Glucagon-Like Peptide-2

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.

To assess whether patient and physician global assessment of gastrointestinal tract (GIT) disease in systemic sclerosis (SSc) are associated with a meaningful change in disease status. One hundred forty-three participants from the Australian Scleroderma Cohort Study were recruited to this study. Using logistic regression analysis, we evaluated the relationship between patient-reported and physician-assessed GIT disease status and symptoms, measures of health-related quality of life (36-item Short Form Health Survey [SF-36]) and GIT disease severity, measured by the Scleroderma Clinical Trials Consortium UCLA Gastrointestinal Tract 2.0 (GIT 2.0) score. Patient-reported worsening of GIT symptoms in the month preceding assessment was significantly associated with more severe GIT disease (odds ratio [OR] 6.14, P < 0.01) and progressive worsening GIT disease severity as measured by the GIT 2.0 score (OR 45.98, P < 0.01). The new onset of reflux was the only specific symptom associated with patient-reported GIT disease activity (OR 2.98, P = 0.04). Physician-assessed GIT disease activity was not significantly associated with higher GIT 2.0 scores or increasing severity of disease. Patient-reported and physician-assessed GIT activity was not associated with SF-36 scores. In the absence of objective measures of GIT disease activity in SSc, patient-reported symptoms of GIT disease could be used to indicate disease activity and should merit consideration for inclusion in a multisystem disease activity index.

The benefits of dietary macronutrients for weight management depend on the integrity of gut hormones. The role of food temperature in the release of satiety hormones and satiety needs elucidation. We aimed to determine the impact of different food temperatures with varying macronutrient compositions on satiety-related gut hormones glucagon-like peptide-1 (GLP-1) and cholecystokinin (CCK) and find the correlation of satiety hormones with appetite scores and remainder-day food (energy) intake. Thirteen healthy participants (eight males and five females) aged 25-35 years with body mass index 18.5-24.9 kg/m2 with no medical illnesses or eating disorders consumed three compositions of meals (high carbohydrate, high fat, and high protein meals) each at three temperatures (cold, warm, and hot) in a randomized, double-blinded, controlled crossover design. Plasma concentrations of peptide hormones were determined at 0, 30, and 240 minutes by enzyme-linked immunosorbent assay, and 24-hours food recall was used for remainder-day food intake (remainder energy). Data were analyzed using SPSS version 27.0. The change in plasma levels of gut hormones with time was assessed using Friedman test; Kruskal-Wallis test was employed to compare GLP-1 and CCK hormonal levels across nine meals. A comparison of the three meals at the three temperatures (total of nine groups), showed that the GLP-1 and CCK plasma concentrations were significantly different (P < 0.001). GLP-1 and CCK responses increased more after hot meals than cold meals. Overall, high-fat meals had more effective gut hormone secretions. The area under the curve was increased for GLP-1 in high-fat meals and for CCK in hot meals. The peptide hormones (GLP-1 and CCK) were positively correlated with satiety scores and inversely with remainder food intake. The temperature of food was found to be an effective stimulus for the regulation of CCK and GLP-1 secretion. Hot food temperature increased satiety hormones (CCK and GLP-1), independent of food macronutrient composition.

Disclosure: L. Coassolo: None. Peptide hormones, a class of pharmacologically active molecules, play a critical role in regulating energy homeostasis. Prohormone convertase 1/3 (PCSK1/PCSK3) represents a key enzymatic mechanism in peptide processing, as exemplified with the therapeutic target glucagon-like peptide-1 (GLP-1). However, the full spectrum of peptides generated by PCSK1 and their functional roles remain largely unknown. We developed Peptide Predictor, a computational drug discovery tool that systematically maps over 2,600 previously uncharacterized human proteolytic peptide fragments cleaved by prohormone convertases, enabling the identification of novel bioactive peptides. Using this approach, we identified an orphan brain-derived 12-mer peptide, BRINP2-Related Peptide (BRP), which is endogenously circulating in human cerebrospinal fluid and cleaved by PCSK1. BRP exhibits potent properties in suppressing food intake and reversing obesity in both rodent and non-rodent species when administered pharmacologically. BRP acts as a signaling ligand in the central nervous system to regulate food intake without affecting insulin release, energy expenditure, locomotor activity, or anxiety-like behavior and without inducing nausea or aversion. Mechanistically, BRP administration triggers a central cAMP/PKA/CREB/Fos signaling pathway in POMC-negative hypothalamic neurons. Specifically, BRP induced Fos activation in the dorsomedial hypothalamic nucleus (DMH), preoptic hypothalamic nucleus, tuberal nucleus, and arcuate nucleus of the hypothalamus but did not activate Fos in the hindbrain or brainstem. In addition, BRP acts independently of leptin, glucagon-like receptor-1, and melanocortin-4 receptor indicating an independent pathway for control of appetite. Together, these data introduce Peptide Predictor as a drug discovery method to identify new bioactive peptides and establish pharmacological proof-of-concept that BRP may be useful for therapeutic modulation of appetite and body weight. Presentation: Monday, July 14, 2025

Association between neuroticism and gastrointestinal tract (GIT) diseases may not be attributable to the genetic overlaps between neuroticism and psychiatric disorders. We aim to explore the genetic links and mechanisms of neuroticism and GIT diseases. We obtained European genome-wide association data of neuroticism (n = 390,278) or subclusters (depressed, n = 357,957; worry, n = 348,219) and six GIT diseases: gastroesophageal reflux disease (GERD, n = 456,327), inflammatory bowel disease (IBD, n = 456,327), peptic ulcer disease (PUD, n = 456,327), irritable bowel syndrome (IBS, n = 486,601), Crohn's disease (CD, n = 20,883), and ulcerative colitis (UC, n = 21,895). We performed genetic correlation analysis (high-definition likelihood method and cross-trait linkage disequilibrium score regression), pairwise pleiotropic analysis, single nucleic acid polymorphism annotation, Bayesian colocalization, gene-level analysis, transcriptome-wide association analysis, and gene set enrichment analysis. Neuroticism and its subclusters are associated with most GIT diseases (15 of 18 trait-pairs). GERD and PUD were highly correlated with depressed affect. We identified pleiotropic loci 11q23.2 (mapped gene: NCAM1/DRD2) and 18q12.2 (mapped gene: CELF4) in neuroticism and IBS/GERD, supporting the genetic overlap between neuroticism and depression. We found that 16q12.1 (mapped gene: NKD1/ZNF423/NOD2) and 2q37.1 (mapped gene: ATG16L1/SP140) are only highlighted in depressed/neuroticism CD, revealing pleiotropic loci with dissimilarities between neuroticism and different GIT diseases. MR analysis suggested that genetic liability to neuroticism is associated with increased risks of IBS, PUD, and GERD. Our findings document the genetic links between neuroticism and six GIT diseases, highlighting the genetic overlaps and heterogeneity between neuroticism and psychiatric disorders in the context of gastrointestinal disorders. Both the shared and unique pleiotropic loci identified between neuroticism and different GIT diseases could facilitate mechanistic understandings and may stimulate further translational implications.

Background: Glucagon-like peptide 1 (GLP-1) is involved in the regulation of energy and glucose homeostasis. As GLP-1 has similar effects on the energy homeostasis as the hypophysiotropic thyrotropin-releasing hormone (TRH) neurons that regulate the hypothalamic-pituitary-thyroid (HPT) axis, we raised the possibility that the TRH neurons are involved in the mediation of the effects of GLP-1. Therefore, the relationship and interaction of the GLP-1 system and the TRH neurons of the hypothalamic paraventricular nucleus (PVN) were studied. Methods: To examine the anatomical and functional relationship of TRH neurons and the GLP-1 system in the PVN, immunocytochemistry, in situ hybridization, in vitro patch-clamp electrophysiology, metabolic phenotyping, and explant experiments were performed. Results: Our data demonstrate that the TRH neurons of the PVN are innervated by GLP-1 producing neurons and express the GLP-1 receptor (GLP-1R). However, not only do the GLP-1-innervated TRH neurons express GLP-1R but the receptor is also present in the axons of the hypophysiotropic TRH neurons in the blood-brain barrier free median eminence (ME) suggesting that peripherally derived GLP-1 may also influence the TRH neurons. In vitro, GLP-1 increased the firing rate of TRH neurons and depolarized them. In addition, GLP-1 directly stimulated the GABAergic input of a population of TRH neurons. Furthermore, GLP-1 inhibited the release of TRH from the hypophysiotropic axons in the ME. In vivo, peripheral GLP-1R agonist administration markedly inhibited the food intake and the energy expenditure, but had no effect on the TRH expression in the PVN and resulted in lower circulating free T4 levels. Conclusions: Our results indicate that GLP-1R activation has a direct stimulatory effect on TRH neurons in the PVN, but the activation of GLP-1R may also inhibit TRH neurons by facilitating their inhibitory inputs or by inhibiting the axon terminals of these cells in the ME. The innervation of TRH neurons by GLP-1 neurons suggests that TRH neurons might be influenced by both circulating GLP-1 and by GLP-1 neurons of the nucleus tractus solitarii. The lack of GLP-1R agonist-induced regulation of TRH neurons in vivo suggests that the HPT axis does not mediate the GLP-1R agonist-induced weight loss.

Paying the Price for Eating Ice Cream: Is Excessive GLP-1 Signaling in the Brain the Culprit?

Glucagon like peptide-1 (GLP-1), a peptide hormone from the intestinal tract, plays a central role in the coordination of postprandial glucose homeostasis through actions on insulin secretion, food intake and gut motility. GLP-1 forms the basis for a variety of current drugs for the treatment of type 2 diabetes and obesity, as well as new agents currently being developed. Here, we provide a concise overview of the core physiology of GLP-1 secretion and action, and the role of the peptide in human health, disease and therapeutics.

Peptide hormones within the secretin-glucagon family are expressed in endocrine cells of the pancreas and gastrointestinal epithelium and in specialized neurons in the brain, and subserve multiple biological functions, including regulation of growth, nutrient intake, and transit within the gut, and digestion, energy absorption, and energy assimilation. Glucagon, glucagon-like peptide-1, glucagon-like peptide-2, glucose-dependent insulinotropic peptide, growth hormone-releasing hormone and secretin are structurally related peptides that exert their actions through unique members of a structurally related G protein-coupled receptor class 2 family. This review discusses advances in our understanding of how these peptides exert their biological activities, with a focus on the biological actions and structural features of the cognate receptors. The receptors have been named after their parent and only physiologically relevant ligand, in line with the recommendations of the International Union of Pharmacology Committee on Receptor Nomenclature and Drug Classification (NC-IUPHAR).

Sensory neurons expressing the sodium channel Nav1.8 contain a repertoire of receptors for nutrient, hormonal, and inflammatory ligands. However, their function in key regulators of energy homeostasis control is not well understood and is completely unexplored in females. Mice lacking neurons expressing the sodium channel Nav1.8 were generated using an ablation strategy based on cre recombinase-mediated expression of diphtheria toxin fragment A (DTA) (Nav1.8-cre/DTA mice) to investigate whether these neurons modulate body weight, food intake, gut hormone secretion, gastrointestinal transit, and glucose tolerance in response to nutrient challenges in a sex-dependent manner. Male Nav1.8-cre/DTA mice show resistance to gain weight in response to high-fat high-sugar diet (HFHSD), whereas females lacking Nav1.8+ neurons have improved oral glucose tolerance accompanied by higher insulin levels and attenuated glucagon secretion after an oral glucose load. Female Nav1.8-cre/DTA mice also show higher fasting and postprandial glucagon like peptide-1 (GLP-1) levels with an increased number of GLP-1-positive cells. Finally, ablation of Nav1.8-expressing neurons accelerates the gastrointestinal transit in female mice under HFHSD. This data demonstrates sex-dependent differences in the Nav1.8-mediated regulation of energy metabolism, and provides new insights that may help in the design of sex-specific neuromodulation therapies for metabolic disorders induced by diets rich in fats and simple sugars.

Glucagon-like peptide-2 (GLP-2) is a pleiotropic hormone synthesized and secreted by the enteroendocrine 'L' cells able to exert intestine-trophic and anti-inflammatory effects. The antineoplastic drug cisplatin causes gastrointestinal alterations with clinical symptoms (nausea and vomiting) that greatly affect the therapy compliance. Experimentally, it has been reported that chronic cisplatin treatment caused mucosal damage and enteric neuropathy in the rat colon. We investigated, through a combined immunohistochemical and functional approach, whether [Gly(2) ]GLP-2, a GLP-2 analog, was able to counteract the detrimental effects of long-term cisplatin administration in the mucosa and myenteric neurons of mouse gastric fundus. Morphological experiments showed a reduction in the epithelium thickness in cisplatin-treated mice, which was prevented by [Gly(2) ]GLP-2 co-treatment. Immunohistochemistry demonstrated that cisplatin caused a significant decrease in myenteric neurons, mainly those expressing neuronal nitric oxide synthase (nNOS), that was prevented by [Gly(2) ]GLP-2 co-treatment. In the functional experiments, [Gly(2) ]GLP-2 co-treatment counteracted the increase in amplitude of the neurally induced contractions observed in strips from cisplatin-treated animals. The NO synthesis inhibitor L-N(G) -nitro arginine caused an increase in amplitude of the contractile responses that was greater in preparations from cisplatin+[Gly(2) ]GLP-2 treated mice compared to the cisplatin-treated ones. The results demonstrate that in cisplatin long-term treated mice [Gly(2) ]GLP-2 is able to counteract both the mucosal gastric fundus damage, by preventing the epithelium thickness decrease, and the neuropathy, by protecting the nNOS neurons. Taken together, the present data suggest that [Gly(2) ]GLP-2 could represent an effective strategy to overcome the distressing gastrointestinal symptoms present during the anti-neoplastic therapy.

This analysis is based on the study of materials from scientific electronic libraries (elibrary.ru, PubMed, scientific library of the Petrovsky National Research Centre of Surgery, Moscow, Russia). The problem of treating the pathology of the upper gastrointestinal tract is caused by the high prevalence of benign and malignant diseases of this zone, their severity, the complexity of diagnosis and often the low efficiency of conservative therapy. Intensive implementation of innovative scientific technologies in medical practice, aimed at increasing the effectiveness of treatment and diagnostic measures, minimizing their negative impact on the patient’s body and reducing the risk of complications, which, at the same time, have sufficient economic attractiveness. In full, all of the above can be attributed to endoscopy, which has been actively developing in recent years, both in the diagnostic and in the operational areas. In the treatment of various diseases of the gastrointestinal tract in recent years, combined methods based on the use of two or more minimally invasive technologies, for example, endoluminal endoscopic and thoraco or laparoscopic methods, have entered the world practice. The data of scientific articles on the problem of surgical treatment of patients with benign and malignant diseases of the upper gastrointestinal tract, carried out using intraoperative intraluminal endoscopic assistant, are analyzed. The use of intraluminal endoscopy, in particular, allows to increase the radicality of surgical interventions in patients with malignant neoplasms of the upper gastrointestinal tract, perform intraoperative topical diagnosis of non-palpable tumors, and use it in the surgical treatment of esophageal diverticulums of various localization. Also, another area of application of intraoperative intraluminal endoscopy is the assessment of tightness and anastomosis zone during surgical interventions on the organs of the gastrointestinal tract. However, this technique is in the process of implementation in clinical practice and has not been sufficiently studied both in foreign and domestic literature.

Glucagon-like peptide 1 (GLP-1) stimulates insulin secretion and holds significant pharmacological potential. Nevertheless, the regulation of energy homeostasis by centrally-produced GLP-1 remains partially understood. Preproglucagon cells, known to release GLP-1, are found in the olfactory bulb (OB). We show that activating GLP-1 receptors (GLP-1R) in the OB stimulates insulin secretion in response to oral glucose in lean and diet-induced obese male mice. This is associated with reduced noradrenaline content in the pancreas and blocked by an α2-adrenergic receptor agonist, implicating functional involvement of the sympathetic nervous system (SNS). Inhibiting GABAA receptors in the paraventricular nucleus of the hypothalamus (PVN), the control centre of the SNS, abolishes the enhancing effect on insulin secretion induced by OB GLP-1R. Therefore, OB GLP-1-dependent regulation of insulin secretion relies on a relay within the PVN. This study provides evidence that OB GLP-1 signalling engages a top-down neural mechanism to control insulin secretion via the SNS.

Preoperative considerations of new long-acting glucagon-like peptide-1 receptor agonists in diabetes mellitus

Purpose of review The prevalence of obesity is increasing in both developed and developing countries along with associated diseases such as type 2 diabetes and coronary heart disease. The recent discovery of a number of gut hormones that play a role in appetite regulation and are released or suppressed in response to a meal may offer new nutritional targets for weight management. Recent findings This review focuses on the relationship between foods and nutrients and hormones released from the gastrointestinal tract. We have highlighted the effect of nutrients on gut hormones that are of specific interest: peptide YY, glucagon-like peptide 1, ghrelin and cholecystokinin. Summary Cholecystokinin, peptide YY, glucagon-like peptide 1 and ghrelin are all affected by the intake of food. In response to single nutrient loads all are influenced by fat (to a lesser extent ghrelin). The effect of fat on cholecystokinin, peptide YY and ghrelin is to suppress appetite and food intake. In the case of glucagon-like peptide 1, however, dietary fat in some studies is linked to an increase in hunger rating, which contradicts the evidence that glucagon-like peptide 1 slows gastric emptying. This raises the possibility that gut hormones are regulating the flow of fat through the gastrointestinal tract with secondary effects on appetite. It is interesting to consider the long-term implications of this with regard to weight loss advice.