Fluorescent GLP1R/GIPR dual agonist probes reveal cell targets in the pancreas and brain PMID: 40830598

ADC Targets in Oncology

2026-04-10

Fluorescent GLP1R/GIPR dual agonist probes reveal cell targets in the pancreas and brain

Nat Metab. 2025 Aug;7(8):1536-1549. doi: 10.1038/s42255-025-01342-6.

Anne de Bray ¹ ² , Anna G Roberts ³ , Sarah Armour ² , Jason Tong ² , Christiane Huhn ⁴ , Blaise Gatin-Fraudet ⁴ , Kilian Roßmann ⁴ , Ali H Shilleh ² , Wanqing Jiang ³ , Natalie S Figueredo Burgos ³ , James P P Trott ³ , Katrina Viloria ¹ ² , Daniela Nasteska ¹ ² , Abigail Pearce ⁵ , Satsuki Miyazaki ⁶ , Jeremy W Tomlinson ² , Dylan M Owen ⁷ ⁸ ⁹ , Daniel J Nieves ⁷ ⁸ , Julia Ast ¹ ¹⁰ , Malgorzata Cyranka ¹⁰ , Alexey Epanchintsev ¹⁰ , Carina Ämmälä ¹⁰ , Frank Reimann ¹¹ , Tolga Soykan ⁴ , Graham Ladds ⁵ , Alice E Adriaenssens ³ , Stefan Trapp ³ , Ben Jones ¹² , Johannes Broichhagen ¹³ , David J Hodson ¹⁴ ¹⁵

Affiliations

1. Department of Metabolism and Systems Science, College of Medicine and Health, University of Birmingham, Birmingham, UK.
2. Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM), NIHR Oxford Biomedical Research Centre, Churchill Hospital, Radcliffe Department of Medicine, University of Oxford, Oxford, UK.
3. Centre for Cardiovascular and Metabolic Neuroscience, Department of Neuroscience, Physiology & Pharmacology, UCL, London, UK.
4. Leibniz-Forschungsinstitut für Molekulare Pharmakologie, Berlin, Germany.
5. Department of Pharmacology, University of Cambridge, Cambridge, UK.
6. Division of Stem Cell Regulation Research, Center for Medical Research and Education, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
7. Department of Immunology and Immunotherapy, School of Infection, Inflammation and Immunology, College of Medicine and Health, University of Birmingham, Birmingham, UK.
8. Centre of Membrane Proteins and Receptors, University of Birmingham, Birmingham, UK.
9. School of Mathematics, University of Birmingham, Birmingham, UK.
10. Novo Nordisk Research Centre Oxford, Innovation Building, Oxford, UK.
11. Institute of Metabolic Science-Metabolic Research Laboratories & MRC-Metabolic Diseases Unit, University of Cambridge, Cambridge, UK.
12. Section of Endocrinology and Investigative Medicine, Imperial College London, London, UK.
13. Leibniz-Forschungsinstitut für Molekulare Pharmakologie, Berlin, Germany. [email protected].
14. Department of Metabolism and Systems Science, College of Medicine and Health, University of Birmingham, Birmingham, UK. [email protected].
15. Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM), NIHR Oxford Biomedical Research Centre, Churchill Hospital, Radcliffe Department of Medicine, University of Oxford, Oxford, UK. [email protected].

Abstract

Dual agonists targeting glucagon-like peptide-1 receptor (GLP1R) and glucose-dependent insulinotropic polypeptide receptor (GIPR) are breakthrough treatments for patients with type 2 diabetes and obesity. Compared to GLP1R agonists, dual agonists show superior efficacy for glucose lowering and weight reduction. However, delineation of dual agonist cell targets remains challenging. Here, we develop and test daLUXendin and daLUXendin+, non-lipidated and lipidated fluorescent GLP1R/GIPR dual agonist probes, and use them to visualize cellular targets. daLUXendins are potent GLP1R/GIPR dual agonists that advantageously show less functional selectivity for mouse GLP1R over mouse GIPR. daLUXendins label rodent and human pancreatic islet cells, with a signal intensity of β cells > α cells = δ cells. Systemic administration of daLUXendin strongly labels GLP1R⁺ and GIPR⁺ neurons in circumventricular organs characterized by an incomplete blood-brain barrier but does not penetrate the brain beyond labelling seen with single (ant)agonists. At the single-molecule level, daLUXendin targets endogenous GLP1R-GIPR nanodomains, which differ in organization and composition from those targeted by a single agonist. daLUXendins reveal dual agonist targets in the pancreas and brain and exclude a role for brain penetration in determining the superior efficacy of dual agonists, shedding new light on different modes of action of dual agonists versus single agonists.