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Article History

Received: 11 June 2025

Accepted: 30 October 2025

First Online: 4 March 2026

Acknowledgements

: The authors would like to thank S. Rothery of the Facility for Imaging by Light Microscopy at Imperial College London for his support and assistance in this work.

: All data, methods and unique/stable reagents generated in this study will be made available from the corresponding author upon reasonable request, but may require a completed Materials Transfer Agreement. RNA sequencing data are available from the Gene Expression Omnibus under accession number GSE306720.

: The Section of Endocrinology and Investigative Medicine, Hammersmith Hospital, London, is funded by grants from the MRC, BBSRC and NIHR, and is supported by the NIHR Biomedical Research Centre Funding Scheme. The views expressed are those of the authors and not necessarily those of the MRC or BBSRC, the NHS, the NIHR or the Department of Health and Social Care. PP is funded by a National Science Scholarship from A*STAR, Singapore. KGM is supported by Diabetes UK (18/0005886 and 20/0006295), the BBSRC (BB/W001497/1 and BB/X017273/1), the MRC (MR/Y013980/1) and the Wellcome Trust (310835/Z/24/Z). BJ acknowledges funding support from the Medical Research Council (MR/Y00132X/1 and MR/X021467/1), the Wellcome Trust (301619/Z/23/Z), Diabetes UK, the Eli Lilly LRAP programme and Metsera Inc. BYHL and GSHY are supported by BBSRC project grant BB/S017593/1 and the MRC Metabolic Diseases Unit (MC_UU_00014/1). Next-generation sequencing was performed at the IMS Genomics and Bioinformatics Core, supported by the MRC (MC_UU_00014/5 and RGAG/542 MC_UU_00039), the Wellcome Trust (208363/Z/17/Z and RGAG/546 226800/Z/22/Z), and the Cancer Research UK Cambridge Institute Genomics Core. The FR/FMG laboratories were funded by the Wellcome Trust (220271/Z/20/Z) and the MRC (MRC_MC_UU_12012/3). The study’s funders were not involved in the design of the study, the collection, analysis and interpretation of data, or writing the report, and did not impose any restrictions regarding publication of the report.

: BYHL provides remunerated consultancy for Nuntius Therapeutics. GSHY receives grant funding from Novo Nordisk and Amgen Inc; he also consults for both Novo Nordisk and Eli Lilly and Company. The remaining authors declare that there are no relationships or activities that might bias, or be perceived to bias, their work.

: PP was responsible for conceptualisation, investigation, formal analysis, project administration, and the writing of the original draft. MN contributed to methodology and investigation. SC, AGR, DP, LM, P-EC, CD, EO and SA were involved in investigation. RK carried out investigation and formal analysis. BYHL contributed to methodology, visualisation and formal analysis. FMG and FR provided resources and helped to design the experiments and interpret data. ACH contributed to methodology. GSHY also assisted with methodology. GAB contributed to visualisation and formal analysis. BJ was involved in methodology and provision of resources. BO contributed to methodology. KGM was responsible for conceptualisation, formal analysis, data curation, manuscript review and editing, supervision, and funding acquisition. All authors were involved in drafting the article or reviewing it critically for important intellectual content, and gave final approval of the version to be published. KGM is the guarantor of this work.