Giuliana Ventriglia1,2,3, Francesca Mancarella1,2, Guido Sebastiani1,2, Dana P Cook3, Roberto Mallone4, Chantal Mathieu3, Conny Gysemans3, Francesco Dotta5,6. 1. Diabetes Unit, Department of Medicine, Surgery and Neurosciences, University of Siena, V.le Bracci, 16 - 53100, Siena, Italy. 2. Fondazione Umberto Di Mario ONLUS c/o Toscana Life Sciences, Siena, Italy. 3. Clinical and Experimental Endocrinology (CEE), Katholieke Universiteit Leuven (KU LEUVEN), Leuven, Belgium. 4. Inserm, U1016, CNRS, UMR8104, Paris Descartes University, Sorbonne Paris Cité, Cochin Institute, Paris, France. 5. Diabetes Unit, Department of Medicine, Surgery and Neurosciences, University of Siena, V.le Bracci, 16 - 53100, Siena, Italy. francesco.dotta@unisi.it. 6. Fondazione Umberto Di Mario ONLUS c/o Toscana Life Sciences, Siena, Italy. francesco.dotta@unisi.it.
Abstract
AIMS/HYPOTHESIS: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS/ INTERPRETATION: We propose that miR-409-3p may represent a new circulating biomarker of islet inflammation and type 1 diabetes severity.
AIMS/HYPOTHESIS: 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. METHODS: 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 NODmice. Moreover, we validated the findings during disease progression and remission after anti-CD3 therapy in NODmice, as well as in individuals with type 1 diabetes. RESULTS: 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 diabeticmice, 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. CONCLUSIONS/ INTERPRETATION: We propose that miR-409-3p may represent a new circulating biomarker of islet inflammation and type 1 diabetes severity.
Entities:
Keywords:
Anti-CD3 therapy; Biomarker; Inflammation; MicroRNA; Progression; Type 1 diabetes
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