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Lipid handling in the intestine is important for maintaining energy homeostasis and overall health. Mishandling of lipids in the intestine contributes to dyslipidemia and atherosclerotic cardiovascular diseases. Despite advances in this field over the past few decades, significant gaps remain. The gut hormone glucagon-like peptide-2 (GLP-2) has been shown to play pleotropic roles in the regulation of lipid handling in the intestine. Of note, GLP-2 exhibits unique actions on post-prandial lipid absorption and post-absorptive release of intestinally stored lipids. This review aims to summarize current knowledge in how GLP-2 regulates lipid processing in the intestine. Elucidating the mechanisms of GLP-2 regulation of intestinal lipid handling not only improves our understanding of GLP-2 biology, but also provides insights into how lipids are processed in the intestine, which offers opportunities for developing novel strategies towards prevention and treatment of dyslipidemia and atherosclerotic cardiovascular diseases. [ABSTRACT FROM AUTHOR]

OBJECTIVE To compare plasma glucagon-like peptide-2 (GLP-2) concentrations in dogs with treatment-naïve chronic enteropathies to healthy dogs and describe changes over time in dogs with chronic enteropathies (CE). ANIMALS 18 client-owned dogs with treatment-naïve CE and 17 client-owned healthy control dogs. METHODS This was a prospective study. Fasting, 1-hour, and 3-hour postprandial plasma GLP-2 concentrations were measured using a commercial immunoassay in healthy dogs and dogs with uncontrolled, untreated CE. Repeated fasting and postprandial plasma concentrations were measured in dogs with CE after initiating directed treatment for gastrointestinal disease. RESULTS There was no significant difference between fasting and postprandial GLP-2 concentrations in either group. Dogs with treatment-naïve CE had lower fasting (mean, 424 ± SD 176 pg/mL) plasma GLP-2 concentrations than healthy dogs (1184 ± 435 pg/mL; P < .0001). Fasted plasma GLP-2 concentrations (624 ± 314 pg/mL) remained lower in dogs with CE than in healthy dogs at recheck. CLINICAL RELEVANCE Dogs with CE have disrupted GLP-2 secretion. Future studies are required to evaluate subsets of CE and changes in response to therapy. [ABSTRACT FROM AUTHOR]

Lipid handling in the intestine is important for maintaining energy homeostasis and overall health. Mishandling of lipids in the intestine contributes to dyslipidemia and atherosclerotic cardiovascular diseases. Despite advances in this field over the past few decades, significant gaps remain. The gut hormone glucagon-like peptide-2 (GLP-2) has been shown to play pleotropic roles in the regulation of lipid handling in the intestine. Of note, GLP-2 exhibits unique actions on post-prandial lipid absorption and post-absorptive release of intestinally stored lipids. This review aims to summarize current knowledge in how GLP-2 regulates lipid processing in the intestine. Elucidating the mechanisms of GLP-2 regulation of intestinal lipid handling not only improves our understanding of GLP-2 biology, but also provides insights into how lipids are processed in the intestine, which offers opportunities for developing novel strategies towards prevention and treatment of dyslipidemia and atherosclerotic cardiovascular diseases.

Introduction: The human intestinal tract reacts to extensive resection with spontaneous intestinal adaptation. We analyzed whether gene expression analyses or intestinal permeability (IP) testing could provide biomarkers to describe regulation mechanisms in the intestinal barrier in short bowel syndrome (SBS) patients during adaptive response or treatment with the glucagon-like peptide-2 analog teduglutide. Methods: Relevant regions of the GLP-2 receptor gene were sequenced. Gene expression analyses and immunohistochemistry were performed from mucosal biopsies. IP was assessed using a carbohydrate oral ingestion test. Results: The study includes 59 SBS patients and 19 controls. Increases in gene expression with teduglutide were received for sucrase-isomaltase, sodium/glucose cotransporter 1, and calcium/calmodulin serine protein kinase. Mannitol recovery was decreased in SBS but elevated with teduglutide (Δ 40%), showed a positive correlation with remnant small bowel and an inverse correlation with parenteral support. Conclusions: Biomarkers predicting clinical and functional features in human SBS are very limited. Altered specific gene expression was shown for genes involved in nutrient transport but not for genes controlling tight junctions. However, mannitol recovery proved useful in describing the absorptive capacity of the gut during adaptation and treatment with teduglutide. [ABSTRACT FROM AUTHOR]

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]

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.

Introduction: Ulcerative colitis (UC) is an inflammatory bowel disease characterized by recurrent and remitting inflammation of the mucosa of the colon and rectum, the incidence of which is on the rise. Glucagon-like peptide-2 (GLP-2) is a newly discovered neurotrophic factor, but its efficacy and mechanism of action in UC remain unclear. In this study, we investigated the protective effects and potential targets of GLP-2 on dextran sodium sulfate (DSS)-induced UC in mice through integrative analysis. Methods: The effects of GLP-2 on UC were assessed by calculating the disease activity index, colonic mucosal damage index, and pathological histological scores. Enzyme-linked immunosorbent assay (ELISA) and immunohistochemistry were used to detect the expression of GLP-2, nuclear factor kappa-B (NF-kB), interleukin-6 (IL-6), and signal transducer and activator of transcription-3 (STAT3). The 16SrRNA gene was used to detect changes in gutmicrobiota inmouse colonic tissues, and oral glucose tolerance test (OGTT) blood glucose levels were used to analyze the differences in flora. Results: The results showed that GLP-2 could reduce the inflammation of UC mice, which may be achieved by inhibiting the potential targets of NF-kB, and Janus kinase (JAK)/STAT3 inflammatory pathways, regulating sugar metabolism, increasing dominant species, and improving microbial diversity. Discussion: This study provides new insight into the potential of GLP-2 for achieving more ideal UC treatment goals in future. [ABSTRACT FROM AUTHOR]

Context: A portion of ingested fats are retained in the intestine for many hours before they are mobilized and secreted in chylomicron (CM) particles. Factors such as glucagon-like peptide-2 (GLP-2) and glucose can mobilize these stored intestinal lipids and enhance CM secretion. We have recently demonstrated in rodents that GLP-2 acutely enhances CM secretion by mechanisms that do not involve the canonical CM synthetic assembly and secretory pathways. Objective: To further investigate the mechanism of GLP-2’s potent intestinal lipid mobilizing effect, we examined intracellular cytoplasmic lipid droplets (CLDs) in intestinal biopsies of humans administered GLP-2 or placebo. Design, setting, patients, and interventions: A single dose of placebo or GLP-2 was administered subcutaneously 5 hours after ingesting a high-fat bolus. In 1 subset of participants, plasma samples were collected to quantify lipid and lipoprotein concentrations for 3 hours after placebo or GLP-2. In another subset, a duodenal biopsy was obtained 1-hour after placebo or GLP-2 administration for transmission electron microscopy and proteomic analysis. Results: GLP-2 significantly increased plasma triglycerides by 46% (P=0.009), mainly in CM-sized particles by 133% (P=0.003), without reducing duodenal CLD size or number. Several proteins of interest were identified that require further investigation to elucidate their potential role in GLP-2-mediated CM secretion. Conclusions: Unlike glucose that mobilizes enterocyte CLDs and enhances CM secretion, GLP-2 acutely increased plasma CMs without significant mobilization of CLDs, supporting our previous findings that GLP-2 does not act directly on enterocytes to enhance CM secretion and most likely mobilizes secreted CMs in the lamina propria and lymphatics. [ABSTRACT FROM AUTHOR]

Background: Quality of life (QoL) data of chronic intestinal failure (cIF) patients treated with the GLP-2 analogue teduglutide are scarce. This study aims to analyze QoL changes over time in teduglutide-treated patients and compare the results to a matched non-treated cIF control group in a real-world setting. Methods: QoL data (SF-36 and SBS-QoLTM) were obtained from adult cIF patients being treated with teduglutide and compared to previously collected QoL data from a PNLiver trial (DRKS00010993), during which patients had been therapy naive. The dataset was then extended by a pairwise matched control group (non-teduglutide-treated PNLiver trial patients) and follow-up data from this group were collected accordingly. Results: Median teduglutide treatment duration and the follow-up period of controls were both 4.3 years. SBS-QoLTM subscales and the SBS-QoLTM sum score showed significant improvements over time in teduglutide-treated patients, as well as for the SF-36 physical and mental component summary scores (all p < 0.02), while non-treated patients showed no significant changes in any of the mentioned scores. Significant differences of QoL changes between treated and non-treated patients were seen for both SF-36 summary scores (p = 0.031 and 0.012). Conclusions: We herein demonstrate for the first time that QoL significantly improved during teduglutide treatment in SBS-cIF patients in a real-world setting compared to individually matched non-treated SBS-cIF patients, indicating relevant clinical benefits. [ABSTRACT FROM AUTHOR]

Purpose of reviewShort-chain fatty acids (SCFAs), the main bacterial fermentation products in the hindgut of hindgut fermenters, are also present in the foregut lumen. We discuss the impact of SCFAs in the duodenal defense mechanisms and in the gastrointestinal (GI) pathogenesis.Recent findingsLuminal SCFAs augment the duodenal mucosal defenses via release of serotonin (5-HT) and glucagon-like peptide-2 (GLP-2) from enteroendocrine cells. Released GLP-2 protects the small intestinal mucosa from nonsteroidal anti-inflammatory drug-induced enteropathy. SCFAs are also rapidly absorbed via SCFA transporters and interact with afferent and myenteric nerves. Excessive SCFA signals with 5-HT3 receptor overactivation may be implicated in the pathogenesis of irritable bowel syndrome symptoms. SCFA production exhibits diurnal rhythms with host physiological responses, suggesting that oral SCFA treatment may adjust the GI clocks. SCFAs are not only a source of energy but also signaling molecules for the local regulation of the GI tract and systemic regulation via release of gut hormones. Targeting SCFA signals may be a novel therapeutic for GI diseases and metabolic syndrome.

Introdiction. In recent years, many new technologies for the management of patients with short bowel syndrom (SBS), including SBS-IF (short bowel syndrom with intestinal failor), have appeared. The implemented surgical techniques are aimed at slowing down the progress of intestinal contents (antiperistaltic inserts, the creation of artificial valves in the small intestine, loops or pockets from the small intestine, etc.); surgical elongation of the small intestine (the most common STEP, Bianchy technique); intestinal transplantation. At the same time, when the intestine is shortened to 1.5–2,0 m, the adaptive rearrangements are still able to provide (albeit suppressed), but partially preserved absorption processes (in 80% of cases, the surface of the intestine is sufficient for slow transport of nutrients from the intestine to the blood). Therefore, it is important to increase the efficiency of adaptive rearrangements in any conservative way shown.Аim. Тo evaluate the role of hormonal stimulation of adaptive rearrangements in the residual bowel stump.Materials and methods. Рarameters of the well-known alimentary-volemic diagnosis, assessment of adaptive changes in the gastrointestinal tract (performed by determining citruline and GLP-2, as well as by morphological method). To stimulate the regulation of adaptive processes, a hormone preparation GLP-2 (teduglutide) was used in the nutritional support program.Results. It was shown that the length of the intestinal stump up to 1.5–2.0 m allows for digestive and transport processes due to adaptive rearrangements of the intestinal epithelium. With a super-short intestine, it is advisable to choose surgical methods of correction.Conclusion. For conservative correction of adaptive processes in the intestine, it is advisable to use a GLP-2 hormone preparation, in particular, teduglutide.

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]

In our previous study, we created a glucagon-like peptide-2 (GLP-2) derivative with the functional sequence PAS-CPP to achieve efficient uptake by the respiratory epithelium and trigeminal nerve. By using octaarginine for cell penetrating peptides (CPP) and FFLIPKG, a reverse sequence of a part of the cathepsin D sequence for the penetration accelerating sequence (PAS), we found that the derivative was taken up by the cells through macropinocytosis and efficiently escaped from the endosomes and exited the cells. Moreover, it showed drug effects by intranasal (in.) administration at the same dose as intracerebroventricular (icv.) administration, which is direct drug administration into the brain. The purpose of this study was to elucidate the cause of the drug effect of in. administered PAS-CPP-GLP-2 at the same dose as that by icv. administration. The present results suggested that although icv. administered PAS-CPP-GLP-2 entered the cerebrospinal fluid, it barely penetrated the perivascular space of the brain, and therefore, only a small amount of the administered dose may have reached the site of action in the brain. In contrast, it was qualitatively suggested that in. administered PAS-CPP-GLP-2 migrates from the trigeminal nerve to the central nervous system via the principal sensory trigeminal nucleus and then through the trigeminal lemniscus. The present results show that nose-to-brain delivery by trigeminal axons, which is assumed to be a transcellular pathway, may be possible. As the drug can be delivered into the nerve, it is expected to be applied not only as a central delivery route but also for the treatment of neurological diseases. [Display omitted] • Migration route of PAS-CPP-GLP-2 to brain differed in icv. vs. in. administration. • Intracerebroventricularly administered PAS-CPP-GLP-2 entered CSF and perivascular space. • Intranasally administered PAS-CPP-GLP-2 localized in the axon of the trigeminal nerve. [ABSTRACT FROM AUTHOR]

• GLP-2 ameliorated D-galactose induced muscle atrophy in mice. • GLP-2 promoted protein synthesis and alleviated protein degradation and apoptosis. • The IGF-1/PI3K/Akt/FoxO3 pathway played a role in the protective effect of GLP-2. The study aimed to investigate the effect of Glucagon-like peptide-2 (GLP-2) on muscle aging in vivo and in vitro. Six-week-old C57BL/6J mice were administered with D-galactose (200 mg/kg/day, intraperitoneally) for 8weeks, followed by daily subcutaneous injections of GLP-2 (300 or 600 μg/kg/day) for 4weeks. Skeletal muscle function and mass were evaluated using relative grip strength and muscle weight. The sizes and types of muscle fibers and apoptosis were assessed through histological analysis, immunofluorescence staining, and TUNEL staining, respectively. C2C12 myotubes were treated with D-galactose (40 mg/mL) and GLP-2. Protein expression of differentiation-related myogenic differentiation factor D (MyoD), myogenin (MyoG), and myosin heavy chain (Myhc), degradation-related Muscle RING finger 1 (MuRF-1), and muscle atrophy F-box (MAFbx)/Atrogin-1, and apoptosis-related B-cell leukemia/lymphoma 2 (Bcl-2) and Bax, were assessed using western blots. The Pi3k inhibitor LY294002 was applied to investigate whether GLP-2 regulated myogenesis and myotube aging via IGF-1/Pi3k/Akt/FoxO3a signaling pathway. The results demonstrated that GLP-2 significantly reversed the decline in muscles weight, relative grip strength, diameter, and cross-sectional area of muscle fibers induced by D-galactose in mice. Apart from suppressing the expressions of MuRF-1 and Atrogin-1 in the muscles and C2C12 myotubes, GLP-2 significantly increased the expressions of MyoD, MyoG, and Myhc compared to the D-galactose. GLP-2 significantly suppressed cell apoptosis. Western blot analysis indicated that the regulation of GLP-2 may be attributed to the activation of theIGF-1/Pi3k/Akt/FoxO3a phosphorylation pathway. This study suggested that GLP-2 ameliorated D-galactose induced muscle aging by IGF-1/Pi3k/Akt/FoxO3a pathway. [Display omitted] [ABSTRACT FROM AUTHOR]

Introduction: The human intestinal tract reacts to extensive resection with spontaneous intestinal adaptation. We analyzed whether gene expression analyses or intestinal permeability (IP) testing could provide biomarkers to describe regulation mechanisms in the intestinal barrier in short bowel syndrome (SBS) patients during adaptive response or treatment with the glucagon-like peptide-2 analog teduglutide. Methods: Relevant regions of the GLP-2 receptor gene were sequenced. Gene expression analyses and immunohistochemistry were performed from mucosal biopsies. IP was assessed using a carbohydrate oral ingestion test. Results: The study includes 59 SBS patients and 19 controls. Increases in gene expression with teduglutide were received for sucrase-isomaltase, sodium/glucose cotransporter 1, and calcium/calmodulin serine protein kinase. Mannitol recovery was decreased in SBS but elevated with teduglutide (Δ 40%), showed a positive correlation with remnant small bowel and an inverse correlation with parenteral support. Conclusions: Biomarkers predicting clinical and functional features in human SBS are very limited. Altered specific gene expression was shown for genes involved in nutrient transport but not for genes controlling tight junctions. However, mannitol recovery proved useful in describing the absorptive capacity of the gut during adaptation and treatment with teduglutide.

Objectives: Patients with short bowel syndrome-associated intestinal failure (SBS-IF) require long-term parenteral nutrition and/or intravenous fluids (PN/IV) to maintain fluid or nutritional balance. We report the long-term safety, efficacy, and predictors of response in pediatric patients with SBS-IF receiving teduglutide over 96 weeks., Methods: This was a pooled, post hoc analysis of two open-label, long-term extension (LTE) studies (NCT02949362 and NCT02954458) in children with SBS-IF. Endpoints included treatment-emergent adverse events (TEAEs) and clinical response (≥20% reduction in PN/IV volume from baseline). A multivariable linear regression identified predictors of teduglutide response; the dependent variable was mean change in PN/IV volume at each visit over 96 weeks., Results: Overall, 85 patients were analyzed; 78 patients received teduglutide in the parent and/or LTE studies (any teduglutide [TED] group), while seven patients did not receive teduglutide in either the parent or LTE studies. Most TEAEs were moderate or severe in intensity in both groups. By week 96, 82.1% of patients from the any TED group achieved a clinical response, with a mean fluid decrease of 30.1 mL/kg/day and an energy decrease of 21.6 kcal/kg/day. Colon-in-continuity, non-White race, older age at baseline, longer duration of teduglutide exposure, and increasing length of remaining small intestine were significantly associated with a reduction in mean PN/IV volume requirements., Conclusions: In pediatric patients with SBS-IF, teduglutide treatment resulted in long-term reductions in PN/IV requirements. The degree of PN/IV volume reduction depended on the duration of teduglutide exposure, underlying bowel anatomy, and demographics., (© 2024 Takeda Pharmaceuticals U.S.A., Inc. Journal of Pediatric Gastroenterology and Nutrition published by Wiley Periodicals LLC on behalf of European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.)

Molecular dynamics (MD) simulation was used to study the influence of electric field on Glucagon-like Peptide-2 (GLP-2). Different electric field strengths (0 V/nm ≤ E ≤ 1 V/nm) were mainly carried out on GLP-2. The structural changes in GLP-2 were analyzed by the Root Mean Square Deviation (RMSD), Root Mean Square Fluctuation (RMSF), Radius of Gyration (Rg), Solvent Accessible Surface Area (SASA), Secondary Structure and the number of hydrogen bonds. The stable α—helix structure of GLP-2 was unwound and transformed into an unstable Turn and Coil structure since the stability of the GLP-2 protein structure was reduced under the electric field. Our results show that the degree of unwinding of the GLP-2 structure was not linearly related to the electric field intensity. E = 0.5 V/nm was a special point where the degree of unwinding of the GLP-2 structure reached the maximum at this electric field strength. Under a weak electric field, E < 0.5 V/nm, the secondary structure of GLP-2 becomes loose, and the entropy of the chain increases. When E reaches a certain value (E > 0.5 V/nm), the electric force of the charged residues reaches equilibrium, along the z-direction. Considering the confinement of moving along another direction, the residue is less free. Thus, entropy decreases and enthalpy increases, which enhance the interaction of adjacent residues. It is of benefit to recover hydrogen bonds in the middle region of the protein. These investigations, about the effect of an electric field on the structure of GLP-2, can provide some theoretical basis for the biological function of GLP-2 in vivo. [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]

BackgroundTherapy with nonsteroidal anti-inflammatory drugs (NSAIDs) is associated with enteropathy in humans and experimental animals, a cause of considerable morbidity. Unlike foregut NSAID-associated mucosal lesions, most treatments for this condition are of little efficacy. We propose that the endogenously released intestinotrophic hormone glucagon-like peptide-2 (GLP-2) prevents the development of NSAID-induced enteropathy. Since the short-chain fatty acid receptor FFA3 is expressed on enteroendocrine L cells and on enteric nerves in the gastrointestinal tract, we further hypothesized that activation of FFA3 on L cells protects the mucosa from injury via GLP-2 release with enhanced duodenal HCO3- secretion. We thus investigated the effects of synthetic selective FFA3 agonists with consequent GLP-2 release on NSAID-induced enteropathy.MethodsWe measured duodenal HCO3- secretion in isoflurane-anesthetized rats in a duodenal loop perfused with the selective FFA3 agonists MQC or AR420626 (AR) while measuring released GLP-2 in the portal vein (PV). Intestinal injury was produced by indomethacin (IND, 10 mg/kg, sc) with or without MQC (1-10 mg/kg, ig) or AR (0.01-0.1 mg/kg, ig or ip) treatment.ResultsLuminal perfusion with MQC or AR (0.1-10 µM) dose-dependently augmented duodenal HCO3- secretion accompanied by increased GLP-2 concentrations in the PV. The effect of FFA3 agonists was inhibited by co-perfusion of the selective FFA3 antagonist CF3-MQC (30 µM). AR-induced augmented HCO3- secretion was reduced by iv injection of the GLP-2 receptor antagonist GLP-2(3-33) (3 nmol/kg), or by pretreatment with the cystic fibrosis transmembrane conductance regulator (CFTR) inhibitor CFTRinh-172 (1 mg/kg, ip). IND-induced small intestinal ulcers were dose-dependently inhibited by intragastric administration of MQC or AR. GLP-2(3-33) (1 mg/kg, ip) or CF3-MQC (1 mg/kg, ig) reversed AR-associated reduction in IND-induced enteropathy. In contrast, ip injection of AR had no effect on enteropathy.ConclusionThese results suggest that luminal FFA3 activation enhances mucosal defenses and prevents NSAID-induced enteropathy via the GLP-2 pathway. The selective FFA3 agonist may be a potential therapeutic candidate for NSAID-induced enteropathy.

Background: Quality of life (QoL) data of chronic intestinal failure (cIF) patients treated with the GLP-2 analogue teduglutide are scarce. This study aims to analyze QoL changes over time in teduglutide-treated patients and compare the results to a matched non-treated cIF control group in a real-world setting. Methods: QoL data (SF-36 and SBS-QoLTM) were obtained from adult cIF patients being treated with teduglutide and compared to previously collected QoL data from a PNLiver trial (DRKS00010993), during which patients had been therapy naive. The dataset was then extended by a pairwise matched control group (non-teduglutide-treated PNLiver trial patients) and follow-up data from this group were collected accordingly. Results: Median teduglutide treatment duration and the follow-up period of controls were both 4.3 years. SBS-QoLTM subscales and the SBS-QoLTM sum score showed significant improvements over time in teduglutide-treated patients, as well as for the SF-36 physical and mental component summary scores (all p < 0.02), while non-treated patients showed no significant changes in any of the mentioned scores. Significant differences of QoL changes between treated and non-treated patients were seen for both SF-36 summary scores (p = 0.031 and 0.012). Conclusions: We herein demonstrate for the first time that QoL significantly improved during teduglutide treatment in SBS-cIF patients in a real-world setting compared to individually matched non-treated SBS-cIF patients, indicating relevant clinical benefits.

Peptide hormones play a crucial role in body weight and glucose homeostasis. In this study, we aimed to explore this association and recruited 43 obese and 31 age- and sex-matched lean participants. We assessed their body mass index (BMI), waist circumference (WC), waist-to-height ratio (WtHR), percentage body fat (PBF), fasting blood levels of peptide hormones (GLP-1, GLP-2, insulin, leptin, ghrelin, CCK, and PYY), fasting blood sugar (FBS), and Homeostatic Model Assessment of Insulin Resistance (HOMA-IR). We tested the associations between peptide hormones and markers of obesity and insulin resistance (IR) by using the Independent-Samples t-test and Mann-Whitney U test, partial correlation, and logistic regression. FBS, insulin, HOMA-IR, GLP-1, GLP-2, and leptin were significantly higher in the obese group; ghrelin and CCK were significantly higher in lean participants, and no difference was seen for PYY. Controlling for BMI, GLP-1 was positively correlated with WtHR, while ghrelin was inversely correlated with WtHR. GLP-1 was correlated with HOMA-IR. GLP-1 was associated with obesity and IR markers in the regression model. Our results show that obese and lean adults display significant differences in plasma peptide hormone levels. GLP-1 levels were independently associated with markers of obesity and IR. Restoring the appetite hormone balance in obesity may represent a potential therapeutic target. [ABSTRACT FROM AUTHOR]

Metabolic dysfunction-associated fatty liver disease (MAFLD) is a hepatic manifestation of the metabolic syndrome. It is one of the most common liver diseases worldwide and shows increasing prevalence rates in most countries. MAFLD is a progressive disease with the most severe cases presenting as advanced fibrosis or cirrhosis with an increased risk of hepatocellular carcinoma. Gut microbiota play a significant role in the pathogenesis and progression of MAFLD by disrupting the gut-liver axis. The mechanisms involved in maintaining gut-liver axis homeostasis are complex. One critical aspect involves preserving an appropriate intestinal barrier permeability and levels of intestinal lumen metabolites to ensure gut-liver axis functionality. An increase in intestinal barrier permeability induces metabolic endotoxemia that leads to steatohepatitis. Moreover, alterations in the absorption of various metabolites can affect liver metabolism and induce liver steatosis and fibrosis. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are a class of drugs developed for the treatment of type 2 diabetes mellitus. They are also commonly used to combat obesity and have been proven to be effective in reversing hepatic steatosis. The mechanisms reported to be involved in this effect include an improved regulation of glycemia, reduced lipid synthesis, β-oxidation of free fatty acids, and induction of autophagy in hepatic cells. Recently, multiple peptide receptor agonists have been introduced and are expected to increase the effectiveness of the treatment. A modulation of gut microbiota has also been observed with the use of these drugs that may contribute to the amelioration of MAFLD. This review presents the current understanding of the role of the gut-liver axis in the development of MAFLD and use of members of the GLP-1 RA family as pleiotropic agents in the treatment of MAFLD., Competing Interests: Conflict-of-interest statement: The authors declare no conflict of interest related to this article., (©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.)

Background: Chronic hepatic complications are common in patients with short bowel syndrome-associated intestinal failure (SBS-IF). Teduglutide, a glucagon-like peptide-2 analogue, demonstrated efficacy in reducing parenteral nutrition and/or intravenous fluid dependence among patients with SBS-IF in phase 3 clinical studies., Methods: This was a post hoc analysis of pooled data from two separate randomized, double-blind, placebo-controlled, multinational phase 3 clinical studies. Adult patients with SBS-IF with parenteral nutrition and/or intravenous fluid dependence without liver disease at baseline were randomized to treatment with the glucagon-like peptide-2 analogue teduglutide (0.05 or 0.10 mg/kg/day) or placebo subcutaneously once daily for 24 weeks. Mixed-effects models assessed the baseline predictors of change in liver chemistries., Results: Between baseline and week 24, teduglutide treatment (n = 109) was associated with least squares mean reductions in aspartate aminotransferase (-7.51 IU/L; P = 0.014), alanine aminotransferase (-12.15 IU/L; P = 0.002), and bilirubin (-5.03 µmol/L [-0.057 mg/dl]; P < 0.001) compared with that of the placebo (n = 59). These values were independent of reductions in parenteral nutrition and/or intravenous fluid dependence., Conclusion: Teduglutide treatment was associated with reductions in liver chemistries by week 24, which is beneficial for patients with SBS-IF beyond improvements in parenteral nutrition and/or intravenous fluid dependence. Future studies should examine how long-term teduglutide might mitigate the risk of liver disease in patients with SBS-IF., (© 2024 Takeda Pharmaceuticals U.S.A., Inc. Nutrition in Clinical Practice published by Wiley Periodicals LLC on behalf of American Society for Parenteral and Enteral Nutrition.)

Background: Glucagon-like peptide-2 (GLP-2) has protective effects on gastrointestinal functions. Our previous study found that GLP-2 could significantly reduce intestinal permeability and bacterial translocation in total parenteral nutrition (TPN) animal model. However, the effects of GLP-2 on the impairment of the intestinal Paneth cells immune function and gut inflammation during intravenous fluid infusion mainly consisted of nutritional materials is currently scattered.Objective: The current study was aimed to investigate the efficacy of the GLP-2 in alleviating gut inflammation and modulating enteric Paneth cells immune response in parenterally fed mice and its underlying mechanisms.Methods: Thirty-six male ICR mice underwent venous catheterization were divided into 3 groups: Chow, TPN, and TPN+GLP-2 groups. GLP-2 was administered intravenously at 60 μg/day for 5 days. The small intestine tissue and serum samples were collected on the 7th day.Results: Compared with the TPN group, the expression of tight junction proteins occludin and claudin-1 were significantly increased in the TPN+GLP-2 group. In addition, the expression of lysozyme, sPLA2, insulin-like growth factor-1, and epithelial protection and repair genes were improved in the TPN+GLP-2 group. The levels of IL-6 and TNF-α proteins and mRNAs in the ileum tissues were remarkably reduced in the TPN+GLP-2 group, while IL-10 protein and mRNA level were elevated in the TPN+GLP-2 group (all p < 0.05). Moreover, the TPN+GLP-2 group has higher levels of serum endotoxin, D-lactic acid, and MPO than those of the TPN group.Conclusions: GLP-2 alleviated gut inflammation and improved enteric Paneth cells immune responses through intravenous fluid infusion, possibly by improving the functioning of epithelial protection and repair, and reducing mucosal inflammatory responses.

BackgroundBerberine is a plant alkaloid that has multiple beneficial effects against intestine inflammation. In our previous study, we have found that berberine also possesses an antidiabetic effect. However, whether berberine is useful in the prevention of type 2 diabetes mellitus (T2DM) through its effect on intestine endocrine function and gut microbiota is unclear.AimTo investigate the effects of berberine in the prevention of T2DM, as well as its effects on intestine GLP-2 secretion and gut microbiota in ZDF rats.MethodsTwenty Zucker Diabetic Fatty (ZDF) rats were fed a high-energy diet until they exhibited impaired glucose tolerance (IGT). The rats were then divided into two groups to receive berberine (100 mg/kg/d; berberine group) or vehicle (IGT group) by gavage for 3 weeks. Five Zucker Lean (ZL) rats were used as controls. Fasting blood glucose (FBG) was measured, an oral glucose tolerance test was performed, and the Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) was calculated. Intestinal expression of TLR-4, NF-κB, TNF-α, mucin, zona occludens-1 (ZO-1) and occludin were assessed (immunohistochemistry). Plasma levels and glutamine-induced intestinal secretion of glucagon-like peptide-1 (GLP-1) and GLP-2 were measured (enzyme-linked immunosorbent assay). The plasma lipopolysaccharide (LPS) level was measured. Fecal DNA extraction, pyrosequencing, and bioinformatics analysis were performed.ResultsAfter 3 weeks of intervention, diabetes developed in all rats in the IGT group, but only 30% of rats in the berberine group. Treatment with berberine was associated with reductions in food intake, FBG level, insulin resistance, and plasma LPS level, as well as increases in fasting plasma GLP-2 level and glutamine-induced intestinal GLP-2 secretion. Berberine could increase the goblet cell number and villi length, and also reverse the suppressed expressions of mucin, occludin, ZO-1 and the upregulated expressions of TLR-4, NF-κB and TNF-α induced in IGT rats (P

Neuropeptides are expected as therapeutic drug candidates for central nervous system (CNS) disorders. Intracerebroventricular (i.c.v.) administration of glucagon-like peptide-2 (GLP-2) has an antidepressant-like effect not only in depression model mice but also in treatment-resistant depression model mice. However, because i.c.v. administration is very invasive, research is progressing on brain delivery using intranasal administration as a non-invasive method. After intranasal administration of the drug, there are two routes to the brain. That of direct delivery from the paracellular route of olfactory epithelium to the brain via the olfactory bulb has been studied, and that of systemic absorption via the paracellular route of respiratory epithelium has been put to practical use. The high degree of vascularization and permeability of the nasal mucosa enables drug delivery via the paracellular route that leads to systemic delivery. Therefore, suppressing systemic absorption may increase drug delivery to brain, so we focused on the transcellular route. We created a GLP-2 derivative by adding cell-penetrating peptides (CPP) and penetration accelerating sequences (PAS), which are reported to provide efficient intracellular uptake, to GLP-2. However, to deliver GLP-2 by the transcellular route, GLP-2 must not only be taken up into cells but also move out of the cells. We investigated in vitro and in vivo function of PAS-CPP-GLP-2 to enable the translocation of GLP-2 directly from the nose to the brain. Derivatization of PAS-CPP-GLP-2 prevented its degradation. In the evaluation of intracellular dynamics, PAS-CPP-GLP-2 enhanced cellular uptake by macropinocytosis with CPP and promoted escape from endosomal vesicles by PAS. This study also showed that PAS-CPP-GLP-2 can move out of cells. Furthermore, only this PAS-CPP-GLP-2 showed an antidepression-like effect within 20 min of intranasal administration. Intranasal administered PAS-CPP-GLP-2 surprisingly showed the effect at the same dose with i.c.v. administration, but intravenous administered PAS-CPP-GLP-2 did not show the effect. These results suggested that PAS-CPP-GLP-2 can be efficiently delivered from the nose to the CNS and show a pharmacological effect, demonstrating the usefulness of PAS and CPP for nose-to-brain delivery of GLP-2. [Display omitted] [ABSTRACT FROM AUTHOR]

Background: Berberine is a plant alkaloid that has multiple beneficial effects against intestine inflammation. In our previous study, we have found that berberine also possesses an antidiabetic effect. However, whether berberine is useful in the prevention of type 2 diabetes mellitus (T2DM) through its effect on intestine endocrine function and gut microbiota is unclear. Aim: To investigate the effects of berberine in the prevention of T2DM, as well as its effects on intestine GLP-2 secretion and gut microbiota in ZDF rats. Methods: Twenty Zucker Diabetic Fatty (ZDF) rats were fed a high-energy diet until they exhibited impaired glucose tolerance (IGT). The rats were then divided into two groups to receive berberine (100 mg/kg/d; berberine group) or vehicle (IGT group) by gavage for 3 weeks. Five Zucker Lean (ZL) rats were used as controls. Fasting blood glucose (FBG) was measured, an oral glucose tolerance test was performed, and the Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) was calculated. Intestinal expression of TLR-4, NF-κB, TNF-α, mucin, zona occludens-1 (ZO-1) and occludin were assessed (immunohistochemistry). Plasma levels and glutamine-induced intestinal secretion of glucagon-like peptide-1 (GLP-1) and GLP-2 were measured (enzyme-linked immunosorbent assay). The plasma lipopolysaccharide (LPS) level was measured. Fecal DNA extraction, pyrosequencing, and bioinformatics analysis were performed. Results: After 3 weeks of intervention, diabetes developed in all rats in the IGT group, but only 30% of rats in the berberine group. Treatment with berberine was associated with reductions in food intake, FBG level, insulin resistance, and plasma LPS level, as well as increases in fasting plasma GLP-2 level and glutamine-induced intestinal GLP-2 secretion. Berberine could increase the goblet cell number and villi length, and also reverse the suppressed expressions of mucin, occludin, ZO-1 and the upregulated expressions of TLR-4, NF-κB and TNF-α induced in IGT rats (P<0.05). Berberine also improved the structure of the gut microbiota and restored species diversity. Conclusion: Berberine may slow the progression of prediabetes to T2DM in ZDF rats by improving GLP-2 secretion, intestinal permeability, and the structure of the gut microbiota. [ABSTRACT FROM AUTHOR]

The objective of this study was to evaluate the effects of tributyrin (TB) supplementation in calf starter on development of the rumen and small intestine for calves fed two milk replacers differing in fatty acid composition. Fifty-four Holstein calves (38 heifers and 16 bull calves) were assigned to one of the four treatments: (1) milk replacer containing 31 g/kg C8:0 and 29 g/kg C10:0 in total fatty acids (MR-) and calf starter without TB (ST-) (MR-ST-; n = 14), (2) MR- and calf starter with a TB supplement (600 g/kg TB and 400 g/kg silicon dioxide) at 6 g/kg of DM (ST+) (MR-ST+; n = 13), (3) milk replacer containing 26 g/kg C4:0, 57 g/kg C8:0, and 56 g/kg C10:0 in total fatty acids (MR+) and ST- (MR+ST-; n = 13), and (4) MR+ and ST+ (MR+ST+; n = 14). Milk replacers were offered at 600 g/d (powder basis) from 8 to 14 d, increased up to 1300 g/d from 15 to 21 d, 1400 g/d from 22 to 49 d, decreased down to 700 g/d from 50 to 56 d, and 600 g/d from 57 to 63 d, and then weaned at 64 d of age. Data and samples were collected until 91 d of age. All the calves were fed one of the calf starters and chopped hay ad libitum from 8 d of age. Bull calves were euthanized at weaning to determine weights of digestive organs and evaluate ruminal and small intestinal morphology. Calf starter and milk replacer treatments did not affect dry matter intake, growth performance, digestive organs weights (kg/100 kg of body weight), and rumen papillae length. However, calves fed ST+ had greater ratio of villus height to crypt depth (2.20 vs. 1.84; P < 0.01) in the ileum compared to those fed ST-. In addition, calves fed MR+ had less crypt depth (240 vs. 298 µm; P = 0.02) and greater ratio of villus height to crypt depth (2.22 vs. 1.91; P < 0.01) in the ileum compared to those fed MR-. A tendency for interaction between milk replacer and calf starter treatments was observed for the ratio of villus height to crypt depth in the jejunum, in which TB in calf starter increased the ratio only for calves fed MR-. Milk replacer treatment did not affect plasma glucagon-like peptide-2 (GLP-2) concentration. However, calves fed ST+ had greater plasma GLP-2 concentration compared to those fed ST- after weaning (1.16 vs. 0.80 ng/mL; P < 0.02). These results suggest that TB supplementation for dairy calves may affect small intestinal morphology at weaning, and increase plasma GLP-2 concentration after weaning. [Display omitted] • Feeding tributyrin (TB) did not affect feed intake, growth and rumen development. • Feeding TB increased small intestinal villus height/crypt depth at weaning. • Calf starter with TB increased plasma glucagon-like peptide-2 level after weaning. [ABSTRACT FROM AUTHOR]

Backgrounds and aimsWe studied the intestinotrophic hormone glucagon-like peptide-2 (GLP-2) as a possible therapy for non-steroidal anti-inflammatory drug (NSAID)-induced intestinal ulcers. Luminal nutrients release endogenous GLP-2 from enteroendocrine L cells. Since GLP-2 is degraded by dipeptidyl peptidase IV (DPPIV), we hypothesized that DPPIV inhibition combined with luminal administration of nutrients potentiates the effects of endogenous GLP-2 on intestinal injury.MethodsIntestinal injury was induced by indomethacin (10 mg/kg, sc) in fed rats. The long-acting DPPIV inhibitor K579 was given intragastrically (ig) or intraperitoneally (ip) before or after indomethacin treatment. L-Alanine (L-Ala) and inosine 5'-monophosphate (IMP) were co-administered ig after the treatment.ResultsIndomethacin treatment induced intestinal ulcers that gradually healed after treatment. Pretreatment with ig or ip K579 given at 1 mg/kg reduced total ulcer length, whereas K579 at 3 mg/kg had no effect. Exogenous GLP-2 also reduced intestinal ulcers. The preventive effect of K579 was dose-dependently inhibited by a GLP-2 receptor antagonist. Daily treatment with K579 (1 mg/kg), GLP-2, or L-Ala + IMP after indomethacin treatment reduced total ulcer length. Co-administration (ig) of K579 and L-Ala + IMP further accelerated intestinal ulcer healing.ConclusionDPPIV inhibition and exogenous GLP-2 prevented the formation and promoted the healing of indomethacin-induced intestinal ulcers, although high-dose DPPIV inhibition reversed the preventive effect. Umami receptor agonists also enhanced the healing effects of the DPPIV inhibitor. The combination of DPPIV inhibition and luminal nutrient-induced GLP-2 release may be a useful therapeutic tool for the treatment of NSAIDs-induced intestinal ulcers.

Molecular dynamics (MD) simulation was used to study the influence of electric field on Glucagon-like Peptide-2 (GLP-2). Different electric field strengths (0 V/nm ≤ E ≤ 1 V/nm) were mainly carried out on GLP-2. The structural changes in GLP-2 were analyzed by the Root Mean Square Deviation (RMSD), Root Mean Square Fluctuation (RMSF), Radius of Gyration (Rg), Solvent Accessible Surface Area (SASA), Secondary Structure and the number of hydrogen bonds. The stable α—helix structure of GLP-2 was unwound and transformed into an unstable Turn and Coil structure since the stability of the GLP-2 protein structure was reduced under the electric field. Our results show that the degree of unwinding of the GLP-2 structure was not linearly related to the electric field intensity. E = 0.5 V/nm was a special point where the degree of unwinding of the GLP-2 structure reached the maximum at this electric field strength. Under a weak electric field, E < 0.5 V/nm, the secondary structure of GLP-2 becomes loose, and the entropy of the chain increases. When E reaches a certain value (E > 0.5 V/nm), the electric force of the charged residues reaches equilibrium, along the z-direction. Considering the confinement of moving along another direction, the residue is less free. Thus, entropy decreases and enthalpy increases, which enhance the interaction of adjacent residues. It is of benefit to recover hydrogen bonds in the middle region of the protein. These investigations, about the effect of an electric field on the structure of GLP-2, can provide some theoretical basis for the biological function of GLP-2 in vivo.

Glucagon-like peptide-1 (GLP-1), a product of partial proteolysis of proglucagon, is involved not only in regulation of carbohydrates, but also in water-salt metabolism. The study examined the role of proglucagon derivatives GLP-1, GLP-2, and oxyntomodulin in rat osmoregulation. Of them, only blood plasma GLP-1 increased in response to water load (20 ml/kg). Administration of glucose (1.5 g/kg) elevated GLP-1 and oxyntomodulin but did not change the level of GLP-2. GLP-1 accelerated excretion of excess water during hyperhydration, whereas GLP-2 decreased this parameter. No physiological effects of oxyntomodulin in the kidneys were revealed. Probably, the blood levels of proglucagon derivatives are independently regulated for each peptide. In contrast to GLP-2 and oxyntomodulin, GLP-1 is involved in osmoregulation. [ABSTRACT FROM AUTHOR]

Peptide hormones play a crucial role in body weight and glucose homeostasis. In this study, we aimed to explore this association and recruited 43 obese and 31 age- and sex-matched lean participants. We assessed their body mass index (BMI), waist circumference (WC), waist-to-height ratio (WtHR), percentage body fat (PBF), fasting blood levels of peptide hormones (GLP-1, GLP-2, insulin, leptin, ghrelin, CCK, and PYY), fasting blood sugar (FBS), and Homeostatic Model Assessment of Insulin Resistance (HOMA-IR). We tested the associations between peptide hormones and markers of obesity and insulin resistance (IR) by using the Independent-Samples t-test and Mann-Whitney U test, partial correlation, and logistic regression. FBS, insulin, HOMA-IR, GLP-1, GLP-2, and leptin were significantly higher in the obese group; ghrelin and CCK were significantly higher in lean participants, and no difference was seen for PYY. Controlling for BMI, GLP-1 was positively correlated with WtHR, while ghrelin was inversely correlated with WtHR. GLP-1 was correlated with HOMA-IR. GLP-1 was associated with obesity and IR markers in the regression model. Our results show that obese and lean adults display significant differences in plasma peptide hormone levels. GLP-1 levels were independently associated with markers of obesity and IR. Restoring the appetite hormone balance in obesity may represent a potential therapeutic target.

Intrauterine growth restriction (IUGR) results in abnormal morphology and gastrointestinal function, such as reduced villi height and crypt depth, thinner mucosa and muscle layers, and reduced brush border enzyme activities, delayed gastric emptying, increased stress response. As a gastrointestinal growth factor, the manner by which the porcine glucagon-like peptide-2 (pGLP-2) microsphere administration restored the gastrointestinal function and growth performance of IUGR piglets was investigated. Fourteen newborn Duroc × (Yorkshire × Landrace) IUGR piglets (0.92 ± 0.113 kg) were assigned into the IUGR (negative control group) and pGLP-2 microsphere groups. The piglets in group pGLP-2 were intraperitoneally administered with 100 mg pGLP-2 microspheres on day 1 after birth. From days 15 to 26 of trial, the body weight of the pGLP-2 group was significantly higher than that of the control. IUGR piglets of group pGLP-2 showed a significantly increased pancreas weight, serum insulin content and activity of lipase and amylase. Injection of pGLP-2 microspheres restored the intestinal absorptive capacity by significantly increasing the mRNA expression of the sodium-glucose cotransporter 1 in the jejunum and the peptide transporter 1 in the jejunum. It also restored the redox balance by increasing the catalase mRNA expression and decreasing the heat shock protein 70 mRNA expression. In addition, this improvement was associated with the significant increase in gut diameter, length and weight. Therefore, it was concluded that the injection of pGLP-2 microspheres was a suitable therapeutic strategy for compensatory growth in low birth weight IUGR piglets. [ABSTRACT FROM AUTHOR]

Intestinal handling of dietary triglycerides has important implications for health and disease. Following digestion in the intestinal lumen, absorption, and re-esterification of fatty acids and monoacylglycerols in intestinal enterocytes, triglycerides are packaged into lipoprotein particles (chylomicrons) for secretion or into cytoplasmic lipid droplets for transient or more prolonged storage. Despite the recognition of prolonged retention of triglycerides in the post-absorptive phase and subsequent release from the intestine in chylomicron particles, the underlying regulatory mechanisms remain poorly understood. Chylomicron secretion involves multiple steps, including intracellular assembly and post-assembly transport through cellular organelles, the lamina propria, and the mesenteric lymphatics before being released into the circulation. Contrary to the long-held view that the intestinal lymphatic vasculature acts mainly as a passive conduit, it is increasingly recognized to play an active and regulatory role in the rate of chylomicron release into the circulation. Here, we review the latest advances in understanding the role of lymphatics in intestinal lipid handling and chylomicron secretion. We highlight emerging evidence that oral glucose and the gut hormone glucagon-like peptide-2 mobilize retained enteral lipid by differing mechanisms to promote the secretion of chylomicrons via glucose possibly by mobilizing cytoplasmic lipid droplets and via glucagon-like peptide-2 possibly by targeting post-enterocyte secretory mechanisms. We discuss other potential regulatory factors that are the focus of ongoing and future research. Regulation of lymphatic pumping and function is emerging as an area of great interest in our understanding of the integrated absorption of dietary fat and chylomicron secretion and potential implications for whole-body metabolic health.

Glucagon-like peptide (GLP)-1 and -2-secreting L cells have been shown to express the bile acid receptor Takeda G protein-receptor-5 (TGR5) and increase secretion upon receptor activation. Previous studies have explored GLP-1 secretion following acute TGR5 activation, but chronic activation and GLP-2 responses have not been characterized. In this study, we aimed to investigate the consequences of pharmacological TGR5 receptor activation on L cell hormone production in vivo using the specific TGR5 agonist RO5527239 and the GLP-2 receptor knockout mouse. Here, we show that 1) TGR5 receptor activation led to increased GLP-1 and GLP-2 content in the colon, which 2) was associated with an increased small intestinal weight that 3) was GLP-2 dependent. Additionally, we report that TGR5-mediated gallbladder filling occurred independently of GLP-2 signaling. In conclusion, we demonstrate that pharmacological TGR5 receptor activation stimulates L cells, triggering GLP-2-dependent intestinal adaption in mice. NEW & NOTEWORTHY Using the specific Takeda G protein-receptor-5 (TGR5) agonist RO5527239 and GLP-2 receptor knockout mice, we show that activation of TGR5 led to the increase in colonic GLP-1 and GLP-2 concomitant with a GLP-2 dependent growth response in the proximal portion of the small intestine. [ABSTRACT FROM AUTHOR]

This study evaluated how feeding colostrum- or a colostrum-milk mixture for 3 d postnatal affects plasma glucagon-like peptide-2 (GLP-2), serum insulin-like growth factor-1 (IGF-1), and small intestinal histomorphology in calves. Holstein bulls (n = 24) were fed colostrum at 2 h postnatal and randomly assigned to receive either colostrum (COL), whole milk (WM), or a 1:1 COL:WM mixture (MIX) every 12 h from 12 to 72 h. A jugular venous catheter was placed at 1 h postnatal to sample blood frequently for the duration of the experiment. Samples were collected at 1, 2, 3, 6, 9, 11, and 12 h. Following the 12-h meal, blood was collected at half-hour intervals until 16 h and then at 1-h intervals from 16 to 24 h. A 27-h sample was taken, then blood was sampled every 6 h from 30 to 60 h. Again, blood was taken at half-intervals from 60 to 64 h, then at 65 and 66 h, following which, a 2-h sampling interval was used until 72 h. Plasma GLP-2 (all time points) and serum IGF-1 (at time points: 1, 6, 12, 18, 24, 36, 48, and 72 h) were both analyzed. Duodenal, jejunal, and ileal tissues were collected at 75 h of age to assess histomorphology and cellular proliferation. Feeding COL, rather than WM, increased plasma GLP-2 by 60% for 2 h and tended to increase GLP-2 by 49.4% for 4 h after the 60-h meal. Insulin-like growth factor-1 area under the curve (from 12 to 72 h) tended to be 27% greater for COL than WM calves but was otherwise unaffected by treatment. Ileal crypts tended to proliferate more with MIX than WM, whereas ileal crypt proliferation did not differ for COL compared with MIX or WM and was not different between treatments in the proximal jejunum. Villi height was increased 1.8 and 1.5× (COL and MIX vs. WM) in the proximal and distal jejunum, respectively, whereas MIX duodenal and ileal villi height tended to be 1.5 and 1.4× that of WM. Crypt depth did not differ in any region. Surface area of the gastrointestinal tract was reduced for WM by 60 and 58% (proximal jejunum) and 38 and 52% (ileum) relative to COL and MIX and was 54% less than MIX in the distal jejunum. Overall, extended COL feeding minimally increased plasma GLP-2 and serum IGF-1 compared with WM feeding. As COL and MIX similarly promoted small intestinal maturation, feeding calves transition milk to promote intestinal development could be a strategy for producers. [ABSTRACT FROM AUTHOR]

The objective of this study was to evaluate effects of butyrate supplementation on plasma concentration of glucagon-like peptide-2 (GLP-2), apparent total-tract digestibility, and responses to a grain challenge of lactating dairy cows fed diets differing in starch content. Eight Holstein cows averaging 58.6 ± 9.96 d in milk (4 primiparous cows fitted with rumen cannula and 4 multiparous intact cows) were blocked by parity and assigned to one of two 4 × 4 Latin squares balanced for carryover effects with a 2 × 2 factorial arrangement of treatments. Treatments were dietary starch content [20.6 vs. 27.5%, respectively, for low starch (LS) and high starch (HS)] and butyrate supplementation (butyrate vs. control) with 21-d periods. Butyrate was provided as Gustor BP70 WS (Norel, S.A., Madrid, Spain), containing 70% sodium butyrate and 30% fatty acid mixture, at 2% of dietary dry matter (providing butyrate at 1.1% of dietary dry matter), and control premix contained 70% wheat bran and 30% fatty acid mixture. Feeds, orts, and fecal samples were collected from d 17 to 19 to determine apparent total-tract nutrient digestibility. Blood and rumen fluid samples were collected on d 19. The baseline of dry matter intake (DMI) was determined as average DMI from d 17 to 19 for each cow, and cows were feed-restricted at 60% of the baseline DMI on d 20, and a grain challenge was conducted by providing steam-flaked corn grain at 0.6% of body weight, on an as-fed basis, in addition to each treatment diet on d 21, and blood and ruminal fluid samples were collected. The interaction of dietary starch content by butyrate supplementation was significant for plasma GLP-2 concentration, being greater for cows fed butyrate with the HS diet than those fed the other 3 diets. Cows fed butyrate increased n-butyrate concentration in the ruminal fluid and tended to increase dry matter and organic matter digestibility compared with the control. During the grain challenge, rumen endotoxin concentration increased over time and was higher for cows fed the HS diets compared with those fed LS diets. However, response variables related to inflammation were not affected by the grain challenge. However, serum haptoglobin, lipopolysaccharide-binding protein, and serum amyloid-A concentrations were greater for cows fed butyrate with the LS diet, but not for those fed the HS diet. These results indicate that butyrate supplementation may increase plasma GLP-2 concentration for cows fed HS diets, and total-tract digestibility regardless of dietary starch content. However, butyrate supplementation did not mitigate inflammation in this study. [ABSTRACT FROM AUTHOR]

Intestinal handling of dietary triglycerides has important implications for health and disease. Following digestion in the intestinal lumen, absorption, and re-esterification of fatty acids and monoacylglycerols in intestinal enterocytes, triglycerides are packaged into lipoprotein particles (chylomicrons) for secretion or into cytoplasmic lipid droplets for transient or more prolonged storage. Despite the recognition of prolonged retention of triglycerides in the post-absorptive phase and subsequent release from the intestine in chylomicron particles, the underlying regulatory mechanisms remain poorly understood. Chylomicron secretion involves multiple steps, including intracellular assembly and post-assembly transport through cellular organelles, the lamina propria, and the mesenteric lymphatics before being released into the circulation. Contrary to the long-held view that the intestinal lymphatic vasculature acts mainly as a passive conduit, it is increasingly recognized to play an active and regulatory role in the rate of chylomicron release into the circulation. Here, we review the latest advances in understanding the role of lymphatics in intestinal lipid handling and chylomicron secretion. We highlight emerging evidence that oral glucose and the gut hormone glucagon-like peptide-2 mobilize retained enteral lipid by differing mechanisms to promote the secretion of chylomicrons via glucose possibly by mobilizing cytoplasmic lipid droplets and via glucagon-like peptide-2 possibly by targeting post-enterocyte secretory mechanisms. We discuss other potential regulatory factors that are the focus of ongoing and future research. Regulation of lymphatic pumping and function is emerging as an area of great interest in our understanding of the integrated absorption of dietary fat and chylomicron secretion and potential implications for whole-body metabolic health. [ABSTRACT FROM AUTHOR]

Short bowel syndrome (SBS) is a rare disease that results from extensive resection of the intestine. When the remaining absorption surface of the intestine cannot absorb enough macronutrients, micronutrients, and water, SBS results in intestinal failure (IF). Patients with SBS who suffer from IF require parenteral nutrition for survival, but long-term parenteral nutrition may lead to complications such as catheter sepsis and metabolic diseases. Spontaneous intestinal adaptation occurs weeks to months after resection, resulting in hyperplasia of the remnant gut, modification of gut hormone levels, dysbiosis, and hyperphagia. Oral nutrition and presence of the colon are two major positive drivers for this adaptation. This review aims to summarize the current knowledge of the mechanisms underlying spontaneous intestinal adaptation, particularly in response to modifications of luminal content, including nutrients. In the future, dietary manipulations could be used to treat SBS. [ABSTRACT FROM AUTHOR]

Purpose: Short bowel syndrome (SBS) patients require long-term parenteral nutrition following massive bowel resection, which causes intestinal failure-associated liver disease (IFALD). Previous reports have shown that glucagon-like peptide-2 (GLP-2) resulted in the bowel adaptation for SBS. The aim of this study was to evaluate the effect of GLP-2 for IFALD in a parenterally fed rat model.Methods: Using rat, a catheter was placed in the jugular vein, and 90% small bowel resection (SBR) was performed. Animals were divided into three groups: SBR and total parenteral nutrition (TPN) (SBS/TPN group), SBR and TPN plus GLP-2 at 1 µg/kg/h [SBS/TPN/GLP-2 (low) group], and SBR and TPN plus GLP-2 at 10 µg/kg/h [SBS/TPN/GLP-2 (high) group]. On day 13, the liver was harvested and analyzed by using nonalcoholic fatty liver disease (NAFLD) score.Results: Histologically, hepatic steatosis in the SBS/TPN group and SBS/TPN/GLP-2 (high) group was observed. Both steatosis and lobular inflammation score in the SBS/TPN/GLP-2 (low) group were significantly lower compared with those in the other two groups (p < 0.05). Active NAFLD score in the SBS/TPN/GLP-2 (low) group was significantly lower compared with that in the SBS/TPN/GLP-2 (high) group (p < 0.01).Conclusion: Low-dose GLP-2 intravenous administration improves hepatic steatosis of IFALD following in an SBS parenterally fed rat model. [ABSTRACT FROM AUTHOR]

Background: The interaction of adropin, glucagon-like peptide-2 (GLP2), angiopoietin-like protein 4 (ANGPTL4), and with childhood obesity and glucose metabolism is inconsistent. This study is to evaluate the association of the three cytokines and glucose homeostasis. Methods: This was a cross-sectional study of children with obesity ranging from 5 to 14 years compared to age- and sex-matched children of normal weight. Fasting plasma glucose (FPG), oral glucose tolerance test 2-hour plasma glucose (OGTT2hPG), and insulin (INS) were measured, and serum adropin, GLP2, and ANGPTL4 levels were measured by enzyme-linked immunosorbent assay. The body mass index (BMI), BMI-Z scores, waist-to-hip ratio (WHR), and homeostasis model assessment of insulin resistance (HOMA-IR) were calculated. Results: Thirty-nine children (9.70 ± 1.71 years, 18 females) with obesity and 29 normal weight children (8.98 ± 1.98 years, 16 females) were assessed. The levels of INS, HOMA-IR and GLP2 of the obesity group were significantly higher than the controls (P < 0.05). Pearson correlation analysis showed that serum GLP2 was positively associated with WHR, FPG, and OGTT2hPG, and adropin was negatively associated with BMI, BMI-Z, WHR, INS, and HOMA-IR (all P < 0.05). Furthermore, GLP2 were negatively associated with adropin and ANGPTL4 (both P < 0.05). By binary logistic regression, adropin and GLP2 were found to be independent markers of obesity. Multiple linear regression showed that GLP2 was associated with OGTT2hPG, and adropin was associated with INS and HOMA-IR (all P < 0.05). Conclusions: Obese children had elevated GLP2 concentrations, and adropin and GLP2 associated with both childhood obesity and glucose homeostasis. Furthermore, there may be a physiologic interplay between adropin and GLP2 in obese children. [ABSTRACT FROM AUTHOR]

Background: The gut hormone GLP-2 (glucagon-like peptide-2) plays important roles in lipid handling in the intestine. During postabsorptive stage, it releases preformed chylomicrons stored in the intestine, the underlying mechanisms of which are not well understood. Previous studies implicate the involvement of neural pathways in GLP-2's actions on lipid absorption in the intestine, but the role of such mechanisms in releasing postabsorptive lipid storage has not been established., Methods: Here, in mesenteric lymph duct cannulated rats, we directly tested whether gut-brain neural communication mediates GLP-2's effects on postabsorptive lipid mobilization in the intestine. We performed total subdiaphragmatic vagotomy to disrupt the gut-brain neural communication and analyzed lipid output 5 hours after a lipid load in response to intraperitoneal GLP-2 or saline., Results: Peripheral GLP-2 administration led to increased lymph lipid output and activation of proopiomelanocortin neurons in the arcuate nucleus of hypothalamus. Disruption of gut-brain neural communication via vagotomy blunted GLP-2's effects on promoting lipid release in the intestine., Conclusions: These results, for the first time, demonstrate a novel mechanism in which postabsorptive mobilization of intestinal lipid storage by GLP-2 enlists a gut-brain neural pathway., Competing Interests: Disclosures None.

We investigated the role of dietary carbohydrates in the maintenance of the enterocyte microvillar structure in the chicken ileum. Male chickens were divided into the control and three experimental groups, and the experimental groups were fed diets containing 50%, 25%, and 0% carbohydrates of the control diet. The structural alterations in enterocytes were examined using transmission electron microscopy and immunofluorescent techniques for β-actin and villin. Glucagon-like peptide (GLP)-2 and proglucagon mRNA were detected by immunohistochemistry and in situ hybridization, respectively. Fragmentation and wide gap spaces were frequently observed in the microvilli of the 25% and 0% groups. The length, width, and density of microvilli were also decreased in the experimental groups. The experimental groups had shorter terminal web extensions, and there were substantial changes in the mitochondrial density between the control and experimental groups. Intensities of β-actin and villin immunofluorescence observed on the apical surface of enterocytes were lower in the 0% group. The frequency of GLP-2-immunoreactive and proglucagon mRNA-expressing cells decreased with declining dietary carbohydrate levels. This study revealed that dietary carbohydrates contribute to the structural maintenance of enterocyte microvilli in the chicken ileum. The data from immunohistochemistry and in situ hybridization assays suggest the participation of GLP-2 in this maintenance system., (© 2024 Japanese Society of Animal Science.)

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]

Highlights • d -serine and l -arginine inhibited the antidepressant-like effects of GLP-2 in the mouse FST. • PDE5 inhibitor inhibited the antidepressant-like effects of GLP-2. • GLP-2 and NMDA receptor-NO-cGMP pathway exerted synergistic effects in the FST. Abstract We previously demonstrated that glucagon-like peptide-2 (GLP-2) exerted antidepressant-like effects in mice. The aim of the present study was to investigate the relationship between N -methyl- D -aspartate (NMDA) receptor-nitric oxide-cyclic guanosine monophosphate (NO-cGMP) pathway and the antidepressant-like effects of GLP-2 in the forced-swim test (FST) in mice. Intracerebroventricularly administered GLP-2 (3 μg/mouse) decreased the immobility time in the FST. The pretreatment of mice with l -arginine (750 mg/kg, i.p.), a substrate for nitric oxide synthase, sildenafil (5 mg/kg, i.p.), a phosphodiesterase 5 inhibitor, or d -serine (300 mg/kg, i.p.), a NMDA receptor co-agonist, inhibited the antidepressant-like effects of GLP-2 (3 μg/mouse) in the FST. Meanwhile, l -nitroarginine methyl ester (10 mg/kg, i.p.), a non-specific nitric oxide synthase (NOS) inhibitor, 7-nitroindazole (30 mg/kg, i.p.), a neuronal NOS inhibitor, methylene blue (10 mg/kg, i.p.), an inhibitor of both NOS and soluble guanylate cyclase (sGC), ODQ (30 pmol/site, i.c.v.), a sGC inhibitor, or MK-801 (0.05 mg/kg, i.p.), an NMDA receptor antagonist, in combination with a sub-effective dose of GLP-2 (1.5 μg/mouse) also decreased the immobility time in the FST. The present study provided evidence for the synergistic antidepressant-like effects of GLP-2 and inhibition of the NMDA receptor- l -arginine-NO-cGMP pathway in the FST, thereby contributing to our understanding of the mechanisms underlying the antidepressant-like effects of GLP-2. [ABSTRACT FROM AUTHOR]

Introduction: Short bowel syndrome (SBS) is the major cause of chronic intestinal failure (IF), defined as 'the reduction of gut function below the minimum necessary for the absorption of macronutrients and/or water and electrolytes, such that intravenous supplementation is required to maintain health and/or growth'. Areas covered: Spontaneous intestinal adaptation, including increased hormonal secretion, development of hyperphagia and gut microbiota dysbiosis, occurs 2 years after resection, improving intestinal absorption and decreasing PN dependency. Hormonal treatments, promoting intestinal hyperadaptation, have been proposed in patients with SBS with chronic IF. Clinical studies showed teduglutide to increase urine production and reduce the need for parenteral support volume in these patients. According to the latest ESPEN Guidelines, if a growth factor treatment is considered, the GPL2 analog, teduglutide, should be the first-choice treatment. Expert opinion: These therapies underline the importance of patient monitoring at home and the complexity for HPN adaptation. A multidisciplinary approach should be a gold standard. [ABSTRACT FROM AUTHOR]

Radiation-induced acute intestinal injury after abdominal and pelvic irradiation is a common and serious problem in the clinical setting. Glucagon-like peptide-2 (GLP-2), a 33-amino acid peptide, exerts diverse effects related to the regulation of gastrointestinal growth and function. However, GLP-2 is relatively unstable in vivo. The aim of the present study was to improve GLP-2 stability in vivo and to evaluate its therapeutic effect on acute radiation enteritis. We generated long-lasting intestinal protection peptides by conjugating human GLP-2 (hGLP-2) peptides to polyethyleneglycol (PEG) to produce mPEGylation hGLP-2 (Mono-PEG-hGLP-2) through an enzymatic site-specific transglutamination reaction. Mono-PEG-hGLP-2 synthesized under optimal reaction conditions and separated by one-step ion-exchange chromatography was found to be resistant to degradation in vitro. Pretreatment with Mono-PEG-hGLP-2 reduced the severity of radiation-induced intestinal injury, oxidative stress, and the expression of NF-κB in rats with irradiation-induced acute radiation enteritis. The enhanced biological potency of Mono-PEG-hGLP-2 highlights its potential as a therapeutic agent for intestinal diseases. [ABSTRACT FROM AUTHOR]