Plasma circulating miR-23~27~24 clusters correlate with the immunometabolic derangement and predict C-peptide loss in children with type 1 diabetes

Abstract

Aims/hypothesis We aimed to analyse the association between plasma circulating microRNAs (miRNAs) and the immunometabolic profile in children with type 1 diabetes and to identify a composite signature of miRNAs/immunometabolic factors able to predict type 1 diabetes progression. Methods Plasma samples were obtained from children at diagnosis of type 1 diabetes (n = 88) and at 12 (n = 32) and 24 (n = 30) months after disease onset and from healthy control children with similar sex and age distribution (n = 47). We quantified 60 robustly expressed plasma circulating miRNAs by quantitative RT-PCR and nine plasma immunometabolic factors with a recognised role at the interface of metabolic and immune alterations in type 1 diabetes. Based on fasting C-peptide loss over time, children with type 1 diabetes were stratified into the following groups: those who had lost >90% of C-peptide compared with diagnosis level; those who had lost <10% of C-peptide; those showing an intermediate C-peptide loss. To evaluate the modulation of plasma circulating miRNAs during the course of type 1 diabetes, logistic regression models were implemented and the correlation between miRNAs and immunometabolic factors was also assessed. Results were then validated in an independent cohort of children with recent-onset type 1 diabetes (n = 18). The prognostic value of the identified plasma signature was tested by a neural network-based model. Results Plasma circulating miR-23~27~24 clusters (miR-23a-3p, miR-23b-3p, miR-24-3p, miR-27a-3p and miR-27b-3p) were upmodulated upon type 1 diabetes progression, showed positive correlation with osteoprotegerin (OPG) and were negatively correlated with soluble CD40 ligand, resistin, myeloperoxidase and soluble TNF receptor in children with type 1 diabetes but not Electronic supplementary material The online version of this article (

miRNA-Mediated Immune Regulation in Islet Autoimmunity and Type 1 Diabetes

“…Based on the high numbers of miRNAs and their involvement in virtually all biological processes, including immune regulation, multiple studies investigated their biomarker potential in the context of islet autoimmunity and T1D (42,56,66,(85)(86)(87)(88)(89)(90)(91). In contrast to the majority of disease symptoms, biomarkers enable the objectively quantifiable characterization of a disease and its progression.…”

“…Similarly, levels of the miR23~27~24 cluster were increased during disease progression in children with T1D and correlated with osteoprotegerin abundance. Importantly, combining the levels of osteoprotegerin and the miR23~27~24 cluster in plasma of newly diagnosed T1D patients enabled the prediction of insulin secretion 12 months after diagnosis (86).…”

Does microRNA Perturbation Control the Mechanisms Linking Obesity and Diabetes? Implications for Cardiovascular Risk

“…In addition, distinct circulating miRNA profiles between subjects with obesity and T2D aroused considerable attention given their potential as biomarkers for these diseases. Indeed, strong correlations were found between some circulating miR-NAs and the development of metabolic syndrome [59], obesity [60,61], diabetes [32,62,63] and/or linked to CVD [37,64]. Nowadays, miRNAs are attractive candidates as innovative biomarkers and have been proposed to promote the progression to diabetes [29,33,62].…”

“…Indeed, strong correlations were found between some circulating miR-NAs and the development of metabolic syndrome [59], obesity [60,61], diabetes [32,62,63] and/or linked to CVD [37,64]. Nowadays, miRNAs are attractive candidates as innovative biomarkers and have been proposed to promote the progression to diabetes [29,33,62]. Furthermore, in bariatric metabolic surgery (BMS), miRs might be effective for making the decision about surgery and/or predicting weight loss after BMS [65], providing targets for future treatments.…”

Dysregulation of Circulating miR-24-3p in Children with Obesity and Its Predictive Value for Metabolic Syndrome

“…For example, Dong et al [8] identified miR-182 as a new negative regulator of fat formation and a potential therapeutic target for obesity. In addition, Garavelli et al [9] reported that miR-24-3p is upregulated in the progression of type 1 diabetes. Many investigations reported that obesity is associated with a series of metabolic syndrome, of which diabetes is one of the main complications [10].…”