The influence of metformin treatment on the circulating proteomeResearch in context

The influence of metformin treatment on the circulating proteomeResearch in context

Summary: Background: Metformin is one of the most used drugs worldwide. Given the increasing use of proteomics in trials, bioresources, and clinics, it is crucial to understand the influence of metformin on the levels of the circulating proteome. Methods: We analysed a combined longitudinal proteom...

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Main Authors: Ben Connolly, Laura McCreight, Roderick C. Slieker, Khaled F. Bedair, Louise Donnelly, Juliette A. de Klerk, Joline W.J. Beulens, Petra J.M. Elders, Göran Bergström, Mun-Gwan Hong, Robert W. Koivula, Paul W. Franks, Jochen M. Schwenk, Anders Gummesson, Ewan R. Pearson, Leen M. ‘t Hart, Moustafa Abdalla, Jonathan Adam, Jerzy Adamski, Kofi Adragni, Rosa Lundbye L. Allesøe, Kristine H. Allin, Anna A. Artati, Manimozhiyan Arumugam, Naeimeh Atabaki Pasdar, Tania Baltauss, Karina Banasik, Anna Barnett, Patrick Baum, Jimmy D. Bell, Susanna Bianzano, Roberto Bizzotto, Amelie Bonnefond, Caroline Anna A. Brorsson, Andrew A. Brown, Søren Brunak, Louise Cabrelli, Robert Caiazzo, Henna Cederberg, Elizaveta Chabanova, Marc Clos-Garcia, Matilda Dale, David Davtian, Adem Y. Dawed, Federico De Masi, Nathalie de Preville, Koen F. Dekkers, Harshal A. Deshmukh, Christiane Dings, Avirup Dutta, Beate Ehrhardt, Line Engelbrechtsen, Rebeca Eriksen, Yong Fan, Juan Fernandez, Jorge Ferrer, Hugo Fitipaldi, Ian M. Forgie, Annemette Forman, Francesca Frau, Philippe Froguel, Gary Frost, Johann Gassenhuber, Giuseppe (Nick) N. Giordano, Toni Giorgino, Stephen Gough, Harald Grallert, Rolf Grempler, Lenka Groeneveld, Leif Groop, Valborg Gudmundsdóttir, Ramneek Gupta, Mark Haid, Torben Hansen, Tue H. Hansen, Andrew T. Hattersley, Ragna Haussler, Alison J. Heggie, Anita M. Hennige, Anita V. Hill, Reinhard W. Holl, Michelle Hudson, Bernd Jablonka, Ulrik Plesner Jacobsen, Christopher Jennison, Joachim Johansen, Angus G. Jones, Tugce Karaderi, Jane Kaye, Gwen Kennedy, Maria Klintenberg, Tarja Kokkola, Anitra D. Koopman, Azra Kurbasic, Teemu Kuulasmaa, Markku Laakso, Thorsten Lehr, Heather Loftus, Agnete Troen T. Lundgaard, Liwei Lyu, Anubha Mahajan, Andrea Mari, Gianluca Mazzoni, Mark I. McCarthy, Timothy J. McDonald, Donna McEvoy, Nicky McRobert, Ian McVittie, Miranda Mourby, Petra Musholt, Pascal Mutie, Rachel Nice, Claudia Nicolay, Giel Nijpels, Birgitte Nilsson, Colin N. Palmer, Francois Pattou, Imre Pavo, Helle K. Pedersen, Oluf Pedersen, Mandy H. Perry, Hugo Pomares-Millan, Cornelia P. Prehn, Anna Ramisch, Simon Rasmussen, Violeta Raverdi, Martin Ridderstråle, Neil Robertson, Marianne Rodriquez, Hartmut Ruetten, Femke Rutters, Peter Sackett, Nina Scherer, Nisha Shah, Sapna Sharma, Iryna Sihinevich, Nadja B. Sondertoft, Hans-Henrik Staerfeldt, Birgit Steckel-Hamann, Harriet Teare, Cecilia Engel E. Thomas, Elizabeth Louise L. Thomas, Melissa K. Thomas, Henrik S. Thomsen, Barbara Thorand, Claire E. Thorne, Joachim Tillner, Konstantinos D. Tsirigos, Andrea Tura, Mathias Uhlen, Sabine van Oort, Jagadish Vangipurapu, Helene Verkindt, Henrik Vestergaard, Ana Viñuela, Josef K. Vogt, Peter W. Wad Sackett, Mark Walker, Agata Wesolowska-Andersen, Brandon Whitcher, Margaret W. White, Alexander Efanov, Giuseppe N. Giordano, Gerard A. Bouland, Frédéric Burdet, Iulian Dragan, Andreas Festa, Michael K. Hansen, Dmitry Kuznetsov, Florence Mehl, Diana Marek, Kevin Duffin, Samreen K. Syed, Janice L. Shaw, Over Cabrera, Timothy J. Pullen, Bernard Thorens, Mark Ibberson, Guy A. Rutter
Format: Article
Language:English
Published: Elsevier 2025-08-01
Series:EBioMedicine
Subjects:
Metformin
Proteomics
Type 2 diabetes
Biomarker
Online Access:http://www.sciencedirect.com/science/article/pii/S2352396425003032
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Summary:Summary: Background: Metformin is one of the most used drugs worldwide. Given the increasing use of proteomics in trials, bioresources, and clinics, it is crucial to understand the influence of metformin on the levels of the circulating proteome. Methods: We analysed a combined longitudinal proteomics dataset from the IMPOCT, RAMP and S3WP-T2D clinical trials in 98 participants before and after metformin exposure. This discovery analysis contained 372 proteins measured by proximity extension assays (Olink). We followed up experiment–wise statistically significant findings in two cross-sectional cohorts of people with type 2 diabetes comparing metformin treated and untreated individuals: IMI-DIRECT (784 participants, 372 proteins, Olink) and IMI-RHAPSODY (1175 participants, 1195 proteins, SomaLogic). Findings: Overall, 23 protein analytes were robustly associated with exposure to metformin in the discovery and replication. This includes 11 protein-metformin associations that replicated in both replication sets and platforms (REG4, GDF15, REG1A, t-PA, TFF3, CDH5, CNTN1, OMD, NOTCH3, THBS4 and CD93), with the remaining 12 protein-metformin associations replicated using the Olink platform (EPCAM, SPINK1, SAA-4, COMP, ITGB2, ADGRG2, FAM3C, MERTK, COL1A1, HAOX1, VCAN, TIMD4) but not measured on the SomaLogic platform. Gene-set enrichment analysis revealed that the metformin exposure was associated with intestinal associated proteins. Interpretation: These data highlight the need to account for exposure to metformin, and potentially other drugs, in proteomic studies and where protein biomarkers are used for clinical care. Funding: Innovative Medicines Initiative Joint Undertaking 2, under grant agreement no. 115881 (RHAPSODY) and the Innovative Medicines Initiative Joint Undertaking under grant agreement no. 115317 (DIRECT), resources of which are composed of financial contribution from the European Union's Seventh Framework Programme (FP7/2007-2013) and EFPIA companies in kind contribution as well as the Swiss State Secretariat for Education Research' and Innovation (SERI), under contract no. 16.0097 (RHAPSODY).
ISSN:2352-3964

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