miRNA-375 a Sensor of Glucotoxicity Is Altered in the Serum of Children with Newly Diagnosed Type 1 Diabetes

Abstract

Background. The use of miRNAs as biomarkers for Type 1 Diabetes (T1D) risk is attractive as T1D is usually diagnosed in front of acute symptoms. As miR-375 is highly expressed in the endocrine pancreas, we postulated that its circulating level might reflect beta cell alterations and might be altered in the blood of T1D patients recently diagnosed. Methods. Sera were obtained from 22 T1D children at onset of the disease, before subcutaneous insulin treatment, and from 10 nondiabetic pediatric controls. MiR-375 seric level was quantified by stem-loop RT-PCR-based assay. MiRNAs regulations in isolated human islets in response to high glucose concentrations were determined by TaqMan Low-Density Array. Results. The abundance of miR-375, among the 410 miRNAs detected in human islets, mirrored its well-established role in rodent islet biology. Upregulated miRNAs targeted genes involved in islet homeostasis and regulation of beta cell mass. Downregulated miRNAs, including miR-375, were involved in pancreas secretion and protein turnover. Seric level of miR-375 was lower in T1D children versus age-matched controls, without any correlations with HbA1c, glycaemia, and number of autoantibodies. Conclusion. Altered circulating level of miR-375 at onset of T1D might be a general biomarker of metabolic alterations and inflammation associated with the disease.

Profiling of circulating microRNAs in children with recent onset of type 1 diabetes

“…The control group was chosen from children who visited the British Columbia Children's Hospital endocrinology division and were found to be healthy, with normal variations in growth and puberty and no evidence of either autoimmune disease or diabetes following comprehensive outpatient assessment. We first sought to investigate whether miR-375, a miRNA that we reported to be increased in the circulation of prediabetic mice (6) and a miRNA reported to be lower in the sera of children with newly diagnosed T1D (13), was altered in the sera of children with recent onset of diabetes. Measurement of miR-375 levels with qRT-PCR indicated that miR-375 was not significantly different in the sera of children with recent onset of diabetes ( Figure 1A), prompting us to perform an unbiased miR-NA screen.…”

Association of serum microRNAs with islet autoimmunity, disease progression and metabolic impairment in relatives at risk of type 1 diabetes

“…In the setting of type 1 diabetes, serum levels of miR-375, an islet cell miRNA, reflect beta cell destruction in mice [21] and islet transplant recipients [22], although this may be limited to acute damage and miR-375 is not exclusively of pancreatic beta cell origin. A few studies have reported perturbed serum miRNA levels in individuals with newly diagnosed type 1 diabetes compared with healthy participants [23, 24]. …”

miRNAs: novel regulators of autoimmunity-mediated pancreatic β-cell destruction in type 1 diabetes

“…109 Interestingly, another study showed that the serum miR-375 level was lower in children with newly diagnosed T1D than in the age-matched control individuals. 110 Therefore, we speculated that a sudden increase in circulating miR-375 prior to T1D onset was likely to result from a pool of miR-375 immediately released during the process of β-cell death; in turn, this level will decrease after T1D onset, which may reflect β-cell residual functions.…”