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We hypothesised that inflammatory stress elicits a reproducible microRNA (miRNA) program in human islets and islet-derived extracellular vesicles (EVs) that can be detected in plasma EVs to stratify diabetes risk, while also providing insight into molecular pathways linked to beta cell dysfunction.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Human islets were exposed to IL-1\u03b2+IFN-\u03b3, and small RNA-seq was performed on islets and islet-derived EVs. Differentially expressed miRNAs were validated in islets, using RT-PCR, in plasma-derived EVs from individuals with autoantibody positivity (AAb\n                      <jats:sup>+<\/jats:sup>\n                      ) or recent-onset type 1 diabetes and matched control individuals using ultrasensitive, label-free localised surface plasmon resonance (LSPR) biosensors, and in pancreatic sections from organ donors using in situ hybridisation and spatial feature analysis. Finally, beta cell-targeted in vivo inhibition of miR-155 was tested in the NOD mouse model.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Inflammatory cytokine exposure altered a restricted subset of miRNAs, identifying 20 differentially expressed miRNAs in islets and 14 in islet-derived EVs. Only two miRNAs, miR-155-5p and miR-146a-5p, were concordantly upregulated in both compartments. Machine learning prioritised an EV miRNA panel for translational validation, and custom LSPR biosensors enabled quantification of these miRNAs in plasma EVs. This plasma EV miRNA signature, consisting of miR-155-5p, miR-146a-5p, miR-30c-1-3p, miR-802 and miR-124-3p, differentiated individuals with AAb\n                      <jats:sup>+<\/jats:sup>\n                      and those with recent-onset type 1 diabetes from control individuals with good sensitivity and specificity. In pancreatic tissue, miR-155 abundance and beta cell spatial\/subcellular distribution were altered in donors with AAb\n                      <jats:sup>+<\/jats:sup>\n                      and type 1 diabetes compared with non-diabetic control individuals. Functionally, beta cell-targeted inhibition of miR-155 improved glucose tolerance and reduced insulitis in prediabetic NOD mice.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions\/interpretation<\/jats:title>\n                    <jats:p>\n                      Using an organ-based model system of inflammatory stress, we validated a signature of EV-associated miRNAs capable of stratifying type 1 diabetes risk. Furthermore, we provided new mechanistic and imaging insights into miRNA expression patterns in pancreatic sections from human organ donors with type 1 diabetes or AAb\n                      <jats:sup>+<\/jats:sup>\n                      , and we used a preclinical model of type 1 diabetes to demonstrate the potential therapeutic efficacy of targeting these miRNAs.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Data availability<\/jats:title>\n                    <jats:p>The data from small RNA sequencig of human islets and islet-derived EVs have been deposited in the GEO database (accession no. GSE160391).<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1007\/s00125-026-06720-7","type":"journal-article","created":{"date-parts":[[2026,4,21]],"date-time":"2026-04-21T12:34:34Z","timestamp":1776774874000},"page":"1975-1996","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Beta cell microRNAs function as molecular hubs of type 1 diabetes pathogenesis and as biomarkers of diabetes risk"],"prefix":"10.1007","volume":"69","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0284-0631","authenticated-orcid":false,"given":"Farooq","family":"Syed","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6957-385X","authenticated-orcid":false,"given":"Preethi","family":"Krishnan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-0741-7588","authenticated-orcid":false,"given":"Garrick","family":"Chang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9683-4592","authenticated-orcid":false,"given":"Jyoti","family":"Rana","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-9673-847X","authenticated-orcid":false,"given":"Sarah R.","family":"Langlais","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4165-8314","authenticated-orcid":false,"given":"Sumon","family":"Hati","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-3132-7604","authenticated-orcid":false,"given":"Kentaro","family":"Yamada","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8830-9349","authenticated-orcid":false,"given":"Anh K.","family":"Lam","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1693-9413","authenticated-orcid":false,"given":"Sayali","family":"Talware","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-9818-1832","authenticated-orcid":false,"given":"Jacqueline","family":"Del Carmen Aquino","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7686-062X","authenticated-orcid":false,"given":"Eli","family":"Hagedorn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4139-1127","authenticated-orcid":false,"given":"Xiaowen","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9680-1301","authenticated-orcid":false,"given":"Rajesh","family":"Sardar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4912-4560","authenticated-orcid":false,"given":"Jing","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5013-6075","authenticated-orcid":false,"given":"Raghavendra G.","family":"Mirmira","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7764-8663","authenticated-orcid":false,"given":"Carmella","family":"Evans-Molina","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,4,21]]},"reference":[{"issue":"10138","key":"6720_CR1","doi-asserted-by":"publisher","first-page":"2449","DOI":"10.1016\/S0140-6736(18)31320-5","volume":"391","author":"LA DiMeglio","year":"2018","unstructured":"DiMeglio LA, Evans-Molina C, Oram RA (2018) Type 1 diabetes. 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Anderson-Baucum (Indiana University School of Medicine, Department of Pediatrics, USA) for her assistance in editing the text of this manuscript.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Acknowledgements"}},{"value":"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.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Data availability"}},{"value":"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\n                      \n                      . 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.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Funding"}},{"value":"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.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Authors\u2019 relationships and activities"}},{"value":"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.","order":5,"name":"Ethics","group":{"name":"EthicsHeading","label":"Contribution statement"}}]}}