Circulating microRNA-21 is an early predictor of ROS-mediated damage in subjects with high risk of developing diabetes and in drug-naïve T2D

Abstract

Background Impaired glucose tolerance (IGT) is a risk factor for the development of diabetes and related complications that ensue. Early identification of at-risk individuals might be beneficial to reduce or delay the progression of diabetes and its related complications. Recently, microRNAs emerged as potential biomarkers of diseases. The aim of the present study was to evaluate microRNA-21 as a potential biomarker for the risk of developing diabetes in adults with IGT and to investigate its downstream effects as the generation of reactive oxygen species (ROS), the induction of manganese-superoxide dismutase-2 (SOD2), and the circulating levels of 4-HNE (4-hydroxynonenal). Methods To evaluate the prognostic and predictive values of plasmatic microRNA-21 in identifying metabolic derangements, we tested a selected cohort (n = 115) of subjects enrolled in the DIAPASON Study, whom were selected on ADA criteria for 2hPG. Statistical analysis was performed using ANOVA or the Kruskal–Wallis test as appropriate. ROC curves were drawn for diagnostic accuracy of the tests; positive and negative predictive values were performed, and Youden’s index was used to seek the cut-off optimum truncation point. ROS, SOD2 and 4-HNE were also evaluated. Results We observed significant upregulation of microRNA-21 in IGT and in T2D subjects, and microRNA-21 was positively correlated with glycaemic parameters. Diagnostic performance of microRNA-21 was high and accurate. We detected significant overproduction of ROS by electron paramagnetic resonance (EPR), significant accumulation of the lipid peroxidation marker 4-HNE, and defective SOD2 antioxidant response in IGT and newly diagnosed, drug-naïve T2D subjects. In addition, ROC curves demonstrated the diagnostic accuracy of markers used. Conclusions our data demonstrate that microRNA-21 is associated with prediabetic status and exhibits predictive value for early detection of glucose imbalances. These data could provide novel clues for miR-based biomarkers to evaluate diabetes. Electronic supplementary material The online version of this article (10.1186/s12933-019-0824-2) contains supplementary material, which is available to authorized users.

Targeting microRNAs as a Therapeutic Strategy to Reduce Oxidative Stress in Diabetes

“…Furthermore, in IGT and T2D subjects there was a significant overproduction of ROS, detected by Electron Paramagnetic Resonance (EPR), an accumulation of lipid peroxidation marker 4-HNE (4-Hydroxynonemal) and defective SOD2 antioxidant response. These results suggest that miR-21 is an early predictor of ROS damage prior to the onset of diabetes and could represent a promising biomarker and a therapeutic target as well [72].…”

“…MiR-21 has also been demonstrated to be hyperexpressed in HUVEC (Human Umbelical Vein Endothelial Cells) cells uponconstant or oscillating high glucose exposure, and its upregulation is able to inhibit expression and function of several specific target genes such as KRIT1(Krev/Rap1 Interaction Trapped-1), NRF2 (Nuclear Factor erythroid Related Factor 2), and SOD2 (Superoxide Dismutase 2) (which have anti-oxidant functions), thus generating mitochondrial dysfunction. Circulating miR-21 was also found upregulated in T1D, T2D, and in IGT patients, in which increased ROS production has been observed [72]. Moreover, as antagomiR-21 conveyed with different NPs resulted in efficient uptake by target tissue, a miR-21 nano-based drug could also be promising for diabetes therapies targeting oxidative stress.…”

The link between diabetes and atherosclerosis

“…miRNAs have been proposed as surrogate markers of the prediabetes state, 38,39 diabetes and cardiovascular complications, 40 being detectable in a stable form in blood circulation and biological fluids. Many studies have revised the involvement of miRNAs in the vascular complications of diabetes 29 as well as in atherosclerosis, 41 determining a branch of investigation deserving special attention due to potential diagnostic and therapeutic implications.…”

The Role of microRNAs in Metabolic Syndrome-Related Oxidative Stress

“…Interestingly, other studies by La Sala et al confirmed that elevated levels of miR-21 are associated with increased abundance of ROS and reduced SOD2 antioxidant defense. Moreover, the authors suggested that miR-21 might serve as a predictive parameter for the early detection of glucose imbalances in prediabetic patients [224]. There is also a strong link between obesity and miR-21.…”