Abstract
This study aims to identify key miRNAs in circulation, which predict ongoing beta-cell destruction and regeneration in children with newly diagnosed Type 1 Diabetes (T1D). We compared expression level of sera miRNAs from new onset T1D children and age-matched healthy controls and related the miRNAs expression levels to beta-cell function and glycaemic control. Global miRNA sequencing analyses were performed on sera pools from two T1D cohorts (n = 275 and 129, resp.) and one control group (n = 151). We identified twelve upregulated human miRNAs in T1D patients (miR-152, miR-30a-5p, miR-181a, miR-24, miR-148a, miR-210, miR-27a, miR-29a, miR-26a, miR-27b, miR-25, miR-200a); several of these miRNAs were linked to apoptosis and beta-cell networks. Furthermore, we identified miR-25 as negatively associated with residual beta-cell function (est.: −0.12, P = 0.0037), and positively associated with glycaemic control (HbA1c) (est.: 0.11, P = 0.0035) 3 months after onset. In conclusion this study demonstrates that miR-25 might be a “tissue-specific” miRNA for glycaemic control 3 months after diagnosis in new onset T1D children and therefore supports the role of circulating miRNAs as predictive biomarkers for tissue physiopathology and potential intervention targets.
Highlights
As an autoimmune disease-type 1 diabetes (T1D) results from an immune-mediated destruction of the insulin producing beta-cells reflected by the appearance of the pancreatic autoantibodies
Comparing Serum miRNAs Expression Levels between Two Paediatric Type 1 Diabetes Cohorts and an Age-Matched Control Group. miRNA was purified from a pool of serum from each cohort, and the presence and levels of miRNAs were identified by global Solexa sequencing
We identified in total 240 different miRNAs from these cohorts; this corresponds to approx. 15% of all known human miRNAs. 47 miRNAs fulfilled our criteria for differential expression between the diabetes cohorts and the control group (>100 copy number and 2-fold altered expression)
Summary
As an autoimmune disease-type 1 diabetes (T1D) results from an immune-mediated destruction of the insulin producing beta-cells reflected by the appearance of the pancreatic autoantibodies. The destruction of these cells implies a progressive, irreversible loss of the endogenous insulin production, leading to daily treatment with exogenous insulin. The stability of serum miRNAs has been investigated under harsh conditions including boiling, low/high pH, extended storage, and freezethaw cycles without any significant difference compared to nontreated serum samples [8] Taken together these results show that serum miRNAs, are stable and that they may reflect cellular dysfunctions in various chronic diseases. Several miRNAs clearly have a role in metabolic pathways for example, miR-33a/b inhibition in nonhuman primates raises plasma HDL cholesterol and lowers triglycerides [9], and silencing of miR103/107 seems to have beneficial effects on insulin sensitivity in obese mice possibly through its target gene caveolin-1 which is a critical regulator of the insulin receptor [10]
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