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Key Clinical Message: Amyloidosis is a heterogeneous disease characterized by tissue deposition of abnormally folded fibrillary proteins that can manifest itself by a wide variety of symptoms depending on the affected organs. GI involvement among amyloidosis patients is common. Its clinical manifestation often presents with nonspecific symptoms such as weight loss, diarrhea, and malabsorption. With no specific treatment existing for GI amyloidosis, therapy focuses on impeding amyloid deposition and managing the patients' symptoms with supportive measures. Here, we present an AL‐amyloidosis patient with GI involvement and intestinal failure (IF) who was successfully treated with the glucagon‐like peptide‐2 (GLP‐2) analogue teduglutide. Over the course of treatment with teduglutide, the patient was able to achieve independence from parenteral nutrition and experienced a significant improvement in quality of life (QoL) as stool frequency and consistency improved, urinary output was stabilized and body weight as well as body composition improved over the course of teduglutide therapy. With no longer being exposed to the burden and associated risks of parenteral nutrition, we were able to reduce the potential morbidity and mortality rate as well as to improve the patient's overall QoL. Intestinal tissue biopsy workup revealed a histopathological correlate for the clinical response; Congo‐Red‐positive intestinal depositions almost completely disappeared within 6 months of teduglutide therapy. Implementing intestinotrophic GLP‐2 analogue teduglutide may enrich the spectrum of treatment options for amyloidosis patients with IF who are dependent on parenteral support. [ABSTRACT FROM AUTHOR]

Background: The proadaptive effects of glucagon‐like peptide‐2 (GLP‐2) include stimulation of intestinal mucosal growth as well as intestinal blood flow and angiogenesis. We have recently reported that daily subcutaneous injections of glepaglutide, a long‐acting GLP‐2 analog, improved intestinal absorptive function in patients with short bowel syndrome (SBS). As secondary and exploratory end points, the effects of glepaglutide on intestinal morphology and perfusion are reported. Methods: The following assessments were done in 18 patients with SBS in a randomized, crossover, dose‐finding, phase 2 trial before and after three weeks of treatment with glepaglutide: plasma citrulline and mucosa biopsies to assess changes in (1) intestinal morphology by immunohistochemistry and (2) gene expressions associated with absorption, proliferation, and markers of tight‐junction integrity by quantitative polymerase chain reaction. Intestinal perfusion was assessed in stoma nipples by laser speckle contrast imaging and quantitative fluorescence angiography with indocyanine green. Results: In the 1‐ and 10‐mg dose groups, glepaglutide significantly increased plasma citrulline by 15.3 µmol/L (P = 0.001) and 15.6 µmol/L (P = 0.001), respectively. Trends toward an increase in villus height, crypt depth, and epithelium height were seen in the same groups. No significant changes were seen in gene expressions or intestinal perfusion. Conclusion: The increase in plasma citrulline and the morphological improvements may partly account for improvement in the intestinal absorptive function. However, the finding of a stability in perfusion after three weeks of treatment with glepaglutide may have been preceded by a more profound acute‐phase increase in intestinal perfusion at treatment initiation. [ABSTRACT FROM AUTHOR]

Background: The gut‐liver axis and enterohepatic circulation have gained increasing attention lately. Patients with short bowel syndrome (SBS) are, in fact, human knock‐out models that may assist in the understanding of bile acid synthesis and regulation. We evaluated effect of glepaglutide (a long‐acting glucagon‐like peptide‐2 analog) on bile acid synthesis (the enterohepatic circulation of bile acids and liver biochemistry in patients with SBS). Method: In a single‐center, double‐blinded, dose‐finding, crossover phase 2 trial, 18 patients with SBS were randomly assigned to 2 of 3 treatment arms (0.1, 1, and 10 mg) with daily subcutaneous injections of glepaglutide for 3 weeks. The washout period between the 2 treatment periods was 4–8 weeks. Measurements were performed at baseline and at the end of each treatment period and included postprandial plasma samples for fibroblast growth factor 19 (FGF19), 7α‐hydroxy‐4‐cholesten‐3‐one (C4), total excretion of fecal bile acids, gene expression of farnesoid X receptor (FXR) in intestinal mucosal biopsies, total plasma bile acids, and liver biochemistry. Results: Compared with baseline, the median (interquartile range) postprandial response (area under the curve 0–2h) of FGF19 increased by 150 h × ng/L (41, 195; P = 0.001) and C4 decreased by 82 h × µg/L (−169, −28; p = 0.010) in the 10‐mg dose. FXR gene expression did not change in any of the groups. Alkaline phosphatase significantly decreased. Conclusion: Glepaglutide may stimulate the bile acid/FXR/FGF19 axis, leading to increased plasma concentrations of FGF19. Thereby, glepaglutide may ameliorate the accelerated de novo bile acid synthesis and play a role in the prevention and/or treatment of intestinal failure–associated liver disease. [ABSTRACT FROM AUTHOR]

Background: Treatment with glucagon‐like peptide‐2 (GLP‐2) analogs improve intestinal adaptation in patients with short bowel syndrome–associated intestinal failure (SBS‐IF) and may reduce parenteral support requirements. Apraglutide is a novel, long‐acting GLP‐2 analog designed for once‐weekly dosing. This trial investigated the safety and efficacy of apraglutide in patients with SBS‐IF. Methods: In this placebo‐controlled, double‐blind, randomized, crossover phase 2 trial, eight adults with SBS‐IF were treated with once‐weekly 5‐mg apraglutide doses and placebo for 4 weeks, followed by once‐weekly 10‐mg apraglutide doses for 4 weeks, with a washout period of 6–10 weeks between treatments. Safety was the primary end point. Secondary end points included changes from baseline in urine volume output compared with placebo, collected for 48 h before and after each treatment period. Results: Common treatment‐related adverse events (AEs) were mild to moderate and included polyuria, decreased stoma output, stoma complications, decreased thirst, and edema. No serious AEs were considered to be related to apraglutide treatment. The safety profile was comparable for the lower and higher doses. Treatment with once‐weekly 5‐ and 10‐mg apraglutide doses significantly increased urine volume output by an adjusted mean of 714 ml/day (95% CI, 490–939; P <.05) and 795 ml/day (95% CI, 195–1394; P <.05), respectively, compared with placebo, with no significant differences between doses. Conclusions: Once‐weekly apraglutide was well tolerated at both tested doses and significantly increased urine volume output, providing evidence for increased intestinal fluid absorption. A phase 3 trial is underway in adults with SBS‐IF. [ABSTRACT FROM AUTHOR]

The objective of this study was to test the hypothesis that aspartame supplementation in starter diet accelerates small intestinal cell cycle by stimulating secretion and expression of glucagon‐like peptide −2 (GLP‐2) in pre‐weaned lambs using animal and cell culture experiments. In vivo, twelve 14‐day‐old lambs were selected and allocated randomly to two groups; one was treated with plain starter diet (Con, n = 6) and the other was treated with starter supplemented with 200 mg of aspartame/kg starter (APM, n = 6). Results showed that the lambs received APM treatment for 35 d had higher (p < .05) GLP‐2 concentration in the plasma and greater jejunum weight/live body weight (BW) and jejunal crypt depth. Furthermore, APM treatment significantly upregulated (p < .05) the mRNA expression of cyclin D1 in duodenum; and cyclin A2, cyclin D1, cyclin‐dependent kinases 6 (CDK6) in jejunum; and cyclin A2, cyclin D1, CDK4 in ileum. Moreover, APM treatment increased (p < .05) the mRNA expression of glucagon (GCG), insulin‐like growth factor 1 (IGF‐1) in the jejunum and ileum and mRNA expression of GLP‐2 receptor (GLP‐2R) in the jejunum. In vitro, when jejunal cells were treated with GLP‐2 for 2 hr, the 3‐(4,5‐dimethyl‐2‐thiazolyl)‐2,5‐diphenyl‐2‐H‐tetrazolium bromide (MTT) OD, IGF‐1 concentration, and the mRNA expression of IGF‐1, cyclin D1 and CDK6 were increased (p < .05). Furthermore, IGF‐1 receptor (IGF‐1R) inhibitor decreased (p < .05) the mRNA expression of IGF‐1, cyclin A2, cyclin D1 and CDK6 in GLP‐2 treatment jejunal cells. These results suggest that aspartame supplementation in starter accelerates small intestinal cell cycle that may, in part, be related to stimulate secretion and expression of GLP‐2 in pre‐weaning lambs. Furthermore, GLP‐2 can indirectly promote the proliferation of jejunal cells mainly through the IGF‐1 pathway. These findings provide new insights into nutritional interventions that promote the development of small intestines in young ruminants. [ABSTRACT FROM AUTHOR]

Aims/Introduction A dietary supplementation product enriched with glutamine, dietary fiber and oligosaccharide ( GFO) is widely applied for enteral nutrition support in Japan. The aim of the present study was to evaluate the effects of GFO ingestion on secretion of incretins, gastric inhibitory polypeptide ( GIP) and glucagon-like peptide-1 ( GLP-1), and glucagon-like peptide-2 ( GLP-2). Materials and Methods We carried out a cross-over study involving 20 healthy Japanese volunteers. The participants received GFO or 17 g of glucose, the equivalent carbohydrate in GFO as the control. Plasma glucose, serum insulin, and plasma total GIP, total GLP-1 and total GLP-2 levels during GFO or glucose loading were determined. Results GFO loading produced significantly higher plasma GLP-1 levels at 30 min and 60 min, area under the curve- GLP-1 value, and area under the curve- GLP-2 value after administration compared with those by glucose loading. In contrast, plasma GIP levels at both 30 and 60 min, and area under the curve- GIP value after glucose loading were significantly higher than those after GFO loading. Conclusions These results show that GFO ingestion stimulates GLP-1 and GLP-2 secretion, and reduces GIP secretion compared with glucose ingestion. Therefore, GFO could have an intestinotrophic effect as well as an ameliorating effect on metabolic disorders through modification of release of gut hormones. [ABSTRACT FROM AUTHOR]

Abstract: Glucagon-like peptide-2 (GLP-2) is a therapeutic target used in the treatment of short bowel syndrome. In this paper, we present the three dimensional solution structure of GLP-2 peptide determined using nuclear magnetic resonance (NMR) and molecular modelling. The GLP-2 adopts an α-helical conformation similar to that of secretin family of hormones. In order to understand the molecular details governing the ligand binding and receptor activation, macromolecular docking studies were performed between the N-terminal extracellular domain of GLP-2 receptor and the GLP-2 hormone using a data driven docking program. [ABSTRACT FROM AUTHOR]

GLP‐1 and GLP‐2 are gut‐derived hormones used in the treatment of diabetes type‐2 and short bowel syndrome, respectively. GLP‐1 attenuates insulin resistance and GLP‐2 reduces enterocyte apoptosis and enhances crypt cell proliferation in the small intestine. In addition, both hormones have vasoactive effects and may be useful in situations with impaired microcirculation. The aim of this systematic review was to provide an overview of the potential effects of GLP‐1 and GLP‐2 on microcirculation. A systematic search was performed independently by two authors in the following databases: PubMed, EMBASE, Cochrane library, Scopus, and Web of Science. Of 1111 screened papers, 20 studies were included in this review: 16 studies in animals, three in humans, and one in humans and rats. The studies were few and heterogeneous and had a high risk of bias. However, it seems that GLP‐1 regulates the pancreatic, skeletal, and cardiac muscle flow, indicating a role in the glucose homeostasis, while GLP‐2 acts primarily in the regulation of the microcirculation of the mid‐intestine. These findings may be useful in gastrointestinal surgery and in situations with impaired microcirculation of the gut. [ABSTRACT FROM AUTHOR]