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Food intake regulation is a complex mechanism involving the interaction between central and peripheral structures. Among the latter, the gastrointestinal tract represents one of the main sources of both nervous and hormonal signals, which reach the central nervous system that integrates them and sends the resulting information downstream to effector organs involved in energy homeostasis. Gut hormones released by nutrient-sensing enteroendocrine cells can send signals to central structures involved in the regulation of food intake through more than one mechanism. One of these is through the modulation of gastric motor phenomena known to be a source of peripheral satiety signals. In the present review, our attention will be focused on the ability of the glucagon-like peptide 2 (GLP-2) hormone to modulate gastrointestinal motor activity and discuss how its effects could be related to peripheral satiety signals generated in the stomach and involved in the regulation of food intake through the gut-brain axis. A better understanding of the possible role of GLP-2 in regulating food intake through the gut-brain axis could represent a starting point for the development of new strategies to treat some pathological conditions, such as obesity., Competing Interests: The authors declare no conflicts of interest.

Bone resorption follows a circadian rhythm, with a marked reduction in circulating markers of resorption (such as carboxy-terminal telopeptide region of collagen type I in serum) in the postprandial period. Several gut hormones, including glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide 1 (GLP1) and GLP2, have been linked to this effect in humans and rodent models. These hormones are secreted from enteroendocrine cells in the gastrointestinal tract in response to a variety of stimuli and effect a wide range of physiological processes within and outside the gut. Single GLP1, dual GLP1-GIP or GLP1-glucagon and triple GLP1-GIP-glucagon receptor agonists have been developed for the treatment of type 2 diabetes mellitus and obesity. In addition, single GIP, GLP1 and GLP2 analogues have been investigated in preclinical studies as novel therapeutics to improve bone strength in bone fragility disorders. Dual GIP-GLP2 analogues have been developed that show therapeutic promise for bone fragility in preclinical studies and seem to exert considerable activity at the bone material level. This Review summarizes the evidence of the action of gut hormones on bone homeostasis and physiology., (© 2024. Springer Nature Limited.)

Postprandial dyslipidemia is a metabolic condition commonly associated with insulin-resistant states, such as obesity and type 2 diabetes. It is characterized by the overproduction of intestinal chylomicron particles and excess atherogenic chylomicron remnants in circulation. We have previously shown that glucagon-like peptide 2 (GLP-2) augments dietary fat uptake and chylomicron production in insulin-resistant states; however, the underlying mechanisms remain unclear. Previous studies have implicated nitric oxide (NO) in the absorptive actions of GLP-2. In this study, we report a novel role for neuronal NO synthase (nNOS)-mediated NO generation in lipid uptake and chylomicron formation based on studies in C57BL/6J mice, nNOS-/- mice, and Syrian golden hamsters after intraduodenal and oral fat administration. GLP-2 treatment in wild-type (WT) mice significantly increased postprandial lipid accumulation and circulating apolipoprotein B48 protein levels, while these effects were abolished in nNOS-/- mice. nNOS inhibition in Syrian golden hamsters and protein kinase G (PKG) inhibition in WT mice also abrogated the effect of GLP-2 on postprandial lipid accumulation. These studies demonstrate a novel mechanism in which nNOS-generated NO is crucial for GLP-2-mediated lipid absorption and chylomicron production in both mouse and hamster models. Overall, our data implicate an nNOS-PKG-mediated pathway in GLP-2-mediated stimulation of dietary fat absorption and intestinal chylomicron production., (© 2022 by the American Diabetes Association.)

Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Glucagon-like peptide-2 (GLP-2) has been reported to indirectly relax gastric smooth muscle. In the present study we investigated, through a combined mechanical and immunohistochemical approach, whether GLP-2 interferes with the electrical field stimulation (EFS)-induced vipergic relaxant responses and the mechanism through which it occurs. For functional experiments, strips from the mouse gastric fundus were mounted in organ baths for isometric recording of the mechanical activity. Vasoactive intestinal peptide (VIP) immunoreactivity in GLP-2 exposed specimens was also evaluated by immunohistochemistry. In carbachol pre-contracted strips, GLP-2 (20 nM) evoked a tetrodotoxin (TTX)-sensitive relaxation, similar in shape to the TTX-insensitive of 100 nM VIP. In the presence of GLP-2, VIP had no longer effects and no more response to GLP-2 was observed following VIP receptor saturation. EFS (4-16 Hz) induced a fast relaxant response followed, at the higher stimulation frequencies (≥ 8 Hz), by a slow one. This latter was abolished either by GLP-2 or VIP receptor saturation as well as by the VIP receptor antagonist, VIP 6-28 (10 μM). A decrease of VIP-immunoreactive nerve structures in the GLP-2 exposed specimens was observed. These results suggest that, in the mouse gastric fundus, GLP-2 influences the EFS-induced slow relaxant response by promoting neuronal VIP release., Competing Interests: Declaration of Competing Interest None., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

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.

Background: Equine insulin dysregulation (ID) is a common and poorly understood disorder that increases the risk of laminitis. Recent data show that the condition may be associated with alteration of the enteroinsular axis and enhanced glucose bioavailability. Upregulation of glucagon-like peptide-2 (GLP-2), an intestinotrophic peptide, leads to enhanced nutrient uptake and metabolic dysfunction in other species., Objectives: The study aimed to 1) determine whether GLP-2 is differentially expressed in insulin-dysregulated ponies, compared with healthy ponies, and 2) confirm intestinal expression of the GLP-2 receptor in horses (eGLP-2R)., Study Design: Cohort study., Methods: Fasting and post-prandial GLP-2 concentrations were measured in archived plasma samples obtained from 25 mixed-breed ponies during two feeding studies. Measurements were undertaken with an ELISA that was validated for equine use as part of the current study. Ponies were designated as healthy or insulin-dysregulated based on an oral glucose test, and the results were compared between groups. The gene expression of the eGLP-2R was determined with polymerase chain reaction., Results: Basal, fasted plasma GLP-2 concentrations were higher in ponies with ID, compared with healthy ponies. Grazing increased GLP-2 in healthy, but not in insulin-dysregulated, ponies. The eGLP-2R gene was expressed in the small intestine and pancreas., Main Limitations: The study was performed with a relatively small sample size. The specificity of the GLP-2 assay could not be determined due to the lack of equine-specific assay standards., Conclusions: This study has demonstrated that GLP-2 may be important in the pathogenesis of equine ID and suggests that the eGLP-2R may be a novel therapeutic target for the treatment of equine ID., (© 2018 EVJ Ltd.)

The treatment paradigm for pediatric patients with short bowel syndrome (SBS) and intestinal failure (IF) has changed significantly over recent years; the development of dedicated IF teams, refinements in PN and surgical treatments have greatly improved survival. The majority of SBS patients undergo intestinal adaptation such that nutrient absorption from enteral feeds increases and the child can come off of PN. This "adaptation" or upregulation in nutrient absorptive capacity is still poorly understood; the enteric hormone Glucagon like peptide 2 (GLP-2) appears to be a key regulator in this process. The development of Teduglutide, a long acting GLP-2 ligand as a therapy to specifically enhance adaptation has been anticipated as a further shift in the paradigm. This article reviews the physiology of GLP-2 with an emphasis on the known or potential roles in infants and children with SBS and IF. The results and implications of the present studies and approved indications for GLP-2 and its ligands are discussed. Finally, the potential future uses of GLP-2 ligands in the pediatric population are considered., (Copyright © 2018 Elsevier Inc. All rights reserved.)

The central administration of glucagon-like peptide-2 (GLP-2) decreases blood pressure in rats. In the present study, we investigated the hypotensive effects of GLP-2 using spontaneously hypertensive rats (SHRs), an animal model of hypertension. The central administration of GLP-2 (0.6 μg) decreased mean arterial pressure (MAP) in SHRs (-24.1 ± 4.5%; P < 0.05), but not in normotensive Wistar-Kyoto (WKY) rats (-10.6 ± 7.4%; P > 0.05), whereas GLP-2 (6 μg) decreased MAP in WKY rats (-23.5 ± 4.2%; P < 0.05) and SHRs (-46.7 ± 11.6%; P < 0.01) under anesthesia with urethane and α-chloralose. Histological analyses revealed that the central administration of GLP-2 (6 μg) induced Fos immunoreactivity (Fos-IR) in the hypothalamic and medullary areas in WKY rats and SHRs. However, the distribution of Fos-IR in GABAergic neurons in the rostral ventrolateral medulla (RVLM) differed between WKY rats and SHRs. GLP-2 directly modulated the excitability of RVLM neurons in brainstem slices from SHRs, but not WKY rats. These results suggest that neuronal activity through the activation of GLP-2 receptors in the RVLM contributes to lowering blood pressure in SHRs., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: This paper aimed to evaluate the influence of modified biliopancreatic diversion (BPD) on the levels of GLP-1 and GLP-2 and correlate them with satiety regulation., Methods: This is a pilot prospective cohort study that evaluated six mildly obese individuals with type 2 diabetes mellitus, which underwent modified BPD and were followed-up for 12 months. Levels of GLP-1 and GLP-2 after a standard meal tolerance test were determined and correlated with satiety scores obtained by means of a visual analogue scale (VAS)., Results: There were significant changes in BMI (33 ± 2.2 versus 26.3 ± 2.2 kg/m 2 ; p < 0.001), HbA1c (7.9 ± 1.6 versus 5.8 ± 1.2%; p = 0.026), total cholesterol (172.3 ± 11.1 versus 134.7 ± 16.1 mg/dL; p < 0.001), LDL-c (103.3 ± 13 versus 64.6 ± 12.2 mg/dL; p < 0.001), and postprandial GLP-2 (972.7 ± 326.2 versus 1993.2 ± 1024.7; p = 0. 044). None of the scores obtained in the VAS significantly changed after surgery. After surgery, there were significant correlations of VAS scores and GLP-1 levels in question 01 ("how hungry do you feel?"; R = -0.928; p = .008) and GLP-2 levels in questions 02 ("how full do you feel?" R = 0.943; p = 0.005) and 04 ("how much do you think you can eat now? R = -0.829; p = 0.042)., Conclusions: Modified BPD does not lead to significant changes in satiety evaluated by the VAS; different aspects of satiety regulation are correlated with the postprandial levels of GLP-1 (hunger feeling) and GLP-2 (satiation feeling and desire to eat) 1 year after modified BPD, signaling a specific postoperative gut hormone-related modulation of appetite.

Aim: To investigate whether glucagon-like peptide-2 (GLP-2) influences the neurally-induced responses in gastric strips from mice, since no data are available., Methods: For functional experiments, gastric fundal strips were mounted in organ baths containing Krebs-Henseleit solution. Mechanical responses were recorded via force-displacement transducers, which were coupled to a polygraph for continuous recording of isometric tension. Electrical field stimulation (EFS) was applied via two platinum wire rings through which the preparation was threaded. The effects of GLP-2 (2 and 20 nmol/L) were evaluated on the neurally-induced contractile and relaxant responses elicited by EFS. Neuronal nitric oxide synthase (nNOS) enzyme was evaluated by immunohistochemistry., Results: In the functional experiments, electrical field stimulation (EFS, 4-16 Hz) induced tetrodotoxin (TTX)-sensitive contractile responses, which were reduced in amplitude by GLP-2 ( P < 0.05). In the presence of the nitric oxide (NO) synthesis inhibitor L-NNA, GLP-2 no longer influenced the neurally-evoked contractile responses ( P > 0.05). The direct smooth muscle response to methacholine was not influenced by GLP-2 ( P > 0.05). In the presence of guanethidine and carbachol, the addition of GLP-2 to the bath medium evoked TTX-sensitive relaxant responses that were unaffected by L-NNA ( P > 0.05). EFS induced a fast NO-mediated relaxation, whose amplitude was enhanced in the presence of the hormone ( P < 0.05). Immunohistochemical experiments showed a significant increase ( P < 0.05) in nNOS immunoreactivity in the nerve structures after GLP-2 exposure., Conclusion: The results demonstrate that in gastric fundal strips, GLP-2 influences the amplitude of neurally-induced responses through the modulation of the nitrergic neurotransmission and increases nNOS expression., Competing Interests: Conflict-of-interest statement: No conflicts of interest, financial or otherwise, are declared by the authors.

Glucagon-like peptide (GLP)-2 stimulates intestinal epithelial proliferation by acting, in part, via IGF release from sub-epithelial myofibroblasts. The response of myofibroblasts to GLP-2 remains incompletely understood. We studied the action of GLP-2 on myofibroblasts from colon cancer and adjacent tissue, and the effects of conditioned medium from these cells on epithelial cell proliferation, migration and invasion. GLP-2 stimulated proliferation, migration and invasion of myofibroblasts and the proliferative and invasive responses of cancer-associated myofibroblasts were greater than those of myofibroblasts from adjacent tissue. The responses were inhibited by an IGF receptor inhibitor, AG1024. Conditioned medium from GLP-2 treated myofibroblasts increased proliferation, migration and invasion of SW480, HT29, LoVo epithelial cells and these responses were inhibited by AG1024; GLP-2 alone had no effect on these cells. In addition, when myofibroblasts and epithelial cells were co-cultured in Ibidi chambers there was mutual stimulation of migration in response to GLP-2. The latter increased both IGF-1 and IGF-2 transcript abundance in myofibroblasts. Moreover, a number of IGF binding proteins (IGFBP-4, -5, -7) were identified in myofibroblast medium; in the presence of GLP-2 there was increased abundance of the cleavage products of IGBBP-4 and IGFBP-5 suggesting activation of a degradation mechanism that might increase IGF bioavailability. The data suggest that GLP-2 stimulates cancer myofibroblast proliferation, migration and invasion; GLP-2 acts indirectly on epithelial cells partly via increased IGF expression in myofibroblasts and partly, perhaps, by increased bioavailability through degradation of IGFBPs., (Copyright © 2017 Elsevier Inc. All rights reserved.)

In recent years, more and more studies have noted the close association between gut microbiota and the development and progression of obesity. Gut microbiota may act on obesity by increasing energy intake, affecting the secretion of intestinal hormones, inducing chronic systemic inflammation, and producing insulin resistance. This article reviews the association between childhood obesity and gut microbiota, as well as possible mechanisms, in an attempt to provide a reference for the etiology, prevention and treatment of childhood obesity.

Objective: Glucagon-like peptide-2 (GLP-2) is co-secreted with GLP-1 from gut endocrine cells, and both peptides act as growth factors to expand the surface area of the mucosal epithelium. Notably, GLP-2 also enhances glucose and lipid transport in enterocytes; however, its actions on control of amino acid (AA) transport remain unclear. Here we examined the mechanisms linking gain and loss of GLP-2 receptor (GLP-2R) signaling to control of intestinal amino acid absorption in mice., Methods: Absorption, transport, and clearance of essential AAs, specifically lysine, were measured in vivo by Liquid Chromatography triple quadrupole Mass Spectrometry (LC-MS/MS) and ex vivo with Ussing chambers using intestinal preparations from Glp2 r +/+ and Glp2r - / - mice. Immunoblotting determined jejunal levels of protein components of signaling pathways (PI3K-AKT, and mTORC1-pS6-p4E-BP1) following administration of GLP-2, protein gavage, and rapamycin to fasted Glp2 r +/+ and Glp2r - / - mice. Expression of AA transporters from full thickness jejunum and 4F2hc from brush border membrane vesicles (BBMVs) was measured by real-time PCR and immunoblotting, respectively., Results: Acute administration of GLP-2 increased basal AA absorption in vivo and augmented basal lysine transport ex vivo . GLP-2-stimulated lysine transport was attenuated by co-incubation with wortmannin, rapamycin, or tetrodotoxin ex vivo . Phosphorylation of mTORC1 effector proteins S6 and 4E-BP1 was significantly increased in wild-type mice in response to GLP-2 alone, or when co-administered with protein gavage, and abolished following oral gavage of rapamycin. In contrast, activation of GLP-1R signaling did not enhance S6 phosphorylation. Disruption of GLP-2 action in Glp2r -/- mice reduced lysine transport ex vivo and attenuated the phosphorylation of S6 and 4E-BP1 in response to oral protein. Moreover, the expression of cationic AA transporter slc7a9 in response to refeeding, and the abundance of 4F2hc in BBMVs following protein gavage, was significantly attenuated in Glp2r -/- mice., Conclusions: These findings reveal an important role for GLP-2R signaling in the physiological and pharmacological control of enteral amino acid sensing and assimilation, defining an enteroendocrine cell-enterocyte axis for optimal energy absorption.

Glucagon like peptide-2 (GLP-2) is a gastrointestinal hormone released from enteroendocrine L-type cells together with glucagon like peptide-1 in response to dietary nutrients. GLP-2 acts through a specific receptor, the GLP-2 receptor, mainly located in the gut and in the brain. Classically, GLP-2 is considered a trophic hormone involved in the maintenance of intestinal epithelial morphology and function. This role has been targeted for therapies promoting repair and adaptive growth of the intestinal mucosa. Recently, GLP-2 has been shown to exert beneficial effects on glucose metabolism specially in conditions related to increased uptake of energy, such as obesity. Several actions of GLP-2 are related to a positive energy balance: GLP-2 increases not only the absorptive surface, but also expression and activity of epithelial brush-border nutrient transporters and digestive enzymes, intestinal blood flow, postprandial chylomicron secretion and it inhibits gastrointestinal motility, providing the opportunity to increase absorption of nutrients. Other actions, including anorexigenic effects, appear in opposition to the energy intake. In this review, we discuss the GLP-2 functions related to energy homeostasis. GLP-2 could be considered an hormone causing positive energy balance, which, however has the role to mitigate the metabolic dysfunctions associated with hyper-adiposity., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Purpose of Review: To summarize and illuminate the recent findings regarding gastroduodenal mucosal defense mechanisms and the specific biomolecules involved in regulating this process, such as glucagon-like peptides (GLPs)., Recent Findings: There has been a growing interest in luminal nutrient chemosensing and its physiological effects throughout the digestive system. From the ingestion of food in the oral cavity to the processing and absorption of nutrients in the intestines, nutrient chemosensing receptors signal the production and release of numerous bioactive peptides from enteroendocrine cells, such as the proglucagon-derived peptides. There has been a major emphasis on two proglucagon-derived peptides, namely GLP-1 and GLP-2, due to their apparent beneficial effect on gut structure, function, and on metabolic processes. As an incretin, GLP-1 not only enhances the effect and release of insulin on pancreatic βcells but also has been implicated in having trophic effects on the intestinal epithelium. In addition, GLP-2, the other major proglucagon-derived peptide, has potent intestinotrophic effects, such as increasing the rate of mucosal stem cell proliferation, mucosal blood flow, and fluid absorption, as well as augmenting the rate of duodenal bicarbonate secretion to improve gastric mucosal health and longevity., Summary: Understanding the mechanisms underlying nutrient chemosensing and how it relates to GLP release can further elucidate how the gut functions in response to cellular changes and disturbances. Furthermore, a more in-depth comprehension of GLP release and its tissue-specific effects will help improve the utility of GLP-1 and GLP-2 receptor agonists in clinical settings. This, in turn, should help patients suffering from intestinal failure, malabsorption, and mucosal injury.

Introduction: Glucagon-like peptide-2 (GLP-2) is a gastrointestinal hormone whose effects are predominantly trophic on the intestinal mucosa., Aim: Critically evaluate the current literature on the influence of bariatric/metabolic surgery on the levels of GLP-2 and its potential clinical implications., Methods: Narrative review through online research on the databases Medline and Lilacs. There were six prospective human studies, two cross-sectional human studies, and three experimental animal studies selected., Results: There is evidence demonstrating significant increase in the levels of GLP-2 following gastric bypass, Scopinaro operation, and sleeve gastrectomy. There are no differences between gastric bypass and sleeve gastrectomy in regards to the increase in the GLP-2 levels. There is no correlation between the postoperative levels of GLP-2 and the occurrence of adequate or insufficient postoperative weight loss., Conclusion: GLP-2 plays significant roles on the regulation of nutrient absorption, permeability of gut mucosa, control of bone resorption, and regulation of satiety. The overall impact of these effects potentially exerts a significant adaptive or compensatory effect within the context of varied bariatric surgical techniques., Competing Interests: none

The regulatory mechanisms underlying food intake in chickens have been a focus of research in recent decades to improve production efficiency when raising chickens. Lines of evidence have revealed that a number of brain-gut peptides function as a neurotransmitter or peripheral satiety hormone in the regulation of food intake both in mammals and chickens. Glucagon, a 29 amino acid peptide hormone, has long been known to play important roles in maintaining glucose homeostasis in mammals and birds. However, the glucagon gene encodes various peptides that are produced by tissue-specific proglucagon processing: glucagon is produced in the pancreas, whereas oxyntomodulin (OXM), glucagon-like peptide (GLP)-1 and GLP-2 are produced in the intestine and brain. Better understanding of the roles of these peptides in the regulation of energy homeostasis has led to various physiological roles being proposed in mammals. For example, GLP-1 functions as an anorexigenic neurotransmitter in the brain and as a postprandial satiety hormone in the peripheral circulation. There is evidence that OXM and GLP-2 also induce anorexia in mammals. Therefore, it is possible that the brain-gut peptides OXM, GLP-1 and GLP-2 play physiological roles in the regulation of food intake in chickens. More recently, a novel GLP and its specific receptor were identified in the chicken brain. This review summarizes current knowledge about the role of glucagon-related peptides in the regulation of food intake in chickens., (© 2016 The Authors. Animal Science Journal published by John Wiley & Sons Australia, Ltd on behalf of Japanese Society of Animal Science.)

Numerous endocrine cell subtypes exist within the intestinal mucosa and produce peptides contributing to the regulation of critical physiological processes including appetite, energy metabolism, gut function, and gut health. The mechanisms of action and the extent of the physiological effects of these enteric peptides are only beginning to be uncovered. One peptide in particular, glucagon-like peptide 2 (GLP-2) produced by enteroendocrine L cells, has been fairly well characterized in rodent and swine models in terms of its ability to improve nutrient absorption and healing of the gut after injury. In fact, a long-acting form of GLP-2 recently has been approved for the management and treatment of human conditions like inflammatory bowel disease and short bowel syndrome. However, novel functions of GLP-2 within the gut continue to be demonstrated, including its beneficial effects on intestinal barrier function and reducing intestinal inflammation. As knowledge continues to grow about GLP-2's effects on the gut and its mechanisms of release, the potential to use GLP-2 to improve gut function and health of food animals becomes increasingly more apparent. Thus, the purpose of this review is to summarize: (1) the current understanding of GLP-2's functions and mechanisms of action within the gut; (2) novel applications of GLP-2 (or stimulators of its release) to improve general health and production performance of food animals; and (3) recent findings, using dairy calves as a model, that suggest the therapeutic potential of GLP-2 to reduce the pathogenesis of intestinal protozoan infections., (Published by Elsevier Inc.)

GLP-1 secretion in response to meals is dramatically increased after gastric bypass operations. GLP-1 is a powerful insulinotropic and anorectic hormone, and analogs of GLP-1 are widely used for the treatment of diabetes and recently approved also for obesity treatment. It is, therefore, reasonable to assume that the exaggerated GLP-1 secretion contributes to the antidiabetic and anorectic effects of gastric bypass. Indeed, human experiments with the GLP-1 receptor antagonist, Exendin 9-39, have shown that the improved insulin secretion, which is responsible for part of the antidiabetic effect of the operation, is reduced and or abolished after GLP-1 receptor blockade. Also the postoperative improvement of glucose tolerance is eliminated and or reduced by the antagonist, pointing to a key role for the exaggerated GLP-1 secretion. Indeed, there is evidence that the exaggerated GLP-1 secretion is also responsible for postprandial hypoglycemia sometimes observed after bypass. Other operations (biliopancreatic-diversion and or sleeve gastrectomy) appear to involve different and/or additional mechanisms, and so does experimental bariatric surgery in rodents. However, unlike bypass surgery in humans, the rodent operations are generally associated with increased energy metabolism pointing to an entirely different mechanism of action in the animals., (Copyright © 2016 American Society for Bariatric Surgery. Published by Elsevier Inc. All rights reserved.)

Individuals with metabolic syndrome and frank type 2 diabetes are at increased risk of atherosclerotic cardiovascular disease, partially due to the presence of lipid and lipoprotein abnormalities. In these conditions, the liver and intestine overproduce lipoprotein particles, exacerbating the hyperlipidemia of fasting and postprandial states. Incretin-based, antidiabetes therapies (i.e., glucagon-like peptide [GLP]-1 receptor agonists and dipeptidyl peptidase-4 inhibitors) have proven efficacy for the treatment of hyperglycemia. Evidence is accumulating that these agents also improve fasting and postprandial lipemia, the latter more significantly than the former. In contrast, the gut-derived peptide GLP-2, cosecreted from intestinal L cells with GLP-1, has recently been demonstrated to enhance intestinal lipoprotein release. Understanding the roles of these emerging regulators of intestinal lipoprotein secretion may offer new insights into the regulation of intestinal lipoprotein assembly and secretion and provide new opportunities for devising novel strategies to attenuate hyperlipidemia, with the potential for cardiovascular disease reduction., (© 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.)

Purpose of Review: Chemotherapy often causes adverse effects, including pain, bloating, diarrhea, and inflammation and ulceration of the mucous membranes lining the digestive tract, which are collectively referred to as mucositis. Unfortunately, no remedy has been found yet to manage these side-effects., Recent Findings: The intestinal glucagon-like peptide-2 (GLP-2) is secreted from the intestinal endocrine L cells after nutrient intake, but recent findings show that the peptide concentration in the plasma also rises after intestinal injury and that GLP-2 receptor activation is crucial for intestinal healing. The antidiabetic hormone GLP-1, cosecreted with GLP-2, diminished mucositis in an animal model of the condition. Therefore, both peptides could be involved in the pathophysiology of mucositis., Summary: The intestinal GLPs have shown beneficial effects in experimental trials and have potential for therapeutic use. In type 2 diabetic and obese patients, GLP secretion is impaired. Elucidating the role of these endogenous hormones could lead to the identification of mucositis risk factors and an alternative preventive therapy for these patients.

Glucagon-related peptides, such as glucagon-like peptide (GLP)-1, GLP-2 and oxyntomodulin (OXM), are processed from an identical precursor proglucagon. In mammals, all of these peptides are suggested to be involved in the central regulation of food intake. We previously showed that intracerebroventricular administration of chicken OXM and GLP-1 significantly suppressed food intake in chicks. Here, we show that central administration of chicken GLP-2 potently suppresses food intake in chicks. Male 8-day-old chicks (Gallus gallus domesticus) were used in all experiments. Intracerebroventricular administration of chicken GLP-2 significantly suppressed food intake in chicks. Plasma glucose concentration was significantly decreased by chicken GLP-2, whereas plasma nonesterified fatty acid concentration was significantly increased. Intracerebroventricular administration of chicken GLP-2 did not affect plasma corticosterone concentration. In addition, the anorexigenic effect of GLP-2 was not reversed by the corticotropin-releasing factor (CRF) receptor antagonist α-helical CRF, suggesting that CRF is not a downstream mediator of the anorexigenic pathway of GLP-2 in chicks. Intracerebroventricular administration of an equimolar amount of GLP-1 and GLP-2, but not OXM, significantly suppressed food intake in both broiler and layer chicks. All our findings suggest that GLP-2 functions as a potent anorexigenic peptide in the brain, as well as GLP-1, in chicks., (© 2014 Japanese Society of Animal Science.)

Glucagon-like peptide-2 (GLP-2) is a 33-amino acid peptide derived from proteolytic cleavage of proglucagon by prohormone convertase 1/3 in enteroendocrine L cells. Studies conducted in humans, in rodent models, and in vitro indicate that GLP-2 is secreted in response to the presence of molecules in the intestinal lumen, including fatty acids, carbohydrates, amino acids, and bile acids, which are detected by luminal chemosensors. The physiological actions of GLP-2 are mediated by its G protein-coupled receptor expressed primarily in the intestinal tract on enteric neurons, enteroendocrine cells, and myofibroblasts. The biological activity of GLP-2 is further regulated by dipeptidyl peptidase IV, which rapidly cleaves the N-terminus of GLP-2 that is responsible for GLP-2 receptor activation. Within the gut, GLP-2 increases nutrient absorption, crypt cell proliferation, and mesenteric blood flow and decreases gut permeability and motility, epithelial cell apoptosis, and inflammation. Outside the gut, GLP-2 reduces bone resorption, can suppress appetite, and is cytoprotective in the lung. Thus, GLP-2 has been studied intensively as a therapeutic to improve intestinal function of humans during parenteral nutrition and following small bowel resection and, more recently, as a treatment for osteoporosis and obesity-related disorders and to reduce cellular damage associated with inflammation of the gut and lungs. Recent studies demonstrate that many biological actions and properties of GLP-2 in ruminants are similar to those in nonruminants, including the potential to reduce intestinal nitro-oxidative stress in calves caused by parasitic diseases such as coccidiosis. Because of its beneficial impacts on nutrient absorption, gut healing, and normal gut development, GLP-2 therapy offers significant opportunities to improve calf health and production efficiency. However, GLP-2 therapies require an extended time course to achieve desired physiological responses, as well as daily administration because of the hormone's short half-life. Thus, practical means of administration and alternative strategies to enhance basal GLP-2 secretion (e.g., through specific feed additives), which are more likely to achieve consumer acceptance, are needed. Opportunities to address these challenges are discussed.

Overproduction of hepatic apoB100-containing VLDL particles has been well documented in animal models and in humans with insulin resistance such as the metabolic syndrome and type 2 diabetes, and contributes to the typical dyslipidemia of these conditions. In addition, postprandial hyperlipidemia and elevated plasma concentrations of intestinal apoB48-containing chylomicron and chylomicron remnant particles have been demonstrated in insulin resistant states. Intestinal lipoprotein production is primarily determined by the amount of fat ingested and absorbed. Until approximately 10 years ago, however, relatively little attention was paid to the role of the intestine itself in regulating the production of triglyceride-rich lipoproteins (TRL) and its dysregulation in pathological states such as insulin resistance. We and others have shown that insulin resistant animal models and humans are characterized by overproduction of intestinal apoB48-containing lipoproteins. Whereas various factors are known to regulate hepatic lipoprotein particle production, less is known about factors that regulate the production of intestinal lipoprotein particles. Monosacharides, plasma free fatty acids (FFA), resveratrol, intestinal peptides (e.g. GLP-1 and GLP-2), and pancreatic hormones (e.g. insulin) have recently been shown to be important regulators of intestinal lipoprotein secretion. Available evidence in humans and animal models strongly supports the concept that the small intestine is not merely an absorptive organ but rather plays an active role in regulating the rate of production of chylomicrons in fed and fasting states. Metabolic signals in insulin resistance and type 2 diabetes and in some cases an aberrant intestinal response to these factors contribute to the enhanced formation and secretion of TRL. Understanding the regulation of intestinal lipoprotein production is imperative for the development of new therapeutic strategies for the prevention and treatment of dyslipidemia. Here we review recent developments in this field and present evidence that intestinal lipoprotein production is a process with metabolic plasticity and that modulation of intestinal lipoprotein secretion may be a feasible therapeutic strategy in the treatment of dyslipidemia and possibly prevention of atherosclerosis., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Purpose of Review: Teduglutide, a recombinant analog of human glucagon-like peptide 2, has recently been approved in the US and Europe (Gattex and Revestive, respectively) as the first targeted treatment of short bowel syndrome-associated intestinal failure (SBS-IF). Glucagon-like peptide 2 improves structural and functional intestinal adaptation following intestinal resection by decelerating a rapid gastric emptying, by decreasing gastric hypersecretion, by increasing intestinal blood flow and by promoting intestinal growth. This review summarizes the findings from phase 2 and 3 studies preceding the US Food and Drug Administration and the European Medicines Agency approval of subcutaneous teduglutide for this orphan condition., Recent Findings: In a 3-week, phase 2, metabolic balance study, teduglutide increased intestinal wet weight absorption by approximately 700 g/day and reduced fecal energy losses by approximately 0.8 MJ/day (∼200 kcal/day). In two subsequent 24-week, phase 3 studies, teduglutide reduced the need for parenteral support in the same magnitude. Teduglutide had an acceptable tolerability profile, where adverse events generally were of gastrointestinal origin consistent with the known mechanism of action., Summary: Teduglutide will add incremental benefit to the limited medical treatment armamentarium in SBS patients by maximizing intestinal absorption, decreasing fecal losses, thereby decreasing or even eliminating the need for parenteral support. Future research should target and implement other key hormones with similar and possible additive or synergistic effects, thereby further promoting structural and functional adaptation and intestinal rehabilitation in these severely disabled SBS patients.

Glucagon-like peptide-2 (GLP-2) is a 33-amino-acid proglucagon-derived peptide secreted from enteroendocrine L cells. GLP-2 circulates at low basal levels in the fasting period, and plasma levels rise rapidly after food ingestion. Renal clearance and enzymatic inactivation control the elimination of bioactive GLP-2. GLP-2 increases mesenteric blood flow and activates proabsorptive pathways in the gut, facilitating nutrient absorption. GLP-2 also enhances gut barrier function and induces proliferative and cytoprotective pathways in the small bowel. The actions of GLP-2 are transduced via a single G protein-coupled receptor (GLP-2R), expressed predominantly within the gastrointestinal tract. Disruption of GLP-2R signaling increases susceptibility to gut injury and impairs the adaptive mucosal response to refeeding. Sustained augmentation of GLP-2R signaling reduces the requirement for parenteral nutrition in human subjects with short-bowel syndrome. Hence GLP-2 integrates nutrient-derived signals to optimize mucosal integrity and energy absorption.

Nutritional status is an essential component in determining whole body energy homeostasis. The balance between energy/food intake and metabolism is governed by a range of hormones secreted from various parts of the body. Their subsequent dissemination via the blood results in a wide range of biological responses including satiety, hunger, and glucose uptake. The roles of these systemic hormones also extend to bone regulation with animal and clinical studies establishing a relationship between these regulatory pathways. This review covers the gastrointestinal hormones, ghrelin, PYY, GIP, GLP-1, and GLP-2, and the adipokines, leptin, and adiponectin and their roles in regulating bone homeostasis. Their known actions are reviewed, with an emphasis upon recent advances in understanding. Taken together, this review outlines an expanding appreciation of the interactions between bone mass and the nutritional control of whole body energy balance by gut and adipose tissue.

Glucagon-like peptides (GLP-1/GLP-2) are coproduced and highlighted as key modulators to improve glucose homeostasis and insulin sensitivity after bariatric surgery. However, it is unknown if CNS GLP-2 plays any physiological role in the control of glucose homeostasis and insulin sensitivity. We show that mice lacking GLP-2 receptor (GLP-2R) in POMC neurons display glucose intolerance and hepatic insulin resistance. GLP-2R activation in POMC neurons is required for GLP-2 to enhance insulin-mediated suppression of hepatic glucose production (HGP) and gluconeogenesis. GLP-2 directly modulates excitability of POMC neurons in GLP-2R- and PI3K-dependent manners. GLP-2 initiates GLP-2R-p85α interaction and facilitates PI3K-Akt-dependent FoxO1 nuclear exclusion in POMC neurons. Central GLP-2 suppresses basal HGP and enhances insulin sensitivity, which are abolished in POMC-p110α KO mice. Thus, CNS GLP-2 plays a key physiological role in the control of HGP through activating PI3K-dependent modulation of membrane excitability and nuclear transcription of POMC neurons in the brain., (Copyright © 2013 Elsevier Inc. All rights reserved.)

The gut derived peptides, glucagon-like peptides 1 and 2 (GLP-1 and GLP-2), are secreted following nutrient ingestion. GLP-1 and another gut peptide, glucose-dependent insulinotropic polypeptide (GIP) are collectively referred to as 'incretin' hormones, and play an important role in glucose homeostasis. Incretin secretion shares a complex interdependent relationship with both postprandial glycemia and the rate of gastric emptying. GLP-1 based therapies are now well established in the management of type 2 diabetes, while recent literature has suggested potential applications to treat obesity and protect against cardiovascular and neurological disease. The mechanism of action of GLP-2 is not well understood, but it shows promise as an intestinotropic agent., (Copyright © 2013 Elsevier Inc. All rights reserved.)

We investigated the effectiveness of glucagon-like peptide-2 (GLP-2) against refractory depression in adrenocorticotropic hormone (ACTH)-treated mice as a model of tricyclic antidepressant (TCA)-resistant depression. Chronic ACTH treatment (0.45 mg/kg, s.c., 14 days) weakened the antidepressant-like effects of imipramine (20 mg/kg, i.p., 6 days) in the forced-swim test (FST). Conversely, GLP-2 (3 μg/mice, i.c.v., 6 days) induced antidepressant-like effects in the ACTH-treated mice in the FST. ACTH-treatment increased basal serum corticosterone levels, with an additional increase induced by the FST. Imipramine or GLP-2 had no effect on the basal corticosterone level, but GLP-2 attenuated the additional increase caused by the FST. Moreover, GLP-2 increased 5-HT levels, but not 5-HIAA. These results suggest that GLP-2 induced antidepressant-like effects under imipramine-resistant conditions through increase in 5-HT levels., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Background: In animal and human studies glucagon-like peptide-2 (GLP-2) has been shown to increase blood flow in the superior mesenteric artery and the portal vein. This study describes the effect of GLP-2 measured directly on the intestinal mucosal blood flow by laser Doppler flowmetry (LDF) in end-jejunostomy short bowel syndrome (SBS) patients., Methods: In five SBS patients with end-jejunostomy a specially designed laser Doppler probe was inserted into the stoma nipple, and blood flow measured directly on the jejunal mucosa for 105 min in relation to no treatment, systemic saline infusion, topical adrenaline application and a subcutaneous injection of 800 μg native GLP-2., Results: The GLP-2 injection increased jejunal mucosal blood flow by 79±37% compared to conditions, where no treatment was given (p<0.001). The significant effect was present at least 105 min. Systemic saline infusion and topical, mucosal adrenaline application did not affect mucosal microcirculation., Conclusions: GLP-2 raises jejunal microcirculation in SBS patients with end-jejunostomy. This may explain the redness and increase in the end-jejunostomy nipple size imminently after commencing GLP-2 injections. The potential beneficial effects of this GLP-2-mediated increase of blood flow in the mesenteric bed should be investigated in clinical conditions other than the short bowel syndrome., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Background: Recent advancements in understanding the roles and functions of glucagon-like peptide 1 (GLP-1) and 2 (GLP-2) have provided a basis for targeting these peptides in therapeutic strategies., Aim: To summarise the preclinical and clinical research supporting the discovery of new therapeutic molecules targeting GLP-1 and GLP-2., Methods: This review is based on a comprehensive PubMed search, representing literature published during the past 30 years related to GLP-1 and GLP-2., Results: Although produced and secreted together primarily from L cells of the intestine in response to ingestion of nutrients, GLP-1 and GLP-2 exhibit distinctive biological functions that are governed by the expression of their respective receptors, GLP-1R and GLP-2R. Through widespread expression in the pancreas, intestine, nervous tissue, et cetera, GLP-1Rs facilitates an incretin effect along with effects on appetite and satiety. GLP-1 analogues resistant to degradation by dipeptidyl peptidase-IV and inhibitors of dipeptidyl peptidase-IV have been developed to aid treatment of diabetes and obesity. The GLP-2R is expressed almost exclusively in the stomach and bowel. The most apparent role for GLP-2 is its promotion of growth and function of intestinal mucosa, which has been targeted for therapies that promote repair and adaptive growth. These are used as treatments for intestinal failure and related conditions., Conclusions: Our growing understanding of the biology and function of GLP-1, GLP-2 and corresponding receptors has fostered further discovery of fundamental biological function as well as new categories of potent therapeutic medicines., (© 2012 Blackwell Publishing Ltd.)

Introduction: Tight junctions are intercellular permeability seals that regulate paracellular transport across epithelia. Tight junction function, expression and localisation of constituent proteins are significantly altered by cytokines such as TNFα. Glucagon-like peptide-2 (GLP-2) is an intestinotrophic enteroendocrine peptide. It is not known whether GLP-2 regulates the barrier or tight junctions. The aim of this study was to investigate whether GLP-2 has an effect on tight junction function or protein expression, alone or in response to TNFα exposure., Methods: Caco-2 cells were grown to confluence on filters in the presence or absence of GLP-2. The time course of transepithelial electrical resistance developing across the monolayer was measured; tight junction protein expression was quantified by immunoblotting. At day 20, TNFα in the presence or absence of GLP-2 was added. Changes in TEER and tight junction proteins expression were quantified. Both TNFα and GLP-2 were added on the basolateral side., Results: GLP-2 exposed Caco-2 cell monolayers showed a significant increase in transepithelial electrical resistance compared to that in untreated control cells. At the same time, expression of the tight junction proteins occludin and zona occludens-1 (ZO-1) was increased at day 17 post-seeding (1.6-fold; p=0.037 and 4.7 fold; p=0.039 respectively). Subsequent TNFα exposure induced a significant 9.3-fold (p<0.001) decrease in transepithelial electrical resistance and a corresponding reduction in the expression of ZO-1 (5.3 fold; p<0.01). However, the TNFα-induced reduction in transepithelial electrical resistance in GLP-2-exposed cells was highly attenuated to 1.8-fold (p<0.01). No change in tight junction protein expression was noted in GLP-2 exposed cells after cytokine exposure., Conclusion: GLP-2 enhances formation of the epithelial barrier and its constituent proteins in Caco-2 cells, and diminishes the effects of TNFα. If these effects are replicated in vivo the GLP-2 receptor may present a therapeutic target in intestinal inflammation., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Objective: To investigate the protective effect of glucagon-like peptide 2 (GLP-2) on intestinal barrier dysfunction in severe acute pancreatitis and to explore the putative mechanism of this effect., Methods: Thirty rats were randomly divided into 3 groups. Group 1 received sham operation. Severe acute pancreatitis was induced in group 2 and group 3 via retrograde injection of 3% sodium taurocholate to the pancreatic duct. Rats in group 3 were peritoneally injected with GLP-2. Intestinal barrier dysfunction was characterized by the histological measurements and concentration of plasma diamine oxidase. The tissue sections of ileum were collected for the detection of proliferating cell nuclear antigen protein and apoptosis., Results: Glucagon-like peptide 2 administration improved the ileal mucosal injury, which was also demonstrated by the histological score of ileal mucosa. The concentration of diamine oxidase was decreased in rats with acute pancreatitis treated with GLP-2. Acute pancreatitis-induced epithelial cell apoptosis was partly prevented by GLP-2. Immunohistochemical staining of proliferating cell nuclear antigen protein was increased in group 3 compared with that in group 2., Conclusions: Results from this study suggest that GLP-2 has a protective effect on intestinal barrier dysfunction in rats with severe acute pancreatitis via mechanisms closely involving promotion of cell growth and inhibition of intestinal epithelial cell apoptosis.

Proglucagon-derived glucagon-like peptide-2 (GLP-2) is released from enteroendocrine cells and neurons. GLP-2 regulates energy absorption and epithelial integrity in the gastrointestinal tract, but its effect on blood-pressure regulation remains unknown. In the present study, we found that GLP-2 administered both peripherally and centrally dose-dependently reduced mean arterial blood pressure (MAP) in male Wistar rats anesthetized with urethane and α-chloralose. Immunohistochemical detection of the c-fos protein (Fos) revealed that the peripherally and centrally administered GLP-2 induced Fos-immunoreactivity (Fos-IR) in the nucleus of the solitary tract (NTS) and the caudal ventrolateral medulla (CVLM). In contrast, Fos-IR in brainstem catecholamine neurons decreased after the administration of GLP-2. These results suggest that GLP-2 acts on specific brain nuclei to inhibit sympathetic nerve activity and this leads to hypotension., (Copyright © 2012 IBRO. Published by Elsevier Ltd. All rights reserved.)

The regulation of nutrient absorptive capacity is a critical factor in the normal growth and development of infants of all species. In human infants this is a common problem after surgical resection; the process of adaptation or upregulation of nutrient transport capacity is the physiologic process, which allows patients to transition to enteral feeding. The specific mechanisms that control this are still relatively poorly understood but are likely relevant for most mammals with an ontogeny of intestinal function related to the weaning process. Many actions of the entero-endocrine hormone glucagon-like peptide (GLP)-2 indicate that it may be a key factor in regulating physiologic intestinal development, nutrient absorptive capacity, and the process of adaptative upregulation of nutrient absorption after resection. This article will review the biology of GLP-2, which is preserved across a broad range of species. This will include the production of GLP-2 in the L cell, the regulation of GLP-2 release, and the mechanism of action. The GLP-2 receptor is specifically located on enteric neurons and pericryptal myofibroblast; thus, effects on the intestinal mucosa involve a second messenger. We will review the functioning of this system in the developing human infant and the role of GLP-2 in the regulation of adaptation, with the general implications for nutrient absorption in animals and humans.

Background and Purpose: The glucagon-like peptides GLP-1 and GLP-2 are secreted from enteroendocrine L-cells following nutrient ingestion. Drugs that increase activity of the GLP-1 axis are highly successful therapies for type 2 diabetes, and boosting L-cell secretion is a potential strategy for future diabetes treatment. The aim of the present study was to further our understanding of the bile acid receptor GPBA (TGR5), an L-cell target currently under therapeutic exploration., Experimental Approach: GLUTag cells and mixed primary murine intestinal cultures were exposed to bile acids and a specific agonist, GPBAR-A. Secretion was measured using hormone assays and intracellular calcium and cAMP responses were monitored using real-time imaging techniques., Key Results: Bile acid-triggered GLP-1 secretion from GLUTag cells was GPBA-dependent, as demonstrated by its abolition following tgr5 siRNA transfection. Bile acids and GPBAR-A increased GLP-1 secretion from intestinal cultures, with evidence for synergy between the effects of glucose and GPBA activation. Elevation of cAMP was observed following GPBA activation in individual GLUTag cells. Direct calcium responses to GPBAR-A were small, but in the presence of the agonist, a subpopulation of cells that was previously poorly glucose-responsive exhibited robust glucose responses. In vivo, increased delivery of bile to more distal regions of the ileum augmented L-cell stimulation., Conclusions and Implications: GPBA signalling in L-cells involves rapid elevation of cAMP, and enhanced calcium and secretory responses to glucose. Modulation of this receptor therapeutically may be an attractive strategy to enhance GLP-1 secretion and achieve better glycaemic control in diabetic patients., (© 2011 The Authors. British Journal of Pharmacology © 2011 The British Pharmacological Society.)

Introduction: Glucagon-like peptide-2 (GLP-2) is a pleiotropic intestinotrophic hormone that enhances digestive and absorptive capacity by acting through a limited population of intestinal GLP-2 receptors. The development of protease-resistant analogs or GLP-2/IgG fusion proteins confers a longer circulating half life than the native peptide. GLP-2 has garnered interest as a therapeutic most notably by reducing reliance on total parenteral nutrition in patients with short bowel syndrome., Areas Covered: The clinical evidence for benefit in conditions requiring longer term treatment with GLP-2 receptor agonists, for example short bowel syndrome and inflammatory bowel disease. Benefits of short-term GLP-2 treatment are emerging in pre-clinical models, such as post-operative ileus, GI mucositis and conditions of altered intestinal permeability. The therapeutic utility of GLP-2 receptor agonists is limited by concern that it predisposes patients to gastrointestinal cancers, or their re-occurrence in cancer patients. This affects the types of diseases treated and, possibly, the duration of dosing., Expert Opinion: GLP-2 is therapeutically attractive in diseases to enhance absorptive capacity, restore mucosal health and reduce inflammation. Long-term surveillance studies with a marketed therapeutic agent are needed to weigh the benefits of GLP-2 treatment against the potential effects on co-morbidities and increased risk of intestinal carcinogenesis.

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

The effects of glucagon-like peptide 2 (GLP-2) on expression and activity of jejunal multidrug resistance-associated protein 2 (Mrp2; Abcc2) and glutathione transferase (GST) were evaluated. After GLP-2 treatment (12 μg/100 g b.wt. s.c., every 12 h, for 5 consecutive days), Mrp2 and the α class of GST proteins and their corresponding mRNAs were increased, suggesting a transcriptional regulation. Mrp2 was localized at the apical membrane of the enterocyte in control and GLP-2 groups, as detected by confocal immunofluorescence microscopy. As a functional assay, everted intestinal sacs were incubated in the presence of 1-chloro-2,4-dinitrobenzene in the mucosal compartment, and the glutathione-conjugated derivative, dinitrophenyl-S-glutathione (DNP-SG; model Mrp2 substrate), was detected in the same compartment by high-performance liquid chromatography. A significant increase in apical secretion of DNP-SG was detected in the GLP-2 group, consistent with simultaneous up-regulation of Mrp2 and GST. GLP-2 also promoted an increase in cAMP levels as detected in homogenates of intestinal mucosa. Treatment of rats with 2',3'-dideoxyadenosine (DDA), a specific inhibitor of adenylyl cyclase, abolished the increase in cAMP levels and Mrp2 protein promoted by GLP-2, suggesting cAMP as a mediator of Mrp2 modulation. Increased expression of Mrp2 and cAMP levels in response to GLP-2 occurred not only at the tip but also at the middle region of the villus, where constitutive expression of Mrp2 is normally low. In conclusion, our study suggests a role for GLP-2 in the prevention of cell toxicity of the intestinal mucosa by increasing Mrp2 chemical barrier function.

Glucagon-like peptide-2 (GLP-2) is a neuropeptide secreted from endocrine cells in the gut and neurons in the brain. GLP-2 stimulates intestinal crypt cell proliferation and mucosal blood flow while decreasing gastric emptying and gut motility. However, a GLP-2-mediated signaling network has not been fully established in primary cells. Since the GLP-2 receptor mRNA and protein were highly expressed in the mouse hippocampus, we further characterized that human (125)I-labeled GLP-2(1-33) specifically bound to cultured hippocampal neurons with K(d) = 0.48 nM, and GLP-2 acutely induced subcellular translocalization of the early gene c-Fos. Using the whole cell patch clamp, we recorded barium currents (I(Ba)) flowing through voltage-gated Ca(2+) channels (VGCC) in those neurons in the presence of GLP-2 with and without inhibitors. We showed that GLP-2 (20 nM) enhanced the whole cell I(Ba) mediated by L-type VGCC that was defined using an L-type Ca(2+) channel blocker (nifedipine, 10 microM). Moreover, GLP-2-potentiation of L-type VGCC was abolished in neurons pretreated with a PKA inhibitor (PKI(14-22), 1 microM). Finally, using a fluorescent nonmetabolized glucose analog (6-NBDG) tracing imaging, we showed that glucose was taken up directly by cultured neurons. GLP-2 increased 2-deoxy-d-[(3)H]glucose uptake that was dependent upon dosage, activation of PKA, and potentiation of L-type VGCC. We conclude that GLP-2 potentiates L-type VGCC activity through activating PKA signaling, partially stimulating glucose uptake by primary cultured hippocampal neurons. The potentiation of L-type VGCC may be physiologically relevant to GLP-2-induced neuroendocrine modulation of neurotransmitter release and hormone secretion.

Background & Aims: Excessive postprandial lipemia is a prevalent condition that results from intestinal oversecretion of apolipoprotein B48 (apoB48)-containing lipoproteins. Glucagon-like peptide-2 (GLP-2) is a gastrointestinal-derived intestinotropic hormone that links nutrient absorption to intestinal structure and function. We investigated the effects of GLP-2 on intestinal lipid absorption and lipoprotein production., Methods: Intestinal lipid absorption and chylomicron production were quantified in hamsters, wild-type mice, and Cd36(-/-) mice infused with exogenous GLP-2. Newly synthesized apoB48 was metabolically labelled in primary hamster jejunal fragments. Fatty acid absorption was measured, and putative fatty acid transporters were assessed by immunoblotting., Results: Human GLP-2 increased secretion of the triglyceride (TG)-rich lipoprotein (TRL)-apoB48 following oral administration of olive oil to hamsters; TRL and cholesterol mass each increased 3-fold. Fast protein liquid chromatography profiling indicated that GLP-2 stimulated secretion of chylomicron/very low-density lipoprotein-sized particles. Moreover, GLP-2 directly stimulated apoB48 secretion in jejunal fragments cultured ex vivo, increased expression of fully glycosylated cluster of differentiation 36/fatty acid translocase (CD36), and induced intestinal absorption of [(3)H]triolein. The ability of GLP-2 to increase intestinal lipoprotein production was lost in Cd36(-/-) mice., Conclusions: GLP-2 stimulates intestinal apoB48-containing lipoprotein secretion, possibly through increased lipid uptake, via a pathway that requires CD36. These findings suggest that GLP-2 represents a nutrient-dependent signal that regulates intestinal lipid absorption and the assembly and secretion of TRLs from intestinal enterocytes.

Purpose of Review: The medical management of short bowel syndrome frequently requires lifelong parenteral nutrition. Methods of increasing intestinal absorption and reducing parenteral nutrition dependence, by improving postresection intestinal adaptation, are increasingly being explored. Glucagon-like peptide-2 (GLP-2) is an important intestinotrophic growth factor and mediator of intestinal adaptation. This review summarizes our current understanding of GLP-2 physiology and provides an update on clinical trials in short bowel syndrome and related conditions., Recent Findings: There is growing understanding how the effects of GLP-2 are mediated by downstream effectors such as insulin-like growth factor-1. In the treatment of short bowel syndrome, GLP-2 and the long-acting GLP-2 analogue teduglutide (Gattex) are effective in improving fluid absorption. A recent multicentre, placebo-controlled study demonstrates that this can translate into meaningful reductions in parenteral nutrition requirements. Treatment dose and timing of treatment initiation might influence the mucosal growth response. Most of the small intestine has to be preserved to facilitate the previously documented benefits of GLP-2 on bone metabolism. Therapeutic uses of GLP-2 in other gastrointestinal conditions are being explored. GLP-2 treatment appears well tolerated, although concerns about the long-term use of this growth-promoting agent remain., Summary: GLP-2 therapy holds promise as an adjuvant treatment modality for short bowel syndrome and other gastrointestinal disorders.

Background and Aims: Obese and diabetic mice display enhanced intestinal permeability and metabolic endotoxaemia that participate in the occurrence of metabolic disorders. Our recent data support the idea that a selective increase of Bifidobacterium spp. reduces the impact of high-fat diet-induced metabolic endotoxaemia and inflammatory disorders. Here, we hypothesised that prebiotic modulation of gut microbiota lowers intestinal permeability, by a mechanism involving glucagon-like peptide-2 (GLP-2) thereby improving inflammation and metabolic disorders during obesity and diabetes., Methods: Study 1: ob/ob mice (Ob-CT) were treated with either prebiotic (Ob-Pre) or non-prebiotic carbohydrates as control (Ob-Cell). Study 2: Ob-CT and Ob-Pre mice were treated with GLP-2 antagonist or saline. Study 3: Ob-CT mice were treated with a GLP-2 agonist or saline. We assessed changes in the gut microbiota, intestinal permeability, gut peptides, intestinal epithelial tight-junction proteins ZO-1 and occludin (qPCR and immunohistochemistry), hepatic and systemic inflammation., Results: Prebiotic-treated mice exhibited a lower plasma lipopolysaccharide (LPS) and cytokines, and a decreased hepatic expression of inflammatory and oxidative stress markers. This decreased inflammatory tone was associated with a lower intestinal permeability and improved tight-junction integrity compared to controls. Prebiotic increased the endogenous intestinotrophic proglucagon-derived peptide (GLP-2) production whereas the GLP-2 antagonist abolished most of the prebiotic effects. Finally, pharmacological GLP-2 treatment decreased gut permeability, systemic and hepatic inflammatory phenotype associated with obesity to a similar extent as that observed following prebiotic-induced changes in gut microbiota., Conclusion: We found that a selective gut microbiota change controls and increases endogenous GLP-2 production, and consequently improves gut barrier functions by a GLP-2-dependent mechanism, contributing to the improvement of gut barrier functions during obesity and diabetes.