Affinage

GLP1R

Glucagon-like peptide 1 receptor · UniProt P43220

Round 2 corrected
Length
463 aa
Mass
53.0 kDa
Annotated
2026-04-28
130 papers in source corpus 44 papers cited in narrative 43 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

GLP1R is a class B1 G-protein-coupled receptor that transduces signals from GLP-1 and related peptide or non-peptide agonists through Gαs-coupled cAMP/PKA and Epac pathways, as well as PLC-mediated Ca²⁺ mobilization, ERK/PKC, PI3K/AKT, and AMPK cascades to control insulin secretion, appetite, intestinal growth, lipid metabolism, and inflammation (PMID:8405712, PMID:25719403, PMID:25738454, PMID:36027914). Structural studies of the extracellular domain, transmembrane core, and full-length receptor–Gs complexes have defined a two-step peptide-binding mechanism—N-terminal domain capture followed by transmembrane insertion—and revealed that agonist-specific contact dynamics at the peptide N-terminus allosterically tune G-protein coupling kinetics, providing a molecular basis for biased signaling (PMID:18287102, PMID:29466332, PMID:35013280, PMID:28514449). Receptor desensitization is governed by GRK2-dependent β-arrestin 2 recruitment that controls internalization, lysosomal targeting, and ubiquitination; loss of β-arrestin 2 impairs acute cAMP generation yet reduces desensitization, and ligand off-rate is a principal determinant of G-protein coupling onset and cAMP duration (PMID:33658023, PMID:37134170, PMID:35300966). In the CNS, GLP1R delineates dissociable neural circuits—NTS neurons driving satiety, area postrema neurons driving aversion, lateral septum neurons suppressing feeding via GABAergic projections to the lateral hypothalamus, and LepRb⁺ hypothalamic neurons required for both leptin- and GLP-1RA-mediated anorexia (PMID:38987598, PMID:39225090, PMID:37581939).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 1993 High

    Cloning of human GLP1R and heterologous reconstitution established that a single receptor couples to both adenylyl cyclase (cAMP) and PLC (Ca²⁺), resolving whether GLP-1 effects required one or multiple receptors.

    Evidence cDNA cloning from pancreatic islets, stable expression in COS-7/fibroblasts, radioligand binding, cAMP and Ca²⁺ assays

    PMID:8404634 PMID:8405712

    Open questions at the time
    • Downstream effectors beyond cAMP and Ca²⁺ not yet mapped
    • Tissue-specific signaling outputs unknown
    • Receptor desensitization mechanism not addressed
  2. 2008 High

    Crystal structures of the GLP1R extracellular domain with exendin-4(9-39) and then GLP-1 defined the peptide-binding interface and showed ligand-specific conformational differences, answering how peptide agonists versus antagonists engage the N-terminal domain.

    Evidence X-ray crystallography at 2.1–2.2 Å resolution plus site-directed mutagenesis

    PMID:18287102 PMID:19861722

    Open questions at the time
    • No transmembrane domain structure yet available
    • Mechanism of signal transduction across the membrane unresolved
    • Contribution of ECL loops to full-length binding unknown
  3. 2014 High

    Systematic immunohistochemistry and radioligand binding in primate/human tissues resolved longstanding controversies about GLP1R tissue distribution, confirming expression in β-cells, vascular smooth muscle, sinoatrial node myocytes, and gut but not in liver or thyroid C cells.

    Evidence Validated monoclonal antibody IHC plus ¹²⁵I-GLP-1 in situ binding on human and primate tissues

    PMID:24467746

    Open questions at the time
    • Neural distribution not systematically mapped in this study
    • Conflicting evidence for hepatocyte GLP-1R from cell-line studies
    • Cell-type resolution within pancreatic islets limited
  4. 2015 High

    Genetic epistasis experiments identified Fgf7 as the obligate downstream mediator of GLP-1R-driven intestinal growth, and pharmacological dissection in cardiomyocytes distinguished PKA- versus Epac-dependent branches for cardioprotection, resolving which cAMP effectors mediate specific tissue outcomes.

    Evidence Glp1r⁻/⁻ and Fgf7⁻/⁻ mice for intestinal growth; selective PKA/Epac activators in cardiomyocytes for anti-apoptotic readouts

    PMID:25719403 PMID:25738454

    Open questions at the time
    • Fgf7-producing cell type not identified
    • Whether Epac arm operates in β-cells independently of PKA not settled
    • Mechanism linking GLP-1R to Fgf7 transcription unknown
  5. 2015 Medium

    Identification of exendin-P5 as a G-protein-biased agonist with reduced β-arrestin recruitment but enhanced metabolic efficacy in diabetic mice demonstrated that GLP-1R signaling bias translates into distinct in vivo therapeutic profiles.

    Evidence Autocrine peptide library screen, cAMP versus β-arrestin assays, T2DM mouse models

    PMID:26621478

    Open questions at the time
    • Structural basis for bias not yet determined at this time
    • Long-term safety of biased agonism unknown
    • Relative contribution of β-arrestin scaffolding versus desensitization unclear
  6. 2017 High

    Crystal structures of the GLP1R transmembrane domain with negative allosteric modulators revealed an allosteric pocket outside helices V–VII, establishing that receptor activation can be modulated from a site distinct from the orthosteric peptide-binding cavity.

    Evidence X-ray crystallography (2.7–3.0 Å) of TMD with PF-06372222 and NNC0640, mutagenesis

    PMID:28514449

    Open questions at the time
    • How positive allosteric modulators engage the same region to facilitate G-protein coupling not fully resolved
    • No full-length inactive-state structure available
    • Dynamics of transition from inactive to active conformation unknown
  7. 2018 High

    Cryo-EM of GLP-1R–Gs complexes with biased versus unbiased agonists showed that agonist-specific conformational differences at the extracellular face propagate through the transmembrane domain to alter the Gαs engagement angle, providing a structural explanation for signaling bias.

    Evidence Phase-plate cryo-EM at 3.3 Å comparing exendin-P5 and GLP-1 bound complexes

    PMID:29466332

    Open questions at the time
    • β-arrestin-bound receptor structure absent
    • Dynamics of conformational propagation not captured in static structures
    • Limited to Gs-coupled state
  8. 2020 High

    Cryo-EM structures of non-peptide agonist-bound GLP-1R–Gs complexes showed that small-molecule agonists can closely mimic peptide binding or adopt entirely different binding modes with distinct receptor conformations, establishing molecular rules for non-peptide agonist design.

    Evidence Cryo-EM structures of PF-06882961 and CHU-128 bound complexes with pharmacological profiling

    PMID:33027691

    Open questions at the time
    • Clinical translation of structural insights to oral drug design not demonstrated
    • Conformational dynamics of non-peptide binding not explored by MD
  9. 2021 High

    GRK2 was identified as the kinase responsible for GLP-1R phosphorylation that enables β-arrestin recruitment and desensitization, with GRK2 hemizygosity enhancing early-phase insulin secretion by increasing the readily releasable granule pool.

    Evidence GRK2⁺/⁻ mice, nanoBRET for GLP-1R–GRK2 interaction, islet capacitance measurements

    PMID:33658023

    Open questions at the time
    • Specific GRK2 phosphorylation sites on GLP-1R not mapped
    • Role of other GRKs not excluded
    • Whether GRK2 inhibition improves GLP-1RA efficacy in vivo not tested
  10. 2021 High

    Electrophysiology and in vivo photometry in hypothalamic circuits showed GLP-1RAs directly activate POMC neurons via TRPC5 channels and indirectly inhibit AgRP neurons, establishing the ion channel effectors and circuit logic underlying central appetite suppression.

    Evidence Neuron-specific transgenics, fiber photometry, patch-clamp, pharmacological channel blockers

    PMID:34626854

    Open questions at the time
    • Whether peripheral versus central GLP-1R pools are differentially engaged by long-acting agonists unclear
    • Role of TRPC5 in human hypothalamic GLP-1R signaling unconfirmed
    • Interaction with other nutrient-sensing circuits not mapped
  11. 2022 High

    Comprehensive biosensor and phosphoproteomic analysis across 15 signaling pathways in 4 cellular compartments revealed that GLP-1R agonist modifications produce pathway- and compartment-selective signaling signatures, and that ligand off-rate governs G-protein coupling kinetics and cAMP duration.

    Evidence Multi-pathway biosensor panel, time-lapse microscopy, phosphoproteomics, kinetic BRET across multiple agonists

    PMID:35300966 PMID:37813859

    Open questions at the time
    • How compartment-specific signals are decoded into cellular outcomes remains unclear
    • In vivo relevance of compartment bias not tested
    • Contribution of receptor recycling versus degradation to sustained signaling not quantified
  12. 2022 High

    GLP-1R on gut intraepithelial lymphocytes was shown to suppress T-cell-mediated inflammation via PKA-dependent dampening of proximal TCR signaling and to shape microbiota composition, identifying an immune-regulatory function independent of glucose homeostasis.

    Evidence IEL-specific conditional Glp1r knockout mice, T-cell activation assays, microbiota sequencing, PKA inhibitor experiments

    PMID:36027914

    Open questions at the time
    • Which specific microbiota taxa are regulated and through what mechanism not defined
    • Relevance of IEL GLP-1R to human IBD not established
    • Downstream PKA substrates in IELs not identified
  13. 2023 High

    β-arrestin 2 conditional knockout in adult β-cells revealed that β-arrestin 2 is required for acute cAMP production yet simultaneously promotes desensitization, lysosomal targeting, and ubiquitination of GLP-1R, resolving the paradoxical dual role of β-arrestin 2 in GLP-1R signaling.

    Evidence Adult β-cell-specific β-arrestin 2 KO mice, islet cAMP measurements, receptor trafficking and ubiquitination assays

    PMID:37134170

    Open questions at the time
    • Mechanism by which β-arrestin 2 loss upregulates β-arrestin 1 and PDE4 not elucidated
    • Sex dimorphism in β-arrestin effects not mechanistically explained
    • Whether trans-Golgi signaling is therapeutically exploitable unknown
  14. 2023 High

    Systematic functional profiling of 60 GLP1R coding variants established that impaired cell-surface expression is a genetically distinct mechanism from signaling loss-of-function, with the former associated with poor glycemic control in humans and rescuable by allosteric ligands.

    Evidence Multi-pathway signaling profiling of 60 variants, INS-1 cell insulin secretion rescue, UK Biobank association

    PMID:37709961

    Open questions at the time
    • Whether allosteric rescue translates to improved clinical outcomes untested
    • Structural basis for expression-defective variants not determined
    • Gain-of-function variant physiology largely unexplored
  15. 2024 High

    In vivo imaging and circuit manipulation in the hindbrain demonstrated that GLP1R neurons in the NTS and area postrema drive dissociable satiety and aversion responses respectively, while lateral septum GLP1R neurons suppress feeding via GABAergic projections to the lateral hypothalamus, mapping the circuit architecture for GLP-1RA-induced appetite control.

    Evidence Two-photon calcium imaging, chemogenetic/optogenetic manipulation, projection tracing in Glp1r-Cre mice

    PMID:38763494 PMID:38987598 PMID:39225090

    Open questions at the time
    • How peripheral GLP-1RA access reaches specific brain nuclei not resolved
    • Human neuroanatomical equivalence of these circuits not confirmed
    • Interaction between hindbrain and forebrain GLP1R populations during chronic treatment unclear
  16. 2024 High

    Ligand-free cryo-EM structures showed that Gs protein alone partially activates GLP-1R by opening the intracellular cavity and rewiring the extracellular pocket, revealing a pre-engagement activation intermediate that facilitates peptide binding.

    Evidence Cryo-EM of ligand-free GLP-1R–Gs complex, comparative structural analysis with GCGR and GIPR

    PMID:38346960

    Open questions at the time
    • Whether this intermediate is populated under physiological ligand concentrations unknown
    • Kinetic lifetime of the ligand-free complex not measured
    • Implications for constitutive activity not explored

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the structural basis of β-arrestin-bound GLP-1R, how compartment-specific signaling is decoded into distinct cellular outcomes in vivo, how peripheral versus central GLP-1R pools are differentially engaged by long-acting agonists, and whether allosteric rescue of expression-defective variants can improve clinical outcomes.
  • No β-arrestin-bound GLP-1R structure
  • Compartment-specific signaling decoded in vivo not demonstrated
  • Mechanism by which GLP-1RAs cross the blood–brain barrier to engage specific neuronal populations unresolved

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 8 GO:0098772 molecular function regulator activity 2
Localization
GO:0005886 plasma membrane 5 GO:0005768 endosome 2
Pathway
R-HSA-162582 Signal Transduction 9 R-HSA-112316 Neuronal System 6 R-HSA-1430728 Metabolism 3 R-HSA-1643685 Disease 3 R-HSA-168256 Immune System 1
Partners
ARRB2FGF7GNA SGRK2PPP1R1ATRPC5
Complex memberships
GLP-1R–Gαs–Gβγ heterotrimer

Evidence

Reading pass · 43 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1993 Cloning and functional expression of the human GLP-1 receptor from pancreatic islet cDNA revealed a 463-amino-acid protein with 90% homology to rat GLP-1R. When expressed in COS-7 cells, the receptor conferred high-affinity GLP-1(7-37) binding (Kd ~0.5 nM), activated adenylyl cyclase (cAMP production, EC50 ~93 pM), and also activated phospholipase C (PLC), increasing intracellular Ca2+ from intracellular pools, demonstrating coupling to multiple signaling pathways. Exendin-4 was identified as an agonist and exendin-(9-39) as an antagonist. cDNA cloning, stable transfection in fibroblasts/COS-7 cells, radioligand binding, cAMP assay, Ca2+ imaging Endocrinology / Diabetes High 8404634 8405712
2008 Crystal structure of the human GLP-1R extracellular domain (nGLP-1R) in complex with the antagonist exendin-4(9-39) at 2.2 Å resolution revealed that exendin-4 binds as an amphipathic α-helix making hydrophobic and hydrophilic contacts; the Trp-cage C-terminal extension does not contact nGLP-1R. The hydrophobic binding site is defined by an N-terminal α-helix and a loop between antiparallel β-strands of nGLP-1R. X-ray crystallography (MAD, 2.2 Å), site-directed mutagenesis The Journal of biological chemistry High 18287102
2009 Crystal structure of the GLP-1R extracellular domain in complex with GLP-1 at 2.1 Å resolution showed GLP-1 binds as a kinked but continuous α-helix (Thr13–Val33). While hydrophobic ligand-receptor interactions are conserved between GLP-1 and exendin-4(9-39) bound forms, specific residues in the binding site adopt a GLP-1-specific conformation. Mutagenesis confirmed differences in binding modes of GLP-1 vs. exendin-4 on the full-length receptor. X-ray crystallography (2.1 Å), site-directed mutagenesis The Journal of biological chemistry High 19861722
2017 Crystal structures of the human GLP-1R transmembrane domain in complex with negative allosteric modulators PF-06372222 and NNC0640 at 2.7 and 3.0 Å revealed a common allosteric binding pocket outside helices V–VII near the intracellular half, distinct from the orthosteric peptide-binding site. Receptor is in an inactive conformation with compounds restricting movement of the intracellular tip of helix VI. Positive allosteric modulators target the same general region but a distinct sub-pocket at the helix V–VI interface facilitating G-protein coupling. X-ray crystallography, molecular modelling, mutagenesis Nature High 28514449
2018 Cryo-EM structure of the human GLP-1R in complex with G-protein-biased agonist exendin-P5 and Gαs heterotrimer at 3.3 Å global resolution revealed differences from the GLP-1-bound structure: distinct organization of ECL3 and proximal transmembrane segments at the extracellular surface, and a six-degree difference in the angle of Gαs-α5 helix engagement at the intracellular face, propagated across the G protein heterotrimer. Different rates and extents of conformational reorganization of Gαs between biased and unbiased agonist-bound structures were demonstrated. Phase-plate cryo-EM (3.3 Å) Nature High 29466332
2020 High-resolution cryo-EM structures revealed that the non-peptide agonist PF-06882961 binding site substantially overlaps with GLP-1's binding site, whereas CHU-128 adopts a unique binding mode with a more open receptor conformation at the extracellular face. Structural differences involving extensive water-mediated hydrogen bond networks correlated with functional data showing that PF-06882961, but not CHU-128, closely mimics pharmacological properties of GLP-1 including signaling and regulation profiles. Cryo-EM structural determination, pharmacological assays, comparative structural analysis Molecular cell High 33027691
2021 Cryo-EM structures of semaglutide- and taspoglutide-bound GLP-1R–Gs complexes revealed similar peptide-receptor interactions to GLP-1 but different motions within the receptor and bound peptides. 3D variability analysis showed distinct receptor conformational dynamics, providing molecular explanation for different signaling efficacies and side effect profiles of distinct GLP-1R peptide agonists. Cryo-EM, 3D variability analysis Cell reports High 34260945
2022 Cryo-EM structures of Boc5 and WB4-24 (non-peptidic GLP-1R agonists) bound to GLP-1R–Gs complex revealed one arm inserted deeply into the orthosteric binding pocket overlapping with GLP-1 residues A8–D15, while other arms extended to TM1-TM7, TM1-TM2, and TM2-TM3 clefts. This unique binding mode creates a distinct conformation conferring both peptidomimetic agonism and biased signaling. Cryo-EM structural determination, pharmacological assays Proceedings of the National Academy of Sciences of the United States of America High 35561211
2022 Combining cryo-EM, molecular dynamics simulations, receptor mutagenesis, and pharmacological assays across four peptide agonists (GLP-1, oxyntomodulin, exendin-4, exendin-P5) showed that distinctions in peptide N-terminal interactions and dynamics with the GLP-1R transmembrane domain are reciprocally associated with differences in allosteric coupling to G proteins. Transient interactions with residues at the base of the binding cavity correlate with enhanced kinetics for G protein activation. Cryo-EM, molecular dynamics simulations, mutagenesis, pharmacological assays Nature communications High 35013280
2023 Cryo-EM structures of GLP-1R or GCGR in complex with Gs protein and three dual GLP-1R/GCGR agonists (peptide 15, cotadutide, SAR425899) identified key residues responsible for ligand recognition and dual agonism. Distinct side chain orientations within the first three residues determine receptor selectivity; ECL1 interaction plays an important role in dual agonism; lipid modification of MEDI0382 interacts with TM1-TM2 cleft correlating with increased GCGR potency. Cryo-EM structural determination, pharmacological assays, mutagenesis Proceedings of the National Academy of Sciences of the United States of America High 37549266
2024 Cryo-EM structures of human GLP-1R, GCGR, and GIPR in complex with Gs proteins without cognate ligands (ligand-free complexes) revealed that Gs protein alone directly opens the intracellular binding cavity and rewires the extracellular orthosteric pocket. In GLP-1R, the extracellular portion adopts a conformation close to the active state in the absence of ligand, revealing a distinct activation intermediate in which intracellular half of the transmembrane domain is mobilized by Gs protein to facilitate peptide N-terminus entry. Cryo-EM structural determination, comparative structural analysis Cell discovery High 38346960
2014 Using a validated monoclonal antibody for immunohistochemistry and in situ ligand binding with 125I-GLP-1, GLP-1R was localized in primate and human tissues: predominantly in pancreatic β-cells (with markedly weaker acinar expression, no ductal expression), smooth muscle cells of renal and pulmonary arteries/arterioles, myocytes of the sinoatrial node, Brunner's gland of the duodenum, parietal cells and smooth muscle of stomach, and myenteric plexus neurons. No GLP-1R was detected in primate liver or thyroid. Immunohistochemistry with validated monoclonal antibody, in situ radioligand binding (125I-GLP-1) Endocrinology High 24467746
2010 GLP-1R mRNA and protein were detected on primary human hepatocytes and hepatocyte cell lines. Exendin-4 stimulated phosphorylation of PDK-1, AKT, and PKC-ζ in HepG2 and Huh7 cells; siRNA against GLP-1R abolished these effects. Exendin-4 also quantitatively reduced triglyceride stores in these cells, demonstrating a direct GLP-1R-dependent effect on hepatic steatosis independent of insulin. RT-PCR, Western blotting, receptor internalization assay, siRNA knockdown, lipid quantification Hepatology Medium 20225248
2010 GLP-1R is present on human coronary artery endothelial cells (HCAECs). Exendin-4 stimulated DNA synthesis and cell proliferation dose-dependently through PKA, PI3K/AKT, and eNOS activation pathways. These effects were abolished by a GLP-1R antagonist (exendin-(9-39)) and by individual pathway inhibitors, establishing a GLP-1R→PKA→PI3K/AKT→eNOS signaling cascade mediating endothelial proliferation. DNA synthesis assay, cell counting, pharmacological inhibitor panel, GLP-1R antagonist blockade Molecular and cellular endocrinology Medium 20452396
2011 GLP-1R is expressed in human hepatocytes (reduced in NASH patients). In hepatocytes from high-fat diet rats, exenatide increased PPARγ expression (reducing JNK phosphorylation for insulin sensitization), increased PKA activity, and stimulated Akt and AMPK phosphorylation, leading to PKA-dependent increase of PPARα activity and enhanced fatty acid β-oxidation. RT-PCR, Western blotting, hepatocyte culture with pharmacological treatments, liver biopsy analysis Liver international Medium 21745271
2011 GLP-1 and liraglutide activate GLP-1R on pre-adipocytes to promote proliferation and inhibit apoptosis through activation of ERK, PKC, and AKT signaling pathways, inducing adipogenesis. Loss of GLP-1R expression caused reduction in adipogenesis through induction of apoptosis in pre-adipocytes via inhibition of these same pathways. In vitro adipocyte differentiation assays, loss-of-function (GLP-1R knockout), pharmacological agonism, pathway inhibitors The Journal of biological chemistry Medium 22207759
2015 GLP-1R agonist exendin-4 attenuated H2O2-induced reactive oxygen species production in cardiomyocytes through an Epac-dependent pathway, and increased antioxidant enzymes (catalase, glutathione peroxidase-1, manganese superoxide dismutase). The antiapoptotic effect (decreased apoptotic cells, inhibited caspase-3, enhanced Bcl-2) was mediated through both PKA- and Epac-dependent pathways downstream of GLP-1R activation. Pharmacological dissection of cAMP effectors (PKA vs. Epac) in cardiomyocytes, ROS measurement, caspase activity, Western blotting Molecular endocrinology Medium 25719403
2015 GLP-1R agonist P5 was identified as a G-protein-biased agonist that promotes G-protein signaling comparable to GLP-1 and Exendin-4 but exhibits significantly reduced β-arrestin recruitment. In preclinical T2DM mouse models, P5 was a weak insulin secretagogue but increased adipogenesis, reduced adipose tissue inflammation and hepatic steatosis, and was more effective at correcting hyperglycemia than Exendin-4, demonstrating that GLP-1R signaling bias has distinct in vivo consequences. Autocrine-based peptide library screening, cAMP and β-arrestin assays, mouse diabetes models Nature communications Medium 26621478
2015 GLP-1R signaling controls mucosal expansion of the small bowel and colon. These actions did not require EGF receptor or intestinal IGF1 receptor but were absent in Glp1r−/− mice. Exendin-4 increased Fgf7 expression in intestinal tissue and failed to increase intestinal growth in Fgf7-deficient mice, placing Fgf7 downstream of GLP-1R signaling in mediating intestinal proliferation. Conditional knockout mice, genetic epistasis (Glp1r−/−, Fgf7−/−, EGF/IGF1R knockouts), pharmacological GLP-1R agonist treatment Cell metabolism High 25738454
2019 Systematic investigation using Wnt1-Cre2 and Phox2b-Cre conditional Glp1r knockout mice showed that widespread neural Glp1r loss had no effect on basal food intake or gastric emptying but preserved the glucoregulatory actions of GLP-1R agonists. In contrast, selective Glp1r loss in Phox2b+ neurons impaired glucose homeostasis, gastric emptying, and attenuated weight loss from sustained GLP-1R agonism, identifying Phox2b+ neural cells as required for physiological GLP-1R-mediated gut-brain axis regulation. Conditional Cre-lox knockout mice, GLP-1R agonist treatment, metabolic phenotyping Cell reports High 31189118
2021 In vivo fiber photometry and patch-clamp electrophysiology showed that liraglutide and semaglutide directly activate hypothalamic POMC neurons, requiring GLP-1Rs in POMC neurons and a downstream TRPC5-subunit mixed cation channel. They also indirectly upregulate excitatory input to POMC neurons from glutamatergic cells requiring TRPC5. GLP-1RAs inhibit NPY/AgRP neurons indirectly through activation of K-ATP and TRPC5 channels in GABAergic neurons. These temporal effects depend on metabolic (fed/fasted) state. Neuron-specific transgenic mice, in vivo fiber photometry, patch-clamp electrophysiology, pharmacological channel blockers Molecular metabolism High 34626854
2022 The gut IEL GLP-1R is not required for enteroendocrine L cell GLP-1 secretion or glucose homeostasis, but is essential for the full effects of GLP-1RAs on gut microbiota composition. The anti-inflammatory actions of GLP-1RAs require the gut IEL GLP-1R to selectively restrain T cell-induced (but not LPS-induced) inflammation, mediated by suppression of IEL effector functions through dampening of proximal TCR signaling in a protein-kinase-A-dependent manner. IEL-specific conditional Glp1r knockout mice, microbiota analysis, T cell activation assays, PKA inhibitor experiments Cell metabolism High 36027914
2022 GLP-1 regulates skeletal muscle remodeling to enhance exercise endurance via GLP-1R signaling-mediated phosphorylation of AMPK. AAV-mediated GLP-1 overexpression in skeletal muscle enhanced endurance and promoted glycogen synthesis, glucose uptake, type I fiber proportion, and mitochondrial biogenesis. In vitro, AMPK knockdown reversed the effects of GLP-1R activation on glucose uptake, type I fiber formation, and mitochondrial respiration. AAV-mediated GLP-1 overexpression, siRNA AMPK knockdown, in vitro exendin-4 treatment, metabolic/functional assays Biochimica et biophysica acta. Molecular cell research Medium 35636559
2022 GLP-1R agonists activate 15 signaling pathways in 4 cellular compartments. Using biosensors, time-lapse microscopy, and phosphoproteomics, modifications to GLP-1R agonists were shown to greatly influence compound efficacy, potency, and safety in a pathway- and compartment-selective manner. Unique signaling signatures at the level of receptor conformation, functional selectivity, and location bias were associated with functionally distinct cellular outcomes and adverse clinical events. Biosensor panel (15 pathways/4 compartments), comparative structural analysis, time-lapse microscopy, phosphoproteomics Nature communications High 37813859
2022 Ligand dissociation kinetics (Koff), but not association kinetics (Kon), of GLP-1R peptide agonists were positively correlated with onset of receptor-G protein coupling/conformational change, onset of cAMP production, and duration of cAMP signaling. This established that peptide off-rate is a key determinant of the kinetics of GLP-1R–G protein coupling and downstream signaling. Kinetic binding assays, BRET-based receptor-G protein conformational biosensors, cAMP time-course measurements across multiple GLP-1R agonists Biochemical pharmacology Medium 35300966
2023 In adult β cell-specific β-arrestin 2 knockout mice, acute GLP-1R agonist (exendin-4, semaglutide, tirzepatide) responses were sex-dimorphically impaired, but improved 6 hours post-injection. β-arrestin 2 KO impaired acute cAMP increases (attributed to enhanced β-arrestin 1 and phosphodiesterase 4 activities) but reduced desensitization, co-occurring with impaired GLP-1R recycling and lysosomal targeting, increased trans-Golgi network signaling, and reduced GLP-1R ubiquitination. Biased agonist exendin-phe1 did not show this phenotype. Adult β cell-specific conditional knockout mice, islet cAMP measurements, GLP-1R trafficking/ubiquitination assays, in vivo glucose tolerance Science advances High 37134170
2023 Functional profiling of 60 GLP1R variants across four signaling pathways revealed unexpected diversity including defective cell surface expression, complete or pathway-specific gain/loss-of-function. Defective insulin secretion of GLP1R loss-of-function variants was rescued by allosteric GLP1R ligands or high concentrations of exendin-4/semaglutide. Impaired GLP1R cell surface expression (a distinct variant category) was associated with poor glucose control and increased adiposity in UK Biobank analysis. Functional signaling profiling of 60 variants (4 pathways), INS-1 cell insulin secretion rescue experiments, UK Biobank genetic association Nature metabolism High 37709961
2021 GRK2 negatively regulates GLP-1R-mediated insulin secretion. GRK2 hemizygous mice showed enhanced early-phase (but not late-phase) insulin release upon oral glucose, GLP-1R agonists, or feeding, correlated with an increased readily releasable pool of insulin granules. Using nanoBRET in β-cells, GLP-1R stimulation promoted GRK2 association with GLP-1R, and GRK2 kinase activity was required for subsequent β-arrestin recruitment. GRK2+/− mice, isolated islets, nanoBRET in β-cell lines, patch-clamp/capacitance measurements of readily releasable pool BMC biology High 33658023
2021 GLP-1R shows increased cell surface levels, internalization, degradation, and endosomal vs. plasma membrane signaling activity compared to GIPR in pancreatic β-cells. GIPR is instead associated with increased plasma membrane recycling, reduced desensitization, and enhanced downstream signal amplification. These differences in spatiotemporal signaling profiles underlie distinct pharmacological responses to each incretin receptor. Comparative surface expression, trafficking, and multi-compartment signaling analysis between GLP-1R and GIPR in pancreatic β-cells Endocrinology Medium 36774542
2020 Exendin-4 (GLP-1R agonist) restored airway mucus homeostasis via a GLP1R→PKA→PPARγ-dependent signaling cascade that activated phosphatases PTEN and PTP1B, which in turn inhibited key kinases within both EGFR and STAT6 signaling cascades to restore FOXA2 expression and attenuate mucin production in COPD and CF airway cells. Pharmacological dissection, signaling pathway analysis, siRNA, human airway cell culture, mouse lung model Mucosal immunology Medium 32034274
2020 GABA requires GLP-1R to inhibit TxNIP in pancreatic β-cells; this function was attenuated in GLP-1R−/− islets. In GLP-1R−/− mice, GABA failed to alleviate STZ-induced diabetic syndrome or increase β-cell mass. GABA treatment increased cellular cAMP and β-catenin S675 phosphorylation in WT but not GLP-1R−/− islets, identifying TxNIP as a common downstream target of both GABA and GLP-1 acting through GLP-1R-cAMP-β-catenin signaling. GLP-1R knockout mice, isolated islets, INS-1 cells, siRNA knockdown of TxNIP, STZ challenge model The Journal of endocrinology Medium 32544878
2024 In vivo two-photon imaging of hindbrain GLP1R neurons showed that area postrema (AP) GLP1R neurons are broadly responsive to both nutritive and aversive stimuli, whereas NTS GLP1R neurons are biased toward nutritive stimuli. Selective activation of NTS GLP1R neurons triggered satiety without aversion, while AP GLP1R neurons triggered aversion with food intake reduction. GLP1R agonists reduce food intake even when the aversion pathway is inhibited, demonstrating dissociable neural circuits for satiety vs. aversion. In vivo two-photon calcium imaging, chemogenetic activation/inhibition of subregion-specific GLP1R populations, anatomical projection tracing Nature High 38987598
2023 GABAergic LepRb neurons expressing Glp1r (LepRbGlp1r neurons) are required for food intake suppression by both leptin and GLP1R agonists. Ablating Lepr from LepRbGlp1r cells caused hyperphagic obesity. Restoration of Glp1r expression in LepRb neurons on an otherwise Glp1r-null background enabled food intake suppression by liraglutide, demonstrating that GLP1R expression in this specific hypothalamic population is sufficient for the anorectic effect. Cell-specific knockout/reactivation mouse models, single-nucleus RNA-Seq, chemogenetic and GLP1R agonist challenges The Journal of clinical investigation High 37581939
2024 GLP-1R-positive neurons in the lateral septum (LS) mediate anorectic and weight-lowering effects of liraglutide. Chemogenetic activation of LS GLP1R neurons suppressed feeding; targeted knockdown of GLP-1R in LS (but not hypothalamus) attenuated liraglutide's anorectic and weight-lowering effects. Synaptic inactivation of LS GLP1R neurons diminished liraglutide-triggered anorexia, establishing LS GLP1R neurons as a critical circuit node. Chemogenetics (DREADD), targeted shRNA knockdown, synaptic inactivation, in vivo feeding assays in Glp1r-Cre mice The Journal of clinical investigation High 39225090
2024 GLP-1R activation in gut IELs modulates microbiota composition and restrains T cell inflammation via PKA-dependent suppression of TCR signaling (established previously, 2022); separately, dorsolateral septal (dLS) GLP-1R neurons project GABAergically to the lateral hypothalamic area (LHA) and regulate food intake. Chemogenetic inhibition of dLSGLP-1R neurons or the dLSGLP-1R→LHA pathway increased food intake; optogenetic terminal stimulation in LHA rapidly suppressed feeding. Exendin-4 enhanced dLSGLP-1R→LHA GABA release. Channelrhodopsin-assisted circuit mapping, chemogenetics, electrophysiology, optogenetics, GABA release measurement in Glp1r-ires-Cre mice Molecular metabolism High 38763494
2025 GLP-1RAs alleviate AD-related phenotypes by activating CaMKK2-AMPK signaling, which reduces BACE1-mediated cleavage of APP and Aβ generation. GLP-1RAs also increased AMPK activity in microglia, inhibiting neuroinflammation and promoting Aβ phagocytosis. GLP-1 plasma levels were reduced in AD model mice and negatively correlated with Aβ load. AD transgenic mouse models, GLP-1RA treatment, CaMKK2-AMPK pathway analysis, BACE1 activity assay, microglial phagocytosis assay Nature aging Medium 40394225
2021 The MafA-target gene PPP1R1A is expressed in pancreatic β-cells and its silencing in INS-1 cells impaired GLP-1-mediated GSIS amplification, PKA-target protein phosphorylation, and mitochondrial coupling efficiency. PPP1R1A mRNA levels positively correlated with GLP-1-mediated GSIS amplification in human islets and were reduced in type 2 diabetic islets, placing PPP1R1A as a required downstream effector of GLP1R-PKA signaling in β-cells. siRNA knockdown in INS-1 cells, human islet correlational analysis, PKA substrate phosphorylation, mitochondrial coupling assay Metabolism: clinical and experimental Medium 33631146
2025 VTA dopamine (VTADA) neuron responsiveness was suppressed during food consumption by semaglutide (a GLP-1R agonist). Mice recovered palatable food appetite and VTADA neuron activity during repeated semaglutide treatment, which was reversed by consumption-triggered VTADA neuron inhibition. A neural pathway from peri-locus ceruleus to VTA controls hedonic eating, and GLP-1R agonism opposes VTADA neuron activation to reduce palatable food intake. Photometry-calibrated optogenetics, in vivo calcium imaging, chemogenetics, semaglutide treatment Science High 40146831
2024 GLP-1R activation attenuates pulmonary fibrosis by inhibiting the interaction between NLRP3 inflammasome and PFKFB3-driven glycolysis in lung fibroblasts, reducing lactate production. This prevents lactate-mediated histone H3K9 lactylation at profibrotic gene promoters (demonstrated by ChIP-qPCR) and reduces EMT-related fibrotic gene expression. GLP-1R activation also represses p300-mediated histone lactylation in exogenous lactate-treated fibroblasts. In vivo silica fibrosis model, in vitro TGF-β1+IL-1β fibroblast activation, ChIP-qPCR for histone lactylation, glycolysis/mitochondrial respiration assays, RNA-seq Journal of translational medicine Medium 39434134
2024 Dual activation of GCGR and GLP1R reduces intestinal fibrosis; downregulation of GLP1R led to lactate accumulation and histone H3K9 lactylation driving EMT-mediated fibrosis. Dual agonist peptide 1907B reduced H3K9 lactylation in epithelial cells and ameliorated intestinal fibrosis in vivo, identifying lactate-mediated epigenetic regulation as downstream of GLP1R signaling. Crohn's disease patient tissue analysis, mouse chronic colitis model, dual agonist treatment, H3K9 lactylation measurement, GLP1R/GCGR knockdown Acta pharmaceutica Sinica. B Medium 40041889
2023 GLP1R inhibits endometrial carcinoma progression by activating the cAMP/PKA signaling pathway. GLP1R overexpression increased cAMP content and p-PKA, promoting apoptosis and inhibiting proliferation, migration, and invasion. These effects were blunted by PKA knockdown (siRNA), establishing a direct GLP1R→cAMP→PKA axis mediating tumor suppression. GLP1R overexpression vector transfection, siRNA-PKA knockdown, cAMP ELISA, Western blotting, cell functional assays, xenograft tumor model Journal of clinical laboratory analysis Medium 35989517
2024 GLP-1R activation (liraglutide) ameliorated oxidized LDL-induced endothelial dysfunction via GLP-1R-dependent downregulation of LOX-1, which reduced NOX4/NF-κB-mediated oxidative stress and ICAM-1/VCAM-1 expression. The protective effects were abrogated by GLP-1R knockdown or LOX-1 overexpression, establishing a GLP-1R→LOX-1 suppression axis in endothelial protection. LDLR-KO mouse model, HUVECs with GLP-1R knockdown/LOX-1 overexpression, vascular reactivity measurements, ROS assays, Western blotting Redox report Medium 37278349
2024 GLP-1R signaling is required for maintenance of colonic physiology during energy deprivation; GF GLP-1R KO mice showed 25% mortality associated with enlarged ceca, increased cecal water content, increased colonic apical ion transporter expression, reduced goblet cells, and loss of colonic epithelial integrity. Colonocytes were energy-deprived with increased ER stress, mitochondrial fragmentation, and loss of stemness. Restoring energy (Western diet or microbiota colonization) normalized gut phenotypes and prevented lethality. GF GLP-1R KO mice, histology, organoid stemness assays, metabolic rescue experiments (diet/microbiota colonization) Molecular metabolism Medium 38521185

Source papers

Stage 0 corpus · 130 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2014 A proteome-scale map of the human interactome network. Cell 977 25416956
2020 A reference map of the human binary protein interactome. Nature 849 32296183
2000 DNA cloning using in vitro site-specific recombination. Genome research 815 11076863
2014 GLP-1 receptor localization in monkey and human tissue: novel distribution revealed with extensively validated monoclonal antibody. Endocrinology 696 24467746
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
1993 Cloning and functional expression of the human islet GLP-1 receptor. Demonstration that exendin-4 is an agonist and exendin-(9-39) an antagonist of the receptor. Diabetes 489 8405712
2004 The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome research 438 15489334
2010 Glucagon-like peptide-1 receptor is present on human hepatocytes and has a direct role in decreasing hepatic steatosis in vitro by modulating elements of the insulin signaling pathway. Hepatology (Baltimore, Md.) 431 20225248
2007 GLP-1 receptor expression in human tumors and human normal tissues: potential for in vivo targeting. Journal of nuclear medicine : official publication, Society of Nuclear Medicine 394 17475961
1995 Tissue-specific expression of the human receptor for glucagon-like peptide-I: brain, heart and pancreatic forms have the same deduced amino acid sequences. FEBS letters 356 7843404
2011 Glucagon-like peptide-1 receptor activation stimulates hepatic lipid oxidation and restores hepatic signalling alteration induced by a high-fat diet in nonalcoholic steatohepatitis. Liver international : official journal of the International Association for the Study of the Liver 343 21745271
2014 GLP-1 receptor activation modulates appetite- and reward-related brain areas in humans. Diabetes 332 25071023
2018 Phase-plate cryo-EM structure of a biased agonist-bound human GLP-1 receptor-Gs complex. Nature 245 29466332
2008 Crystal structure of the ligand-bound glucagon-like peptide-1 receptor extracellular domain. The Journal of biological chemistry 242 18287102
2003 The DNA sequence and analysis of human chromosome 6. Nature 242 14574404
2018 GLP-1 Receptor Expression Within the Human Heart. Endocrinology 240 29444223
2009 Crystal structure of glucagon-like peptide-1 in complex with the extracellular domain of the glucagon-like peptide-1 receptor. The Journal of biological chemistry 235 19861722
2005 The expression of GLP-1 receptor mRNA and protein allows the effect of GLP-1 on glucose metabolism in the human hypothalamus and brainstem. Journal of neurochemistry 233 15686481
2015 Topical Administration of GLP-1 Receptor Agonists Prevents Retinal Neurodegeneration in Experimental Diabetes. Diabetes 218 26384381
2023 GLP-1 Receptor Agonists in Non-Alcoholic Fatty Liver Disease: Current Evidence and Future Perspectives. International journal of molecular sciences 211 36675217
2009 Decreased TCF7L2 protein levels in type 2 diabetes mellitus correlate with downregulation of GIP- and GLP-1 receptors and impaired beta-cell function. Human molecular genetics 210 19386626
2008 Expression of the GLP-1 receptor in mouse, rat, and human pancreas. The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society 208 18541709
2010 Exendin-4 stimulates proliferation of human coronary artery endothelial cells through eNOS-, PKA- and PI3K/Akt-dependent pathways and requires GLP-1 receptor. Molecular and cellular endocrinology 201 20452396
2009 Glucagon-like peptide-1 receptor imaging for localization of insulinomas. The Journal of clinical endocrinology and metabolism 195 19820010
2018 Anti-obesity effects of GIPR antagonists alone and in combination with GLP-1R agonists in preclinical models. Science translational medicine 190 30567927
2017 Human GLP-1 receptor transmembrane domain structure in complex with allosteric modulators. Nature 182 28514449
2000 Glucagon receptors on human islet cells contribute to glucose competence of insulin release. Diabetologia 172 10990079
2011 A GLP-1 receptor agonist liraglutide inhibits endothelial cell dysfunction and vascular adhesion molecule expression in an ApoE-/- mouse model. Diabetes & vascular disease research 171 21562063
1993 Cloning and functional expression of the human glucagon-like peptide-1 (GLP-1) receptor. Endocrinology 166 8404634
2009 Gene-centric association signals for lipids and apolipoproteins identified via the HumanCVD BeadChip. American journal of human genetics 164 19913121
2020 Differential GLP-1R Binding and Activation by Peptide and Non-peptide Agonists. Molecular cell 160 33027691
1996 Glucagon-like peptide-1 receptor (GLP1-R) mRNA in the rat hypothalamus. Endocrinology 157 8895391
2011 Regulation of adipocyte formation by GLP-1/GLP-1R signaling. The Journal of biological chemistry 127 22207759
2015 GLP-1R agonists promote normal and neoplastic intestinal growth through mechanisms requiring Fgf7. Cell metabolism 117 25738454
2015 Autocrine selection of a GLP-1R G-protein biased agonist with potent antidiabetic effects. Nature communications 114 26621478
2022 Divergent roles for the gut intraepithelial lymphocyte GLP-1R in control of metabolism, microbiota, and T cell-induced inflammation. Cell metabolism 108 36027914
2024 Dissociable hindbrain GLP1R circuits for satiety and aversion. Nature 103 38987598
2022 BI 456906: Discovery and preclinical pharmacology of a novel GCGR/GLP-1R dual agonist with robust anti-obesity efficacy. Molecular metabolism 101 36356832
2020 The GLP-1R agonist liraglutide limits hepatic lipotoxicity and inflammatory response in mice fed a methionine-choline deficient diet. Translational research : the journal of laboratory and clinical medicine 101 32711187
2023 GIPR/GLP-1R dual agonist therapies for diabetes and weight loss-chemistry, physiology, and clinical applications. Cell metabolism 97 37591245
2019 Distinct Neural Sites of GLP-1R Expression Mediate Physiological versus Pharmacological Control of Incretin Action. Cell reports 91 31189118
2013 DNA methylation of the glucagon-like peptide 1 receptor (GLP1R) in human pancreatic islets. BMC medical genetics 83 23879380
2022 GLP-1 regulates exercise endurance and skeletal muscle remodeling via GLP-1R/AMPK pathway. Biochimica et biophysica acta. Molecular cell research 81 35636559
2023 Semaglutide ameliorates cognition and glucose metabolism dysfunction in the 3xTg mouse model of Alzheimer's disease via the GLP-1R/SIRT1/GLUT4 pathway. Neuropharmacology 80 37730113
2022 Targeting the GLP-1/GLP-1R axis to treat osteoarthritis: A new opportunity? Journal of orthopaedic translation 70 35280931
2021 Time and metabolic state-dependent effects of GLP-1R agonists on NPY/AgRP and POMC neuronal activity in vivo. Molecular metabolism 65 34626854
2017 GLP-1R as a Target for the Treatment of Diabetic Retinopathy: Friend or Foe? Diabetes 64 28533296
2022 Dynamics of GLP-1R peptide agonist engagement are correlated with kinetics of G protein activation. Nature communications 62 35013280
2013 Recent advances in understanding GLP-1R (glucagon-like peptide-1 receptor) function. Biochemical Society transactions 61 23356279
2015 Epac is required for GLP-1R-mediated inhibition of oxidative stress and apoptosis in cardiomyocytes. Molecular endocrinology (Baltimore, Md.) 60 25719403
2021 Glucagon-like peptide 1 receptor (GLP-1R) agonist relieved asthmatic airway inflammation via suppression of NLRP3 inflammasome activation in obese asthma mice model. Pulmonary pharmacology & therapeutics 54 33588055
2015 Blockade of cannabinoid 1 receptor improves GLP-1R mediated insulin secretion in mice. Molecular and cellular endocrinology 53 26724516
2021 Structure and dynamics of semaglutide- and taspoglutide-bound GLP-1R-Gs complexes. Cell reports 47 34260945
2021 GLP-1R activation ameliorated novel-object recognition memory dysfunction via regulating hippocampal AMPK/NF-κB pathway in neuropathic pain mice. Neurobiology of learning and memory 46 34015440
2013 GLP-1R agonist therapy for diabetes: benefits and potential risks. Current opinion in endocrinology, diabetes, and obesity 45 23403741
2023 Suppression of food intake by Glp1r/Lepr-coexpressing neurons prevents obesity in mouse models. The Journal of clinical investigation 44 37581939
2014 Hyperglycemia-induced GLP-1R downregulation causes RPE cell apoptosis. The international journal of biochemistry & cell biology 44 25483438
2016 A missense variant in GLP1R gene is associated with the glycaemic response to treatment with gliptins. Diabetes, obesity & metabolism 42 27160388
2024 GLP-1R-positive neurons in the lateral septum mediate the anorectic and weight-lowering effects of liraglutide in mice. The Journal of clinical investigation 40 39225090
2024 The effect of GLP-1R agonists on the medical triad of obesity, diabetes, and cancer. Cancer metastasis reviews 38 38801466
2019 Chronic Suppression of Glucagon-Like Peptide-1 Receptor (GLP1R) mRNA Translation in the Rat Bed Nucleus of the Stria Terminalis Reduces Anxiety-Like Behavior and Stress-Induced Hypophagia, But Prolongs Stress-Induced Elevation of Plasma Corticosterone. The Journal of neuroscience : the official journal of the Society for Neuroscience 37 30683681
2023 Human GLP1R variants affecting GLP1R cell surface expression are associated with impaired glucose control and increased adiposity. Nature metabolism 36 37709961
2021 Reagents and models for detecting endogenous GLP1R and GIPR. EBioMedicine 36 34911028
2018 Glucagon-like peptide-1 receptor (GLP-1R) signaling ameliorates dysfunctional immunity in COPD patients. International journal of chronic obstructive pulmonary disease 36 30349227
2025 The role of glucagon-like peptide-1 receptor (GLP-1R) agonists in enhancing endothelial function: a potential avenue for improving heart failure with preserved ejection fraction (HFpEF). Cardiovascular diabetology 34 39920668
2024 Comparative efficacy of THR-β agonists, FGF-21 analogues, GLP-1R agonists, GLP-1-based polyagonists, and Pan-PPAR agonists for MASLD: A systematic review and network meta-analysis. Metabolism: clinical and experimental 34 39357599
2023 Enhanced Endosomal Signaling and Desensitization of GLP-1R vs GIPR in Pancreatic Beta Cells. Endocrinology 34 36774542
2023 The pleiotropic of GLP-1/GLP-1R axis in central nervous system diseases. The International journal of neuroscience 33 33941038
2023 GLP-1R signaling neighborhoods associate with the susceptibility to adverse drug reactions of incretin mimetics. Nature communications 33 37813859
2021 Design of a highly potent GLP-1R and GCGR dual-agonist for recovering hepatic fibrosis. Acta pharmaceutica Sinica. B 32 35646543
2013 Minireview: Signal bias, allosterism, and polymorphic variation at the GLP-1R: implications for drug discovery. Molecular endocrinology (Baltimore, Md.) 32 23864649
2025 Hedonic eating is controlled by dopamine neurons that oppose GLP-1R satiety. Science (New York, N.Y.) 31 40146831
2024 GLP-1R activation attenuates the progression of pulmonary fibrosis via disrupting NLRP3 inflammasome/PFKFB3-driven glycolysis interaction and histone lactylation. Journal of translational medicine 29 39434134
2023 Divergent acute versus prolonged pharmacological GLP-1R responses in adult β cell-specific β-arrestin 2 knockout mice. Science advances 29 37134170
2023 Topical and systemic GLP-1R agonist administration both rescue retinal ganglion cells in hypertensive glaucoma. Frontiers in cellular neuroscience 29 37362000
2022 Structural basis of peptidomimetic agonism revealed by small- molecule GLP-1R agonists Boc5 and WB4-24. Proceedings of the National Academy of Sciences of the United States of America 29 35561211
2023 Structural analysis of the dual agonism at GLP-1R and GCGR. Proceedings of the National Academy of Sciences of the United States of America 28 37549266
2023 Cold Exposure and Oral Delivery of GLP-1R Agonists by an Engineered Probiotic Yeast Strain Have Antiobesity Effects in Mice. ACS synthetic biology 28 37827516
2022 Anti-Inflammatory Effects of GLP-1R Activation in the Retina. International journal of molecular sciences 28 36293281
2021 The MafA-target gene PPP1R1A regulates GLP1R-mediated amplification of glucose-stimulated insulin secretion in β-cells. Metabolism: clinical and experimental 28 33631146
2020 Exendin-4 restores airway mucus homeostasis through the GLP1R-PKA-PPARγ-FOXA2-phosphatase signaling. Mucosal immunology 28 32034274
2020 The supramammillary nucleus controls anxiety-like behavior; key role of GLP-1R. Psychoneuroendocrinology 28 32563174
2025 Activation of AMPK by GLP-1R agonists mitigates Alzheimer-related phenotypes in transgenic mice. Nature aging 27 40394225
2023 GLP-1R Signaling and Functional Molecules in Incretin Therapy. Molecules (Basel, Switzerland) 27 36677809
2022 Differential association between the GLP1R gene variants and brain functional connectivity according to the severity of alcohol use. Scientific reports 27 35906358
2021 Geniposide Ameliorated Dexamethasone-Induced Cholesterol Accumulation in Osteoblasts by Mediating the GLP-1R/ABCA1 Axis. Cells 26 34943934
2023 Combination of an ACLY inhibitor with a GLP-1R agonist exerts additive benefits on nonalcoholic steatohepatitis and hepatic fibrosis in mice. Cell reports. Medicine 25 37729871
2023 Liraglutide Attenuates Myocardial Ischemia/Reperfusion Injury Through the Inhibition of Necroptosis by Activating GLP-1R/PI3K/Akt Pathway. Cardiovascular toxicology 24 36934206
2023 GLP-1R agonists demonstrate potential to treat Wolfram syndrome in human preclinical models. Diabetologia 24 36995380
2023 Geniposide stimulates autophagy by activating the GLP-1R/AMPK/mTOR signaling in osteoarthritis chondrocytes. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 23 37769389
2020 Sitagliptin improves functional recovery via GLP-1R-induced anti-apoptosis and facilitation of axonal regeneration after spinal cord injury. Journal of cellular and molecular medicine 23 32573108
2024 Dorsolateral septum GLP-1R neurons regulate feeding via lateral hypothalamic projections. Molecular metabolism 22 38763494
2013 Effect of GLP1R agonists taspoglutide and liraglutide on primary thyroid C-cells from rodent and man. Journal of molecular endocrinology 22 23463748
2024 Molecular features of the ligand-free GLP-1R, GCGR and GIPR in complex with Gs proteins. Cell discovery 20 38346960
2024 Glp1r-Lepr coexpressing neurons modulate the suppression of food intake and body weight by a GLP-1/leptin dual agonist. Science translational medicine 20 39630884
2021 Long-term functional alterations following prenatal GLP-1R activation. Neurotoxicology and teratology 20 33864929
2014 GLP-1R activation for the treatment of stroke: updating and future perspectives. Reviews in endocrine & metabolic disorders 20 24777909
2024 Specific loss of GIPR signaling in GABAergic neurons enhances GLP-1R agonist-induced body weight loss. Molecular metabolism 19 39612941
2023 Loganin alleviates myocardial ischemia-reperfusion injury through GLP-1R/NLRP3-mediated pyroptosis pathway. Environmental toxicology 19 37497884
2022 Expanded LUXendin Color Palette for GLP1R Detection and Visualization In Vitro and In Vivo. JACS Au 19 35557759
2019 A free-energy landscape for the glucagon-like peptide 1 receptor GLP1R. Proteins 18 31294890
2015 Cyclic alpha-conotoxin peptidomimetic chimeras as potent GLP-1R agonists. European journal of medicinal chemistry 18 26352676
2025 GIPR-Ab/GLP-1 peptide-antibody conjugate requires brain GIPR and GLP-1R for additive weight loss in obese mice. Nature metabolism 17 40301582
2024 Potential Role of Phytochemicals as Glucagon-like Peptide 1 Receptor (GLP-1R) Agonists in the Treatment of Diabetes Mellitus. Pharmaceuticals (Basel, Switzerland) 16 38931402
2024 GLP-1R agonist promotes proliferation of neuroendocrine neoplasm cells expressing GLP-1 receptors. Surgery 16 39665969
2023 Schisandrin B, a potential GLP-1R agonist, exerts anti-diabetic effects by stimulating insulin secretion. Molecular and cellular endocrinology 16 37495090
2022 Implications of ligand-receptor binding kinetics on GLP-1R signalling. Biochemical pharmacology 16 35300966
2024 The GLP-1R as a model for understanding and exploiting biased agonism in next-generation medicines. The Journal of endocrinology 15 38451873
2024 Baicalein: A potential GLP-1R agonist improves cognitive disorder of diabetes through mitophagy enhancement. Journal of pharmaceutical analysis 15 39258173
2023 Liraglutide ameliorates oxidized LDL-induced endothelial dysfunction by GLP-1R-dependent downregulation of LOX-1-mediated oxidative stress and inflammation. Redox report : communications in free radical research 15 37278349
2015 Insulin dose adjustments with add-on glucagon-like peptide-1 receptor (GLP-1R) agonists in clinical practice. Expert opinion on pharmacotherapy 15 26077113
2025 Structural pharmacology and mechanisms of GLP-1R signaling. Trends in pharmacological sciences 14 40221226
2024 Novel Angiogenesis Role of GLP-1(32-36) to Rescue Diabetic Ischemic Lower Limbs via GLP-1R-Dependent Glycolysis in Mice. Arteriosclerosis, thrombosis, and vascular biology 14 38511325
2020 Loureirin B activates GLP-1R and promotes insulin secretion in Ins-1 cells. Journal of cellular and molecular medicine 14 33300675
2007 Genetic variation in Glp1r expression influences the rate of gastric emptying in mice. American journal of physiology. Regulatory, integrative and comparative physiology 14 18077508
2025 Semaglutide Reprograms Macrophages via the GLP-1R/PPARG/ACSL1 Pathway to Suppress Papillary Thyroid Carcinoma Growth. The Journal of clinical endocrinology and metabolism 13 39908200
2024 Dual activation of GCGR/GLP1R signaling ameliorates intestinal fibrosis via metabolic regulation of histone H3K9 lactylation in epithelial cells. Acta pharmaceutica Sinica. B 13 40041889
2022 GLP1R inhibits the progression of endometrial carcinoma through activation of cAMP/PKA pathway. Journal of clinical laboratory analysis 13 35989517
2022 Association of GLP1R variants rs2268641 and rs6923761 with obesity and other metabolic parameters in a Polish cohort. Frontiers in endocrinology 13 36339410
2022 Loureirin B promotes insulin secretion through GLP-1R and AKT/PDX1 pathways. European journal of pharmacology 13 36347320
2021 GRK2 regulates GLP-1R-mediated early phase insulin secretion in vivo. BMC biology 13 33658023
2021 Functional GLP-1R antibodies identified from a synthetic GPCR-focused library demonstrate potent blood glucose control. mAbs 13 33706686
2020 GABA requires GLP-1R to exert its pancreatic function during STZ challenge. The Journal of endocrinology 13 32544878
2019 Mutagenesis facilitated crystallization of GLP-1R. IUCrJ 13 31709055
2018 Do glucagon-like peptide-1 receptor (GLP-1R) agonists have potential as adjuncts in the treatment of type 1 diabetes? Expert opinion on pharmacotherapy 13 30234389
2025 Biased agonism of GLP-1R and GIPR enhances glucose lowering and weight loss, with dual GLP-1R/GIPR biased agonism yielding greater efficacy. Cell reports. Medicine 12 40460831
2024 GLP-1R signaling modulates colonic energy metabolism, goblet cell number and survival in the absence of gut microbiota. Molecular metabolism 12 38521185
2024 Binding sites and design strategies for small molecule GLP-1R agonists. European journal of medicinal chemistry 12 38959726
2014 Reduced GLP-1R expression in gastric glands of patients with type 2 diabetes mellitus. The Journal of clinical endocrinology and metabolism 12 24878048