glucagon-like-peptide-2 and Intestinal-Diseases

Advances in the field of intestinal failure continue to reduce mortality rates of this complex syndrome. Over the last 20 months (January 2021- October 2022), several important papers were published that relate to the nutritional and medical management of intestinal failure and rehabilitation.. New reports on the epidemiology of intestinal failure have shown that short bowel syndrome (SBS) remains the most common cause of intestinal failure worldwide in both adults and children. Advances in the provision of parenteral nutrition (PN), the advent of Glucagon-like peptide-2 (GLP-2) analogs, and the development of interdisciplinary centers have allowed for safer and longer courses of parenteral support. Unfortunately, rates of enteral anatomy continue to lag behind these advancements, requiring greater focus on quality of life, neurodevelopmental outcomes, and management of sequalae of long-term PN such as Intestinal Failure Associated Liver Disease (IFALD), small bowel bacterial overgrowth (SBBO), and Metabolic Bone Disease (MBD).. There have been significant advances in the nutritional and medical approaches in intestinal failure, including advances in PN, use of GLP-2 analogs, and key developments in the medical management of this condition. As children with intestinal failure increasingly survive to adulthood, new challenges exist with respect to the management of a changing population of patients with SBS. Interdisciplinary centers remain standard of care for this complex patient population.

Topics: Adult; Child; Glucagon-Like Peptide 2; Humans; Intestinal Diseases; Intestinal Failure; Intestine, Small; Parenteral Nutrition; Quality of Life; Short Bowel Syndrome

Glucagon-like peptide-2 (GLP-2) is a gut hormone that promotes highly specific growth and function of the intestinal epithelium. Recent studies have begun to elucidate the complex mechanism of action of GLP-2, which is mediated indirectly through other intestinal factors. Although a long-acting GLP-2 analog has recently been approved for treatment of adult patients with short bowel syndrome, there remain numerous conditions characterized by intestinal insufficiency for which pre-clinical studies, as well as some limited clinical data, support further consideration of GLP-2 for expanded therapeutic use.

Topics: Adult; Animals; Delayed-Action Preparations; Glucagon-Like Peptide 2; Humans; Intestinal Diseases; Intestinal Mucosa; Intestines; Short Bowel Syndrome

The pharmacological application of intestinal growth factors has been recognized because of the protective and reparative actions of these factors in the intestinal tract. This review highlights the use of keratinocyte growth factor (KGF), IGF-1 and glucagon-like peptide 2 (GLP-2) in efficacy studies of intestinal damage; the results from these studies support potential clinical applications of these factors in treating intestinal diseases. In particular, GLP-2 has been assessed in preclinical and clinical investigations for its capacity to prevent or treat an increasing number of intestinal diseases, including short bowel syndrome, chemotherapy-induced intestinal mucositis and inflammatory bowel disease.

Topics: Animals; Fibroblast Growth Factor 7; Glucagon-Like Peptide 2; Humans; Insulin-Like Growth Factor I; Intestinal Diseases; Mice; Rats

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

Glucagon-like peptide 2 (GLP-2) is an important peptide growth factor secreted from the human intestine. The trophic properties of GLP-2 are very specific to the gut where it is pivotal in the regulation of mucosal morphology, function and integrity.. This review details the current understanding of the molecular biology of GLP-2, its mechanisms of action and physiological properties. A major focus is the discussion of recent clinical data evaluating the use of GLP-2 as a therapeutic agent.. Relevant articles were identified using Medline searches and from the reference lists of key papers.. In the treatment of short bowel syndrome, GLP-2 has been shown to be highly effective in improving fluid absorption. In Crohn's disease, GLP-2 is superior to placebo in the induction of remission. Early data also suggest that the effects of GLP-2 on bone metabolism can provide a new treatment approach for patients with osteoporosis. In the future, the positive effects of GLP-2 on intestinal barrier function, splanchnic perfusion and mucosal healing could be utilized to expand its therapeutic application to other causes of intestinal injury. However, important safety aspects need to be considered when using this potent growth-promoting agent for a long term.

Topics: Amino Acid Sequence; Animals; Glucagon-Like Peptide 2; Humans; Intercellular Signaling Peptides and Proteins; Intestinal Diseases; Mice; Molecular Sequence Data; Osteoporosis; Rats

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 and the glucagon-like peptides (GLPs) are derived from single proglucagon gene and exhibit an increasing number of biologically important actions. As a counter-regulatory hormone for insulin, glucagon plays a critical role in maintaining glucose homeostasis in vivo in both animals and humans. To increase blood glucose, glucagon promotes hepatic glucose output by increasing glycogenolysis and gluconeogenesis and by decreasing glycogenesis and glycolysis in a concerted fashion via multiple mechanisms. The glucagon-like peptides GLP-1 and GLP-2 are produced in enteroendocrine L cells of the small and large intestine and secreted in a nutrient-dependent manner. GLP-1 regulates nutrient assimilation via inhibition of gastric emptying and food intake. GLP-1 controls blood glucose following nutrient absorption via stimulation of glucose-dependent insulin secretion, insulin biosynthesis, islet proliferation, and neogenesis and inhibition of glucagon secretion. Glucagon-like peptide-1 (GLP-1 is an insulinotropic hormone, GLP-1 also inhibits glucagon secretion. GLP-1 lowers blood glucose in normal subjects and in patients with type 2 diabetes. The major biological action of GLP-2 appears to be the stimulation of small-bowel hyperplasia, manifested by an increases in both villous height and small-bowel weight. A pilot study of GLP-2 administration in human subjects with short bowel syndrome demonstrated significant improvements in energy absorption, bone density, increased body weight, which correlated with increased crypt plus villus height on intestinal biopsy sections. The biological actions of two of these glucagon-related peptides, suggest that they may have therapeutic relevance for the treatment of human diseases such as diabetes, selective intestinal disorders and cardiac diseases.

Topics: Animals; Blood Glucose; Gastrointestinal Hormones; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptide 2; Humans; Intestinal Diseases; Intestinal Mucosa; Islets of Langerhans; Peptide Fragments; Peptides; Pilot Projects; Protein Precursors; Short Bowel Syndrome; Signal Transduction

The glucagon-like peptides (GLP-1 and GLP-2) are proglucagon-derived peptides cosecreted from gut endocrine cells in response to nutrient ingestion. GLP-1 acts as an incretin to lower blood glucose via stimulation of insulin secretion from islet beta cells. GLP-1 also exerts actions independent of insulin secretion, including inhibition of gastric emptying and acid secretion, reduction in food ingestion and glucagon secretion, and stimulation of beta-cell proliferation. Administration of GLP-1 lowers blood glucose and reduces food intake in human subjects with type 2 diabetes. GLP-2 promotes nutrient absorption via expansion of the mucosal epithelium by stimulation of crypt cell proliferation and inhibition of apoptosis in the small intestine. GLP-2 also reduces epithelial permeability, and decreases meal-stimulated gastric acid secretion and gastrointestinal motility. Administration of GLP-2 in the setting of experimental intestinal injury is associated with reduced epithelial damage, decreased bacterial infection, and decreased mortality or gut injury in rodents with chemically induced enteritis, vascular-ischemia reperfusion injury, and dextran sulfate-induced colitis. GLP-2 also attenuates chemotherapy-induced mucositis via inhibition of drug-induced apoptosis in the small and large bowel. GLP-2 improves intestinal adaptation and nutrient absorption in rats after major small bowel resection, and in humans with short bowel syndrome. The actions of GLP-2 are mediated by a distinct GLP-2 receptor expressed on subsets of enteric nerves and enteroendocrine cells in the stomach and small and large intestine. The beneficial actions of GLP-1 and GLP-2 in preclinical and clinical studies of diabetes and intestinal disease, respectively, has fostered interest in the potential therapeutic use of these gut peptides. Nevertheless, the actions of the glucagon-like peptides are limited in duration by enzymatic inactivation via cleavage at the N-terminal penultimate alanine by dipeptidyl peptidase IV (DP IV). Hence, inhibitors of DP IV activity, or DP IV-resistant glucagon-like peptide analogues, may be alternative therapeutic approaches for treatment of human diseases.

Topics: Animals; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Glucagon-Like Peptide 2; Humans; Intestinal Diseases; Peptides

The glucagon-like peptides GLP-1 and GLP-2 are synthesised and then released from enteroendocrine cells in the small and large intestine. GLP-1 promotes efficient nutrient assimilation while GLP-2 regulates energy absorption via effects on nutrient intake, gastric acid secretion and gastric emptying, nutrient absorption, and mucosal permeability. Preliminary human studies indicate that GLP-2 may enhance energy absorption and reduce fluid loss in subjects with short bowel syndrome suggesting that GLP-2 functions as a key regulator of mucosal integrity, permeability, and nutrient absorption. Hence GLP-2 may be therapeutically useful in diseases characterised by injury or dysfunction of the gastrointestinal epithelium.

Topics: Adaptation, Physiological; Animals; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptide 2; Humans; Intestinal Diseases; Intestines; Mice; Peptide Fragments; Peptides; Protein Precursors; Rats; Short Bowel Syndrome

The glucagon-like peptides GLP-1 and GLP-2 are produced in enteroendocrine L cells of the small and large intestine and secreted in a nutrient-dependent manner. GLP-1 regulates nutrient assimilation via inhibition of gastric emptying and food intake. GLP-1 controls blood glucose following nutrient absorption via stimulation of glucose-dependent insulin secretion, insulin biosynthesis, islet proliferation, and neogenesis and inhibition of glucagon secretion. Experiments using GLP-1 antagonists and GLP-1 receptor-/- mice indicate that the glucoregulatory actions of GLP-1 are essential for glucose homeostasis. In the central nervous system, GLP-1 regulates hypothalamic-pituitary function and GLP-1-activated circuits mediate the CNS response to aversive stimulation. GLP-2 maintains the integrity of the intestinal mucosal epithelium via effects on gastric motility and nutrient absorption, crypt cell proliferation and apoptosis, and intestinal permeability. Both GLP-1 and GLP-2 are rapidly inactivated in the circulation as a consequence of amino-terminal cleavage by the enzyme dipeptidyl peptidase IV (DP IV). The actions of these peptides on nutrient absorption and energy homeostasis and the efficacy of GLP-1 and GLP-2 in animal models of diabetes and intestinal diseases, respectively, suggest that analogs of these peptides may be clinically useful for the treatment of human disease.

Topics: Animals; Central Nervous System; Diabetes Mellitus; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptide 2; Humans; Intestinal Diseases; Intestines; Pancreas; Peptide Fragments; Peptides; Protein Precursors

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

Glucagon-like peptides 1 and 2 (GLP-1 and GLP-2) are coencoded within a single mammalian proglucagon precursor, and are liberated in the intestine and brain. GLP-1 exerts well known actions on islet hormone secretion, gastric emptying, and food intake. Recent studies suggest GLP-1 plays a central role in the development and organization of islet cells. GLP-1 receptor signaling appears essential for beta cell signal transduction as exemplified by studies of GLP-1R-/- mice. GLP-2 promotes energy assimilation via trophic effects on the intestinal mucosa of the small and large bowel epithelium via a recently cloned GLP-2 receptor. The actions of GLP-2 are preserved in the setting of small and large bowel injury and inflammation. The biological actions of the glucagon-like peptides suggest they may have therapeutic efficacy in diabetes (GLP-1) or intestinal disorders (GLP-2).

Topics: Animals; Diabetes Mellitus; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptide 2; Glucagon-Like Peptide-1 Receptor; In Vitro Techniques; Intestinal Diseases; Intestinal Mucosa; Islets of Langerhans; Mice; Mice, Knockout; Peptide Fragments; Peptides; Protein Precursors; Receptors, Glucagon; Signal Transduction

Glucagon-like peptide 2 (GLP-2) analogues are approved for adults with intestinal failure (IF), but no studies have included infants. This study examined the pharmacokinetics (PK), safety, and nutritional effects of GLP-2 in infants with IF.. With parental consent (Health Canada Protocol:150,979), parenteral nutrition (PN)-dependent infants were treated with 5-20-μg/kg/day GLP-2 for 3days (phase 1), and if tolerated continued for 42days (phase 2). Nutritional therapy was by primary caregivers, and follow-up was to one year.. Six patients were enrolled, age 5.4±3.2months, bowel length: 27±12% of predicted, PN dependent (67±18% of calories). GLP-2 did not affect vital signs, nor were there significant adverse events during the trial. Dosing 5μg/kg/day gave GLP-2 levels of 52-57pmol/L, with no change in half-life or endogenous GLP-2 levels. Enteral feeds, weight, Z scores, stooling frequency, and citrulline levels improved numerically. The trial was discontinued early because of a drop in potency.. GLP-2 was well tolerated in infants, and pK was similar to children with no changes in endogenous GLP-2 release. The findings suggest that GLP-2 ligands may be safely used in infants and may have beneficial effects on nutritional status. Further study is required.. 2b Prospective Interventional Study.

Topics: Combined Modality Therapy; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Follow-Up Studies; Gastrointestinal Agents; Glucagon-Like Peptide 2; Half-Life; Humans; Infant; Infant, Newborn; Intestinal Diseases; Male; Nutritional Status; Parenteral Nutrition; Prospective Studies; Treatment Outcome

Short bowel syndrome (SBS)-intestinal failure (IF) patients have impaired quality of life (QoL) and suffer from the burden of malabsorption and parenteral support (PS). A phase III study demonstrated that treatment with teduglutide, a glucagon-like peptide 2 analogue, reduces PS volumes by 32% while maintaining oral fluid intake constant; placebo-treated patients had reduced PS by 21%, but oral fluid intake increased accordingly. As effects of teduglutide on QoL are unknown, they were investigated here.. QoL analyses from a double-blind, randomised Phase III study in 86 SBS-IF patients receiving teduglutide (0.05 mg/kg/day s.c.) or placebo over 24 weeks. At baseline and every 4 weeks, QoL was assessed using the validated SBS-QoL™ scale.. PS reductions were associated with QoL improvements (ANCOVA, p = 0.0194, SBS-QoL per-protocol). Compared to baseline, teduglutide significantly improved the SBS-QoL™ total score and the score of 9 of 17 items at week 24. These changes were not significant compared to placebo. Teduglutide-treated patients with remaining small intestine >100 cm experienced more gastrointestinal adverse events (GI-AE), unfavourably affecting QoL.. Overall, PS volume reductions were associated with improvements in SBS-QoL™ scores. The short observation period, imbalances in oral fluid intake in relation to PS reductions, large patient and effect heterogeneity and occurrence of GI-AE in a subgroup of teduglutide-treated patients may account for the inability to show statistically significant effects of teduglutide on SBS-QoL™ scores compared to placebo.

Topics: Adult; Aged; Cost of Illness; Double-Blind Method; Drinking; Drug Resistance; Gastrointestinal Agents; Glucagon-Like Peptide 2; Glucagon-Like Peptide-2 Receptor; Humans; Injections, Subcutaneous; Intestinal Diseases; Intestine, Small; Middle Aged; Organ Dysfunction Scores; Organ Size; Parenteral Nutrition, Home; Peptides; Quality of Life; Receptors, Glucagon; Short Bowel Syndrome

Short bowel syndrome (SBS) is a rare condition defined as a reduced residual functional small intestinal length to less than 200 cm often resulting from extensive intestinal resection, and can lead to chronic intestinal failure (CIF). Patients with SBS-CIF are unable to absorb sufficient nutrients or fluids to maintain metabolic homeostasis through oral or enteral intake and require long-term parenteral nutrition and/or fluids and electrolytes. However, complications may arise from both SBS-IF and life-sustaining intravenous support, such as intestinal failure-associated liver disease (IFALD), chronic renal failure, metabolic bone disease and catheter-related complications. An interdisciplinary approach is required to optimize intestinal adaptation and decrease complications. In the last two decades, glucagon-like peptide 2 (GLP-2) analogs have sparked pharmacological interest as a potential disease-modifying therapy for SBS-IF. Teduglutide (TED) is the first developed and marketed GLP-2 analog for SBS-IF. It is approved in the United States, Europe, and Japan for use in adults and children with SBS-IF who are intravenous supplementation dependent. This article discusses the indications, candidacy criteria and results of the use of TED in patients with SBS.

Topics: Adult; Child; Chronic Disease; Gastrointestinal Agents; Glucagon-Like Peptide 2; Humans; Intestinal Diseases; Intestinal Failure; Intestine, Small; Intestines; Short Bowel Syndrome

Patients with severely orally decompensated malsaborption due to surgical rescetion suffer from short bowel syndrome (SBS). The resultant decrease in intestinal surface area after rescetion of parts of the intestines leads to chronic functional intestinal insufficiency or even complete failure (cIF) which requires parenteral fluid and nutrient restoration for establishment of metabolc stability. Since the introduction of glucagon-like peptide (GLP)-2 analogues such as teduglutide functional rehabilitation of the remaining gastrointestinal tract has become a causal treatment option. Teduglutide functionally and effectively enhances intestinal absorption of fluid as well micro- and macronutrients allowing a reduction of parenteral nutrition and/or volume with even complete weaning off in some patients. This results increased metabolic stability, oral autonomy, quality of life and putatively less complications.. Das chronische Darmversagen (CVD) bei Kurzdarmsyndrom (KDS) wird sowohl durch die postoperative Anatomie als auch funktionell anhand des parenteralen Kalorien- und Volumenbedarfs klassifiziert.. Die postoperative Anpassungsreaktion nach Darmresektion verläuft in 3 Phasen, die jeweils eines interdisziplinären Managements bedürfen.. Ziel der Therapie ist eine ausreichende Kalorien- und Nährstoffversorgung unter Vermeidung einer Hyperalimentation bzw. die Linderung/Beherrschung der Diarrhöen. CHIRURGISCHE MAßNAHMEN EINSCHLIEßLICH TRANSPLANTATION: Die chirurgische Wiederherstellung der Kontinuität ausgeschalteter Darmabschnitte ist unverzichtbar. Es bestehen prinzipiell verschiedene Optionen der Transplantation, der Nachweis für eine Verbesserung der Gesamtprognose steht allerdings noch aus. FUNKTIONELLE INTESTINALE REHABILITATION DURCH GLP-2-ANALOGA:  Durch die Einführung von Glucagon-like-peptide-2-Analoga (GLP-2-Analoga) in die funktionelle intestinale Rehabilitation von KDS-Patienten ist nunmehr eine kausale Behandlung dieses Malabsorptionssyndroms möglich. Durch die GLP-2-Analoga-vermittelte Steigerung der Flüssigkeits-, Nährstoff- und Kalorienabsorption ist eine Reduzierung der parenteralen Substitution (PS), im Idealfall mit kompletter Entwöhnung, möglich.

Topics: Chronic Disease; Glucagon-Like Peptide 2; Humans; Intestinal Diseases; Short Bowel Syndrome

Environmental Enteric Dysfunction (EED), a syndrome characterized by chronic gut inflammation, contributes towards stunting and poor response to enteric vaccines in children in developing countries. In this study, we evaluated major putative biomarkers of EED using growth faltering as its clinical proxy. Newborns (n = 380) were enrolled and followed till 18 months with monthly anthropometry. Biomarkers associated with gut and systemic inflammation were assessed at 6 and 9 months. Linear mixed effects model was used to determine the associations of these biomarkers with growth faltering between birth and 18 months. Fecal myeloperoxidase (neutrophil activation marker) at 6 months [β = -0.207, p = 0.005], and serum GLP 2 (enterocyte proliferation marker) at 6 and 9 months [6M: β = -0.271, p = 0.035; 9M: β = -0.267, p = 0.045] were associated with decreasing LAZ score. Ferritin at 6 and 9 months was associated with decreasing LAZ score [6M: β = -0.882, p < 0.0001; 9M: β = -0.714, p < 0.0001] and so was CRP [β = -0.451, p = 0.039] and AGP [β = -0.443, p = 0.012] at 9 months. Both gut specific and systemic biomarkers correlated negatively with IGF-1, but only weakly correlated, if at all with each other. We therefore conclude that EED may be contributing directly towards growth faltering, and this pathway is not entirely through the pathway of systemic inflammation.

Topics: Biomarkers; Cohort Studies; Enterocytes; Environmental Exposure; Female; Glucagon-Like Peptide 2; Humans; Infant; Infant, Newborn; Insulin-Like Growth Factor I; Intestinal Diseases; Male; Models, Statistical; Neutrophil Activation; Pakistan; Peroxidase; Prospective Studies; Syndrome

Glukagon-like-peptide-1 (GLP-1) and -2 (GLP-2), produced by intestinal L-cells, are key hormones regulating intestinal transit, secretion, absorption, and mucosal growth. We evaluated naïve fasting serum GLP-1 and GLP-2 levels in pediatric intestinal failure (IF).. Fifty-five IF patients with median age 4.2 (IQR 1.3-12) years and 47 matched healthy controls underwent measurement of fasting serum GLP-1 and GLP-2.. Serum GLP-2 [19.9 (13.8-27.9) vs 11.6 (7.0-18.6) ng/mL, P < 0.001], but not GLP-1 [6.1 (4.0-15.7) vs 6.4 (3.9-10.7) ng/mL, P = 0.976], levels were increased in IF patients. Serum GLP-2 concentrations were higher in patients with small bowel-colic continuity [21.1 (15.0-30.7) ng/mL] compared to patients with an endostomy [10.4 (6.6-17.9) ng/mL, P = 0.028], whereas no association with preservation of ileum or ileocecal valve was observed. During PN delivery, GLP-2 inversely associated with remaining small bowel length (r = -0.500, P = 0.041) and frequency of PN infusions (r = -0.549, P = 0.042). Serum GLP-1 levels were lower in patients receiving PN currently [4.1 (2.8-5.1)] compared to patients, who had weaned off PN [6.5 (5.1-21.1), P = 0.005], and correlated positively with duration of PN (r = 0.763, P = 0.002) and negatively with percentage parenteral energy requirement (r = -0.716, P = 0.006).. In pediatric IF, serum GLP-2 levels increase in patients with small bowel-colic continuity proportionally to the length of resected small intestine. Increase in serum GLP-1 and GLP-2 levels paralleled reducing requirement for parenteral support. These findings support regulation of intestinal adaption by GLP-2 and GLP-1 in children with IF.

Topics: Adaptation, Physiological; Adolescent; Body Mass Index; Case-Control Studies; Child; Child, Preschool; Citrulline; Cross-Sectional Studies; Fasting; Female; Glucagon-Like Peptide 1; Glucagon-Like Peptide 2; Humans; Infant; Intestinal Diseases; Intestines; Male; Parenteral Nutrition

Glucagon-like peptide-2 (GLP-2) has been suggested for the treatment of mucositis, but the peptide has also been shown to accentuate colonic dysplasia in carcinogen-treated mice. Recently, an effect on intestinal growth was discovered for glucagon-like peptide-1 (GLP-1), OBJECTIVE: To determine whether endogenous GLP-1 contributes to the healing processes and if exogenous GLP-1 has a potential role in treating mucositis.. Mice were injected with 5-fluorouracil (5-FU) or saline to induce mucositis and were then treated with GLP-1, GLP-2, GLP-2 (3-33), exendin (9-39) or vehicle. The mice were sacrificed 48 or 96 h after the 5-FU injections. The end points were intestinal weight, villus height, proliferation and histological scoring of mucositis severity. Rats were injected with 5-FU or saline, and after 48 h, blood was drawn and analysed for GLP-1 and GLP-2 concentration.. GLP-1 and GLP-2 significantly prevented the loss of mucosal mass and villus height and significantly decreased the mucositis severity score in the duodenum and jejunum 48 h after chemotherapy. The effect was equivalent. Exendin (9-39) reduced the intestinal weight 96 h after chemotherapy. The GLP-1 levels in blood were increased more than 10-fold, and GLP-2 levels were increased sevenfold.. GLP-1 and GLP-2 were secreted after intestinal injury, and recovery was delayed after treatment with exendin (9-39), indicating an important role for the peptides in the protection of the intestine from injury. GLP-1 treatment ameliorated mucositis, which suggests that mucositis and other acute intestinal disorders might benefit from treatment with GLP-1 analogues.

Topics: Animals; Antimetabolites, Antineoplastic; Female; Fluorouracil; Glucagon-Like Peptide 1; Glucagon-Like Peptide 2; Intestinal Diseases; Intestinal Mucosa; Male; Mice; Mucositis; Peptide Fragments; Rats, Wistar

Tumor necrosis factor-alpha (TNF-α) is a multifunctional cytokine, which has the ability to produce cytotoxicity via induction of cell death and cell cycle arrest. Blocking the synthesis of protective proteins through a transcriptional inhibitor such as actinomycin D (Act D) sensitizes many cell types to TNF-α toxicity. Teduglutide, h[Gly(2)]GLP-2, is a protease-resistant synthetic analog of glucagon-like peptide-2 (GLP-2) which is an intestinotrophic peptide. In this study, we evaluated this potential of GLP-2 on apoptosis, cell proliferation, and oxidant-antioxidant system on a mouse model of intestinal injury induced by TNF-α/Act D. The intestinal injury was induced by intraperitoneal administration of 15 μg/kg TNF-α and 800 μg/kg Act D per mouse. Animals were injected subcutaneously 200 μg/kg h[Gly(2)]GLP-2 every 12 h for 10 consecutive days prior to the administration of TNF-α and Act D. The model of intestinal injury induced by TNF-α/Act D, which is the new animal model for the intestinal disorders, was characterized by the degeneration of intestinal mucosa, an increase in apoptotic index, expression of active caspase-3, lipid peroxidation and glutathione (GSH) levels, glutathione peroxidase (GPx) and superoxide dismutase (SOD) activities; a decrease in cell proliferation and catalase (CAT) activity. h[Gly(2)]GLP-2 pretreatment prevented the TNF-α/Act D-induced oxidative injury by a significant reduction in the intestinal injury, apoptotic index, expression of active caspase-3, lipid peroxidation and GSH levels, GPx and SOD activities; a markedly increase in cell proliferation, and CAT activity. These results demonstrate that GLP-2 has a protective, antiapoptotic, proliferative, and antioxidant effects against to TNF-α/Act D-induced intestinal injury. It is suggested that GLP-2 may potentially be useful as a therapeutic agent in TNF-α-mediated intestinal disorders.

Topics: Animals; Antioxidants; Apoptosis; Cell Proliferation; Dactinomycin; Disease Models, Animal; Drug Evaluation, Preclinical; Gastrointestinal Agents; Glucagon-Like Peptide 2; Intestinal Diseases; Male; Mice; Mice, Inbred BALB C; Oxidants; Tumor Necrosis Factor-alpha

Expansion of intestinal progenitors and putative stem cells (pISC) occurs early and transiently following ileo-cecal resection (ICR). The mechanism controlling this process is not defined. We hypothesized that glucagon-like peptide-2 (GLP-2) would augment jejunal pISC expansion only when administered to mice immediately after ICR. Since recent reports demonstrated increases in intestinal insulin-like growth factor (IGF)-I following GLP-2 administration, we further hypothesized that increased intestinal IGF-I expression would correlate with pISC expansion following ICR. To assess this, GLP-2 or vehicle was administered to mice either immediately after resection (early) or before tissue harvest 6 wk following ICR (late). Histological analysis quantified proliferation and intestinal morphometrics. Serum levels of GLP-2 were measured by ELISA and jejunal IGF-I mRNA by qRT-PCR. Expansion of jejunal pISC was assessed by fluorescent-activated cell sorting of side population cells, immunohistochemistry for phosphorylated beta-catenin at serine 552 (a pISC marker), percent of crypt fission, and total numbers of crypts per jejunal circumference. We found that early but not late GLP-2 treatment after ICR significantly augmented pISC expansion. Increases in jejunal IGF-I mRNA correlated temporally with early pISC expansion and effects of GLP-2. Early GLP-2 increased crypt fission and accelerated adaptive increases in crypt number and intestinal caliber. GLP-2 increased proliferation and intestinal morphometrics in all groups. This study shows that, in mice, GLP-2 promotes jejunal pISC expansion only in the period immediately following ICR. This is associated with increased IGF-I and accelerated adaptive increases in mucosal mass. These data provide clinical rationale relevant to the optimal timing of GLP-2 in patients with intestinal failure.

Topics: Animals; beta Catenin; Cecum; Cell Division; Glucagon-Like Peptide 2; Ileum; Insulin-Like Growth Factor I; Intestinal Diseases; Male; Mice; Mice, Inbred C57BL; Phosphorylation; Postoperative Complications; Proteins; Stem Cells; Time Factors; Weight Gain

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