oxyntomodulin and Colitis--Ulcerative

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

The intestinal hormone glucagon-like peptide-2 (GLP-2) enhances bowel growth and reduces the severity of colonic injury in dextran sulfate sodium (DSS)-induced colitis in mice. In humans, ulcerative colitis is normally treated with aminosalicylates (ASAs) and corticosteroids (CSs) to reduce inflammation. However, whether the intestinotropic effects of GLP-2 are altered when combined with ASAs and/or CSs has not previously been explored. Thus, each agent [vehicle, ASA (sulfasalazine), CS (methylprednisolone), and ASA + CS] was administered alone or with GLP-2 to normal mice or mice with 3.5% DSS in the drinking water, for 10 consecutive days. GLP-2 treatment of DSS-mice increased survival and small intestinal weight (p < 0.05), and decreased body weight loss and colonic damage (p < 0.05). Furthermore, GLP-2 increased the number of proliferating cells in the colonic crypts of DSS-mice (p < 0.05). Administration of ASA, CS, or ASA + CS alone did not affect growth of the intestine in DSS-mice. However, administration of GLP-2 in combination with ASA was permissive for the beneficial effects of GLP-2 on survival and colonic damage, whereas CS treatment prevented these effects of GLP-2. Concomitant administration of GLP-2 with ASA + CS resulted in intermediate effects. No differences between colonic myeloperoxidase activity or IkappaB levels (an inhibitor of the nuclear factor-kappaB pro-inflammatory pathway) were found for any of these therapeutic agents. When taken together, the ability of GLP-2 to protect colonic mucosal architecture in DSS-colitis, and its effectiveness when given in combination with ASA, but not with CS, suggests a novel approach for the treatment of patients with colitis.

Topics: Adrenal Cortex Hormones; Aminosalicylic Acids; Animals; Colitis, Ulcerative; Colon; Disease Models, Animal; Drug Therapy, Combination; Female; Glucagon-Like Peptide 2; Glucagon-Like Peptides; Humans; Intestine, Small; Mice; Peptide Fragments; Peptides

Glucagon-like peptide-2 (GLP-2) is a recently characterized intestine-derived peptide that exerts trophic activity in the small and large intestine. Whether circulating levels of GLP-2 are perturbed in the setting of human inflammatory bowel disease (IBD) remains unknown. The circulating levels of bioactive GLP-2-(1-33) compared with its degradation product GLP-2-(3-33) were assessed using a combination of RIA and HPLC in normal and immunocompromised control human subjects and patients hospitalized for IBD. The activity of the enzyme dipeptidyl peptidase IV (DP IV), a key determinant of GLP-2-(1-33) degradation was also assessed in the plasma of normal controls and subjects with IBD. The circulating levels of bioactive GLP-2-(1-33) were increased in patients with either ulcerative colitis (UC) or Crohn's Disease (CD; to 229 +/- 65 and 317 +/- 89%, P < 0.05, of normal, respectively). Furthermore, the proportion of total immunoreactivity represented by intact GLP-2-(1-33), compared with GLP-2-(3-33), was increased from 43 +/- 3% in normal healthy controls to 61 +/- 6% (P < 0.01) and 59 +/- 2% (P < 0.01) in patients with UC and CD, respectively. The relative activity of plasma DP IV was significantly reduced in subjects with IBD compared with normal subjects (1.4 +/- 0.3 vs. 5.0 +/- 1.1 mU/ml, respectively; P < 0.05). These results suggest that patients with active IBD may undergo an adaptive response to intestinal injury by increasing the circulating levels of bioactive GLP-2-(1-33), facilitating enhanced repair of the intestinal mucosal epithelium in vivo.

Topics: Adaptation, Physiological; Adult; Colitis, Ulcerative; Colon; Crohn Disease; Female; Glucagon-Like Peptide 2; Glucagon-Like Peptides; Humans; Intestinal Mucosa; Intestine, Small; Male; Middle Aged; Peptides; Radioimmunoassay; Short Bowel Syndrome

Glucagon-like peptide (7-36) amide (GLP-1) is an incretin hormone of the enteroinsular axis released rapidly after meals despite the fact that GLP-1 secreting cells (L-cells) occur predominantly in the distal gut. The importance of these colonic L-cells for postprandial GLP-1 was determined in healthy control subjects and in ileostomy patients with minimal small bowel resection (<5 cm). Subjects were fed a high complex carbohydrate test meal (15.3 g starch) followed by two carbohydrate-free, high fat test meals (25 g and 48.7 g fat respectively). Circulating levels of glucose, insulin, glucagon, glucose insulinotrophic peptide (GIP) and GLP-1 were measured over a 9-h postprandial period. For both subject groups the complex carbohydrate test meal failed to elicit a rise in either GIP or GLP-1. However, both hormones were elevated after the fat load although the GLP-1 concentration was significantly reduced in the ileostomist group when compared with controls (P=0.02). Associated with this reduction in circulating GLP-1 was an elevation in glucagon concentration (P=0.012) and a secondary rise in the plasma glucose concentration (P=0.006). These results suggest that the loss of colonic endocrine tissue is an important determinant in the postprandial GLP-1 concentration. Ileostomists should not be assumed to have normal enteroinsular function as the colon appears to have an important role in postprandial metabolism.

Topics: Analysis of Variance; Blood Glucose; Case-Control Studies; Colitis, Ulcerative; Colon; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptides; Humans; Ileostomy; Insulin; Male; Middle Aged; Neurotransmitter Agents; Peptide Fragments; Postprandial Period

The aim of this study was to assess if infusion of oleic acid into the ileal pouch would slow gastric emptying and small-bowel transit, delay defecation, and increase plasma levels of enteroglucagon, neurotensin, or peptide YY in patients with colectomy and ileal pouch-anal anastomosis. Eight subjects with chronic ulcerative colitis who had undergone the operation were studied on 2 consecutive days. On 1 day, saline (154 mM NaCl) was infused into the ileal pouch, and on the other day emulsified oleic acid (152 mM) was infused. The subjects ate a 300-kcal mixed meal containing liquid labelled with 99mTc-DTPA. To assess small-bowel transit concurrently with gastric emptying, a second marker, 111In-DTPA, was instilled through a tube into the duodenum at the end of the meal. Transit of both markers was monitored scintigraphically. Infusion of oleic acid into the ileal pouch slowed gastric emptying and small-bowel transit, and delayed the time to defecation compared with saline infusion. Neither the ileal pouch infusion alone or the meal alone altered plasma levels of enteroglucagon, neurotensin, or peptide YY, but the combination of the oleic acid infusion and the meal increased the levels of all 3 hormones. It was concluded that an "ileal brake" on gastrointestinal transit is functional following ileal pouch-anal anastomosis. Oleic acid placed into the ileal pouch slowed gastrointestinal transit and delayed defecation, effects which may have clinical application. The mechanism mediating the ileal brake may in part be hormonal.

Topics: Adult; Anal Canal; Colitis, Ulcerative; Defecation; Female; Gastric Emptying; Gastrointestinal Hormones; Gastrointestinal Transit; Glucagon-Like Peptides; Humans; Ileum; Intestine, Small; Male; Middle Aged; Neurotensin; Oleic Acid; Oleic Acids; Peptide YY; Peptides; Radionuclide Imaging

The study was undertaken to examine regional differences in the concentrations of five regulatory peptides in the human colonic mucosa. Biopsies were obtained during routine colonoscopy from 33 patients whose colonic mucosa was macroscopically and histologically normal. Regulatory peptides were extracted, and measured by specific radioimmunoassays. Concentrations of three peptides that are present predominantly in endocrine cells within colonic mucosa increased significantly towards the rectum: Mean concentrations of peptide YY, enteroglucagon, and somatostatin were about three times greater in the rectum than in the cecum. However, concentrations of two peptides that are present in mucosal nerve fibers diminished significantly towards the rectum: Mean rectal concentrations of vasoactive intestinal peptide and peptide histidine methionine were both about 0.6 of mean cecal concentrations. Concentrations of all five peptides were lower in biopsies taken from colonic polyps than in normal colonic mucosa. Regional differences in colonic mucosal concentrations of regulatory peptides probably reflect differences in the physiological functions of different parts of the colon.

Topics: Adolescent; Adult; Aged; Cecum; Colitis, Ulcerative; Colon; Colonic Polyps; Crohn Disease; Female; Gastrointestinal Hormones; Glucagon-Like Peptides; Humans; Intestinal Mucosa; Male; Middle Aged; Peptide PHI; Peptide YY; Peptides; Radioimmunoassay; Rectum; Somatostatin; Vasoactive Intestinal Peptide

We have studied fasting levels and the response to a standard test breakfast of blood glucose and several gut hormones in 24 patients with ulcerative colitis, in 14 patients with Crohn's disease, and in 14 healthy control subjects. Patients with ulcerative colitis had significantly elevated fasting human pancreatic polypeptide (HPP) concentrations, and both basal and postprandial levels of gastrin, gastric inhibitory polypeptide (GIP), and motilin were greater than normal. In contrast, patients with Crohn's disease had normal gastrin levels but had increased fasting and postprandial levels of GIP and motilin and, in addition, of enteroglucagon, compared with controls. These patients also had greater than normal HPP concentrations 30 min after the breakfast. Normal levels of insulin, pancreatic glucagon, neurotensin, and vasoactive intestinal polypeptide were found in both groups of patients. Much remains to be known about the pathophysiology of these two debilitating diseases, and the abnormal release of gut hormones may be of importance.

Topics: Adolescent; Adult; Aged; Blood Glucose; Colitis, Ulcerative; Crohn Disease; Female; Gastric Inhibitory Polypeptide; Gastrins; Gastrointestinal Hormones; Glucagon-Like Peptides; Humans; Insulin; Male; Middle Aged; Motilin; Neurotensin; Pancreatic Polypeptide; Vasoactive Intestinal Peptide