ESPE Yearbook of Paediatric Endocrinology

Brief Summary: Circulating microRNAs (miRNA) were measured using multiplatform sequencing in longitudinal samples from 262 individuals with newly diagnosed type 1 diabetes (T1D) enrolled in the INNODIA Natural History Study. A set of miRNAs located within the T1D susceptibility chromosomal locus 14q32 distinguished 2 groups of T1D: those with higher miRNA expression showed better glycemic outcomes and immunomics profile.

MicroRNAs (miRNAs) are a class of small noncoding RNAs with critical roles in regulating gene expression. Previous studies suggested a role of miRNA in T1D pathogenesis by mediating function/dysfunction of pancreatic β-cells and immune cells (1). Certain miRNAs have consistently been associated with T1D onset (i.e., miR-24-3p,36–43 miR-146a-5p and miR-375-3p) or progression (i.e., miR-375-3p and miR-24-3p). Other associations were inconsistent, possibly due to variability in miRNA measurements, or differences in study populations, sample collection, or analytical platforms.

This study used 2 different sequencing platforms to measure circulating expression of miRNAs in individuals with recently diagnosed T1D, within the larger INNODIA Natural History Study cohort (2). It identified a set of miRNAs, which defined two clusters of individuals, A and B. Three microRNAs, miR-409-3p, miR-127-3p, and miR-382-5p, which are known to be located within the T1D susceptibility chromosomal locus 14q32 (3), distinguished the two groups, with higher expression in cluster B. The identified miRNAs have several regulatory functions, including modulation of glucose metabolism. Individuals in cluster B showed better glycemic outcomes over time and higher frequency of memory and exhausted T cells.

Although the sample size was not large and replication is needed, the inclusion of a validation cohort and a well-standardized protocol for sample collection and analysis strengthens the findings (4).

These findings support the use of miR-409-3p, miR-382-5p, and/or miR-127-3p as potential biomarkers to stratify individuals with newly diagnosed T1D into two distinct subgroups, with different metabolic and immune phenotypes and potentially differing response to immunotherapies.

References: 1. Margaritis K, Margioula-Siarkou G, Giza S, Kotanidou EP, Tsinopoulou VR, Christoforidis A, Galli-Tsinopoulou A. Micro-RNA Implications in Type-1 Diabetes Mellitus: A Review of Literature. Int J Mol Sci. 2021;22(22):12165.2. Marcovecchio ML, Hendriks AEJ, Delfin C, Battelino T, Danne T, Evans ML, et al. The INNODIA Type 1 Diabetes Natural History Study: a European cohort of newly diagnosed children, adolescents and adults. Diabetologia. 2024;67(6):995-1008.3. Wallace C, Smyth DJ, Maisuria-Armer M, Walker NM, Todd JA, Clayton DG. The imprinted DLK1-MEG3 gene region on chromosome 14q32.2 alters susceptibility to type 1 diabetes. Nature Genetics. 2010;42(1):68-71.4. Grieco GE, Sebastiani G, Fignani D, Brusco N, Nigi L, Formichi C, et al. Protocol to analyze circulating small non-coding RNAs by high-throughput RNA sequencing from human plasma samples. STAR Protoc. 2021;2(3):100606.