oxyntomodulin and Short-Bowel-Syndrome

To examine the most recent literature on the clinical trials associated with the relevant growth factors that have been of interest in the treatment of short bowel.. Short bowel is a rare but devastating condition that condemns patients to lifelong parenteral support. Historically, treatment options negating the need for parenteral support were limited. Therapeutic growth factor use is of interest, but the clinical trial data are inconclusive. The STEPS-2 trial was the first trial that showed a sustained positive effect of the growth factor glucagon-like peptide-2 (GLP-2). This led to a phase shift in the management of short bowel, with the US Food and Drug Administration approval of the GLP-2 analogue teduglutide in 2012. This review summarizes all the relevant clinical trials of growth factors in the treatment of short bowel.. GLP-2 has shown that growth factors can revolutionize the treatment of short bowel. Data however are lacking with regards to the solitary use of other factors. This review highlights the need for further work using the factors in combination as well as considering their use in novel methods for example in the field of regenerative medicine.

Topics: Gastrointestinal Agents; Glucagon-Like Peptides; Humans; Intercellular Signaling Peptides and Proteins; Peptides; Randomized Controlled Trials as Topic; Short Bowel Syndrome

Short bowel syndrome (SBS) reflects a state of malabsorption that occurs due to loss of a significant portion of the small bowel. The pathophysiology of SBS is determined largely by the process of adaptation, which is the innate attempt by the remnant portions of the intestine to increase fluid and nutrient reabsorption. In recent years, emphasis has been placed on intestinal rehabilitation with multidisciplinary teams as a comprehensive approach to the management of patients with SBS. In our institution, the multidisciplinary team members include pediatric gastroenterologists, pediatric surgeons, pediatric dieticians, physical therapists, occupational therapists, neonatologists (especially for patients still under their care), transplant surgeons, transplant coordinators and social workers. Parenteral nutrition plays a significant role in the management of SBS, but its use is associated with many potential complications, including cholestatic liver disease. Fish oil-based lipid emulsions have shown promise in their ability to reverse and also prevent the development of cholestasis in these patients. Clinical trials have shown that growth factors and other trophic hormones facilitate the process of adaptation. The most significant impact has been shown with the use of glucagon-like peptide-2 and its analog (teduglutide). Surgical interventions remain an important part of the management of SBS to facilitate adaptation and treat complications. Intestinal transplantation is a last resort option when the process of adaptation is unsuccessful. This review article is intended to provide an overview of the conventional and emerging therapies for pediatric SBS.

Topics: Adaptation, Physiological; Gastrointestinal Agents; Glucagon-Like Peptide 2; Glucagon-Like Peptides; Humans; Intestine, Small; Intestines; Malabsorption Syndromes; Nutritional Status; Parenteral Nutrition; Parenteral Nutrition, Total; Peptides; Short Bowel Syndrome

Topics: Adaptation, Physiological; Epidermal Growth Factor; Glucagon-Like Peptide 2; Glucagon-Like Peptides; Human Growth Hormone; Humans; Short Bowel Syndrome

Although long-term parenteral nutrition is lifesaving in patients with intestinal failure, it is expensive and associated with serious complications such as catheter sepsis, venous occlusions, and liver failure and severely impairs the quality of life in the short bowel patients. Therefore, treatments that increase the absolute intestinal absorption, thereby eliminating or minimizing the need for parenteral support, are needed. In this respect, glucagon-like peptide 2 (GLP-2) has received attention. In this review, the nature of the short bowel syndrome is described, and the antisecretory, transit-modulating, but also intestinotrophic effects of GLP-2 are presented. As illustrated in 2 pilot studies, one using native GLP-2 and the other a degradation-resistant analogue, teduglutide, these new agents may prove important in optimizing remnant intestinal function, thereby eliminating the need for parenteral support and improving quality of life in short bowel patients with intestinal failure.

Topics: Adaptation, Physiological; Clinical Trials as Topic; Glucagon-Like Peptide 2; Glucagon-Like Peptides; Humans; Jejunostomy; Nutritional Support; Peptides; Short Bowel Syndrome

To date, the hormonal factors used in the treatment of patients with short-bowel syndrome have been growth hormone and glucagon-like peptide (GLP)-2. In high-dose growth hormone studies, the effects on wet-weight absorption of approximately 0.7 kg/day have mainly been described in short-bowel syndrome patients with a preserved colon who also received oral rehydration solutions. Treatment with high doses of growth hormone is associated with severe adverse effects in the majority of patients. Low-dose growth hormone increased energy absorption by approximately 1.8 MJ/day in a group of 12 short-bowel syndrome patients (9 with a preserved colon), but it did not affect wet-weight absorption. Growth hormone does not seem to affect either wet-weight or energy absorption in patients with a jejunostomy. GLP-2 and the analogue teduglutide mainly affect wet-weight absorption, resulting in a mean increase in wet-weight absorption of 0.4-0.7 kg/day. The effects on energy absorption are minor at 0.4-0.8 MJ/day. However, these effects are seen in all short-bowel syndrome patients, regardless of anatomy, and the adverse effects are minor. In all studies employing growth hormone or GLP-2, the effects are transient, disappearing when treatments are discontinued. With the need for long-term treatment, adverse effects and safety issues become important. Therefore, it is recommended that treatment is initiated in research settings only and that close monitoring of the long-term effects is a part of the protocol.

Topics: Body Composition; Body Weight; Creatinine; Drug Monitoring; Energy Intake; Glucagon-Like Peptide 2; Glucagon-Like Peptides; Glutamine; Growth Hormone; Humans; Hyperplasia; Intestinal Absorption; Intestinal Mucosa; Intestines; Peptides; Randomized Controlled Trials as Topic; Short Bowel Syndrome; Time Factors

Short bowel syndrome (SBS) is used to describe a condition of malabsorption and malnutrition resulting from the loss of absorptive area following massive small bowel resection. The key to improved clinical outcome after massive small bowel resection is the ability of the residual bowel to adapt. Although still in experimental stages, a major goal in the management of SBS may be the augmented use of growth factors to promote increased adaptation. A number of growth factors have been implicated in promoting the adaptation process. The best-described growth factors are reviewed: glucagon-like peptide-2 (GLP-2), epidermal growth factor (EGF), and growth hormone (GH). This article reviews the ability of recombinant GLP-2, EGF and GH to modulate structural and functional aspects of intestinal adaptation following small bowel resection. Although these growth factors have shown promise, small sample size, inconsistent measurement parameters and uncontrolled study designs have hampered the acquisition of strong data advocating the use of growth factor treatment for SBS. Multicenter trials using well-defined outcome measures to assess clinical efficacy are needed to direct the clinical indications, timing and duration of therapy and assess potential risks associated with growth factor therapies.

Topics: Adaptation, Physiological; Animals; Epidermal Growth Factor; Glucagon-Like Peptide 2; Glucagon-Like Peptides; Growth Hormone; Growth Substances; Humans; Intestines; Rats; Recombinant Proteins; Short Bowel Syndrome

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.

Topics: Animals; Central Nervous System; Enteric Nervous System; Gastrointestinal Hormones; Glucagon-Like Peptide 2; Glucagon-Like Peptide-2 Receptor; Glucagon-Like Peptides; Humans; Intestinal Absorption; Intestinal Mucosa; Intestine, Small; Malabsorption Syndromes; Postoperative Complications; Receptors, Glucagon; Short Bowel Syndrome

Diarrhoea, malabsorption and malnutrition characterise the short bowel syndrome. The underlying gastrointestinal disorders, the types of intestinal resections performed and the subsequent pathophysiological situations are reviewed. Recommended therapeutic measures in the postoperative period as well as in the rehabilitation of patients with short bowel syndrome are discussed in more detail. In the postoperative period, parenteral nutrition is essential followed by an enteral diet to stimulate bowel adaptation, reduce fluid loss and increase nutrient absorption. The final diet should be based on the anatomy of the retained bowel (presence or absence of a colon and ileum). The importance of the colon as a digestive organ in patients with short bowel and the need of a low-oxalate diet are underlined. The possible benefit of new treatment options (glutamine, growth hormone and glucagon-like peptide 2) is discussed. Both typical complications of the short bowel syndrome and management of these complications are presented.

Topics: Combined Modality Therapy; Enteral Nutrition; Glucagon-Like Peptide 2; Glucagon-Like Peptides; Glutamine; Growth Hormone; Humans; Intestinal Absorption; Jejunostomy; Oxalates; Parenteral Nutrition, Total; Postoperative Complications; Prognosis; Randomized Controlled Trials as Topic; Short Bowel Syndrome; Treatment Outcome; Water-Electrolyte Balance

The nutritional regulation of intestinal adaptation extends beyond the route of nutrient administration as specific nutrients are known to mediate the adaptive response. Dietary carbohydrates are known to enhance intestinal adaptation in patients with short-bowel syndrome. This review discusses SCFA-induced adaptation in intestinal structure and function in adult rat and neonatal piglet models. Potential mechanisms relate to the salvage of energy as SCFA in the colon, direct mediation of intestinal adaptation by SCFA and stimulated release of glucagon-like peptide-2 (GLP-2) from enteroendocrine L cells by SCFA. Among the produced SCFA, butyrate appears to be responsible for increasing plasma GLP-2 concentration, in addition to the enterotrophic effects. Emerging evidence reveals that physiological concentrations of butyrate acutely upregulate the expression of key enterocyte-associated nutrient transporters. Focused experiments are needed to carefully identify the critical components of intestinal adaptation and yield conclusions regarding the relative contributions of SCFA and GLP-2 during the various phases of this process.

Topics: Adaptation, Physiological; Animals; Butyrates; Fatty Acids, Volatile; Glucagon-Like Peptide 2; Glucagon-Like Peptides; Glucose Transporter Type 2; Humans; Intestines; Monosaccharide Transport Proteins; Peptides; Short Bowel Syndrome; Swine

Although long-term parenteral nutrition is lifesaving in patients with intestinal failure, it is expensive, severely impairs the quality of life in the short-bowel patients and is associated with serious complications such as catheter sepsis, venous occlusions and liver disease. Therefore, treatments that aim to minimize intestinal absorption, thereby eliminating or minimizing the need for parenteral support, are needed. As a result, glucagon-like peptide 2 (GLP-2) has received attention. In this review, the nature of short-bowel syndrome is described and the antisecretory, transit modulating and intestinotrophic effects of GLP-2 are presented. As illustrated in a pilot study, GLP-2 may prove to be important in the attempt to optimize remnant intestinal function thereby eliminating the need for parenteral support and improving quality of life in short-bowel patients with intestinal failure.

Topics: Adaptation, Physiological; Glucagon-Like Peptide 2; Glucagon-Like Peptides; Hormones; Humans; Intestines; Peptides; Short Bowel Syndrome

The intestine has an inherent ability to adapt morphologically and functionally in response to internal and external environmental changes. The functional adaptations encompass modifications of the brush border membrane fluidity and permeability, as well as up- or down-regulation of carrier-mediated transport. Intestinal adaptation improves the nutritional status following the loss of a major portion of the small intestine, following chronic ingestion of ethanol, following sublethal doses of abdominal irradiation, in diabetes, in pregnancy and lactation, with ageing, and with fasting and malnutrition. Following intestinal resection, morphological and functional changes occur depending upon the extent of the intestine removed, the site studied, and the lipid content of the diet. Therefore, intestinal adaptation has important implications in the survival potential and welfare of the host. An understanding of the mechanisms of, and signals for, intestinal adaptation in the experimental setting forms the basis for the use of management strategies in humans with the short-bowel syndrome.

Topics: Animals; Biomarkers; Disease Models, Animal; Epidermal Growth Factor; Glucagon-Like Peptides; Glucocorticoids; Glutamine; Growth Hormone; Humans; Insulin-Like Growth Factor I; Intestinal Absorption; Intestinal Mucosa; Intestines; Peptides; Short Bowel Syndrome

Patients who suffer from intestinal failure depend on parenteral support to maintain nutritional equilibrium. In this chapter, recommendations for evaluation the absorptive capacity of patients with intestinal failure are defined, and the evidence and magnitude of the effect of dietary and hormone therapy is given. Regarding dietary advice, the effects of employment of diets with various carbohydrate:fat ratios in short-bowel syndrome (SBS) patients with and without a preserved colon is presented. Focus has been placed on the use of growth hormone but also on the use of a novel intestinotrophic hormone, glucagon-like peptide 2, in the promotion of intestinal adaptation in SBS patients. Overall, the ultimate aim in the treatment of SBS patients is to optimize remnant intestinal function, thereby eliminating the need for parenteral support and improving quality of life in these patients.

Topics: Gastrointestinal Agents; Glucagon-Like Peptide 2; Glucagon-Like Peptides; Growth Hormone; Humans; Intestinal Absorption; Jejunostomy; Peptide Fragments; Short Bowel Syndrome

Topics: Glucagon-Like Peptide 2; Glucagon-Like Peptides; Humans; Peptides; Short Bowel Syndrome

NPS Allelix (formerly Allelix Biopharmaceuticals) is developing the glucagon-like peptide 2 (GLP-2) analog ALX-0600 for the potential treatment of gastrointestinal diseases, including short bowel disease. GLP stimulates the growth of the lining of the small intestine, thus increasing the absorptive area of the intestine [214370], [315107]. ALX-0600 also has potential for mucositis associated with cancer chemotherapy and inflammatory bowel disease [331459]. During the third quarter of 1999, a pilot phase II trial began for short bowel syndrome (SBS) [331459]. ALX-0600 began pivotal phase II trials in 2000 following the completion of the pilot trial which was designed to measure the safety, tolerability, and any other drug-related improvements in nutrient absorption and physical changes in the gut of a small number of patients with SBS. Allelix hopes to bring this drug to the market by 2001 [341519]. Allelix filed an application to the FDA for Orphan Drug designation in the third quarter of 1999 [331459]; in August, the designation was approved [377524]. As of November 1998, Allelix was in discussions with a potential marketing partner for worldwide development and marketing [305000]. In August 1998, the USPTO issued a notice of allowance to Allelix for its basic patent containing claims covering the composition and medical uses of ALX-0600 and related GI drug candidate compounds [2946571.

Topics: Amino Acid Sequence; Animals; Clinical Trials as Topic; Gastrointestinal Agents; Glucagon-Like Peptide 2; Glucagon-Like Peptides; Humans; Molecular Sequence Data; Peptides; Short Bowel Syndrome; Structure-Activity Relationship

The present article reviews the current literature on the role of diet and other trophic factors in the treatment of short-bowel syndrome. Results using glutamine, growth hormone and glucagon-like peptide 2 are reviewed. Although experimental animal data would suggest that various growth factors are of benefit in the treatment of short-bowel syndrome, only a few clinical studies have made the same claim.

Topics: Animals; Colon; Dietary Carbohydrates; Disease Models, Animal; Glucagon-Like Peptide 2; Glucagon-Like Peptides; Glutamine; Growth Substances; Humans; Intestine, Small; Peptides; Short Bowel Syndrome

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 peptide 2 (GLP-2) may improve intestinal absorption in short bowel syndrome (SBS) patients with an end jejunostomy. Teduglutide (ALX-0600), a dipeptidyl peptidase IV resistant GLP-2 analogue, prolongs the intestinotrophic properties of GLP-2 in animal models. The safety and effect of teduglutide were investigated in SBS patients with and without a colon in continuity.. Teduglutide was given subcutaneously for 21 days once or twice daily to 16 SBS patients in the per protocol investigational group, 10 with end jejunostomy (doses of 0.03 (n = 2), 0.10 (n = 5), or 0.15 (n = 3) mg/kg/day), one with <50% colon in continuity (dose 0.03 mg/kg/day), and five with > or = 50% colon in continuity (dose 0.10 mg/kg/day). Nutrient balance studies, D-xylose tests, and intestinal mucosa biopsies were performed at baseline, on the last three days of treatment, and after three weeks of follow up. Pre-study fasting native GLP-2 levels were determined for the five patients with > or = 50% colon in continuity.. Pooled across groups and compared with baseline, teduglutide increased absolute (+743 (477) g/day; p<0.001) and relative (+22 (16)%; p<0.001) wet weight absorption, urine weight (+555 (485) g/day; p<0.001), and urine sodium excretion (+53 (40) mmol/day; p<0.001). Teduglutide decreased faecal wet weight (-711 (734) g/day; p = 0.001) and faecal energy excretion (-808 (1453) kJ/day (-193 (347) kcal/day); p = 0.040). In SBS patients with end jejunostomy, teduglutide significantly increased villus height (+38 (45)%; p = 0.030), crypt depth (+22 (18)%; p = 0.010), and mitotic index (+115 (108)%; p = 0.010). Crypt depth and mitotic index did not change in colonic biopsies from SBS patients with colon in continuity. The most common side effects were enlargement of the stoma nipple and mild lower leg oedema. The improvements in intestinal absorption and decreases in faecal excretion noted after treatment had reversed after the drug free follow up period. A controlled study with a more robust design is ongoing in order to determine the optimal dosage of teduglutide for SBS patients to achieve the maximal effect and utility of this drug in clinical practice.. Teduglutide, at three dose levels for 21 days, was safe and well tolerated, intestinotrophic, and significantly increased intestinal wet weight absorption in SBS patients with an end jejunostomy or a colon in continuity.

Topics: Adult; Aged; Colon; Drug Administration Schedule; Female; Gastrointestinal Agents; Glucagon-Like Peptide 2; Glucagon-Like Peptides; Humans; Intestinal Absorption; Jejunostomy; Jejunum; Male; Middle Aged; Mitotic Index; Pilot Projects; Short Bowel Syndrome

Glucagon-like peptide 2 (GLP-2) is intestinotrophic, antisecretory, and transit-modulating in rodents, and it is mainly secreted from the intestinal mucosa of the terminal ileum and colon after food ingestion. We assessed the effect of GLP-2 on the gastrointestinal function in patients without a terminal ileum and colon who have functional short-bowel syndrome with severe malabsorption of wet weight (>1.5 kg/day) and energy (>2.3 MJ/day) and no postprandial secretion of GLP-2.. Balance studies were performed before and after treatment with GLP-2, 400 microg subcutaneously twice a day for 35 days, in 8 patients (4-17 years from last bowel resection; 6 with Crohn's disease). Four patients received home parenteral nutrition (mean residual jejunum, 83 cm), and 4 did not (mean ileum resection, 106 cm). Biopsy specimens were taken from jejunal/ileal stomas, transit was measured by scintigraphy, and body composition was measured by dual-energy x-ray absorptiometry.. Treatment with GLP-2 improved the intestinal absorption of energy 3.5% +/- 4.0% (mean +/- SD) from 49.9% to 53.4% (P = 0.04), wet weight 11% +/- 12% from 25% to 36% (P = 0.04), and nitrogen 4.7% +/- 5.4% from 47.4% to 52.1% (P = 0.04). Body weight increased 1.2 +/- 1.0 kg (P = 0.01), lean body mass increased 2.9 +/- 1.9 kg (P = 0.004), fat mass decreased 1.8 +/- 1.3 kg (P = 0.007), and 24-hour urine creatinine excretion increased (P = 0.02). The time to 50% gastric emptying of solids increased 30 +/- 16 minutes from 89 to 119 minutes (P < 0.05). Small bowel transit time was not changed. Crypt depth and villus height were increased in 5 and 6 patients, respectively.. Treatment with GLP-2 improves intestinal absorption and nutritional status in short-bowel patients with impaired postprandial GLP-2 secretion in whom the terminal ileum and the colon have been resected.

Topics: Adult; Body Composition; Body Weight; Creatinine; Female; Gastrointestinal Hormones; Gastrointestinal Transit; Glucagon-Like Peptide 2; Glucagon-Like Peptides; Hormones; Humans; Injections, Subcutaneous; Intestinal Absorption; Intestines; Male; Middle Aged; Nutritional Status; Patient Compliance; Peptides; Short Bowel Syndrome

Short bowel syndrome is a low-incidence disorder among pediatric patients, but it is associated with high morbidity and mortality rates. Management of these patients by an interdisciplinary team of experts focused on intestinal rehabilitation improves short- and long-term outcomes. Available resources for treatment include teduglutide, a glucagon-like peptide type 2 (GLP-2) analog made by recombinant techniques. Considering the available evidence and the authors' experience, Delphi-based recommendations for the use of teduglutide are suggested for healthcare professionals who treat pediatric patients with short bowel syndrome, as well as for health authorities.. El síndrome de intestino corto es una entidad de baja incidencia en los pacientes pediátricos, pero se asocia con elevadas tasas de morbimortalidad. El abordaje de estos pacientes por un equipo interdisciplinario de expertos enfocados en la rehabilitación intestinal mejora los resultados a corto y a largo plazo. Entre los recursos disponibles para el tratamiento se incluye el teduglutide, un análogo del péptido similar al glucagón tipo 2 (GLP-2) elaborado mediante técnicas recombinantes. Por medio de la aplicación del método Delphi, a partir de la evidencia disponible y de la experiencia de los autores, se proponen recomendaciones para el uso de teduglutide, dirigidas a los profesionales de la salud que tratan a los pacientes pediátricos con síndrome de intestino corto, así como a las autoridades sanitarias.

Topics: Child; Glucagon-Like Peptide 2; Glucagon-Like Peptides; Humans; Peptides; Short Bowel Syndrome

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

Topics: Glucagon-Like Peptides; Humans; Parenteral Nutrition; Short Bowel Syndrome

Glucagon-like peptide-2 (GLP-2) is an enteroendocrine hormone which is uniquely trophic for the intestine; a physiological role in regulating nutrient absorptive capacity is becoming apparent. GLP-2, independent of enteral feeding, stimulates a classical pattern of intestinal adaptation in terminal ileum following resection. Herein we investigate the effects of GLP-2 on the jejunal remant using a rat model of short bowel syndrome (SBS). Juvenile 250- to 275-g SD rats underwent 80% distal small bowel resection, leaving 20 cm of proximal jejunum and venous catheterization. Animals were maintained with total parenteral nutrition (TPN) or TPN+10 microg/kg/hr GLP-2 (n=8 per group). After 7 days, intestinal permeability was assessed by urinary recovery of gavaged carbohydrate probes. Animals were euthanized, and the intestines taken for analysis of morphology, crypt cell proliferation, apoptosis, and expression of SGLT-1 and GLUT-5 transport proteins. GLP-2 treatment reduced intestinal permeability and increased in vivo glucose absorption, small intestinal weight, surface area, villus height, crypt depth, and microvillus height. Intestinal mucosal DNA and protein content per unit length of the small bowel were increased (P < 0.05 for all comparisons). However, in contrast to previous studies examining GLP-2's effects on remnant ileum, the jejunal crypt apoptotic index was increased in GLP-2-treated animals, with no increase in SGLT-1 or GLUT 5 expression. These results show that exogenous GLP-2 treatment of animals with jejunal remnant reduces intestinal permeability, increases glucose absorption, and stimulates morphological features of intestinal adaptation including increased micovillus height and surface area. However, the pattern of changes seen is different from that in remnant ileum. This suggests that GLP-2's effects are specific to different regions of the bowel. Nonetheless, remnant jejunum is responsive to GLP-2 in the absence of enteral nutrition. Further studies are warranted to establish the mechanisms of action and therapeutic potential of GLP-2 in modulating nutrient absorptive capacity.

Topics: Adaptation, Physiological; Animals; Apoptosis; Caspase 3; Caspases; Cell Proliferation; Disease Models, Animal; Glucagon-Like Peptide 2; Glucagon-Like Peptides; Glucose Transporter Type 5; Ileum; Intestinal Absorption; Intestinal Mucosa; Jejunum; Male; Rats; Rats, Sprague-Dawley; Short Bowel Syndrome

Glucagon-like peptide-2 (GLP-2) is an enteroendocrine peptide that is released in response to luminal nutrients and has unique trophic actions in the gastrointestinal tract. These features suggest GLP-2 may be important in controlling intestinal adaptation. We examined the relationship over time of GLP-2 production and adaptation to intestinal resection, the effects of resection-induced malabsorption on GLP-2 production, and the correlation of endogenous serum GLP-2 levels with adaptation as measured by crypt-cell proliferation (CCP). We initially examined the effect of nutrient malabsorption, induced by a 90% resection of the proximal intestine studied on day 4, on the time course and levels of GLP-2 release. Secondly, the degree of malabsorption was varied by performing intestinal transection or 50, 75, or 90% resection of proximal small intestine. Finally, the relationship of GLP-2 levels over time with adaptation to a 90% resection was examined by determining GLP-2 levels on days 7, 14, and 28, and correlating this with intestinal adaptation, as assessed by morphology and CCP rate. A 90% resection significantly increased basal and postprandial GLP-2 levels, with a net increase in nutrient-stimulated exposure over 90 min; GLP-2 exposure (integrated levels vs. time) increased 12.7-fold in resected animals (P < 0.001). Basal and postprandial GLP-2 levels significantly correlated with the magnitude of intestinal resection (r(2) = 0.71; P < 0.001), CCP (r(2) = 0.48; P < 0.005), and nutrient malabsorption (protein, P < 0.001; fat, P < 0.005). The increase in CCP was maintained to 28 days after small bowel resection and was associated with an ongoing elevation in GLP-2 release. These findings suggest that GLP-2 is important in initiating and maintaining the small intestinal adaptive response to resection.

Topics: Adaptation, Physiological; Animals; Antimetabolites; Body Weight; Bromodeoxyuridine; Cell Proliferation; Dietary Fats; Dietary Proteins; Enzyme-Linked Immunosorbent Assay; Food; Glucagon-Like Peptide 2; Glucagon-Like Peptides; Intestinal Absorption; Intestinal Mucosa; Intestines; Male; Peptides; Rats; Rats, Sprague-Dawley; Short Bowel Syndrome

Glucagon-like peptide-2 (GLP-2) is an intestinal trophic enteroendocrine peptide that is associated with intestinal adaptation following resection. Herein, we investigate the effects of GLP-2 in a total parenteral nutrition (TPN)-supported model of experimental short bowel syndrome. Juvenile Sprague-Dawley rats underwent a 90% small intestinal resection and jugular catheter insertion. Rats were randomized to three groups: enteral diet and intravenous saline infusion, TPN only, or TPN + 10 microg.kg(-1).h(-1) GLP-2. Nutritional maintenance was isocaloric and isonitrogenous. After 7 days, intestinal permeability was assessed by quantifying the urinary recovery of gavaged carbohydrate probes. The following day, animals were euthanized, and intestinal tissue was processed for morphological and crypt cell proliferation (CCP) analysis, apoptosis (caspase-3), and expression of SGLT-1 and GLUT-5 transport proteins. TPN plus GLP-2 treatment resulted in increased bowel and body weight, villus height, intestinal mucosal surface area, CCP, and reduced intestinal permeability compared with the TPN alone animals (P < 0.05). GLP-2 treatment induced increases in serum GLP-2 levels and intestinal SGLT-1 expression (P < 0.01) compared with either TPN or enteral groups. No differences were seen in the villus apoptotic index between resection groups. Enterally fed resected animals had a significant decrease in crypt apoptotic indexes compared with nontreated animals. This study demonstrates that GLP-2 alone, without enteral feeding, stimulates indexes of intestinal adaptation. Secondly, villus hypertrophy associated with adaptation was predominantly due to an increase in CCP and not to changes in apoptotic rates. Further studies are warranted to establish the mechanisms of action and therapeutic potential of GLP-2.

Topics: Adaptation, Physiological; Animals; Caspase 3; Caspases; Cell Division; Enzyme Activation; Glucagon-Like Peptide 2; Glucagon-Like Peptides; Humans; Ileum; Intestinal Absorption; Intestinal Mucosa; Intestines; Male; Membrane Glycoproteins; Monosaccharide Transport Proteins; Parenteral Nutrition, Total; Peptides; Permeability; Rats; Rats, Sprague-Dawley; Recombinant Proteins; Short Bowel Syndrome; Sodium-Glucose Transporter 1

Adaptation of the residual small bowel following resection is dependent on luminal and humoral factors. We aimed to establish if circulating levels of glucagon-like peptide (GLP-2) change under different dietary regimens following resection and to determine if there is a relationship between plasma GLP-2 levels and markers of intestinal adaptation. Four-week-old piglets underwent a 75% proximal small bowel resection (n = 31) or transection (n = 14). Postoperatively they received either pig chow (n = 14), nonpolymeric (elemental) infant formula (n = 7), or polymeric infant formula alone (n = 8) or supplemented either with fiber (n = 6) or with bovine colostrum protein concentrate (CPC; n = 10) for 8 weeks until sacrifice. Plasma GLP-2 levels were measured at weeks 0, 2, 4, and 8 postoperatively. In addition, end-stage parameters were studied at week 8 including weight gain, ileal villus height, crypt depth, and disaccharidase levels. Plasma GLP-2 levels were higher in resected animals compared to transected animals fed the same diet. Plasma GLP-2 levels were significantly increased in the colostrum protein isolate-supplemented animals following resection compared to all other diet groups. The increase in plasma GLP-2 (pM) was greatest in the first 2 weeks postresection (week 0, 15.5; week 2, 30.9), followed by a plateau at weeks 2 to 4 and a decrease in GLP-2 levels from week 4 to week 8. At week 8, no relationships were found between the plasma GLP-2 levels and the measurements of weight gain, villus height, lactase, sucrase, maltase, crypt depth, or villus/crypt ratio. Plasma GLP-2 levels increase in the first weeks following massive small intestinal resection. The increase in plasma GLP-2 levels was enhanced by supplementation of the diet with CPC. The changes in GLP-2 levels observed in this study may suggest that GLP-2 plays a role in the adaptive response in the intestine following resection in this preclinical model.

Topics: Adaptation, Physiological; Animals; Diet; Dietary Supplements; Disease Models, Animal; Energy Intake; Female; Glucagon-Like Peptide 2; Glucagon-Like Peptides; Intestine, Small; Peptides; Postoperative Period; Short Bowel Syndrome; Swine

Glucagon-like peptide 2 (GLP-2) is a newly discovered intestinotrophic hormone. We have recently reported that a 5-week GLP-2 treatment improved the intestinal absorptive capacity of short-bowel patients with no colon. Additionally, GLP-2 treatment was associated with changes in body composition that included a significant increase in total body bone mass. This article describes the effect of GLP-2 on spinal and hip bone mineral density (BMD) and biochemical markers of bone turnover in these patients.. In an open-labelled pilot study, eight short-bowel patients (3M, 5F; mean age 49 years) with small-bowel resection and no colon received 400 microg s.c. of GLP-2 twice daily for 5 weeks. Four received home parenteral nutrition (mean length of residual jejunum 83 cm) and 4 did not (mean length of ileum resected 106 cm). The outcome measures were the mean percent change from baseline in spinal and hip BMD measured by dual-energy X-ray absorptiometry, changes in four biochemical markers of bone-turnover, PTH, 25-hydroxy vitamin-D, and the intestinal absorption of calcium.. Mean +/- s(x) (SEM) percent changes in spinal and hip BMD were 1.1+/-0.4% (P < 0.05) and 1.9+/-0.8% (P = 0.06), respectively. The intestinal calcium absorption increased by 2.7% (P = 0.87). Serum ionized calcium increased in 5/8 patients with a concomitant decrease in serum PTH values. Three of the four markers of bone turnover decreased.. A 5-week GLP-2 administration significantly increased spinal BMD in short-bowel patients with no colon. The mechanism by which GLP-2 affects bone metabolism remains unclear, but may be related to an increased mineralization of bone resulting from an improved intestinal calcium absorption.

Topics: Absorptiometry, Photon; Adult; Alkaline Phosphatase; Amino Acids; Bone Density; Bone Diseases, Metabolic; Bone Remodeling; Calcium; Female; Gastrointestinal Hormones; Glucagon; Glucagon-Like Peptide 2; Glucagon-Like Peptides; Hormones; Humans; Intestinal Absorption; Male; Middle Aged; Osteocalcin; Osteoporosis; Parathyroid Hormone; Peptides; Pilot Projects; Short Bowel Syndrome; Vitamin D

Glucagonlike peptide 2 (GLP-2) is trophic for the small bowel; it is produced by L cells in the distal intestine in response to luminal nutrients. This study tests the hypothesis that distal small bowel and cecal resection would decrease GLP-2 levels and reduce adaptation.. Male Sprague-Dawley rats (200 to 300 g) underwent either ileal transection (controls) or resection of the ileum and cecum, leaving 10 or 20 cm jejunal remnant anastomosed to the ascending colon. Animals were followed up for up to 21 days. Endpoints were daily weights, intestinal histology, in vivo absorption of 3-0 methylglucose (a measurement of active nutrient absorptive capacity), and serum GLP-2 levels.. The control group had a maximum 6% weight loss around day 2, and then recovered with a steady weight gain. The 10-cm jejunal remnant group lost weight continuously and never recovered postsurgery. The 20-cm jejunal remnant group of animals had a maximum of 12% weight loss by day 4 and then slowly gained weight. The average villus height increased significantly (P <.01) in the 10-cm and 20-cm jejunal remnant groups compared with controls. Absorption of 3-0 methylglucose was significantly decreased (P <.01) in both resected groups. Serum GLP-2 levels were increased significantly (P <.05) when compared with controls in both resection groups.. Increased serum GLP-2 levels were found in the ileocecal resection rat model, and these levels correlated with morphologic adaptation. However, this morphologic adaptation was not sufficient to restore nutrient absorption as shown by weight changes and 3-0 methylglucose absorption. Thus, the original hypothesis of this study is incorrect: systemic GLP-2 levels do not limit adaptation following distal ileocecal resection.

Topics: 3-O-Methylglucose; Adaptation, Physiological; Animals; Body Weight; Cecum; Disease Models, Animal; Enteroendocrine Cells; Glucagon-Like Peptide 2; Glucagon-Like Peptides; Ileum; Intestinal Absorption; Jejunum; Male; Peptides; Rats; Rats, Sprague-Dawley; Short Bowel Syndrome

Topics: Gastrointestinal Hormones; Glucagon-Like Peptide 2; Glucagon-Like Peptides; Humans; Peptides; Short Bowel Syndrome

Treatment of short bowel syndrome (SBS) can be difficult; this study examines the effect of parental administration of different peptide hormones in a rat model of SBS.. Juvenile male Lewis rats (220 to 240 g) underwent resection of the proximal 90% of small bowel and were assigned randomly to treatment groups: growth hormone (GH), insulinlike growth factor-1 (IGF-1), glucagonlike peptide-2 (GLP-2; given as ALX-0600, a potent protease resistant analogue of the human GLP-2), control-resected (Con-R), or control-transected (Con-T). Drugs were delivered by continuous subcutaneous infusion via Alzet mini-pumps: controls received equivalent volumes of drug vehicle. Animals were pair-fed (23 g chow per day) and followed up for 14 days monitoring weight gain. Animals were killed and active transport, hormone profiles, and intestinal morphology were assessed.. Hormonal treatments significantly increased weight gain in all groups (GH, 9.9+/-4.9; IGF-1, 6.0+/-9.6; and GLP-2, 0.8+/-2.7 v. -6.2+/-4.7 in untreated resected animals [weight as percentile initial weight]). This was associated with a significant alteration in intestinal morphology in the IGF-1-treated animals, and an increase in glucose transport rates in all hormonally treated animals when compared with untreated control resected animals.. These results show that IGF-1, GH, and GLP-2 all improve short-term weight gain after massive bowel resection in a rat model. The effects seen on weight gain may be caused by improved dietary nutrient absorption from an increase in the intestinal surface area or increase in transporting activity or alterations in the metabolic efficiency of the animal. These findings suggest further studies of these therapies as treatment for short-bowel syndrome are indicated.

Topics: Animals; Evaluation Studies as Topic; Gastrointestinal Hormones; Glucagon-Like Peptide 2; Glucagon-Like Peptides; Growth Substances; Insulin-Like Growth Factor I; Intestinal Absorption; Male; Organ Size; Peptides; Random Allocation; Rats; Rats, Inbred Lew; Short Bowel Syndrome

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

Topics: Gastrointestinal Hormones; Glucagon; Glucagon-Like Peptides; Humans; Peptides; Short Bowel Syndrome

Glucagon-like peptide 2 (GLP-2) is a growth factor for the intestinal epithelium in rodents and may affect intestinal transit.. To study the GLP-2 response to nutrient ingestion in seven short bowel patients with intestinal failure and seven controls.. The patients and controls were admitted twice for two test meals after a night of fasting. Meal A was liquid (300 ml, 1.88 MJ); meal B was a regular breakfast (755 g, 3.92 MJ). Plasma samples were collected for 180 minutes; GLP-2 immunoreactivity was measured with an NH(2) terminal specific radioimmunoassay.. Both meals elicited significant increases in plasma GLP-2 in controls. The magnitude and duration of the responses were dependent on the meal size: the maximum median (25-75%) increases after meal A and B were 24 (3-28) and 48 (33-56) pmol/l. Plasma GLP-2 returned to basal concentrations 180 minutes after meal A, but remained at 50% of peak values after meal B. In the patients neither meal significantly changed the GLP-2 concentration; the maximum median elevation after meal B was 5 (2-8) pmol/l. There were significant differences between patients and controls with respect to the GLP-2 responses to meals A and B.. Identification of GLP-2 as a tissue specific intestinal growth factor and demonstration of an impaired meal stimulated GLP-2 response in short bowel patients raises the possibility that GLP-2 administration may constitute a new therapeutic strategy, enhancing jejunal adaptation in ileum resected short bowel patients with intestinal failure.

Topics: Adult; Aged; Case-Control Studies; Fasting; Female; Food; Gastrointestinal Hormones; Glucagon-Like Peptide 2; Glucagon-Like Peptides; Humans; Ileum; Jejunostomy; Male; Middle Aged; Peptides; Short Bowel Syndrome

The trophic effect of the administration of exogenous neurotensin on the intestinal mucosa was studied in rats following an 80% bowel resection. Villus length and mucosal DNA content were assessed in the jejunal and ileal mucosa of the remnant intestine 14 days after resection. The data obtained in an 80% resected control group (80% group) and an experimental group receiving an infusion of neurotensin (300 micrograms/kg/day) for 14 days subcutaneously (80% + NT group) were compared. The results indicate that the administration of exogenous neurotensin (80% + NT) increases villus length (jejunum: 920 +/- 77 vs 861 +/- 25 microns and ileum length: 975 +/- 23 vs 875 +/- 99 microns) to an extent greater than that observed in the 80% resected group not receiving exogenous neurotensin. The levels of mucosal DNA per milligram of protein increased significantly in both groups but was paradoxically less in the 80% + NT group than in the 80% resection group (jejunum: 8.12 +/- 0.56 vs 10.18 +/- 0.80; ileum: 8.63 +/- 0.43 vs 10.05 +/- 0.46). These data suggest that the administration of exogenous neurotensin to the rat potentiates the growth of intestinal villi and accelerates the intestinal trophic response seen following massive bowel resection. The increase in circulating enteroglucagon levels noted after neurotensin administration (80% + NT: 547 +/- 48 pg/ml vs 80%: 341 +/- 41 pg/ml) suggests that some of the trophic effects of neurotensin may be mediated, at least in part, by enteroglucagon. These data also suggest a potential role for the use of neurotensin in the initial treatment of individuals with short bowel syndrome.

Topics: Adaptation, Physiological; Animals; Glucagon-Like Peptides; Ileum; Intestinal Mucosa; Jejunum; Neurotensin; Parenteral Nutrition, Total; Rats; Rats, Wistar; Short Bowel Syndrome