Fluorescent GLP1R/GIPR dual agonist probes reveal cell targets in the pancreas and brain
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<sup>+</sup> and GIPR<sup>+</sup> 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.
Authors
- Jason Tong (ORCID: https://orcid.org/0000-0003-1027-3662)
- Tolga Soykan (ORCID: https://orcid.org/0000-0002-1324-9601)
- Alice E. Adriaenssens (ORCID: https://orcid.org/0000-0002-1279-4763)
- Dylan M. Owen (ORCID: https://orcid.org/0000-0002-5284-2782)
- Małgorzata Cyranka
- Johannes Broichhagen (ORCID: https://orcid.org/0000-0003-3084-6595)
- Blaise Gatin‐Fraudet (ORCID: https://orcid.org/0000-0002-9000-9820)
- Frank M. Reimann (ORCID: https://orcid.org/0000-0001-9399-6377)
- Christiane Huhn (ORCID: https://orcid.org/0000-0001-9862-8784)
- Daniela Nasteska (ORCID: https://orcid.org/0000-0002-8996-5102)
- Anne de Bray
- Katrina Viloria (ORCID: https://orcid.org/0000-0003-3572-4669)
- Julia Ast (ORCID: https://orcid.org/0000-0002-0039-4762)
- Satsuki Miyazaki (ORCID: https://orcid.org/0000-0003-1781-1590)
- Abigail Pearce (ORCID: https://orcid.org/0000-0001-9845-0541)
- Alexey Epanchintsev
- David J. Hodson (ORCID: https://orcid.org/0000-0002-8641-8568)
- Ali H. Shilleh (ORCID: https://orcid.org/0000-0002-5092-5744)
- Ben Jones (ORCID: https://orcid.org/0000-0003-0461-2584)
- Daniel J. Nieves (ORCID: https://orcid.org/0000-0002-0873-4418)
- Carina Ämmälä (ORCID: https://orcid.org/0000-0003-3180-7563)
- Wanqing Jiang
- Graham Ladds (ORCID: https://orcid.org/0000-0001-7320-9612)
- Kilian Roßmann (ORCID: https://orcid.org/0000-0003-4965-9669)
- Jeremy Tomlinson (ORCID: https://orcid.org/0000-0002-3170-8533)
- Stefan Trapp (ORCID: https://orcid.org/0000-0003-0665-4948)
- Anna G Roberts
- N. Burgos
- James P. P. Trott
- Sarah Armour
Institutions
- University of Cambridge (GB)
- Churchill Hospital (GB)
- University of Oxford (GB)
- Leibniz-Forschungsinstitut für Molekulare Pharmakologie (DE)
- Novo Nordisk (Finland) (FI)
- Wellcome/MRC Institute of Metabolic Science (GB)
- Oxford Centre for Diabetes, Endocrinology and Metabolism (GB)
- University College London (GB)
- Imperial College London (GB)
- University of Birmingham (GB)
- The University of Osaka (JP)
Publication Details
- Journal
- Nature Metabolism
- Published
- 2025-08-19
- DOI
- https://doi.org/10.1038/s42255-025-01342-6
- Citations
- 4
- Primary Topic
- Pancreatic function and diabetes
- Type
- article
- Field-Weighted Citation Impact
- 8.03