The miR-182-5p/NRF2 Axis and Inflammation Across Glycemic States in Type 2 Diabetes Mellitus: An Integrated Clinical and Molecular Study

Abstract

Background: Type 2 Diabetes Mellitus (T2DM) is becoming a worldwide health condition. High blood glucose for a prolonged period of time increases oxidative stress. Ferroptosis is a cell death mediated by iron. May be associated with iron overload, oxidative stress and tissue damage in diabetes. MicroRNA miR-182-5p has the ability to inhibit antioxidant regulator NRF2. Objectives: This study quantified the expression of miR-182-5p and NRF2 gene. It also quantified serum ferritin, interleukin-6 (IL-6) and tumour necrosis factor alpha (TNF-α). Their goal was to evaluate the changes of these markers with worsening glycemic control. Materials and methods: 180 adults classified into 3 equal groups. The groups comprised healthy controls, newly diagnosed T2DM, and poorly controlled T2DM. The expression of the genes was determined by the RT-qPCR method and calculated using the 2-ΔΔCt method. ANOVA, Tukey HSD, correlation, ROC and regression analysis was used to analyze the data. Results: Patients with newly diagnosed T2DM and poorly controlled T2DM showed a progressive rise in miR-182-5p expression, ferritin, IL-6 and TNF-α levels with a significant decrease in NRF2 expression (all p < 0.001). HbA1c was well correlated with all biomarkers with an inverse correlation with NRF2. An inverse relationship between the expression of miR-182-5p and NRF2 was linked to poor glycemic status. Receiver operating characteristic analysis revealed good diagnostic values for miR-182-5p (AUC = 0.991), TNF-α (0.989), IL-6 (0.980), NRF2 (0.979), and ferritin (0.973). The independent predictive value of miR-182-5p, ferritin, IL-6, and insulin for HbA1c was established by multivariable analysis; combined biomarker analysis was able to accurately discriminate poorly controlled from newly diagnosed T2DM. Conclusions: A progressive dysregulation of miR-182-5p/NRF2 axis is closely linked to the deterioration of glycemic control, inflammation and iron metabolism in type 2 diabetes mellitus. These biomarkers could be useful for disease stratification and as potential targets for future therapies and risk assessment.