miR-409-3p is reduced in plasma and islet immune infiltrates of NOD diabetic mice and is differentially expressed in people with type 1 diabetes
MicroRNAs (miRNAs) are a novel class of potential biomarkers emerging in many diseases, including type 1 diabetes. Here, we aim to analyse a panel of circulating miRNAs in non-obese diabetic (NOD) mice and individuals with type 1 diabetes.
We adopted standardised methodologies for extracting miRNAs from small sample volumes to evaluate a profiling panel of mature miRNAs in paired plasma and laser-captured microdissected immune-infiltrated islets of recently diabetic and normoglycaemic NOD mice. Moreover, we validated the findings during disease progression and remission after anti-CD3 therapy in NOD mice, as well as in individuals with type 1 diabetes.
Plasma levels of five miRNAs were downregulated in diabetic vs normoglycaemic mice. Of those, miR-409-3p was also downregulated in situ in the immune islet infiltrates of diabetic mice, suggesting an association with disease pathogenesis. Target-prediction tools linked miR-409-3p to immune- and metabolism-related signalling molecules. In situ miR-409-3p expression correlated with insulitis severity, and CD8+ central memory T cells were found to be enriched in miR-409-3p. Plasma miR-409-3p levels gradually decreased during diabetes development and improved with disease remission after anti-CD3 antibody therapy. Finally, plasma miR-409-3p levels were lower in people recently diagnosed with type 1 diabetes compared with a non-diabetic control group, and levels were inversely correlated with HbA1c levels.
We propose that miR-409-3p may represent a new circulating biomarker of islet inflammation and type 1 diabetes severity.
KeywordsAnti-CD3 therapy Biomarker Inflammation MicroRNA Progression Type 1 diabetes
Standard operating procedure
Central memory T cell
Effector memory T cell
We would like to thank L. Dusaer and J. Laureys (Laboratory for Clinical and Experimental Endocrinology, KU Leuven, Belgium) for their technical assistance.
GV, FM and GS contributed to all aspects of this manuscript, including data acquisition and analysis and drafting and editing the manuscript. DPC, RM and CM were responsible for conception and experimental design, interpretation of the data and editing of the manuscript. FD and CG contributed to conception, experimental design and drafting the manuscript, provided final approval of the submitted manuscript and are guarantors of this work. All authors gave final approval of the version to be published.
This project has received funding from the Innovative Medicines Initiative 2 (IMI2) Joint Undertaking under grant agreement no. 115797 (INNODIA). This joint undertaking receives support from the Union’s Horizon 2020 research and innovation programme and EFPIA, JDRF and the Leona M. and Harry B. Helmsley Charitable Trust. FD is supported by the Italian Ministry of Research (grant no. 2015373Z39_007) and by Fondazione Roma. DPC is a PhD fellow of the FWO-Vlaanderen (Belgium) (11Y6716N).
Duality of interest
The authors declare that there is no duality of interest associated with this manuscript.
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