Temporal dynamics of serum let‐7g expression mirror the decline of residual beta‐cell function in longitudinal observation of children with type 1 diabetes

Abstract

Background/Objective In type 1 diabetes mellitus (T1DM), the introduction of insulin is typically followed by a brief remission period, with subsequent gradual decline in beta‐cell function. Several studies described altered profile of circulating miRNAs (microRNAs) in T1DM patients and proposed them as biomarkers of associated pathologic processes. Hypothesis Serum miRNA expression profile reflects residual beta‐cell function and autoimmunity in T1DM. Subjects The profiling group included patients with: GCK‐MODY (N = 13), T1DM (N = 9), and 10 healthy controls. The longitudinal group included 34 patients with samples collected at diagnosis of T1DM and first, third, and fourth to eighth year since diagnosis. Methods We reanalyzed data from the profiling group for miRNAs differentially expressed between patients with T1DM, other types of diabetes and controls. Afterward, we shortlisted miRNAs on the basis of this reanalysis and literature review and quantified their expression with quantitative polymerase chain reaction. Additionally, we measured the levels of anti‐islet antibodies (islet cell antibodies, glutamic acid decarboxylase antibodies, IA2 antibodies, and ZnT8A) and C‐peptide concentrations across the four timepoints in the longitudinal group. Results miR‐24 and let‐7g serum expression differed significantly between GCK‐MODY, controls, and HbA1c‐matched T1DM patients; P < 0.05, false discovery rate < 0.05. Autoantibodies levels showed decreasing linear trend in repeated timepoints (all P < 0.0001). C‐peptide concentration peaked during the first year after diagnosis, corresponding to remission phase, and declined in consecutive measurements. This dynamic was evidenced for let‐7g expression levels (P = 0.0058). Conclusions The pattern of let‐7g expression change during the course of diabetes mirrors that of C‐peptide levels, hinting at this microRNA's association with the residual mass of the beta cells in patients with T1DM.

MicroRNA Signatures as Future Biomarkers for Diagnosis of Diabetes States

“…This association was lost in patients with more than 5 years of T1D. Alterations in circulating miRNA profiles were also reported in another cohort, where miRNAs with elevated levels at baseline or 1 year after diagnosis were undetectable 4 to 8 years after diagnosis [27]. In fact, as depicted in Figure 1 and mentioned earlier, miRNAs in autoantibody-positive non-diabetic children were identified in independent studies involving recent-onset T1D or children with longstanding T1D (but not consistently in at least 2 studies, thus missing our threshold for inclusion in Figure 1).…”

Blood Co-Circulating Extracellular microRNAs and Immune Cell Subsets Associate with Type 1 Diabetes Severity

“…In the last five years, together with immune cell subsets, several studies have proposed blood circulating microRNAs (miRNAs) as novel promising biomarkers for metabolic and autoimmune diabetes and related complications [19][20][21][22][23][24][25][26][27][28][29][30][31]. Inside cells, these small (~22 nucleotides in length) and highly conserved non-coding RNAs regulate mRNA decay and protein translation [32].…”

Elucidate multidimensionality of type 1 diabetes mellitus heterogeneity by multifaceted information

“…The other miRNAs may play a crucial role in T1D pathogenesis. For example, serum let-7g expression reflected the decline of residual β-cell function and autoimmunity in T1D patients 37 . Eleven miRNAs (miR-100, miR-1275, miR-146a, miR-148a, miR-150, miR-181a, miR-21, miR-210, miR-24, miR-342, and miR-375) seem to be dysregulated in T1D patients 30 .…”