Circulating miR-375 as a Biomarker of β-Cell Death and Diabetes in Mice

Abstract

Type 1 diabetes is a progressive autoimmune disease that is largely silent in its initial stages. Yet, sensitive methods for detection of β-cell death and prediction and prevention of diabetes are lacking. Micro-RNAs (miRNAs) have been found at high concentrations in body fluids. Here in this study we sought to determine whether an islet enriched miRNA, miR-375, is a suitable blood marker to detect β-cell death and predict diabetes in mice. We measured miR-375 levels by quantitative RT-PCR in plasma samples of streptozotocin (STZ)-treated C57BL/6 mice and nonobese diabetic (NOD) mice. We also measured miR-375 levels in media samples of cytokine- or STZ-treated islets in the presence or absence of cell-death inhibitors. High-dose STZ administration dramatically increased circulating miR-375 levels, prior to the onset of hyperglycemia. Similarly, in the NOD mouse model of autoimmune diabetes, circulating miR-375 levels were significantly increased 2 weeks before diabetes onset. Moreover, cytokine- and STZ-induced cell death in isolated mouse islets produced a striking increase in extracellular miR-375 levels, which was reduced by cell death inhibitors. These data suggest that circulating miR-375 can be used as a marker of β-cell death and potential predictor of diabetes.

Application of microRNAs in diabetes mellitus

“…Potential miRNA biomarkers in T1D Circulating miR-375 levels have been shown to be a biomarker of b-cell death, and were significantly increased at 2 weeks before onset of diabetes in NOD mice, a model of autoimmune diabetes (Erener et al 2013). Elevated expression of miR-326 was found in peripheral blood lymphocytes of T1D patients with ongoing islet autoimmunity (Sebastiani et al 2011).…”

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

“…Their differential expression within tissues has been detected in various disorders, including cancer, cardiovascular disease, and T2D (5). Surprisingly perhaps, stable miRNAs can be found at high concentrations in body fluids and can be readily detected and measured by quantitative PCR (qPCR) using sequence-specific primers (6), making them potentially useful as biomarkers. In particular, circulating miRNA patterns are currently being investigated as potential biomarkers for metabolic diseases and cancers as a means of providing noninvasive, rapid, sensitive, and specific diagnostic measures.…”

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

“…Circulating miR-375 is markedly augmented in STZ-injected mice prior to the occurrence of hyperglycemia or in NOD mice 2 weeks before the onset of diabetes, whereas its levels are decreased 1 week post 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.…”