glucagon-like-peptide-2 and Chronic-Disease

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

Teduglutide, a glucagon-like peptide 2 (GLP-2) analog, is an approved medication specific for short bowel syndrome patients with chronic intestinal failure (SBS-IF). Due to its intestinotrophic properties, it improves intestinal absorption of fluids and nutrients, which was shown to reduce the need for parenteral support in clinical trials. The present report aims to describe the experience of teduglutide's effects in routine medical care with focus on clinical and nutritional effects.. Data of adult SBS-IF patients, treated with teduglutide between Sept. 2014 and May 2017 within a structured multidisciplinary program to enhance intestinal rehabilitation, were analyzed retrospectively from a single university medical center.. In total, 27 patients were treated with teduglutide. Parenteral nutrition independency was achieved in 4/19 (21%) patients analyzed, with two remaining on intravenous fluids. A clinically significant reduction of parenteral volume was observed in 15/19 patients (79%) with onset between 1 and 45 weeks. Significant parenteral support reductions were observed, ranging from about -20% in patients treated for 3 months to about -45% in patients treated for 2 years. This was accompanied by an increase in parenteral nutrition-free days. We also report on a clinically relevant and significant effect of teduglutide-mediated improvement of stool frequency and consistency. Furthermore, nutritional status subgroup analysis revealed long-term stability in body weight, albumin levels and body composition albeit parenteral support reduction. Structural effects of teduglutide treatment were observed on small intestinal mucosa with significantly increased villus height, crypt depth and plasma citrulline levels.. Teduglutide can be applied to anatomically and clinically heterogeneous SBS-IF patients and results in an adaptive response with variable time and effect range in routine medical care. Teduglutide-induced functional and structural changes bring on a gradual reduction of parenteral support at no cost to body composition and suggest an improved intestinal function with compensatory effect on nutritional status.

Topics: Adult; Aged; Aged, 80 and over; Chronic Disease; Female; Gastrointestinal Agents; Glucagon-Like Peptide 2; Humans; Intestines; Male; Middle Aged; Nutritional Status; Parenteral Nutrition; Peptides; Retrospective Studies; Short Bowel Syndrome; Young Adult

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

The rapid degradation of porcine glucagon-like peptide-2 (pGLP-2) by the enzyme dipeptidyl peptidase-IV (DPP-IV) is the main impediment in the development of pGLP-2 as a potential therapeutic agent for intestinal dysfunction and damage. In this study, one mono-modified Lys(30)-polyethylene glycol (PEG)-pGLP-2 was prepared using mPEG-succinimidyl propionate. To determine the optimized condition for PEGylation, the reactions were monitored by RP-HPLC and MALDI-TOF-MS. Stability was tested in purified DPP-IV in vitro. In vivo, the protective effects for colonic injury were measured in dextran sulfate sodium (DSS)-induced colitis in mice. The monoPEGylated products reached the maximum yield at 4:1 ratio of mPEG5k-SPA to pGLP-2. An effective method of successfully separating PEGylated pGLP-2 from mPEG-SPA5kD using CM Sepharose Fast Flow resin was established. The half-life of Lys(30)-PEG-pGLP-2 was 16-fold longer than that of pGLP-2 in DPP-IV. The DSS mice exhibited marked weight loss), which was significantly reduced by Lys(30)-PEG-pGLP-2 therapy. DSS treatment significantly increased colonic damage score, which was significantly reduced by administration of Lys(30)-PEG-pGLP-2 in DSS-mice. DSS-induced colitis clearly induced Myeloperoxidase activity in the colon, which was significantly reduced by treatments with 3% DSS-pGLP-2 or 3% DSS-PEG-pGLP-2. These results showed that site-specific Lys(30)-PEG-GLP-2 was resistant to degradation and reduced the severity of colonic injury in murine colitis. The enhanced biological potency of this product highlighted its potential as a therapeutic agent for intestinal diseases.

Topics: Animals; Chronic Disease; Colitis; Colon; Dextran Sulfate; Disease Models, Animal; Glucagon-Like Peptide 2; Male; Mice; Mice, Inbred BALB C; Polyethylene Glycols; Swine

Type 2 diabetes mellitus (DM2) is associated with small intestinal hyperplasia and hypertrophy in rodents. Moreover, the small intestine is increasingly acknowledged to play a role in the pathophysiology of DM2.. The objective of the study was to investigate the relation between plasma markers of small intestinal function and chronic hyperglycemia in man.. We conducted a cross-sectional observational study of 40 severely obese subjects with chronic hyperglycemia and 30 severely obese subjects without chronic hyperglycemia who were indicated for bariatric surgery.. We assessed plasma levels of citrulline, representing small intestinal enterocyte mass, intestinal fatty acid binding protein (I-FABP), a marker of enterocyte loss, and glucagon-like peptide-2, an intestinotrophic factor, and related them to glycated hemoglobin (HbA(1c)) levels.. Plasma citrulline and I-FABP levels were both significantly elevated in subjects with chronic hyperglycemia (HbA(1c) > 6.0%) compared with subjects with a normal HbA(1c) (≤ 6.0%) (citrulline, 35 ± 2.1 μm vs. 26 ± 1.4 μm, P = 0.001; I-FABP, 140 ± 22 pg/ml vs. 69 ± 14 pg/ml, P = 0.001). Moreover, plasma citrulline and I-FABP levels correlated with HbA(1c) levels (citrulline, r(s) = 0.30, P = 0.02; I-FABP, r(s) = 0.33, P = 0.005). The I-FABP to citrulline ratio was higher in subjects with an elevated HbA(1c) (4.0 vs. 3.1, P = 0.03). Plasma glucagon-like peptide-2 levels were not related to citrulline or I-FABP levels (r(s) = 0.06, P = 0.67; r(s) 0.08, P = 0.54, respectively).. Chronically elevated glucose levels in obese individuals are associated with increased small intestinal enterocyte mass and increased enterocyte loss. These findings argue for the further exploration of the role of the intestine in the pathophysiology of DM2.

Topics: Adult; Biopsy; Cell Proliferation; Chronic Disease; Citrulline; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Enterocytes; Fatty Acid-Binding Proteins; Female; Glucagon-Like Peptide 2; Glycated Hemoglobin; Humans; Hyperglycemia; Intestine, Small; Male; Obesity; Organ Size; Reverse Transcriptase Polymerase Chain Reaction

Acute and/or chronic radiation enteritis can develop after radiotherapy for pelvic cancers. Experimental and clinical observations have provided evidence of a role played by acute mucosal disruption in the appearance of late effects. The therapeutic potential of acute administration of glucagon-like peptide-2 (GLP-2) against acute and chronic intestinal injury was investigated in this study.. Intestinal segments were surgically exteriorized and exposed to 16.7 or 19 Gy X-rays. The rats were treated once daily with vehicle or a protease-resistant GLP-2 derivative for 14 days before irradiation, with or without 7 days of GLP-2 after treatment. Macroscopic and microscopic observations were made 2 and 15 weeks after radiation exposure.. In the control animals, GLP-2 induced an increase in intestinal mucosal mass, along with an increase in villus height and crypt depth. GLP-2 administration before and after irradiation completely prevented the acute radiation-induced mucosal ulcerations observed after exposure to 16.7 Gy. GLP-2 treatment strikingly reduced the late radiation damage observed after 19 Gy irradiation. Microscopic observations revealed an improved organization of the intestinal wall and an efficient wound healing process, especially in the smooth muscle layers.. GLP-2 has a clear therapeutic potential against both acute and chronic radiation enteritis. This therapeutic effect is mediated through an increased mucosal mass before tissue injury and the stimulation of still unknown mechanisms of tissue response to radiation damage. Although these preliminary results still need to be confirmed, GLP-2 might be a way to limit patient discomfort during radiotherapy and reduce the risk of consequential late effects.

Topics: Acute Disease; Animals; Chronic Disease; Drug Evaluation, Preclinical; Enteritis; Glucagon-Like Peptide 2; Intestinal Mucosa; Intestine, Small; Male; Radiation Injuries, Experimental; Rats; Rats, Wistar