Accepted: 12/01/2015] [Indexed: 12/02/2022] Open
Abstract
Pancreatic neuroendocrine tumours (pNETs) secreting proglucagon are associated with phenotypic heterogeneity. Here, we describe two patients with pNETs and varied clinical phenotypes due to differential processing and secretion of proglucagon-derived peptides (PGDPs). Case 1, a 57-year-old woman presented with necrolytic migratory erythema, anorexia, constipation and hyperinsulinaemic hypoglycaemia. She was found to have a grade 1 pNET, small bowel mucosal thickening and hyperglucagonaemia. Somatostatin analogue (SSA) therapy improved appetite, abolished hypoglycaemia and improved the rash. Case 2, a 48-year-old male presented with diabetes mellitus, diarrhoea, weight loss, nausea, vomiting and perineal rash due to a grade 1 metastatic pNET and hyperglucagonaemia. In both cases, plasma levels of all measured PGDPs were elevated and attenuated following SSA therapy. In case 1, there was increased production of intact glucagon-like peptide 1 (GLP-1) and GLP-2, similar to that of the enteroendocrine L cell. In case 2, pancreatic glucagon was elevated due to a pancreatic α-cell-like proglucagon processing profile. In summary, we describe two patients with pNETs and heterogeneous clinical phenotypes due to differential processing and secretion of PGDPs. This is the first description of a patient with symptomatic hyperinsulinaemic hypoglycaemia and marked gastrointestinal dysfunction due to, in part, a proglucagon-expressing pNET.
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Affiliation(s)
- Benjamin G Challis
- Wellcome Trust-MRC Institute of Metabolic Science, University of Cambridge , Cambridge, CB2 0QQ , UK ; Wolfson Diabetes and Endocrinology Clinic, Institute of Metabolic Science, Cambridge University Hospitals NHS Foundation Trust, Addenbrookes Hospital , Box 281, Cambridge, CB2 0QQ , UK
| | - Nicolai J Wewer Albrechtsen
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen , Blegdamsvej 3B, Copenhagen, DK-2200 , Denmark ; Faculty of Health and Medical Sciences, Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen , Blegdamsvej 3B, Copenhagen, DK-2200 , Denmark
| | - Vishakha Bansiya
- Wolfson Diabetes and Endocrinology Clinic, Institute of Metabolic Science, Cambridge University Hospitals NHS Foundation Trust, Addenbrookes Hospital , Box 281, Cambridge, CB2 0QQ , UK
| | - Keith Burling
- Wellcome Trust-MRC Institute of Metabolic Science, University of Cambridge , Cambridge, CB2 0QQ , UK
| | - Peter Barker
- Wellcome Trust-MRC Institute of Metabolic Science, University of Cambridge , Cambridge, CB2 0QQ , UK
| | - Bolette Hartmann
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen , Blegdamsvej 3B, Copenhagen, DK-2200 , Denmark ; Faculty of Health and Medical Sciences, Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen , Blegdamsvej 3B, Copenhagen, DK-2200 , Denmark
| | - Fiona Gribble
- Wellcome Trust-MRC Institute of Metabolic Science, University of Cambridge , Cambridge, CB2 0QQ , UK
| | - Stephen O'Rahilly
- Wellcome Trust-MRC Institute of Metabolic Science, University of Cambridge , Cambridge, CB2 0QQ , UK ; Wolfson Diabetes and Endocrinology Clinic, Institute of Metabolic Science, Cambridge University Hospitals NHS Foundation Trust, Addenbrookes Hospital , Box 281, Cambridge, CB2 0QQ , UK
| | - Jens J Holst
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen , Blegdamsvej 3B, Copenhagen, DK-2200 , Denmark ; Faculty of Health and Medical Sciences, Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen , Blegdamsvej 3B, Copenhagen, DK-2200 , Denmark
| | - Helen L Simpson
- Wolfson Diabetes and Endocrinology Clinic, Institute of Metabolic Science, Cambridge University Hospitals NHS Foundation Trust, Addenbrookes Hospital , Box 281, Cambridge, CB2 0QQ , UK
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Vakhrushev YM, Lyapina MV. [Motor-evacuatory function of the gastrointestinal tract in metabolic syndrome]. TERAPEVT ARKH 2015; 87:91-97. [PMID: 26978181 DOI: 10.17116/terarkh2015871091-97] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
AIM To investigate the motor-evacuatory function of the gastrointestinal tract (GIT) in metabolic syndrome (MS). MATERIAL AND METHODS Fifty-eight patients with MS were examined. In addition to clinical findings, an integrated study of GIT motor function by peripheral electrogastroenterocolography was used. The specific features of lipid metabolism and hormonal and autonomic status were studied in patients with MS. RESULTS The local and systemic clinical signs of small bowel lesions were noted in 82.9% of the patients with MS. There were elevated blood lipid levels in the presence of hypomotor dyskinesia of the upper GIT portions in the postprandial period. New pathogenetic trends in the role of hormones and hypersympatheticotonia in impairing the motor function of the small bowel were found in MS. CONCLUSION The results of our investigations suggest that the found changes in GIT motor function are an important component of the complex pathogenesis of MS.
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Affiliation(s)
- Ya M Vakhrushev
- Izhevsk State Medical Academy, Ministry of Health of Russia, Izhevsk, Russia
| | - M V Lyapina
- Izhevsk State Medical Academy, Ministry of Health of Russia, Izhevsk, Russia
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Abstract
Short bowel syndrome (SBS) is the most common cause of intestinal failure in children. It is defined as the inability to maintain adequate nutrition enterally as a result of a major loss of the small intestine. SBS is a life-threatening entity associated with potential significant morbidity and mortality. The etiology in the pediatric age group includes necrotizing enterocolitis (32%), atresia (20%), volvulus (18%), gastroschisis (17%), and aganglionosis (6%). It is characterized by substrate malabsorption, electrolyte imbalance, intestinal bacterial overgrowth, steatorrhea, and weight loss. Current medical management includes parenteral nutrition, progressive feeds as tolerated, various medications, and surgical manipulations. However, frequently this management is not successful in achieving the goal of attaining normal growth and development without parenteral nutrition. It has been known for decades that there is a normal physiologic response of the residual intestine to massive bowel resection referred to as intestinal adaptation. The mechanisms that control this process are unknown. Unfortunately, intestinal adaptation and the current management are not always successful. As a result of new knowledge regarding the pathophysiology of SBS over the past two decades, several novel strategies have been developed in experimental animal models as well as limited clinical trials in infants and children. They can be divided into several categories that potentially influence intestinal (1) absorption, (2) secretion, (3) motility, and (4) adaptation. More recently, newer modalities have been studied including small intestine transplantation, and the use of specific intestinal growth factors. Ultimately, tissue and organ engineering will become the treatment for infants and children with SBS.
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Semrad CE. The long road to a new short-bowel therapy: teduglutide for clinical use. Clin Gastroenterol Hepatol 2013; 11:824-5. [PMID: 23591284 DOI: 10.1016/j.cgh.2013.03.030] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2013] [Revised: 03/27/2013] [Accepted: 03/27/2013] [Indexed: 02/07/2023]
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Korkmaz T, Seber S, Yavuzer D, Gumus M, Turhal NS. Primary renal carcinoid: treatment and prognosis. Crit Rev Oncol Hematol 2013; 87:256-64. [PMID: 23478151 DOI: 10.1016/j.critrevonc.2013.02.003] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2012] [Revised: 11/28/2012] [Accepted: 02/13/2013] [Indexed: 12/20/2022] Open
Abstract
Primary carcinoid tumors of the kidney are very rare, malignant tumors consisting of neuroendocrine cells. The pathogenesis of renal carcinoid is unclear because neuroendocrine cells are not normally found in adult renal parenchyma. Electron microscopy, immunohistochemistry, octreotide scan, positron emission tomography along with conventional radiographic imaging techniques are used in diagnosis and follow-up. Presenting symptoms usually include flank pain and haematuria. Early stage disease is treated with surgery only. However, randomized trials are lacking because of the very low number of reported cases. Thus, the role of debulking surgery, chemotherapy, radiotherapy, octreotide and targeted therapy in the management of advanced disease remains an open question. In this article the clinicopathologic features and prognosis of this very rare disease along with treatment outcomes of the reported cases are reviewed. In addition, we report a new case of a metastatic primary renal atypical carcinoid tumor treated with octreotide therapy.
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Affiliation(s)
- Taner Korkmaz
- Department of Medical Oncology, Dr. Lutfi Kirdar Kartal Education and Research Hospital, Istanbul, Turkey.
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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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Peterson J, Kerner JA. New advances in the management of children with intestinal failure. JPEN J Parenter Enteral Nutr 2011; 36:36S-42S. [PMID: 22190603 DOI: 10.1177/0148607111422069] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Affiliation(s)
- Johann Peterson
- Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Lucile Packard Children's Hospital, Stanford University Medical Center, Palo Alto, California 94304, USA.
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Vipperla K, O'Keefe SJ. Teduglutide for the treatment of short bowel syndrome. Expert Rev Gastroenterol Hepatol 2011; 5:665-78. [PMID: 22017694 DOI: 10.1586/egh.11.82] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
Extensive resection of the intestine impairs its absorptive capacity and results in short bowel syndrome when the nutritional equilibrium is compromised. The remnant intestine adapts structurally to compensate, but nutritional autonomy cannot be achieved in patients with intestinal failure, requiring intravenous fluids and parenteral nutrition (PN) for sustenance of life. PN is expensive and associated with serious complications. Efforts to minimize or eliminate the need for PN heralded research focusing on the therapeutic utility of intrinsic gut factors involved in the postresection adaptation process. With the breakthrough recognition of the intestinotrophic properties of glucagon-like peptide-2, teduglutide, a recombinant analogue of glucagon-like peptide-2, is being investigated as a promising hope to mitigate the requirement of PN. Clinical studies to date have demonstrated a desirable benefit-to-risk profile in regards to its safety and efficacy. If approved for marketing, it will be the first of its class in short bowel syndrome management, offering an innovative therapeutic modality for this debilitating condition.
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Affiliation(s)
- Kishore Vipperla
- Division of General Internal Medicine, University of Pittsburgh Medical Center, 200 Lothrop Street, 933W MUH, Pittsburgh, PA 15213, USA
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Abstract
Objectives: Neuroendocrine tumors (NETs) are uncommon tumors that exhibit a wide range of neuroendocrine differentiation and biological behavior. Primary NETs of the kidney, including carcinoid tumor, small cell carcinoma (SCC), and large cell neuroendocrine carcinoma (LCNEC) are exceedingly rare. Materials and Methods: The clinicopathologic features of renal NETs diagnosed at a single institution were reviewed along with all reported cases in the worldwide literature. Results: Eighty renal NETs have been described, including nine from our institution. Differentiation between renal NETs and the more common renal neoplasms (renal cell carcinoma, transitional cell carcinoma) can be difficult since clinical, radiographic, and histopathologic features overlap. Immunohistochemical staining for neuroendocrine markers, such as synaptophysin and chromogranin, can be particularly helpful in this regard. Renal carcinoids are typically slow-growing, may secrete hormones, and pursue a variable clinical course. In contrast, SCC and LCNEC often present with locally advanced or metastatic disease and carry a poor prognosis. Nephrectomy can be curative for clinically localized NETs, but multimodality treatment is indicated for advanced disease. Conclusions: A spectrum of NETs can rarely occur in the kidney. Renal carcinoids have a variable clinical course; SCC and LCNEC are associated with poor clinical outcomes. Diagnosis of NETs, especially LCNEC, requires awareness of their rare occurrence and prudent use of immunohistochemical neuroendocrine markers.
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Affiliation(s)
- Brian R Lane
- Glickman Urological and Kidney Institute, Cleveland Clinic, Cleveland, Ohio, USA
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Rowland KJ, Brubaker PL. The "cryptic" mechanism of action of glucagon-like peptide-2. Am J Physiol Gastrointest Liver Physiol 2011; 301:G1-8. [PMID: 21527727 DOI: 10.1152/ajpgi.00039.2011] [Citation(s) in RCA: 104] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Glucagon-like peptide-2 (GLP-2) is a peptide hormone with multiple beneficial effects on the intestine, including expansion of the mucosal surface area through stimulation of crypt cell proliferation, as well as enhancement of nutrient digestion and absorption. Recent advances in clinical trials involving GLP-2 necessitate elucidation of the exact signaling pathways by which GLP-2 acts. In particular, the GLP-2 receptor has been localized to several intestinal cell types that do not include the proliferating crypt cells, and the actions of GLP-2 have thus been linked to a complex network of indirect mediators that induce diverse signaling pathways. The intestinotropic actions of GLP-2 on the colon have been shown to be mediated through the actions of keratinocyte growth factor and insulin-like growth factor (IGF)-2, whereas small intestinal growth has been linked to IGF-1, IGF-2, and ErbB ligands, as well as the IGF-1 receptor and ErbB. The cellular source of these mediators remains unclear, but it likely includes the intestinal subepithelial myofibroblasts. Conversely, the anti-inflammatory and blood flow effects of GLP-2 are dependent on vasoactive intestinal polypeptide released from submucosal enteric neurons and nitric oxide, respectively. Finally, recent studies have suggested that GLP-2 not only modulates intestinal stem cell behavior but may also promote carcinogenesis in models of sporadic colon cancer. Further consideration of the molecular cross-talk and downstream signaling pathways mediating the intestinotropic effects of GLP-2 is clearly warranted.
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28
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Schimmack S, Svejda B, Lawrence B, Kidd M, Modlin IM. The diversity and commonalities of gastroenteropancreatic neuroendocrine tumors. Langenbecks Arch Surg 2011; 396:273-98. [DOI: 10.1007/s00423-011-0739-1] [Citation(s) in RCA: 112] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2011] [Accepted: 01/07/2011] [Indexed: 02/07/2023]
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Vanderlan WB, Zhang Z, Abouljoud MS. Duodenal enteroglucagonoma revealed by differential comparison of serum and tissue glucagon reactivity with Siemens' Double Glucagon Antibody and DakoCytomation's Polyclonal Rabbit Anti-Human Glucagon: a case report. J Med Case Rep 2010; 4:178. [PMID: 20550685 PMCID: PMC2896376 DOI: 10.1186/1752-1947-4-178] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2007] [Accepted: 06/15/2010] [Indexed: 11/22/2022] Open
Abstract
Introduction This case report demonstrates that the differential immunohistochemical reactivities of Siemens' Double Antibody Glucagon compared to DakoCytomation's Polyclonal Rabbit Anti-Human Glucagon allow for pathologic distinction of enteral versus pancreatic glucagonoma. Case presentation A 64-year-old Caucasian man was diagnosed with a duodenal enteroglucagonoma following presentation with obstructive jaundice. He had a low serum glucagon level using Siemens' Double Antibody Glucagon, a clinical syndrome consistent with glucagon hypersecretion. A periampullary mass biopsy proved to be a neuroendocrine tumor, with positive immunohistochemical reactivity to DakoCytomation's Polyclonal Rabbit Anti-Human Glucagon. Conclusions Differential comparison of the immunohistochemical reactivities of Siemens' Double Antibody Glucagon and DakoCytomation's Polyclonal Rabbit Anti-Human Glucagon discerns enteroglucagon from pancreatic glucagon.
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Affiliation(s)
- Wesley B Vanderlan
- Department of Surgery, Division of Transplant Surgery and Hepatobiliary Surgery, Henry Ford Hospital, West Grand Boulevard (CFP-2), Detroit, MI 48202, USA.
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Short bowel patients treated for two years with glucagon-like Peptide 2: effects on intestinal morphology and absorption, renal function, bone and body composition, and muscle function. Gastroenterol Res Pract 2009; 2009:616054. [PMID: 19707516 PMCID: PMC2729387 DOI: 10.1155/2009/616054] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/24/2009] [Revised: 06/22/2009] [Accepted: 06/25/2009] [Indexed: 11/17/2022] Open
Abstract
BACKGROUND AND AIMS In a short-term study, Glucagon-like peptide 2 (GLP-2) has been shown to improve intestinal absorption in short bowel syndrome (SBS) patients. This study describes longitudinal changes in relation to GLP-2 treatment for two years. METHODS GLP-2, 400 micrograms, s.c.,TID, were offered, to eleven SBS patients keeping parenteral support constant. 72-hour nutritional balance studies were performed at baseline, weeks 13, 26, 52 during two years intermitted by an 8-week washout period. In addition, mucosal morphometrics, renal function (by creatinine clearance), body composition and bone mineral density (by DEXA), biochemical markers of bone turnover (by s-CTX and osteocalcin, PTH and vitamin D), and muscle function (NMR, lungfunction, exercise test) were measured. RESULTS GLP-2 compliance was >93%. Three of eleven patients did not complete the study. In the remaining 8 patients, GLP-2 significantly reduced the fecal wet weight from approximately 3.0 to approximately 2.0 kg/day. This was accompanied by a decline in the oral wet weight intake, maintaining intestinal wet weight absorption and urinary weight constant. Renal function improved. No significant changes were demonstrated in energy intake or absorption, and GLP-2 did not significantly affect mucosal morphology, body composition, bone mineral density or muscle function. CONCLUSIONS GLP-2 treatment reduces fecal weight by approximately 1000 g/d and enables SBS patients to maintain their intestinal fluid and electrolyte absorption at lower oral intakes. This was accompanied by a 28% improvement in creatinine clearance.
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Skagen DW, Schjønsby H. Intestinal adaptation. ACTA MEDICA SCANDINAVICA. SUPPLEMENTUM 2009; 603:29-33. [PMID: 266833 DOI: 10.1111/j.0954-6820.1977.tb19356.x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
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Obi N, Katabami T, Obi R, Odanaka M, Sasano K, Tanaka Y. Primary malignant hepatic glucagonoma: an autopsy case. Endocr J 2009; 56:715-9. [PMID: 19367016 DOI: 10.1507/endocrj.k09e-058] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
A 73-year-old woman was admitted to our department for treatment of diabetes (plasma glucose 289 mg/dl, HbA(1C) 7.1%, and glycated albumin 34.9%). She displayed the signs and symptoms of glucagonoma syndrome, including necrolytic migratory erythema (NME), low aminoacidemia, and a marked increase of the serum glucagon level (4,940 pg/ ml). Thus, we suspected a glucagonoma causing secondary diabetes. However, we could not detect any mass in the pancreas or the gastrointestinal tract, and only found a liver lesion resembling a hemangioma. Her NME improved markedly after intravenous infusion of amino acids, and her plasma glucose was controlled reasonably well by intensive insulin therapy. However, her general condition deteriorated and she died on day 57 after hospitalization. At autopsy, the only tumor detected was the liver mass. This was a large solid tumor (8 x 6 x 5 cm) with a pattern of white and dark brown stripes located in the left lobe, while two white nodules were also found in the right lobe. Based on the histopathological and immunohistochemical findings, the liver lesion was shown to be a malignant glucagonoma with intrahepatic metastases. Since primary malignant hepatic glucagonoma has not been reported before, we present this extremely rare case of primary malignant glucagonoma of the liver.
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Affiliation(s)
- Naoko Obi
- Division of Metabolism and Endocrinology, St. Marianna University School of Medicine, Kanagawa, Japan
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Rowland KJ, Brubaker PL. Life in the crypt: a role for glucagon-like peptide-2? Mol Cell Endocrinol 2008; 288:63-70. [PMID: 18403107 DOI: 10.1016/j.mce.2008.02.014] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/03/2007] [Revised: 01/31/2008] [Accepted: 02/25/2008] [Indexed: 12/27/2022]
Abstract
The epithelial layer of the intestinal tract serves as a model to study the mechanisms regulating tissue renewal. Central to this process is the intestinal stem cell and, thus, both the intrinsic and extrinsic factors that modulate the function of these cells must be understood. Amongst the intrinsic regulators, both the canonical wnt and bone morphogenic protein (bmp) signaling pathways have been shown to be essential determinants of stem cell dynamics and intestinal homeostasis. The intestinotrophic hormone, glucagon-like peptide-2 (GLP-2), has also recently been demonstrated to exert a variety of effects on the intestinal crypt cells, including enhancement of the putative stem cell marker, musashi-1, as well as stimulating intestinal proliferation. As the GLP-2 receptor is not expressed by the crypt cells, these actions have been hypothesized to be mediated indirectly, through other gut peptides and/or growth factors. Of these, recent studies have demonstrated a requirement for insulin-like growth factor-1 in the proliferative effects of GLP-2, through a pathway that involves activation of the canonical wnt signaling pathway. This extrinsic pathway represents a novel mechanism by which intestinal stem cell dynamics may be regulated.
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Chiba M, Sanada Y, Kawano S, Murofushi M, Okada I, Yoshizawa Y, Gomi A, Yatsuzuka M, Toki A, Hirai Y. Glicentin inhibits internalization of enteric bacteria by cultured INT-407 enterocytes. Pediatr Surg Int 2007; 23:551-4. [PMID: 17333210 DOI: 10.1007/s00383-007-1895-9] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 02/05/2007] [Indexed: 12/01/2022]
Abstract
Glicentin, the main component of enteroglucagon, has trophic effects on intestinal mucosa. It may also have an inhibitory effect on extraintestinal invasion of enteric bacteria. We have established an in vitro bioassay system for determining the effects of recombinant human glicentin on bacterial internalization by confluent enterocytes. An INT-407 cell line was serum-deprived for 2 days and was then treated on transwell filters for 24 h with a medium containing one of the following: glicentin 100 ng-1 microg/ml, glucagons-like peptide-2 (GLP-2) 1 microg/ml, 10% fetal bovine serum (FCS), or without any growth factors. Pure cultures of Salmonella enteritidis, Escherichia coli, and Enterococcus faecalis were introduced to the upper chambers of the filter units. Following 2 h of incubation the numbers of bacteria in the lower chambers were measured. Pretreatment of enterocytes with glicentin inhibited bacterial internalization compared to untreated or GLP-2 enterocytes. Glicentin was associated with inhibition of enterocyte internalization of enteric bacteria by a mechanism that might be related to the integrity of the enterocyte adhesive junctions and tight junctions and to the production of sIgA. Glicentin seems to have a function as a barrier-sustaining agent that inhibits extraintestinal invasion of enteric bacteria.
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Affiliation(s)
- Masahiro Chiba
- Pediatric Surgery Services, Showa University School of Medicine, Fujigaoka Hospital, 1-30 Fujigaoka, Aoba-ku, Yokohama, 227-8501, Japan.
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Abstract
Malabsorption is a key finding in patients with short-bowel syndrome. Malabsorption of nonessential and essential nutrients, fluids, and electrolytes, if not compensated for by increased intake, leads to diminished body stores and subclinical and (eventually) clinical deficiencies. After intestinal resection, adaptation (a spontaneous progressive recovery from the malabsorptive disorder) may be evident. This article describes selected factors responsible for the morphologic and functional changes in the adaptive processes and presents results of clinical trials that use either growth hormone or glucagon-like peptide-2 to facilitate a condition of hyperadaptation in short-bowel patients.
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Affiliation(s)
- Palle Bekker Jeppesen
- Department of Medical Gastroenterology, CA-2121, Rigshospitalet, Blegdamsvej 9, DK-2100 Copenhagen, Denmark.
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Bhalla R, Popp A, Nassar A. Case report: Metastatic renal carcinoid to the thyroid diagnosed by fine needle aspiration biopsy. Diagn Cytopathol 2007; 35:597-600. [PMID: 17703444 DOI: 10.1002/dc.20706] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
We report a case of primary renal carcinoid arising in a horseshoe kidney. To the best of our knowledge this is the first case to be reported in the cytology literature, which has been diagnosed by fine needle aspiration (FNA). A 32-year-old male, presented to the Emory University Hospital, with a renal mass arising in a horseshoe kidney; along with a thyroid mass. FNA of the renal mass resulted in an initial diagnosis of renal cell carcinoma, unclassified. A thyroid aspiration was attempted later, and revealed a neuroendocrine morphology. This was compared with the renal aspiration and both of them were found to have similar morphology. With the help of immunostains, a diagnosis of renal carcinoid tumor metastatic to the thyroid was made. Thus, we demonstrate that renal carcinoid, being a rare entity, can pose a diagnostic challenge.
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Affiliation(s)
- Ritu Bhalla
- Department of Pathology and Laboratory Medicine, Emory University Hospital, School of Medicine, Atlanta, Georgia 30322, USA
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Romero FR, Rais-Bahrami S, Permpongkosol S, Fine SW, Kohanim S, Jarrett TW. Primary Carcinoid Tumors of the Kidney. J Urol 2006; 176:2359-66. [PMID: 17085102 DOI: 10.1016/j.juro.2006.07.129] [Citation(s) in RCA: 89] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2005] [Indexed: 11/29/2022]
Abstract
PURPOSE We describe in detail the features of carcinoid tumors of the kidney. We evaluated possible prognostic factors. MATERIALS AND METHODS An extensive search was performed in the medical literature regarding primary carcinoid tumors of the kidney. Epidemiological, clinical, diagnostic, histopathological, therapeutic and prognostic data were evaluated. Several potential risk factors were compared with the incidence of metastases and clinical outcome of the patients. RESULTS A total of 56 case reports were reviewed. Median patient age was 49 years. Horseshoe kidneys were present in 17.8% of cases. Incidental diagnosis was made in 28.6% of patients. The most common symptom was abdominal or flank pain and neuroendocrine syndromes occurred with only 12.7% of primary renal carcinoid tumors. Of the patients 73.6% presented with tumors larger than 4 cm. Metastases were present in 45.6% of patients at initial diagnosis and almost 60% with tumors greater than 4 cm had metastases. CONCLUSIONS Renal carcinoid is the second most prevalent genitourinary carcinoid in each sex, following testicular carcinoids in men and ovarian tumors in women. Significant adverse prognostic factors include age greater than 40 years, tumor size greater than 4 cm, purely solid tumors on the cut surface, mitotic rate higher than 1/10 high power fields, metastasis at initial diagnosis and tumors extending throughout the renal capsule.
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Affiliation(s)
- Frederico R Romero
- James Buchanan Brady Urological Institute, The Johns Hopkins Medical Institutions, 600 North Wolfe Street, Baltimore, MD 21287, USA.
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Murali R, Kneale K, Lalak N, Delprado W. Carcinoid tumors of the urinary tract and prostate. Arch Pathol Lab Med 2006; 130:1693-706. [PMID: 17076534 DOI: 10.5858/2006-130-1693-ctotut] [Citation(s) in RCA: 52] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/04/2006] [Indexed: 11/06/2022]
Abstract
CONTEXT Carcinoid tumors are exceedingly rare in the genitourinary tract and may occur in the kidney, urinary bladder, urethra, or prostate. OBJECTIVE To review the clinical and pathologic features of carcinoid tumors occurring in the urinary tract and prostate. DATA SOURCES We searched the English language literature using MEDLINE and Ovid. CONCLUSIONS Carcinoid tumors of the urinary tract and prostate share similar morphologic features with their counterparts in other organs. The differential diagnosis includes metastatic carcinoid tumor, paraganglioma, and nested variants of urothelial and prostatic carcinomas. Correlation of the clinical presentation and histopathologic features (including the immunohistochemical profile) will ensure accurate diagnosis of these rare tumors.
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Affiliation(s)
- Rajmohan Murali
- Department of Tissue Pathology, Institute of Clinical Pathology & Medical Research, Westmead Hospital, Sydney, Australia.
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Martin GR, Beck PL, Sigalet DL. Gut hormones, and short bowel syndrome: The enigmatic role of glucagon-like peptide-2 in the regulation of intestinal adaptation. World J Gastroenterol 2006; 12:4117-29. [PMID: 16830359 PMCID: PMC4087358 DOI: 10.3748/wjg.v12.i26.4117] [Citation(s) in RCA: 56] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Short bowel syndrome (SBS) refers to the malabsorption of nutrients, water, and essential vitamins as a result of disease or surgical removal of parts of the small intestine. The most common reasons for removing part of the small intestine are due to surgical intervention for the treatment of either Crohn's disease or necrotizing enterocolitis. Intestinal adaptation following resection may take weeks to months to be achieved, thus nutritional support requires a variety of therapeutic measures, which include parenteral nutrition. Improper nutrition management can leave the SBS patient malnourished and/or dehydrated, which can be life threatening. The development of therapeutic strategies that reduce both the complications and medical costs associated with SBS/long-term parenteral nutrition while enhancing the intestinal adaptive response would be valuable.
Currently, therapeutic options available for the treatment of SBS are limited. There are many potential stimulators of intestinal adaptation including peptide hormones, growth factors, and neuronally-derived components. Glucagon-like peptide-2 (GLP-2) is one potential treatment for gastrointestinal disorders associated with insufficient mucosal function. A significant body of evidence demonstrates that GLP-2 is a trophic hormone that plays an important role in controlling intestinal adaptation. Recent data from clinical trials demonstrate that GLP-2 is safe, well-tolerated, and promotes intestinal growth in SBS patients. However, the mechanism of action and the localization of the glucagon-like peptide-2 receptor (GLP-2R) remains an enigma. This review summarizes the role of a number of mucosal-derived factors that might be involved with intestinal adaptation processes; however, this discussion primarily examines the physiology, mechanism of action, and utility of GLP-2 in the regulation of intestinal mucosal growth.
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Affiliation(s)
- G-R Martin
- Department of Gastrointestinal Sciences, Faculty of Medicine, University of Calgary, 3330 Hospital Drive NW., Calgary, Alberta T2N 4N1, Canada.
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Timmapuri SJ, Otterburn DM, Arafat H, Schwartz MZ. Hepatocyte growth factor increases glucagon immunoreactivity in jejunal cells during intestinal adaptation. J Pediatr Surg 2006; 41:150-4; discussion 150-4. [PMID: 16410125 DOI: 10.1016/j.jpedsurg.2005.10.077] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
BACKGROUND The administration of hepatocyte growth factor (HGF) during intestinal adaptation is known to enhance intestinal adaptation. Glucagon has also been implicated as a potential mediator of intestinal adaptation. Previous studies have shown that HGF and glucagon synergistically increase the proliferation of hepatocytes. HGF has also been shown to be preferentially expressed within the glucagon-positive cells of the pancreas, possibly indicating a paracrine or endocrine effect of HGF on glucagon. This study was designed to determine if HGF stimulation in the small intestine during intestinal adaptation influenced mucosal glucagon expression. METHODS Adult male Sprague-Dawley rats were randomized to either a 70% massive small bowel resection group (MSBR) or an HGF-treated MSBR group (MSBR-HGF). Seven days after surgery, HGF was administered intravenously at 150 mug/kg per day for 14 days. At day 21, the ileal and jejunal mucosa was harvested. The RAE 230A GeneChip (Affymetrix, Santa Clara, Calif) and MAS5 software were used to determine alterations in gene expression in the small intestine mucosa. Immunofluorescent staining of the ileal and jejunal mucosa using an antiglucagon antibody was performed and evaluated qualitatively. RESULTS The MSBR-HGF group had significantly greater protein and DNA content (P < .05) than the MSBR group. Glucagon gene expression in the MSBR-HGF group was decreased compared with the MSBR group, and immunohistostaining for glucagon in the ileum revealed no difference in intensity between the 2 groups. However, the jejunal MSBR-HGF group demonstrated significantly greater glucagon immunoreactivity than the jejunal MSBR group. CONCLUSION Our data suggest that the HGF-induced increase in glucagon availability is disassociated from glucagon gene up-regulation. Thus, HGF may not only enhance intestinal adaptation directly, but also indirectly by increasing the "local" availability of other growth factors in the absence of their gene up-regulation.
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Affiliation(s)
- Shaheen J Timmapuri
- Department of Surgery, Thomas Jefferson University, Philadelphia, PA 19134, USA
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Abstract
Short bowel syndrome occurs when there is insufficient length of the small intestine to maintain adequate nutrition and/or hydration status without supplemental support. This syndrome most frequently occurs following extensive surgical resection of the intestine, and the extent of adaptation depends on the anatomy of the resected bowel and the amount of bowel remaining. Following resection, the intestinal tissue undergoes morphologic and functional changes to compensate for the lost function of the resected bowel. These changes are mediated by multiple interactive factors, including intraluminal and parenteral nutrients, gastrointestinal secretions, hormones, cytokines, and growth factors, many of which have been well characterized in animal models. The amount of small bowel remaining is the most important predictor of adaptive potential; neither structural nor functional adaptative changes have been demonstrated in humans or animal models with more extreme resections resulting in an end-jejunostomy. The current understanding of these processes has led to the recent use of supplemental hormones, such as growth hormone and glucagon-like peptide 2, in intestinal rehabilitation programs and may lead to the development of pharmacologic agents designed to augment the innate adaptive response.
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Affiliation(s)
- Jason J Cisler
- Division of Gastroenterology, Feinburg School of Medicine, Northwestern University, Chicago, IL, USA
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Booth C, Booth D, Williamson S, Demchyshyn LL, Potten CS. Teduglutide ([Gly2]GLP-2) protects small intestinal stem cells from radiation damage. Cell Prolif 2005; 37:385-400. [PMID: 15548172 PMCID: PMC6495530 DOI: 10.1111/j.1365-2184.2004.00320.x] [Citation(s) in RCA: 73] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Glucagon-like peptide-2 and its dipeptidyl peptidase (DP-IV) resistant analogue teduglutide are trophic for the gastrointestinal epithelium. Exposure increases villus height and crypt size and results in increased overall intestinal weight. As these effects may be mediated through stimulation of the stem cell compartment, they may promote intestinal healing and act as potential anti-mucositis agents in patients undergoing cancer chemotherapy. A study was initiated to investigate the protective effects of teduglutide on the murine small intestinal epithelium following gamma-irradiation using the crypt microcolony assay as a measure of stem cell survival and functional competence. Teduglutide demonstrated intestinotrophic effects in both CD1 and BDF1 mouse strains. In BDF1 mice, subcutaneous injection of GLP-2 or teduglutide (0.2 mg/kg/day, b.i.d.) for 14 days increased intestinal weight by 28% and resulted in comparable increases in crypt size, villus height and area. Teduglutide given daily for 6 or 14 days prior to whole body, gamma-irradiation significantly increased crypt stem cell survival when compared with vehicle-treated controls. The mean levels of protection over a range of doses provided protection factors from 1.3 to 1.5. A protective effect was only observed when teduglutide was given before irradiation. These results suggest that teduglutide has the ability to modulate clonogenic stem cell survival in the small intestine and this may have a useful clinical application in the prevention of cancer therapy-induced mucositis.
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Affiliation(s)
- C Booth
- Paterson Institute for Cancer Research, Christie Hospital NHS Trust, Manchester, UK
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Cuperus R, Schäppi MG, Shah N, Lindley KJ, Milla PJ, Smith VV. Hypertrophic eosinophilic gastroenteropathy is associated with reduced enterocyte apoptosis. Histopathology 2005; 46:73-80. [PMID: 15656889 DOI: 10.1111/j.1365-2559.2005.02050.x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
AIMS To investigate the cause of grossly elongated villi in four children presenting with obstruction due to a novel form of eosinophilic gastroenteropathy in which there was profound hyperplasia of the intestinal villi with grossly increased villous/crypt ratio and prominent mucosal eosinophilia. Increased eosinophils were also present in the muscularis propria and submucosa. All had intermittent diarrhoea and signs of a protein-losing enteropathy. METHODS AND RESULTS The cause of the grossly elongated villi was investigated by studying enterocyte proliferation (Ki67), survival factors (bcl-2) and apoptosis (TUNEL) in these patients (n = 4) and normal (jejunum n = 6, ileum n = 6) and disease (n = 6) controls. The most remarkable finding was that apoptotic enterocytes were undetectable in the elongated villi. CONCLUSIONS It seems likely that a defect in the regulation of apoptosis of the epithelium occurs which could explain the remarkable hyperplasia of the villi seen.
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Affiliation(s)
- R Cuperus
- Gastroenterology, Great Ormond Street Hospital for Children NHS Trust, London, UK
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Baggio LL, Drucker DJ. Clinical endocrinology and metabolism. Glucagon-like peptide-1 and glucagon-like peptide-2. Best Pract Res Clin Endocrinol Metab 2004; 18:531-54. [PMID: 15533774 DOI: 10.1016/j.beem.2004.08.001] [Citation(s) in RCA: 48] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
The glucagon-like peptides (glucagon-like peptide-1 (GLP-1) and glucagon-like peptide-2 (GLP-2)) are released from enteroendocrine cells in response to nutrient ingestion. GLP-1 enhances glucose-stimulated insulin secretion and inhibits glucagon secretion, gastric emptying and feeding. GLP-1 also has proliferative, neogenic and antiapoptotic effects on pancreatic beta-cells. More recent studies illustrate a potential protective role for GLP-1 in the cardiovascular and central nervous systems. GLP-2 is an intestinal trophic peptide that stimulates cell proliferation and inhibits apoptosis in the intestinal crypt compartment. GLP-2 also regulates intestinal glucose transport, food intake and gastric acid secretion and emptying, and improves intestinal barrier function. Thus, GLP-1 and GLP-2 exhibit a diverse array of metabolic, proliferative and cytoprotective actions with important clinical implications for the treatment of diabetes and gastrointestinal disease, respectively. This review will highlight our current understanding of the biology of GLP-1 and GLP-2, with an emphasis on both well-characterized and more novel therapeutic applications of these peptides.
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Affiliation(s)
- Laurie L Baggio
- Department of Medicine, The Banting and Best Diabetes Centre, University of Toronto, Toronto General Hospital, 200 Elizabeth Street, MBRW 4R-402, Toronto, Ontario, Canada M5G 2C4
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Abstract
The management of patients with intestinal failure due to short bowel syndrome (SBS) is complex, requiring a comprehensive approach that frequently necessitates long-term, if not life-long, use of parenteral nutrition (PN). Despite tremendous advances in the provision of PN over the past three decades, which have allowed significant improvements in the survival and quality of life of these patients, this mode of nutritional support carries with it significant risks to the patient, is very costly and, ultimately, does not attempt to improve the function of the remaining bowel. Intestinal rehabilitation refers to the process of restoring enteral autonomy and, thus, allowing freedom from parenteral nutrition, usually by means of dietary, medical, and, occasionally, surgical strategies. While recent investigations have focused on the use of trophic substances to increase the absorptive function of the remaining gut, whether intestinal rehabilitation occurs as a consequence of enhanced bowel adaptation or is simply a result of an optimized, comprehensive approach to the care of these patients remains unclear. In Part 1 of this review, an overview of SBS and pathophysiological considerations related to the remaining bowel anatomy in these patients will be provided. Additionally, a review of intestinal adaptation and factors that may enhance the adaptive process, focusing on evidence derived from animal studies, will also be discussed. In Part 2, relevant data on the development of intestinal adaptation in studies involving humans will be reviewed as will the general management of SBS. Lastly, the potential benefits of a multidisciplinary intestinal rehabilitation program in the care of these patients will also be discussed.
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Affiliation(s)
- John K DiBaise
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska 68198-2000, USA
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Kim J, Suh K. Primary carcinoid tumor in a mature teratoma of the kidney: ultrasonographic and computed tomographic findings. JOURNAL OF ULTRASOUND IN MEDICINE : OFFICIAL JOURNAL OF THE AMERICAN INSTITUTE OF ULTRASOUND IN MEDICINE 2004; 23:433-437. [PMID: 15055793 DOI: 10.7863/jum.2004.23.3.433] [Citation(s) in RCA: 19] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/24/2023]
Affiliation(s)
- Jongchul Kim
- Department of Diagnostic Radiology, College of Medicine, Chungnam National University, Daejeon, South Korea.
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van't Land B, van Beek NMA, van den Berg JJM, M'Rabet L. Lactoferrin reduces methotrexate-induced small intestinal damage, possibly through inhibition of GLP-2-mediated epithelial cell proliferation. Dig Dis Sci 2004; 49:425-33. [PMID: 15139492 DOI: 10.1023/b:ddas.0000020497.35250.93] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
A strategy protecting the small intestine against deleterious side effects associated with anti-cancer therapy is arresting epithelial cell cycling temporally. Since endogenous glucagon-like peptide-2 (GLP-2) is a trophic factor specific for intestinal epithelia, the possibility of inhibiting GLP-2-mediated cell proliferation by lactoferrin, thereby protecting the small intestine against deleterious side effects of anticancer therapy, was investigated. In Caco-2 cells, GLP-2-mediated proliferation was reduced in a dose-dependent manner using lactoferrin. Furthermore, in a rat model for methotrexate-induced mucositis, lactoferrin reduced BrdU incorporation in small intestinal epithelial cells, indicating inhibition of epithelial cell proliferation in vivo. Subsequently, protection against methotrexate-induced intestinal damage was found in corresponding regions. These results show, for the first time, that lactoferrin interferes with GLP-2-induced intestinal epithelial proliferation. It may therefore be hypothesized that lactoferrin protects the intestine against anticancer therapy-induced intestinal damage, via inhibition of GLP-2-induced small intestinal epithelial cell proliferation.
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Affiliation(s)
- Belinda van't Land
- Department of Condition and Disease Specific Research, Numico-Research, PO Box 7005, 6700 CA Wageningen, Wageningen, The Netherlands
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