ArticleThe Journal of biological chemistry
Genetic and biased agonist-mediated reductions in β-arrestin recruitment prolong cAMP signaling at glucagon family receptors.
Article in The Journal of biological chemistry. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 51 papers.
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Who cites it
51 citing papers in PubMed, 84 citations in OpenAlex.
- Survodutide for treatment of obesity: Baseline characteristics of participants in a randomized, double-blind, placebo-controlled, phase 3 trial (SYNCHRONIZE™-1).Diabetes, obesity & metabolism · 2026Trial
- Structural basis for small-molecule agonism at GCGR and GIPR via a conserved intracellular allosteric site.Acta pharmacologica Sinica · 2026Article
- Glycemic and bodyweight effects ofScience advances · 2026Article
- Glucagon-like Peptide-1 and Dual GIP/GLP-1 Receptor Agonists in Brain: Exploring the Expanding Role and Safety in Neuropsychiatry.International journal of molecular sciences · 2026Review
- Cooperative Control of Arrestin Activation By Membrane Lipids And Phosphorylation Barcodes.bioRxiv : the preprint server for biology · 2026Article
- GLP-1R biased cAMP agonism maintains glycemic control with reduced malaise and emesis in preclinical mammalian models.Diabetes, obesity & metabolism · 2026Article
- In vivo functional profiling and structural characterization of the humanScience advances · 2026Article
- Signaling architecture of the glucagon-like peptide-1 receptor.The Journal of clinical investigation · 2026Review
- Biased Allosteric Modulation in GPCR Drug Discovery.Handbook of experimental pharmacology · 2026Review
- IUPHAR review: From foe to friend: Repurposing glucagon to treat obesity and type 2 diabetes.Pharmacological research · 2026Review
- GPCR Biased Signaling in Metabolism.Handbook of experimental pharmacology · 2026Review
- From Phytochemistry to Metabolic Regulation: The Insulin-Promoting Effects of Loureirin B Analogous to an Agonist of GLP-1 Receptor.International journal of molecular sciences · 2025Article
- Exploring Conformational Transitions in Biased and Balanced Ligand Binding of GLP-1R.Molecules (Basel, Switzerland) · 2025Article
- Gut Hormones and Inflammatory Bowel Disease.Biomolecules · 2025Review
- 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 · 2025Article
- Molecular mapping and functional validation of GLP-1R cholesterol binding sites in pancreatic beta cells.eLife · 2025Article
- Intersection of GPCR trafficking and cAMP signaling at endomembranes.The Journal of cell biology · 2025Review
- Arrestin-independent internalization of the GLP-1 receptor is facilitated by a GRK, clathrin, and caveolae-dependent mechanism.The FEBS journal · 2025Article
- The N-Linked Glycosylation Asn191 and Asn199 Sites Are Controlled Differently Between PKA Signal Transduction and pEKR1/2 Activity in Equine Follicle-Stimulating Hormone Receptor.Current issues in molecular biology · 2025Article
- Comparison of Exendin-4 and Its Single Amino Acid Substitutions as Parent Peptides for GLP-1 Receptor Imaging Probes.Molecules (Basel, Switzerland) · 2025Article
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Authors and funding
16 authors at 6 institutions in 5 countries.
Funding
Abstract
Receptors for the peptide hormones glucagon-like peptide-1 (GLP-1R), glucose-dependent insulinotropic polypeptide (GIPR), and glucagon (GCGR) are important regulators of insulin secretion and energy metabolism. GLP-1R agonists have been successfully deployed for the treatment of type 2 diabetes, but it has been suggested that their efficacy is limited by target receptor desensitization and downregulation due to recruitment of β-arrestins. Indeed, recently described GLP-1R agonists with reduced β-arrestin-2 recruitment have delivered promising results in preclinical and clinical studies. We therefore aimed to determine if the same phenomenon could apply to the closely related GIPR and GCGR. In HEK293 cells depleted of both β-arrestin isoforms the duration of G protein-dependent cAMP/PKA signaling was increased in response to the endogenous ligand for each receptor. Moreover, in wildtype cells, "biased" GLP-1, GCG, and GIP analogs with selective reductions in β-arrestin-2 recruitment led to reduced receptor endocytosis and increased insulin secretion over a prolonged stimulation period, although the latter effect was only seen at high agonist concentrations. Biased GCG analogs increased the duration of cAMP signaling, but this did not lead to increased glucose output from hepatocytes. Our study provides a rationale for the development of GLP-1R, GIPR, and GCGR agonists with reduced β-arrestin recruitment, but further work is needed to maximally exploit this strategy for therapeutic purposes.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.