Search Results (80)

The glucagon-like peptide-1 receptor (GLP-1R) is a class B G protein-coupled receptor (GPCR) central to metabolic regulation, and its potential modulation by dietary phytochemicals is increasingly recognized as physiologically relevant. Understanding how such compounds interact with GLP-1R is important for clarifying mechanisms that may contribute to gut-to-brain signaling. In this study, we examined three structurally related dietary ginsenosides, Rg1, Rg2, and Rg3, as potential modulators of GLP-1R using luciferase reporter assays and computational analyses. Despite sharing similar molecular weights, a common dammarane scaffold, and comparable sugar moieties, the three ginsenosides displayed distinct effects on GLP-1R activity: Rg2 and Rg3 potently reduced receptor activation in a dose-dependent manner when co-administered with Exendin-4, whereas Rg1 had minimal effect. Computational screening of the GLP-1R structure for binding sites identified a putative extracellular pocket on the protein that can accommodate these compounds, while molecular docking and binding free energy calculations provided predicted affinities qualitatively reflecting the phytochemicals’ experimental activities. These findings point to a plausible extracellular mechanism through which dietary ginsenosides may influence GLP-1R responsiveness at the intestinal interface. Our results point to the possibility that non-absorbed phytochemicals can differentially modulate gut-expressed receptors, suggesting a novel pathway for dietary signaling relevant to ethnopharmacology and metabolic health. Full article

The migrating myoelectric complex (MMC) is the electrical basis of fasting small intestinal motility. Although oxytocin (OT) regulates gastrointestinal functions through oxytocin receptors (OTRs), its effect on jejunal MMC activity during fasting remains unclear. This study investigated the effects of OT on jejunal MMC activity in fasted rats and evaluated the involvement of OTRs, glucagon-like peptide-1 receptors (GLP-1Rs), and nitric oxide (NO) pathways. Bipolar electrodes were implanted at three jejunal sites in adult male Sprague Dawley rats for MMC recordings. After recovery and 18 h fasting, OT was administered intraperitoneally (4–32 µg/kg) following one hour of basal recording. To assess mechanisms, rats were pretreated with the OTR antagonist atosiban (2 mg/kg), the GLP-1R antagonist exendin (9–39) (200 µg/kg), or the nitric oxide synthase inhibitor NG-nitro-L-arginine (L-NNA; 5 mg/kg) before OT (16 µg/kg). Oxytocin dose-dependently reduced spike frequency and MMC cycle number (p < 0.05–0.001 vs. vehicle). Atosiban completely reversed these effects (p < 0.001 vs. OT), while exendin (9–39) partially attenuated them (p < 0.01–0.001 vs. OT). L-NNA showed no significant effect. These findings indicate that OT inhibits jejunal MMC activity via OTR-dependent mechanisms with partial involvement of GLP-1R signaling but not NO pathways. Full article

GLP-1 receptor agonists (GLP-1RAs) are widely used in the treatment of type 2 diabetes and obesity and are increasingly relevant in periodontal and implant practice. This review covers mechanisms, preclinical and early human evidence, and practical periodontal considerations; the structured database search is conducted in accordance with the Scale for the Assessment of Narrative Review Articles (SANRA) and the International Committee of Medical Journal Editors (ICMJE) principles. Two pathways explain GLP-1RAs’ relevance: indirect effects from better glycemic control, weight loss, and reduced inflammation; and direct tissue effects involving GLP-1R signaling and the GLP-1/dipeptidyl peptidase-4 (DPP-4) axis. Preclinical studies show reduced inflammation, osteoclast activity, and alveolar bone loss, along with improved periodontal stem cell function under hyperglycemia or inflammation via Nuclear Factor-kappaB (NF-kappaB), Wingless-related integration site (Wnt)/beta-catenin, and Mitogen-Activated Protein Kinase (MAPK) pathways. Animal studies on implants and local delivery, including exendin-4 platforms, suggest osteometabolic benefits. Human data are limited and mostly observational, and confounders include metabolic status, smoking, medication, and nutrition. Oral side effects such as xerostomia and dehydration are also noted. At present, GLP-1RA therapy should be regarded as a contextual modifier of periodontal risk and healing capacity rather than as a stand-alone periodontal therapy. Full article

Parkinson’s disease (PD) is a complex neurodegenerative disorder characterised by progressive motor and non-motor impairment, in which current therapies remain symptomatic and fail to halt dopaminergic neuron loss. Growing evidence linking metabolic dysfunction, type 2 diabetes, and neurodegeneration has renewed interest in glucagon-like peptide 1 (GLP-1) receptor agonists as potential disease-modifying agents. While several recent reviews have explored the role of incretin-based therapies, the present work provides an integrative perspective by combining a mechanistic analysis of GLP-1 signalling pathways with a model-specific synthesis of preclinical findings and an appraisal of clinical translational relevance. We consolidate evidence across PI3K/Akt, MAPK/ERK, cAMP/PKA–CREB, and AMPK pathways, emphasising their convergence on mitochondrial homeostasis, proteostasis, neuroinflammation, and synaptic resilience. To enhance translational clarity, we summarise preclinical studies across major PD models, evaluate dose comparability and blood–brain barrier penetration, and identify pharmacokinetic and mechanistic factors that may explain divergent clinical outcomes. We also compare the therapeutic potential of key GLP-1 agonists, including exendin-4, liraglutide, semaglutide, lixisenatide, and emerging dual agonists. By integrating biochemical, preclinical, and clinical domains, this review provides a comprehensive framework for interpreting the current evidence and guiding the future development of incretin-based neuroprotective strategies in PD. Full article

The current known data on the involvement of the peptidergic systems in breast cancer progression is overwhelmingly vast. Peptidergic systems are useful tools for imaging, diagnosis, prognosis and treatment of breast cancer. These systems play a crucial role in both basic and clinical breast cancer research by enabling the exploration of novel molecular mechanisms, signaling pathways, and the development of effective drug design strategies. Breast cancer cells overexpress peptide receptors; at the same time they are known to interact with peptides that (a) exert an oncogenic action (adrenomedullin 2, endothelin, gastrin-releasing peptide, neurokinin A, neuromedin, neuropeptide Y, neurotensin, substance P, vasoactive intestinal peptide), (b) exert an anticancer action (angiotensin (1–7), ghrelin, peptide YY) or (c) exert dual oncogenic and anticancer effects (adrenomedullin, angiotensin II, bradykinin, corticotropin-releasing factor, β-endorphin, glucagon-like peptide 1, gonadotropin-releasing hormone, kisspeptin, methionine-enkephalin, oxytocin). This indicates that peptides, as well as peptide receptor agonists and antagonists, may serve as antitumor agents due to their diverse actions against breast cancer development, including the inhibition of cell proliferation, migration and invasion, induction of apoptosis, and anti-angiogenesis. Multiple strategies have been developed to combat breast cancer, including peptide receptor silencing; antibodies conjugated to specific signaling proteins; antibodies targeting specific peptide receptors or oncogenic peptides; and the use of peptides or peptide receptor agonists/antagonists loaded with antitumor cargo. Future lines of research are suggested in breast cancer using promising anti-breast-cancer peptide receptor antagonists (HOE-140, exendin (9–39), bosentan, macitentan, PD168,368, CGP71,683A, SR48,692, aprepitant) or agonists (FR190,997, semaglutide, exendin 4, goserelin) mentioned in this review. Peptidergic systems have tremendous anti-breast-cancer clinical potential which must be exploited and developed. Taken together, the available data highlight the enormous promise of translational research into breast cancer and peptidergic systems for the development of effective treatments. A full understanding of the roles played by the peptidergic systems in breast cancer will serve to improve diagnosis and treatment. Full article

Background/Objectives: Emerging evidence suggests an association between glucagon-like peptide-1 (GLP-1) receptor agonists and sodium–glucose co-transporter 2 (SGLT2) inhibitors with altered risk of damage in the inner ear system. However, limited research exists on the relationship between these medications and subsequent irreversible hearing loss. We conducted this network meta-analysis (NMA) to evaluate the comparative risk of hearing loss associated with such medications. Methods: In this NMA, we used a confirmatory approach to specifically focus on particular adverse effects of interest (i.e., incidence of hearing loss here) based on the Cochrane recommendation. A Bayesian-based NMA of randomized controlled trials (RCTs) of GLP-1 receptor agonists or SGLT2 inhibitors was conducted. The primary outcome was the hearing loss events. Results: Our NMA of 29 RCTs with 145,895 participants found that only two exendin-4 derivatives—lixisenatide and high-dose efpeglenatide (i.e., 6 mg/week)—showed increased hearing loss events compared to controls. No other GLP-1 receptor agonists or SGLT2 inhibitors demonstrated significantly elevated hearing loss risk. Lixisenatide ranked highest in risk among all investigated regimens. Conclusions: This comprehensive NMA identifies a significant association between exendin-4 derivatives (lixisenatide and efpeglenatide) and potential ototoxicity. Clinicians should carefully consider this potential ototoxicity when prescribing exendin-4 derivatives, particularly in patients with pre-existing hearing loss risk factors. Full article

We examined the neuroanatomical substrates and signaling mechanisms underlying the suppressive effect of GLP1 on homeostatic and hedonic feeding. Electrophysiological and behavioral studies were conducted in agouti-related peptide (AgRP)-cre and tyrosine hydroxylase (TH)-cre mice, and AgRP-cre/pituitary adenylyl cyclase-activating polypeptide (PACAP) type I receptor (PAC1R)^fl/fl animals. GLP1 (30 pmol) delivered directly into the arcuate nucleus (ARC) decreased homeostatic feeding and diminished the rate of consumption. This anorexigenic effect was associated with an inhibitory outward current in orexigenic neuropeptide Y (NPY)/AgRP neurons. GLP1 injected into the ventral tegmental area reduced binge feeding, coupled with decrements in the rate of consumption and the percent daily caloric consumption during the binge interval. These reductions were associated with a GLP1-induced outward current in mesolimbic (A₁₀) dopamine neurons. GLP1 administered into the ventromedial nucleus (VMN) reduced homeostatic feeding that again was associated with a diminished rate of consumption and abrogated by the GLP1 receptor antagonist exendin 9–39 and in AgRP-cre/PAC1R^fl/fl mice. This suppressive effect was linked with a GLP-induced inward current in VMN PACAP neurons, and further supported by the fact that GLP1 neurons in the nucleus tractus solitarius project to the VMN. Conversely, intra-VMN GLP1 had modest effects on binge feeding behavior. Finally, apoptotic ablation of VMN PACAP neurons obliterated the anorexigenic effect of intra-VMN GLP1 on homeostatic feeding in PACAP-cre mice but not their wildtype counterparts. Collectively, these data demonstrate that GLP1 acts within the homeostatic and hedonic circuits to curb appetitive behavior by exciting PACAP neurons, and inhibiting NPY/AgRP and A₁₀ dopamine neurons. Full article

Background: GLP-1 analogues are a relatively new class of medications that form the cornerstone of diabetes treatment. They possess invaluable glucose-lowering properties without hypoglycemic effects as well as strong cardioprotective effects. The gut microbiome has become the focus of numerous studies, demonstrating its influence not only on the gut but also on the overall well-being of the entire body. However, the effects of GLP-1 analogs on gut microbiota remain uncertain. Scope of review: Our systematic review (based on PRISMA guidelines) aimed to gather knowledge on the effects of GLP-1 analogue medications on the composition, richness, and abundance of gut microbiota in both animal and human models. Conclusions: Thirty-eight studies were included in this systematic review. GLP-1 analogues have demonstrated a notable impact on the composition, richness, and diversity of gut microbiota. We can conclude, following the obtained research results of our study, that liraglutide promotes the growth of beneficial genera relevant for beneficial metabolic functions. Exenatide and exendin-4 administration showed various effects on the microbiome composition in animal and human studies. In animal models, it increased genera associated with improved metabolism; however, in human models, genera linked to better metabolic functions and escalated inflammation increased. Following dulaglutide administration, increases in Bacteroides, Akkermansia, and Ruminococcus, genera connected to an improved metabolic model, were significant. Finally, varied results were obtained after semaglutide treatment, in which A. muciniphila, known for its positive metabolic functions, increased; however, microbial diversity decreased. Semaglutide treatment provided various results indicating many confounding factors in semaglutide’s impact on the gut microbiota. Results varied due to dissimilarities in the studied populations and the duration of the studies. Further research is essential to confirm these findings and to better recognize their implications for the clinical outcomes of patients. Full article

Glucagon-like peptide-1 receptor (GLP-1R) is an emerging critical target for the diagnosis and treatment of various diseases. Radiolabeled exendin-4 (Ex-4), a GLP-1R agonist, has been widely used as an imaging probe. However, its potential to induce hypoglycemia, especially in patients with insulinoma, limits its applicability. This study evaluated whether Ex-D3, a Glu3Asp substitution of Ex-4 with a higher internalization rate, could enhance the imaging efficacy of Ex-4 while reducing its hypoglycemic effects. We synthesized derivatives with an additional C-terminal Cys (Ex-D3-C40) for site-specific ¹²⁵I labeling. Surface plasmon resonance analysis revealed that C-terminus modification did not significantly alter the binding affinity of Ex-D3-C40 to GLP-1R. In vivo studies in mice demonstrated that Ex-D3-C40 induced weaker hypoglycemic effects than Ex-4-C40. Biodistribution studies showed that ¹²⁵I-labeled Ex-D3 ([¹²⁵I]I-Ex-D3) achieved significantly higher pancreatic accumulation and higher pancreas-to-blood and pancreas-to-muscle ratios than [¹²⁵I]I-Ex-4. Ex vivo autoradiography confirmed the binding specificity of [¹²⁵I]I-Ex-D3 to GLP-1R-expressing pancreatic β-cells. These findings indicate that Ex-D3 is a promising parent peptide for the development of superior GLP-1R imaging probes with reduced hypoglycemic risk, highlighting the importance of considering pharmacological effects in designing molecular imaging probes. Full article

Background/Objectives: The reduction of oleic acid (OA)-induced steatosis in HepG2 cells observed upon treatment with the glucagon-like peptide-1 receptor agonist (GLP-1RA) Exendin-4 (Ex-4) is associated with the modulation of the expression of several microRNAs, long non-coding RNAs (lncRNAs), and mRNAs. Notably, MALAT1, an lncRNA, shows significant downregulation in the presence of Ex-4 as compared to OA alone. In this study, we aimed to explore the role of MALAT1 in the positive impact of Ex-4 on OA-induced lipid accumulation in HepG2 cells. Methods: Steatosis in HepG2 cells was induced by treating them with 400 µM OA. The effect of Ex-4 on steatosis was examined by treating the steatotic cells with 200 nM of EX-4 for 3 h. MALAT1 was silenced with siRNA, while gene expression was quantified using qRT-PCR. Results: In the presence of Ex-4, the silencing of MALAT1 did not exert any discernible influence on de novo lipogenesis genes such as PPARγ and SREBP1. However, MALAT1 silencing significantly affected, to varying degrees, the expression levels of several lipid metabolism genes such as FAS, ACADL, CPT1A, and MTTP. Conclusions: Further investigations are warranted to fully decipher the role of the Ex-4-MALAT1 in the positive impact of GLP-1RAs on steatosis. Full article

Glucagon can increase the force of contraction (FOC) in, for example, canine hearts. Currently, whether glucagon can also increase the FOC via cAMP-increasing receptors in the human atrium is controversial discussed. Glucagon alone did not (up to 1 µM) raise the FOC in human right atrial preparations (HAP). Only in the additional presence of the phosphodiesterase (PDE) 3 inhibitor cilostamide (1 µM) or 1 nM isoprenaline did glucagon raise the FOC, starting at 1 µM. The positive inotropic effects of glucagon in HAP were attenuated by a glucagon receptor antagonist (1 µM SC203972), but not by 100 nM exendin(9-39), a glucagon-like peptide-1 receptor (GLP-1R) antagonist. Glucagon (in the presence of cilostamide) demonstrated a reduced efficacy in elevating the FOC in HAP when compared with isoprenaline. In contrast to glucagon, exenatide alone, a GLP-1R agonist, starting at 1 nM, increased the FOC and was more potent and effective than glucagon in raising the FOC in HAP. The effects of exenatide on the FOC were attenuated by exendin(9-39). Hence, glucagon and GLP-1R agonists act functionally via different receptors in the human right atrium. Clinically, these data suggest that endogenous or exogenous glucagon can stimulate glucagon receptors in the human atrium, but only in the presence of PDE inhibitors. Full article

Background: Gold nanoparticles (NPs) have drawn great attention in the area of biomedical research with their relatively safe and versatile properties. This study aimed to synthesize long-lasting exendin-4-coated gold NPs (EX-ABD-AFF-GoldNPs) and evaluate their anti-diabetic effects in vivo. Methods: In the present study, EX-ABD-AFF-GoldNPs were synthesized using a simple one-step aqueous reduction method. The physical characterization of the prepared particles verified the successful formation of the EX-ABD-AFF-GoldNPs through dynamic light scattering (DLS), transmission electron microscopy (TEM), ultraviolet–visible (UV-VIS) light spectroscopy, and Fourier transform infrared spectroscopy (FTIR). The anti-hyperglycemic and anti-obesity effects were assessed in high-fat diet (HFD)-fed obese diabetic mice. Additionally, pharmacokinetics (PK) and biodistribution studies were performed to verify the long-lasting properties. Results: The EX-ABD-AFF-GoldNPs were conglomerates of smaller globular-shaped particles, and the average size was 110(±14) nm, based on the TEM images. Safety assessments using Min6, HepG2, and B16F10 cell lines demonstrated low cytotoxicity, with over 80% cell viability up to the highest tested concentration of 150 μg/mL (as EX-ABD-AFF). Notably, the animal studies showed that the EX-ABD-AFF-GoldNPs exhibited significant hypoglycemic activity, comparable to the EX-ABD-AFF, in the HFD-fed mice. A 4-week treatment with EX-ABD-AFF-GoldNPs produced similar reductions in blood glucose and body weight to the EX-ABD-AFF, without any apparent toxicity. Furthermore, the PK and biodistribution study results confirmed the long-lasting properties (plasma half-life: 43.6 h) of the particles. Conclusions: Overall, this study demonstrated that the preparation of therapeutic protein-loaded gold NPs is feasible and, despite their much larger size compared with the protein, EX-ABD-AFF-GoldNPs can be successfully absorbed through the subcutaneous route and show nearly equivalent hypoglycemic activity to the EX-ABD-AFF protein. Finally, this study showed that long-lasting properties could be acquired by only coating EX-ABD-AFF onto gold NPs. Full article

Non-somatostatin receptor expressing hypovascular insulinomas can be challenging to prove through imaging. This case highlights the utility of a structured approach to molecular imaging in patients with confirmed endogenous hyperinsulinemia. A 54-year-old woman was admitted because of a sudden loss of consciousness. Her relative reported that she complained of dizziness, intense sweating, blurry vision, and upper extremity tingling before becoming unresponsive for 20 min, after which the patient had little recollection of the event. She experienced similar episodes of shorter duration, trouble recalling everyday events, and unintentional weight gain of over 10 kg during the previous two years. Abdominal magnetic resonance imaging (MRI) and multidetector computerized tomography (MDCT) were unremarkable. Selective arterial calcium stimulation significantly increased hepatic venous insulin concentrations when the superior mesenteric and gastroduodenal arteries were stimulated. Technetium-99m (99mTc) octreotide single-photon emission computed tomography (SPECT) did not localize the lesion. Gallium-68 DOTA-Exendin-4 PET/CT acquisition was performed. A single intense 2 cm hyperperfused pancreatic lesion was located anteriorly in the head of the pancreas. Earlier targeted PET/CT imaging and recognition of significant neuropsychiatric symptoms attributable to the patient’s hypoglycemic state might have accelerated the resolution of her condition and obviated the need for unnecessary testing. Full article

Glucagon-like peptide-1 (GLP-1)-based drugs have been approved by the United States Food and Drug Administration (FDA) and are widely used to treat type 2 diabetes mellitus (T2DM) and obesity. More recent developments of unimolecular peptides targeting multiple incretin-related receptors (“multi-agonists”), including the glucose-dependent insulinotropic polypeptide (GIP) receptor (GIPR) and the glucagon (Gcg) receptor (GcgR), have emerged with the aim of enhancing drug benefits. In this study, we utilized human and mouse microglial cell lines, HMC3 and IMG, respectively, together with the human neuroblastoma SH-SY5Y cell line as cellular models of neurodegeneration. Using these cell lines, we studied the neuroprotective and anti-inflammatory capacity of several multi-agonists in comparison with a single GLP-1 receptor (GLP-1R) agonist, exendin-4. Our data demonstrate that the two selected GLP-1R/GIPR dual agonists and a GLP-1R/GIPR/GcgR triple agonist not only have neurotrophic and neuroprotective effects but also have anti-neuroinflammatory properties, as indicated by the decreased microglial cyclooxygenase 2 (COX2) expression, nitrite production, and pro-inflammatory cytokine release. In addition, our results indicate that these multi-agonists have the potential to outperform commercially available single GLP-1R agonists in neurodegenerative disease treatment. Full article