At present there are no reliable assays measuring on-going beta-cell destruction systemically that can be used as surrogate biomarkers for predicting T1D development or to monitor the efficacy of therapeutic strategies to treat the disease. MicroRNAs (miRNAs) are small non-coding RNAs involved in regulation of gene expression. In beta-cells, miR-375 is highly expressed and is essential for their function. The aim of this study was to investigate whether serum levels of miR-375 can represent a reliable marker of on-going beta-cell damage.
We have established qPCR assay to measure miRNA-375 in serum of BB rats (model for T1D), pre-diabetic human subjects and LADA patients treated with GAD65-alum immunotherapy. MiR-375 levels were measured in relation to reference spike-in miRNAs using TaqMan assays, normalized against the first sample taken in each particular individual and correlated to metabolic and immunological data available from the different groups.
Analysis of serum level of miR-375 in BB rats at different time prior to diabetes development showed extensive fluctuation. However, an increase of miR-375 could be observed close to diabetes development and was followed by a decline at onset. The “baseline” expression level of miR-375 in human serum samples seemed also to be very variable between individuals and within the same individual in separate samples taken within a short time period. Nevertheless, miR-375 negatively correlated to stimulated C-peptide levels in pre-diabetic children. Furthermore, preliminarily, analysis of miR-375 levels in LADA patient during GAD65 immunotherapy did not seem to correlate with the clinical outcome of the trial.
MiR-375 appears not to be a reliable serum biomarker of beta-cell destruction. Perhaps the variations observed in this study could suggest that the process of beta-cell destruction might not be a linear process, but instead reflecting a remitting/relapsing process. Future studies will define whether this marker can be used longitudinally in individual subjects.