glucagon-like-peptide-2 and Inflammatory-Bowel-Diseases

Glucagon-like peptide-2 (GLP-2) is a pleiotropic intestinotrophic hormone that enhances digestive and absorptive capacity by acting through a limited population of intestinal GLP-2 receptors. The development of protease-resistant analogs or GLP-2/IgG fusion proteins confers a longer circulating half life than the native peptide. GLP-2 has garnered interest as a therapeutic most notably by reducing reliance on total parenteral nutrition in patients with short bowel syndrome.. The clinical evidence for benefit in conditions requiring longer term treatment with GLP-2 receptor agonists, for example short bowel syndrome and inflammatory bowel disease. Benefits of short-term GLP-2 treatment are emerging in pre-clinical models, such as post-operative ileus, GI mucositis and conditions of altered intestinal permeability. The therapeutic utility of GLP-2 receptor agonists is limited by concern that it predisposes patients to gastrointestinal cancers, or their re-occurrence in cancer patients. This affects the types of diseases treated and, possibly, the duration of dosing.. GLP-2 is therapeutically attractive in diseases to enhance absorptive capacity, restore mucosal health and reduce inflammation. Long-term surveillance studies with a marketed therapeutic agent are needed to weigh the benefits of GLP-2 treatment against the potential effects on co-morbidities and increased risk of intestinal carcinogenesis.

Topics: Animals; Gastrointestinal Diseases; Glucagon-Like Peptide 2; Glucagon-Like Peptide-2 Receptor; Humans; Ileus; Inflammatory Bowel Diseases; Mucositis; Receptors, Glucagon; Short Bowel Syndrome

Inflammatory bowel disease (IBD) is a chronic, debilitating disease associated with severe damage to the intestinal mucosa. Glucagon-like peptide-2 (GLP-2) is a potent and specific gastrointestinal growth factor that is demonstrating therapeutic potential for the prevention or treatment of an expanding number of intestinal diseases, including short bowel syndrome (SBS), small bowel enteritis and IBD. The biological activity of GLP-2 is limited due to proteolytic inactivation by the protease dipeptidyl peptidase (DP)IV. Inhibitors of DPIV activity may represent a novel strategy to prolong the growth promoting actions of GLP-2. This review outlines evidence for the clinical application of GLP-2, its degradation resistant analogue, Teduglutide, and novel DPIV inhibitors in efficacy studies utilizing pre-clinical models of intestinal damage, in particular IBD.

Topics: Animals; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide 2; Humans; Inflammatory Bowel Diseases; Intestinal Diseases; Neoplasms; Peptides; Short Bowel Syndrome

Topics: Animals; Colitis; Dextran Sulfate; Dipeptidyl Peptidase 4; Disease Models, Animal; Glucagon-Like Peptide 2; Glucagon-Like Peptides; Humans; Indicators and Reagents; Inflammatory Bowel Diseases; Intestinal Mucosa; Intestines; Isoleucine; Mice; Mice, Knockout; Peptide Fragments; Serine Proteinase Inhibitors

Glucagon-like peptide-2 (GLP-2) is a 33 amino acid peptide hormone released from the intestinal endocrine cells following nutrient ingestion. GLP-2 exerts trophic effects on the small and large bowel epithelium via stimulation of cell proliferation and inhibition of apoptosis. GLP-2 also upregulates intestinal glucose transporter activity, and reduces gastric emptying and gastric acid secretion. The activity of GLP-2 is regulated in part via renal clearance and cleavage by the aminopeptidase dipeptidyl peptidase IV. In experimental models of intestinal disease, GLP-2 reversed parenteral nutrition-induced mucosal atrophy and accelerated the process of endogenous intestinal adaptation in rats following major small bowel resection. GLP-2 also markedly attenuated intestinal injury and weight loss in mice with chemically-induced colitis, and significantly reduced mortality, bacterial infection and intestinal mucosal damage in mice with indomethacin-induced enteritis. The actions of GLP-2 are transduced by a recently cloned glucagon-like peptide-2 receptor (GLP-2R) that represents a new member of the G protein-coupled receptor superfamily. The GLP-2R is expressed in a highly tissue-specific manner predominantly in the gastrointestinal tract and GLP-2R activation is coupled to increased adenylate cyclase activity. The available evidence suggests that the biological properties of GLP-2 merit careful therapeutic assessment in selected human diseases characterized by injury and defective repair of the gastrointestinal epithelium.

Topics: Animals; Forecasting; Glucagon-Like Peptide 2; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Humans; Inflammatory Bowel Diseases; Intestines; Mice; Peptides; Rats; Receptors, Glucagon

Glucagon-like peptide-2 (GLP-2) enhances intestinal repair and attenuates inflammation in preclinical inflammatory bowel disease (IBD) models, making GLP-2 analogues attractive candidates for IBD therapy. Glepaglutide is a long-acting GLP-2 receptor agonist in clinical development for treatment of short bowel syndrome. Here, we investigated if glepaglutide is therapeutically beneficial in rats with small intestinal inflammation.. Small intestinal inflammation was induced with indomethacin in naive Wistar rats, followed by glepaglutide administration at different disease stages. Glepaglutide was administered in co-treatment and post-treatment regimens. Small intestinal length and concentrations of inflammatory markers α-1-acid glycoprotein and myeloperoxidase were used to assess anti-inflammatory effects. Small intestinal mass was evaluated to determine intestinotrophic effects.. Glepaglutide co- and post-treatment significantly reduced severity of small intestinal inflammation, evidenced by reversed small intestinal shortening and decreased α-1-acid glycoprotein and/or myeloperoxidase concentration(s). Co- and post-treatment with glepaglutide also significantly increased small intestinal mass, indicating intestinal regenerative effects. Similar effects were observed in naive rats after glepaglutide treatment.. Glepaglutide has anti-inflammatory and intestinotrophic effects without the need for pre-treatment in a rat model of small intestinal inflammation. Thus, glepaglutide is of potential clinical interest for patients with IBD.

Topics: Animals; Anti-Inflammatory Agents; Glucagon-Like Peptide 2; Glycoproteins; Inflammation; Inflammatory Bowel Diseases; Intestinal Mucosa; Models, Theoretical; Peroxidase; Rats; Rats, Wistar

Inflammatory bowel disease (IBD) is a chronic, recurrent, and remitting inflammatory disease resulting from immune dysregulation in the gut. As a clinically frequent disease, it can affect individuals throughout their lives, with multiple complications. Glucagon-like peptide 2 (GLP-2) is a potent epithelium-specific intestinal growth factor. However, native GLP-2 has a relatively short half-life in human circulation because of extensive renal clearance and rapid degradation by the proteolytic enzyme dipeptidyl peptidase-IV (DPP-IV). Previously, We prepared a recombinant GLP-2 variant (GLP-2②), which has increased half-life and activity as compared to the [Gly

Topics: Animals; Anti-Inflammatory Agents; Glucagon-Like Peptide 2; Inflammatory Bowel Diseases; Male; Mice; Mice, Inbred BALB C; Protein Multimerization

Glucagon-like peptide-2 (GLP-2) and peptide YY (PYY) are produced in endocrine L-cells of the intestine and secreted in response to food intake. GLP-2 has a trophic effect on the intestinal epithelium, whereas PYY has pro-absorptive effects. It can be speculated that, in inflammatory bowel disease (IBD), the production and secretion of GLP-2 and PYY could be affected as a part of a regulatory mechanism. Therefore, tissue levels and meal-stimulated secretion of GLP-2 and PYY were studied in IBD patients and compared to controls.. Outpatients with IBD and control patients were included. Mucosal biopsies were taken from the ileum and colon and the content of GLP-2 and PYY was measured. After colonoscopy the patients took a mixed meal and plasma was collected for 90 min for plasma measurements of GLP-2 and PYY.. Tissue levels of GLP-2 in control patients were highest in the terminal ileum (407+/-82 pmol/g tissue, n=10), whereas PYY was highest in the rectum (919+/-249 pmol/g tissue, n=10). In IBD patients with acute inflammation, the content of GLP-2 was similar to controls, whereas PYY was decreased to 72.1+/-17.7% (P=0.03, n=13) of control values. Neither the fasting plasma levels nor the meal responses of GLP-2 and PYY differed between controls and IBD patients.. The similar responses of GLP-2 and PYY in patients and controls do not support the suggestion that L-cell secretion is altered in IBD. The decreased tissue PYY concentrations may contribute to the diarrhoea of some of these patients.

Topics: Colitis, Ulcerative; Colon; Crohn Disease; Glucagon-Like Peptide 2; Glucagon-Like Peptides; Humans; Ileum; Inflammatory Bowel Diseases; Intestinal Mucosa; Peptide YY; Peptides; Postprandial Period; Radioimmunoassay

Glucagon-like peptide 2 (GLP-2) is produced in endocrine L-cells of the intestinal mucosa. Recently, GLP-2 was found to stimulate intestinal mucosal growth. Our objective was to study the content of GLP-2 in the large intestine in a murine model of T-cell-induced inflammatory bowel disease.. Inflammation was induced by adoptive transfer of CD4+ blast T cells from BALB/c mice to SCID mice. The amount of GLP-2 (1-33) was measured with a specific, NH2-terminally directed radioimmunoassay in tissue extracts from the large intestine of transplanted mice developing colitis and from BALB/c and SCID control mice.. In the middle and descending colon segments showing the most severe signs of inflammatory lesions in the CD4+ T-cell-transplanted mice, the amount of GLP-2 was significantly lower than in similar colon segments in both untransplanted SCID mice and normal BALB/c mice (P = 0.0013 and 0.0033). In the descending colon the amount of GLP-2 was 6.7 +/- 1.0 pmol/g protein in the CD4+ transplanted mice compared with 68.4 +/- 20.3 and 42.7 +/- 4.3 in the two groups of control mice. Similar findings were made with regard to the contents of the two other proglucagon-derived intestinal peptides, glicentin and GLP-1.. The amount of GLP-2 is markedly reduced in the colon of mice with a T-cell-induced inflammatory bowel disease histopathologically resembling both Crohn disease and ulcerative colitis. This observation may provide a pathophysiologic rationale for administration of GLP-2 as a trophic factor in inflammatory bowel disease.

Topics: Animals; CD4-Positive T-Lymphocytes; Colon; Disease Models, Animal; Glucagon; Glucagon-Like Peptide 2; Glucagon-Like Peptides; Growth Substances; Inflammatory Bowel Diseases; Mice; Mice, SCID; Peptide Fragments

Microinjection of a Fisher (F344) rat zygote with human HLA-B27 and beta2-microglobulin genes induces spontaneous chronic gastrointestinal (GI) inflammation similar to lesions seen in patients with inflammatory bowel disease (IBD). This study was designed to evaluate the potential therapeutic benefit of GLP-2, an intestinal growth factor, in this transgenic rat model of IBD.. Five F344 (control) and 10 HLA-B27 (on a F344 background) rats at 25 weeks of age were used. Rats were divided into the following 3 groups: group 1, F344 rats, no treatment (n = 5); group 2, HLA-B27, no treatment (n = 5); and group 3, HLA-B27, treated with a 14-day systemic infusion (via the jugular vein) of GLP-2 at 50 microg/kg/d (n = 5). After infusion, all rats underwent laparotomy, and the intestine from the ligament of Treitz to the rectum was harvested. Total mucosal damage (percent surface area) was measured using image analysis software (Sigmascan 2.0). Microscopic analysis was performed by a blinded reviewer and scored as follows: 0, no inflammation; 1, mild inflammation; 2, moderate inflammation; and 3, severe inflammation. Colonic mucosal total RNA was assayed for tumor necrosis factor alpha (TNF-alpha), interferon-gamma (IFN-gamma), interleukin-2 (IL-2), and glyceraldehyde-3-phosphate dehydrogenase (GAPDH), internal standard, mRNA by reverse transcriptase polymerase chain reaction. Statistical analysis was performed using analysis of variance (ANOVA) and expressed as mean +/- SEM.. Normal F344 rats did not show evidence of gross or histological lesions in the small or large intestine. GLP-2 reduced total mucosal damage from 9.0% +/- 0.7% in group 2 to 0.9% +/- 0.5% in group 3 (P < .01). The histological lesion score was reduced from 7.0 +/- 0.6 in group 2 to 4.4 +/- 0.8 in group 3 (P < .01). Furthermore, GLP-2 reduced the mean band intensity (MBI) of TNF-alpha (0.4 +/- 0.04 in group 2 to 0 in group 3, P < .01) and IFN-gamma (0.3 +/- 0.02 in group 2 to 0 in group 3, P < .01).. These data show for the first time that GLP-2 significantly reduces gross (90% decrease) and histological (40% decrease) lesions in this rat model of IBD. This is further supported by a significant decrease in gene expression of the inflammatory mediators TNF-alpha (100% decrease) and IFN-gamma (100% decrease). These data suggest a potential therapeutic role for GLP-2 in IBD.

Topics: Animals; Animals, Genetically Modified; Female; Glucagon-Like Peptide 2; Glucagon-Like Peptides; Growth Substances; Inflammatory Bowel Diseases; Interferon-gamma; Interleukin-2; Intestinal Mucosa; Peptides; Rats; Rats, Inbred F344; Reverse Transcriptase Polymerase Chain Reaction; Tumor Necrosis Factor-alpha