oxyntomodulin and Intestinal-Diseases

Multiple peptide hormones produced within the gastrointestinal system aid in the regulation of energy homeostasis and metabolism. Among these is the intestinotrophic peptide glucagon-like peptide-2 (GLP-2), which is released following food intake and plays a significant role in the adaptive regulation of bowel mass and mucosal integrity. The discovery of GLP-2's potent growth-promoting and cytoprotective effects in the gastrointestinal (GI) tract stimulated interest in its use as a therapeutic agent for the treatment of GI diseases involving malabsorption, inflammation, and/or mucosal damage. Current research has focused on determining the physiological mechanisms contributing to the effects of GLP-2 and factors regulating its biological mechanisms of action. This chapter provides an overview of the biology of GLP-2 with a focus on the most recent findings on the role of this peptide hormone in the normal and diseased GI tract.

Topics: Adaptation, Physiological; Animals; Blood Glucose; Energy Metabolism; Gastrointestinal Agents; Gastrointestinal Hormones; Glucagon-Like Peptide 2; Glucagon-Like Peptides; Humans; Intestinal Diseases; Intestinal Mucosa; Receptors, Glucagon

Glucagon is used for the treatment of hypoglycemia, and glucagon receptor antagonists are under development for the treatment of type 2 diabetes. Moreover, glucagon-like peptide (GLP)-1 and GLP-2 receptor agonists appear to be promising therapies for the treatment of type 2 diabetes and intestinal disorders, respectively. This review discusses the physiological, pharmacological, and therapeutic actions of the proglucagon-derived peptides, with an emphasis on clinical relevance of the peptides for the treatment of human disease.

Topics: Animals; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Disease; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptide 2; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Humans; Intestinal Diseases; Peptide Fragments; Peptides; Proglucagon; Protease Inhibitors; Protein Precursors; Receptors, Glucagon

Glucagon-like peptide 2 (GLP-2) is a 33-amino acid peptide derived from the tissue-specific, post-translational processing of the proglucagon gene expressed in the intestinal enteroendocrine L-cell. The primary stimulus for GLP-2 secretion is nutrient intake, and involves direct luminal stimulation of the L-cell as well as indirect enteroendocrine and neural mechanisms. The biological activity of GLP-2 in circulation is regulated by the proteolytic cleavage of the N-terminus by dipeptidylpeptidase IV. Several studies have shown that GLP-2 has specific trophic effects on the small and large intestine, which are mediated by stimulation of cell proliferation and inhibition of apoptosis and proteolysis. GLP-2 also has been shown to suppress gastric motility and acid secretion, increase hexose transport activity and suppress food intake, specifically when infused centrally. The actions of GLP-2 are mediated by a G-protein-linked, membrane receptor (GLP-2R) that is localized largely to the gastrointestinal tract, but also is found in the brain. The secretion of GLP-2 and expression of the GLP-2R are present in the late gestation fetus. However, the developing intestine does not become responsive to the trophic effect of GLP-2 until after birth. Based on its efficacy in preventing atrophy and stimulating growth in the neonatal gut, GLP-2 may be a promising therapeutic adjuvant for treatment of infants with compromised gut function.

Topics: Cell Division; Gene Expression Regulation, Developmental; Glucagon-Like Peptide 2; Glucagon-Like Peptides; Growth Substances; Humans; Infant, Newborn; Intestinal Diseases; Intestinal Mucosa; Intestines; Peptides

Glucagon-like peptide-2 (GLP-2) is a newly discovered growth factor that has been demonstrated to enhance intestinal growth and function in normal rodents and to prevent damage and facilitate intestinal repair in various animal models of intestinal insufficiency. A recent study has demonstrated that GLP-2 also acts as an intestinotropin in humans with short-bowel syndrome. The high degree of specificity of GLP-2 for induction of intestinal growth, without affecting growth of other peripheral tissues, is determined by the highly localized expression of the GLP-2 receptor in the intestinal epithelium. In this article, we review the regulation of GLP-2 in physiology, from synthesis to metabolism, with a particular emphasis on potential targets in this pathway for therapeutic manipulation of GLP-2 actions. We also discuss the various animal models of intestinal insufficiency that have been used to demonstrate the therapeutic potential of this intestinotropic hormone, including short bowel, intestinal atrophy, enteritis and colitis. The results of these studies indicate that GLP-2 is a promising therapeutic agent for the treatment of various forms of intestinal insufficiency in humans.

Topics: Animals; Gastrointestinal Hormones; Glucagon-Like Peptide 2; Glucagon-Like Peptides; Growth Substances; Humans; Intestinal Diseases; Models, Animal; Peptides

Recently, glucagon-like peptide 2 has emerged as a potent stimulator of epithelial growth, joining insulin-like growth factor I, hepatocyte growth factor and keratinocyte growth factor as potential treatment modalities for intestinal disorders associated with loss of mucosal mass, such as short bowel syndrome. Investigations into other members of the expanded epidermal growth factor peptide family, the development of more potent peptide analogues, and advances in the development of enterally administered bioactive growth factor formulations further expands the repertoire of epithelial growth factors applicable to conditions associated with epithelial insufficiency.

Topics: Adaptation, Physiological; Epidermal Growth Factor; Fibroblast Growth Factor 7; Fibroblast Growth Factors; Glucagon-Like Peptide 2; Glucagon-Like Peptides; Growth Substances; Hepatocyte Growth Factor; Humans; Intestinal Diseases; Intestinal Mucosa; Mucins; Muscle Proteins; Neuropeptides; Peptides; Regeneration; Short Bowel Syndrome; Somatomedins; Transforming Growth Factor alpha; Trefoil Factor-2; Trefoil Factor-3

The lining of the intestinal tract is constantly renewed in a brisk but orderly fashion. Further acceleration of cell renewal is elicited by various stimuli, notably surgical shortening of the intestine and hyperphagia, which lead to prompt but persistent increases in mucosal mass. Progressive hypoplasia ensues when the small and large bowel are deprived of their normal contents, either by fasting (with or without parenteral nutrition) or by exclusion from intestinal continuity. All atrophic changes are reversed by refeeding or restoration of the normal anatomical disposition. Intestine responds to mucosal damage by regeneration from the crypts. Pancreatobiliary secretions mediate some of the tropic effects of chyme; systemic influences, both neurovascular and humoral, also play a part in the adaptive response of the gut.

Topics: Adaptation, Physiological; Adult; Animals; Cell Division; Colectomy; Colostomy; Female; Gastrins; Glucagon-Like Peptides; Humans; Hyperphagia; Hyperplasia; Hypertrophy; Ileum; Intestinal Diseases; Intestinal Mucosa; Intestines; Jejunum; Obesity; Parenteral Nutrition; Rats; Starvation

Teduglutide is a Glucagon-like peptide-2 (GLP-2) agonist indicated for the treatment of patients with parenteral support (PS) dependent short bowel syndrome (SBS) with chronic intestinal failure (cIF). Its application is accompanied by a structured nation-wide home-care service program in Germany. We investigated care characteristics and outcome parameters in a clinical real-world observational setting.. Data generated within a therapy-accompanying home-care service program for adult SBS-cIF patients were analyzed retrospectively for patients treated up to 1 year (data cut: April 2020).. In total, 52 teduglutide-treated patients were included by 6 German cIF centers. At teduglutide administration start, 49/52 patients were on PS, 3 of them without macronutrients. The majority of patients received individualized parenteral nutrition (PN) (n = 32/46), while 13/46 were on commercial premixed bags. PS application was done by patients themselves (37%), home-care nurses (19%), relatives (8%) or by a combination of those (16%). In patients with PS dependency at baseline and available follow-up data (n = 40-44), teduglutide treatment resulted in significantly reduced PN days, caloric needs, infusion time, and infusion volume after 6 and 12 months. After 1 year, reduction of infusion time was positively correlated with a reduction of PN calories and volume; 30 patients (68%) were responders (PS-volume reduction ≥20%), and 6 patients (14%) were completely weaned off PS. Sleep disturbances per night were significantly reduced after 3 months of treatment and stool characteristics improved in consistency and significantly in frequency, while meal frequency remained stable.. Teduglutide treatment associated reduction in PS volume and calories was accompanied by reduced infusion days, infusion times, sleep disturbances, stable oral intake surrogates, and improved stool characteristics, all of these potential parameters for improving quality of life. Furthermore, analyzed care characteristics reflect SBS-cIF treatment as a complex, resource-intensive and demanding task for both, healthcare system and patients.

Topics: Adult; Chronic Disease; Gastrointestinal Agents; Glucagon-Like Peptides; Humans; Intestinal Diseases; Intestinal Failure; Peptides; Quality of Life; Retrospective Studies; Short Bowel Syndrome

Maintaining tumor-bearing rats on total parenteral nutrition (TPN) for eight days significantly reduced mass, protein, and DNA in small intestine and colon. Coinfusion of glucagon-like peptide 2 (GLP-2) significantly increased each of these variables in the duodenum, jejunum, and ileum, but not in the colon. Histological analysis of tissue revealed normal mucosa thickness and villus height in the small intestine of GLP-2-treated rats, whereas non-treated rats maintained on TPN exhibited villus shortening and thinning of the mucosa. Compared with TPN alone, no significant effects of GLP-2 were noted on tumor growth, liver weight, or heart weight. Coinfusion of GLP-2 with TPN had no significant effect on TPN-associated immunosuppression, as measured by mitogen-induced proliferation of cultured splenocytes. Although translocation of bacteria to the mesenteric lymph nodes appeared to be reduced in GLP-2-treated rats, the difference between groups was not statistically significant. These results suggest that hormonal alterations may be more important than an absence of luminal nutrition in TPN-associated mucosa changes in tumor-bearing rats. Additionally, maintenance of gut integrity during TPN does not appear to be a sufficient condition for the avoidance of the negative sequelae associated with this route of supplemental nutrition.

Topics: Animals; Bacterial Translocation; DNA; Glucagon-Like Peptide 2; Glucagon-Like Peptides; Intestinal Diseases; Intestinal Mucosa; Intestine, Small; Male; Microvilli; Neoplasms; Parenteral Nutrition; Peptides; Rats; Rats, Inbred F344

Maintaining rats on total parenteral nutrition (TPN) for 6 days significantly reduced mass (-34%), protein (-32%), and DNA (-35%) in small intestine and colon (29-37% decrease). Coinfusion of glucagon-like peptide-2 (GLP-2) normalized each of these variables in duodenum, jejunum, and ileum, but not in colon. Histological analysis of tissue revealed normal mucosa thickness and villus height in small intestine of GLP-2-treated rats, whereas nontreated rats maintained on TPN exhibited villus shortening (-30%) and thinning (-23%) of mucosa. These results suggest that hormonal alterations may be more important than an absence of luminal nutrition in TPN-associated mucosal changes. Additionally, GLP-2 normalization of gut mucosa permits accurate assessment of the influence of reversal of hypoplasia on gut barrier function.

Topics: Animals; DNA; Glucagon-Like Peptide 2; Glucagon-Like Peptides; Intestinal Diseases; Intestinal Mucosa; Intestine, Small; Male; Microvilli; Parenteral Nutrition; Peptides; Rats; Rats, Inbred F344

Five gnotobiotic calves were each infected with five viruses. Each calf was inoculated with coronavirus at seven days old, followed by astrovirus, Newbury agent, parainfluenzavirus type 3 and rotavirus at intervals of two weeks. Three of the viruses were enteropathogenic (bovine coronavirus, bovine calici-like virus and bovine rotavirus) and two were not (bovine astrovirus and parainfluenzavirus type 3). Plasma levels of the peptide hormones enteroglucagon and neurotensin and faecal output were measured daily and xylose absorption was studied before and after each infection. A close correlation was found between a rise in plasma enteroglucagon and neurotensin and infection with enteropathogenic viruses. The three enteropathogenic viruses caused increased daily faecal output, and elevated plasma levels of enteroglucagon and neurotensin, while the non-enteropathogens did not. The calici-like virus and rotavirus but not the coronavirus caused xylose malabsorption.

Topics: Animals; Cattle; Cattle Diseases; Gastrointestinal Hormones; Germ-Free Life; Glucagon-Like Peptides; Intestinal Absorption; Intestinal Diseases; Male; Neurotensin; Virulence; Virus Diseases; Viruses; Xylose

A number of human diseases with intestinal adaptation have been investigated, including acute infective diarrhoea, intestinal resection, jejuno-ileal bypass, coeliac disease, tropical sprue, chronic pancreatitis and cystic fibrosis. In all, the newly isolated hormone enteroglucagon appeared to be elevated in proportion to the degree of adaptation. In rats after gut resection and cold adaptation, enteroglucagon was also elevated and the degree of elevation correlated closely with the crypt cell production rate (CCPR). Chronic administration of somatostatin suppressed both enteroglucagon and CCPR, while bombesin stimulated both. A crude preparation of enteroglucagon was found to directly stimulate DNA synthesis in enterocyte cultures. It is thus concluded that, at present, the most likely candidate for the humoral component of intestinal adaptation is the hormonal peptide enteroglucagon.

Topics: Adaptation, Physiological; Adult; Animals; Cattle; Diarrhea; Gastrointestinal Hormones; Glucagon-Like Peptides; Humans; Hypertrophy; Infant; Inflammation; Intestinal Diseases; Intestinal Mucosa; Intestine, Small; Intestines; Mice; Motilin; Obesity; Rats

Topics: Gastrointestinal Hormones; Glucagon-Like Peptides; Humans; Intestinal Diseases