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Article History

Received: 30 May 2025

Accepted: 9 December 2025

First Online: 25 February 2026

Acknowledgements

: The authors would especially like to thank the organ donors and their families. The IIDP (NIH grant no. 2UC4DK098085) supported this work by providing human islets. The Vanderbilt Cell Imaging Shared Resource allowed for confocal microscopy of live cells and tissue sections (DK020593). pCAG-ASAP3 ER was a gift from B. Bloodgood (Addgene plasmid no. 195356; ; RRID: Addgene195356; Neurobiology Department, School of Biological Sciences, University of California San Diego, La Jolla, CA, USA). GCEPIA1-SNAPER was a gift from P. Xu (Addgene plasmid no. 172659; ; RRID: Addgene_172659; College of Life Sciences, University of Chinese Academy of Sciences, Beijing, China). ER-RpHLuorin2 was a gift from G. van den Bogaart (Addgene plasmid no. 171717; ; RRID: Addgene_ 171717; Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, the Netherlands). HEK293 cells were kindly provided by R. Colbran (Molecular Physiology and Biophysics Department, Vanderbilt University). Figure schematics were created using BioRender.com. Some of the data were presented as an abstract at the 60 th EASD Annual Meeting of the European Association for the Study of Diabetes meeting in 2024.

: The authors declare that all data supporting the findings of this study are available and will be shared upon request. The eQTL dataset used in this study was obtained from Alonso et al [ ], and the corresponding summary statistics are available through the TIGER portal, . The multi-ancestry GWAS dataset was derived from Suzuki et al [ ], with summary statistics accessible from the DIAGRAM consortium website, .

: This research was funded by grants from the National Institutes of Health (NIH) (DK129340-S1, DK129340, DK136768 and DK097392), NIH training grants (1T32GM139800-01, 5T32DK07563), and the Leona M. and Harry B. Helmsley Charitable Trust (G-1912-03550). MC acknowledges support from the European Union’s Horizon 2020 research and innovation program T2DSystems under grant agreement no. 667191 and the Walloon Region strategic axis Fonds de la Recherche Scientifique (FRFS)–Walloon Excellence in Life Sciences and Biotechnology (WELBIO). AP is funded by Fonds de la Recherche Scientifique (FNRS).

: The authors declare that there are no relationships or activities that might bias, or be perceived to bias, their work.

: JRD and DAJ conceptualised the design of the project and wrote the manuscript. All authors performed experiments and data acquisition detailed here. JRD, SB and PKD assisted with human pseudoislet formation. JRD, MTD and SJP conducted electrophysiology recordings. JRD and SEG performed live cell imaging. AYN and PKD developed the TALK-2 inducible cell line. JRD performed dynamic insulin secretion and statistical analysis. MC and AP performed the co-localisation analysis of human islet eQTL and multi-ancestry GWAS. All authors critically reviewed the manuscript and approve the final version. DAJ is the guarantor of this work.