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Cystic fibrosis-related diabetes (CFRD) is the most common comorbidity in cystic fibrosis (CF). Here we aimed to investigate serum microRNAs in individuals with CF and differing glucose tolerance status. Specifically, we hypothesised that the circulating microRNA profile varies depending on glucose tolerance status and can change rapidly in response to a glucose challenge in individuals with CF.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We studied a cohort of 93 adult Danish participants with CF from four glucose tolerance categories: normal glucose tolerance, indeterminate glucose tolerance, impaired glucose tolerance and CFRD. In a cross-sectional design we sampled during an OGTT at baseline, 10 min, 30 min, 60 min and 180 min. A total serum microRNA sequencing was performed using baseline and 60 min samples from 12 selected individuals, three from each category. We identified 16 candidate microRNAs, and these were further investigated in the full cohort at all OGTT timepoints using a locked nucleic acid reverse transcription quantitative PCR assay. Three microRNAs were selected for in-depth assessment including impact on insulin secretion.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>We identified four microRNAs differentially expressed at baseline (miR-34a-5p, miR-122-5p, miR-885-3 and miR-885-5p) and 12 with differential expression changes in response to glucose ingestion. Locked nucleic acid reverse transcription quantitative PCR assay validated the results of eight of these microRNAs and miR-34a-5p, miR-122-5p and miR-223-3p were selected for in-depth assessment. MiR-34a-5p and miR-122-5p were elevated at baseline in indeterminate glucose tolerance and CFRD and were associated with elevated liver damage markers. MiR-223-3p was differentially expressed during the OGTT, with different patterns depending on glucose tolerance state. Glucose-stimulated insulin secretion was increased after overexpression of miR-122-5p or miR-223-3p and cell viability was decreased after overexpression of miR-34a-5p in insulin-secreting cells.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions\/interpretation<\/jats:title>\n                    <jats:p>MiR-34a-5p and miR-122-5p show potential as biomarkers for CFRD development and liver damage. MiR-122-5p and miR-223-3p could mitigate CFRD development by increasing the secretory capacity of the beta cells while miR-34a-5p might propagate CFRD development by reducing cell viability. We propose that circulating microRNAs can serve as biomarkers for CF complications. We further advocate that circulating microRNAs can play a part in the intricate crosstalk between metabolic organs and the endocrine pancreas in health and disease.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Graphical Abstract<\/jats:title>\n                  <\/jats:sec>","DOI":"10.1007\/s00125-025-06645-7","type":"journal-article","created":{"date-parts":[[2026,1,7]],"date-time":"2026-01-07T04:40:37Z","timestamp":1767760837000},"page":"1370-1383","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Dynamic changes in circulating microRNAs during oral glucose tolerance testing support their potential as diagnostic and monitoring biomarkers in cystic fibrosis-related diabetes"],"prefix":"10.1007","volume":"69","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2383-8549","authenticated-orcid":false,"given":"Efraim","family":"Westholm","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8458-1065","authenticated-orcid":false,"given":"Alexandros","family":"Karagiannopoulos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0622-5262","authenticated-orcid":false,"given":"Bibi U.","family":"Nielsen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2893-3211","authenticated-orcid":false,"given":"James A. 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Veljanovska-Ramsay, E. Cordero Concha, and M. Arnantonaki Unit of Islet Cell Exocytosis, Lund University, and F. Serifler, Cystic Fibrosis Centre, Copenhagen, for technical assistance, and M. Svensson and F. To at the LUDC Sequencing Facility, Lund University. Thanks to R. M\u00f8ller and D. Hass at the Department of Infectious Diseases, Rigshospitalet for their help with the data collection. We acknowledge that a first manuscript of this study was included in the PhD student thesis by E. Westholm, Lund University, Westholm E (2024) Regulation of insulin secretion by local and circulating factors (ISBN: 978-91-8021-636-4) [Doctoral thesis, Lund university] Avaible from","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Acknowledgements"}},{"value":"We cannot readily disclose microRNA sequencing, RT-qPCR or standard laboratory data at an individual level as this is a small participant group with potentially identifiable individuals.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Data availability"}},{"value":"Open access funding provided by Lund University. This work was funded by the UK Cystic Fibrosis Trust (CFRD SRC-019), the Swedish Foundation for Strategic Research (IRC15-0067), the Swedish Research Council (project LE [2019-01406 and 2024-03597] and Strategic Research Area Exodiab [2009-1039]), the Swedish Diabetes Foundation (LE; DIA2022-723), Barndiabetesfonden (LE), the Albert P\u00e5hlsson Foundation (AW), Riksf\u00f6rbundet Cystisk Fibros (EW), the Royal Physiographic Society in Lund (EW) and Svenska Diabetesstiftelsen (EW). The positions of EW and BUN were supported by the UK Cystic Fibrosis Trust (CFRD SRC-019). LE is a SciLifelab group leader.","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":"EW, AK, AW and LE designed the work. EW, AK, BUN and AW performed experiments and analysed data. EW, AK, BUN, JS, AW, DF-J and LE interpreted data. EW, AW and LE drafted the manuscript. All others critically reviewed and approved the final version of the manuscript. LE is the guarantor of this work.","order":5,"name":"Ethics","group":{"name":"EthicsHeading","label":"Contribution statement"}}]}}