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Exocrine\u2013beta cell interactions affect beta cell growth and function. Notably, exocrine abnormalities are frequently observed alongside overloaded beta cells in different types of diabetes, suggesting that exocrine stress may induce beta cell ER stress and loss. While a cause\u2013consequence relationship between exocrine stress and beta cell function cannot be addressed in humans, it can be studied in a zebrafish model. Larvae develop a pancreas with a human-like morphology by 120 h post-fertilisation, providing a valuable dynamic model for studying pancreatic interactions. Our aim was to target exocrine cells specifically and address beta cell status using transgenic zebrafish models and reporters.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods<\/jats:title>\n            <jats:p>To explore the impact of exocrine damage on beta cell fitness, we generated a novel zebrafish model allowing exocrine pancreas ablation, using a nifurpirinol\u2013nitroreductase system. We subsequently assessed the in vivo effects on beta cells by live-monitoring dynamic cellular events, such as ER stress, apoptosis and changes in beta cell number and volume.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results<\/jats:title>\n            <jats:p>Exocrine damage in zebrafish decreased pancreas volume by approximately 50% and changed its morphology. The resulting exocrine damage induced ER stress in 60\u201390% of beta cells and resulted in a ~50% reduction in their number.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions\/interpretation<\/jats:title>\n            <jats:p>The zebrafish model provides a robust platform for investigating the interplay between exocrine cells and beta cells, thereby enhancing further insights into the mechanisms driving pancreatic diseases such as type 1 diabetes.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Graphical Abstract<\/jats:title>\n          <\/jats:sec>","DOI":"10.1007\/s00125-025-06432-4","type":"journal-article","created":{"date-parts":[[2025,4,28]],"date-time":"2025-04-28T11:33:42Z","timestamp":1745840022000},"page":"1754-1768","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Pancreatic exocrine damage induces beta cell stress in zebrafish larvae"],"prefix":"10.1007","volume":"68","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1458-9402","authenticated-orcid":false,"given":"Noura","family":"Faraj","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6061-2576","authenticated-orcid":false,"given":"Willem M. 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Peers for the insulin:gfp zebrafish (University of Li\u00e8ge, Li\u00e8ge, Belgium), the National Institute of Genetics (NIG) scientist for pT2-L200R150-MCS1, S. J. Du for the pT2EF1a xbp1-gfp plasmid (University of Maryland School of Medicine, Baltimore, MD, USA) and T. van Ham for the 3.5ubb:secAnnexinV-mVenus plasmid (University Medical Center Rotterdam, Rotterdam, the Netherlands). We also thank E. Carroll (Delft University of Technology, Delft, the Netherlands) and all laboratory members for input, the Central Animal Facility (CDP) for facilitating and supporting experimental animal research, and the UMCG Microscopy and Imaging Center (UMIC) for supporting access to advanced microscopes and image processing.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Acknowledgements"}},{"value":"Original light microscopy images and raw electron microscopy data are open access via the BioImage Archive (S-BIAD1479, DOI: ). All raw EM data in zoomable format and the ESM Videos are available via .","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Data availability"}},{"value":"Part of the work was performed at the UMCG Microscopy and Imaging Center (UMIC), sponsored by ZonMW grant 91111.006, the Netherlands Electron Microscopy Infrastructure (NEMI), NWO National Roadmap for Large-Scale Research Infrastructure of the Dutch Research Council (NWO 184.034.014), the Network for Pancreatic Organ donors with Diabetes (nPOD; RRID:SCR_014641), a collaborative type 1 diabetes research project sponsored by Breakthrough T1D (nPOD: 5-SRA-2018-557-Q-R), and The Leona M. & Harry B. Helmsley Charitable Trust (grant no. 2018PG-T1D053). The content and views expressed are the responsibility of the authors and do not necessarily reflect the official view of nPOD. Organ Procurement Organizations (OPO) partnering with nPOD to provide research resources are listed at jdrfnpod.org\/for-partners\/npod-partners. BNGG and AZ are supported by ZonMW OPEN: 09120012010107; BHPD, BNGG NWO-ENPPS.LIFT.019.030. NF is supported by De Cock-Hadders Foundation and the European Union\u2019s Horizon 2020 research and innovation programme under the Marie Sk\u0142odowska-Curie grant agreement No. 754425.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Funding"}},{"value":"The authors declare that there are no relationships or activities that might bias, or be perceived to bias, their work.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Authors\u2019 relationships and activities"}},{"value":"The authorship is based on the ICMJE uniform requirements. NF, WMHH, BHPD and AHGW generated plasmids and zebrafish lines. All authors conceived and designed the experiments. NF, WMHH, BHPD, AHGW and KK performed the experiments and acquired and analysed the data. NF wrote the manuscript. All authors contributed to interpretation of data, performed critical review of the manuscript and approved of the final version to be published. BNGG supervised this project. BNGG is the guarantor of this work.","order":5,"name":"Ethics","group":{"name":"EthicsHeading","label":"Contribution statement"}}]}}