miR-150-5p and miR-375-3p are increased in plasma of children (<7y) with recent onset stage 3 T1D

Introduction: Pancreas histopathological evidence suggests two endotypes of type 1 diabetes (T1D): T1DE1 and T1DE2. T1DE1, with onset <7 years, features higher CD20+ B-lymphocytes infiltration in the pancreas and a rapid loss of β-cell function respect to T1DE2, with onset ≥13 years. This study aims to detect circulating miRNAs associated to these endotypes, thus facilitating their identification and a more personalized T1D immunotherapy. Methods: Small RNA seq was carried out on plasma samples collected at baseline from two cohorts (n=115/n=147) of recent onset stage 3 T1D individuals who underwent programmed follow-up visits. Patients were stratified based on their age at onset (<7/≥13y). miRNAs expression levels and clinical parameters were evaluated. Selected miRNAs were validated using ddPCR. Two publicly available datasets of non-diabetic individuals were re-analysed to verify the disease specificity of the miRNAs. Results: miR-150-5p (a B-lymphocytes activation miRNA) and miR-375-3p (islets-enriched miRNA) were significantly elevated (Padj<0.05) in T1DE1 plasma in both cohorts; these results were confirmed by ddPCR. T1DE1 individuals exhibited reduced fasting C-peptide, AUC C-peptide, and fasting c-peptide glucose ratio respect to T1DE2 (p<0.05), over the 12 months of follow-up. T1DE1 individuals also displayed higher IAA titres at baseline. Notably, both miRNAs did not correlate with age, using the same stratification, in publicly available datasets of non-diabetic individuals, thus excluding any association with age. Conclusions: Plasma circulating levels of miR-150-5p and miR-375-3p are selectively increased in T1DE1. This phenomenon was not observed in non-diabetic individuals thus not simply correlated with age but rather a mirroring of the histopathological context in T1D. These miRNAs could be potentially used to categorize individuals with T1DE1 and shed light onto additional mechanisms underlying the heterogeneity of T1D.