Beta cell microRNAs function as molecular hubs of type 1 diabetes pathogenesis and as biomarkers of diabetes risk

AIMS/HYPOTHESIS: Clinically actionable biomarkers that accurately reflect the health status of the beta cell are needed to improve risk stratification and optimise the timing of interventions in type 1 diabetes. 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. METHODS: ) 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. RESULTS: 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. CONCLUSIONS/INTERPRETATION: , and we used a preclinical model of type 1 diabetes to demonstrate the potential therapeutic efficacy of targeting these miRNAs. DATA AVAILABILITY: The data from small RNA sequencig of human islets and islet-derived EVs have been deposited in the GEO database (accession no. GSE160391).