Small RNAs are differentially expressed in autoimmune and non-autoimmune diabetes and controls.

Objective: Diabetes is a heterogeneous disease and a precise diagnosis of diabetes subgroups is necessary to initiate proper early treatment and clinical management of the disease. Circulating small RNAs (sRNAs) are potentially diagnostic biomarkers in diseases, including diabetes. Here we aimed to examine whether profiles of circulating sRNAs differed between patients with autoimmune and non-autoimmune diabetes and non-diabetic controls. Design: This cross-sectional case-control study included participants from the third survey of the HUNT study. Methods: We performed sRNA sequencing in serum from adult-onset type 1 diabetes (n = 51), type 2 diabetes (n = 50) and latent autoimmune diabetes in adult (LADA, n = 51), as well as non-diabetic HUNT3 participants as control group (n = 51). Differential expression analysis of the sRNAs was performed in R using limma-voom. Results: We identified differences in sRNA expression between autoimmune (type 1 diabetes and LADA) and non-autoimmune diabetes (type 2 diabetes) and between patients with diabetes and non-diabetic controls. Focusing on miRNA, we identified 10 differentially expressed mature miRNAs and 30 differentially expressed miRNA variants (isomiRs). We also identified significant changes within other sRNA classes, including a pronounced downregulation of a tRNA fragment in patients with diabetes compared to non-diabetic controls. We created cross-validated sRNA signatures based on the significant sRNAs that distinguished patients with diabetes from non-diabetic controls, and autoimmune from non-autoimmune diabetes, with high specificity and sensitivity. sRNA profiles did not distinguish between type 1 diabetes and LADA. Conclusions: Circulating sRNAs are differentially expressed between patients with diabetes and non-diabetic controls and between autoimmune and non-autoimmune diabetes.