Abstract
Circulating microRNAs (miRNAs) have been implicated in several pathologies including type 1 diabetes. In the present study, we aimed to identify circulating miRNAs affected by disease duration in children with recent onset type 1 diabetes. Forty children and adolescents from the Danish Remission Phase Cohort were followed with blood samples drawn at 1, 3, 6, 12, and 60 months after diagnosis. Pancreatic autoantibodies were measured at each visit. Cytokines were measured only the first year. miRNA expression profiling was performed by RT-qPCR. The effect of disease duration was analyzed by mixed models for repeated measurements adjusted for sex and age. Eight miRNAs (hsa-miR-10b-5p, hsa-miR-17-5p, hsa-miR-30e-5p, hsa-miR-93-5p, hsa-miR-99a-5p, hsa-miR-125b-5p, hsa-miR-423-3p, and hsa-miR-497-5p) were found to significantly change in expression (adjusted p-value < 0.05) with disease progression. Three pancreatic autoantibodies, ICA, IA-2A, and GAD65A, and four cytokines, IL-4, IL-10, IL-21, and IL-22, were associated with the miRNAs at different time points. Pathway analysis revealed associations with various immune-mediated signaling pathways. Eight miRNAs that were involved in immunological pathways changed expression levels during the first five years after diagnosis and were associated with variations in cytokine and pancreatic antibodies, suggesting a possible effect on the immunological processes in the early phase of the disease.
Highlights
There is an increased interest in epigenetic mechanisms to understand disease pathogenesis and progression
Plasma samples from a subset of children and adolescents (n = 40) from this cohort collected at different time-points (1, 3, 6, 12, and 60 months) after diagnosis were subjected to miRNA profiling
The steady expression levels of the RNA spike-ins, added in the RNA isolation and complementary DNA synthesis steps, indicated that the processes of RNA extraction, reverse transcription, and qPCR were efficient, and no inhibitors were present in the samples
Summary
There is an increased interest in epigenetic mechanisms to understand disease pathogenesis and progression. The role of other pathogenic influences, such as diet, environment, viral infections, interferons, and epigenetic modifications, has been suggested to contribute to the development of autoimmune diabetes [3,4,5,6,7]. The promising features of miRNAs as biomarkers associated with insulin production, residual β-cell function, and disease complications of diabetes have been investigated [9,10,11]. The knowledge emerging on the role of epigenetic control, such as miRNAs, DNA methylation patterns, and histone modifications, indicates that these regulatory mechanisms have an important function in T1D [12,13,14]
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