SFEBES2025 Poster Presentations Metabolism, Obesity and Diabetes (68 abstracts)
daLUXendins reveal dual GLP1R/GIPR agonist targets in the pancreas and brain
Anne de Bray 1,2 , Jason Tong 2 , Christiane Huhn 3 , Kilian Roßmann 3 , Ali H. Shilleh 2 , Wanqing Jiang 4 , Anna G. Roberts 4 , 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 7,8,9 , Julia Ast 1,10 , Malgorzata Cyranka 10 , Alexey Epanchintsev 10 , Carina Ämmälä 10 , Frank Reimann 11 , Graham Ladds 5 , Alice Adriaenssens 4 , Stefan Trapp 4 , Ben Jones 12 , Johannes Broichhagen 3 & David J. Hodson 1,2
1IMSR and COMPARE, Birmingham, United Kingdom; 2OCDEM, Oxford, United Kingdom; 3Leibniz-Forschungsinstitut für Molekulare Pharmakologie, Berlin, Germany; 4Centre for Cardiovascular and Metabolic Neuroscience, University College London, London, United Kingdom; 5Department of Pharmacology, University of Cambridge, Cambridge, United Kingdom; 6Center for Medical Research and Education, Osaka University Graduate School of Medicine, Osaka, Japan; 7Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom; 8COMPARE, Birmingham, United Kingdom; 9School of Mathematics, University of Birmingham, Birmingham, United Kingdom; 10Novo Nordisk Research Centre, Oxford, United Kingdom; 11Institute of Metabolic Science-Metabolic Research Laboratories & MRC-Metabolic Diseases Unit, University of Cambridge, Cambridge, United Kingdom; 12Section of Endocrinology and Investigative Medicine, Imperial College London, London, United Kingdom
Background: Tirzepatide is a biased dual GLP1R/GIPR agonist with excellent efficacy for weight loss and glucose control in people living with obesity or type 2 diabetes. However, cellular targets and understanding of its biased agonism is yet to be fully elucidated, but could inform development of further dual and triple incretin therapies.
Method: We synthesised and tested two novel fluorescent GLP1R/GIPR probes, daLUXendin544 and daLUXendin660, allowing visualisation and interrogation of dual agonist cell targets. The probes are structurally similar to tirzepatide except for substitution of a C-terminal serine with cysteine to facilitate Cy3 or Cy5 fluorophore conjugation.
Results: daLUXendin544/660 demonstrate high potency (cAMP) and strong binding affinity at both the mouse and human GLP1R and GIPR. Advantageously, daLUXendin544/660 show 2:1 functional selectivity for mouse GLP1R over mouse GIPR. Through co-localisation studies in cell lines, daLUXendin544/660 show specificity for human and mouse GLP1R and GIPR with no labelling in non-transfected cells. In GLP1RKO islets, probe fluorescence was reduced versus WT islets with further reduction in daLUXendin544 fluorescence following pre-incubation with GIP. In fixed mouse islets, as well as human iPSC-derived islet-like structures, daLUXendin544/660 bind to all cell types with labelling strongest in insulin-positive cells versus glucagon- or somatostatin-positive cells. Further, daLUXendin660 is able to label in vivo, with strong labelling in islets isolated from GLP1R-Cre:tdRFP and GIPR-Cre:GFP mice 60 minutes after injection with daLUXendin660. Following IV injection, daLUXendin660 also labels the median eminence, area postrema and other circumventricular organs with an incomplete blood-brain barrier but does not penetrate any further into the brain. Finally, we use single molecule localisation microscopy to show that daLUXendin660 engages more receptor nanodomains than single GLP1R/GIPR probes.
Conclusion: We present daLUXendin544 and daLUXendin660, highly specific fluorescent GLP1R/GIPR probes that reveal dual agonist targets in the pancreas and brain.
Volume 109
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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