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Article History

Received: 9 July 2025

Accepted: 4 February 2026

First Online: 21 April 2026

Acknowledgements

: We thank E. Anderson-Baucum (Indiana University School of Medicine, Department of Pediatrics, USA) for her assistance in editing the text of this manuscript.

: The data from small RNA-seq of human islets and islet-derived EVs were deposited in GEO database (accession no. GSE160391). All the other data associated with this manuscript can be found in the manuscript or in the ESM files.

: This work was supported by NIH grants R01 DK093954 and DK127308 (to CEM), R01 DK060581 (to RGM) and U01DK127786 and UC4DK104166 (to RGM and CEM), VA Merit Award I01BX001733 (to CEM), 2-SRA-2019-834-S-B and Breakthrough T1D 2-SRA-2018-493-A-B (to CEM and RGM), and gifts from the Sigma Beta Sorority, the Ball Brothers Foundation, and the George and Frances Ball Foundation (to CEM). FS was supported by Breakthrough (formerly JDRF) postdoctoral fellowship (3-PDF-20016-199-A-N) and a Breakthrough T1D CDA (5-CDA-2022-1176-A-N and (CDA)/3-CDA-2025-1692-A-N). FS and JL were supported by NIH/NIDDK dkNET (U24DK097771). SRL, SH and RS thank the National Science Foundation (CBET-2204681) for financial support to perform the LSPR experiments. This research was performed with the support of the Network for Pancreatic Organ Donors with Diabetes (nPOD; RRID:SCR_014641), a collaborative type 1 diabetes research project supported by Breakthrough T1D (nPOD: 5-SRA-2018-557-Q-R) and The Leona M. & Harry B. Helmsley Charitable Trust (Grants 2018PG-T1D053 and G-2108-04793). The content and views expressed are the responsibility of the authors and do not necessarily reflect the official views of nPOD. Organ Procurement Organizations (OPO) partnering with nPOD to provide research resources that are listed at . The authors acknowledge the support of the Islet and Physiology Core and the Translation Core of the Indiana Diabetes Research Center (P30DK097512). The funding sources did not play a role in the writing of the manuscript.

: CEM has served on advisory boards related to type 1 diabetes research clinical trial initiatives for Sanofi, Diogenyx and Neurodon and has a shared grant with Neurodon. CEM and RM are co-inventors on Patent (16/291,668): Extracellular Vesicle Ribonucleic Acid (RNA) Cargo as a Biomarker of Hyperglycemia and Type 1 Diabetes. CEM and FS are co-inventors on a Provisional Patent (63/285,765) Biomarker for Type 1 Diabetes (PDIA1 as a biomarker of beta cell stress). CEM has received investigator-initiated grant funding from Astellas and Lilly Pharmaceuticals and in-kind research support from BMS and Nimbus for an unrelated project. The authors declare that there are no other relationships or activities that might bias, or be perceived to bias, their work.

: FS and CEM conceived and designed the study. FS, JR, SRL, SH, RS, KY, AKL and EH performed experiments and analysed the data. PK, JL, ST, XL, JDCA and GC performed computational analyses. FS and CEM interpreted the data and wrote the manuscript. RGM made substantial contributions to the conception or design of the work, provided materials and edited the manuscript. All authors provided critical revisions and edits to the manuscript. All authors read and approved the final manuscript. CEM and FS serve as guarantors of this work, and both have verified the underlying data of this manuscript.