Dysregulation of the miR-34a/SIRT1 Regulatory Network Is Associated with Cardiometabolic Risk in Type 2 Diabetes
TL;DR
Cardiometabolic risk in T2DM is associated with a coordinated molecular signature characterized by miR-34a upregulation, SIRT1 suppression, systemic inflammation, oxidative stress, and endothelial dysfunction, suggesting that integrated biomarker profiling may complement conventional risk assessment and support future precision cardiometric strategies.
Abstract
Background: Although conventional cardiovascular risk scores are widely used, they do not fully capture the molecular mechanisms underlying vascular injury in type 2 diabetes mellitus (T2DM). This study investigated the association between the miR-34a/SIRT1 regulatory axis and cardiometabolic risk in T2DM by integrating biomarkers of inflammation, oxidative stress, and endothelial dysfunction. Methods: A cross-sectional study included 128 adults (96 with T2DM and 32 non-diabetic controls). Cardiometabolic risk was stratified using the Framingham Risk Score. Circulating miR-34a expression was quantified by RT-qPCR, whereas SIRT1 and biomarkers of inflammation (IL-6, TNF-α, and hs-CRP), oxidative stress (MDA and TAC), and endothelial dysfunction (VCAM-1 and ICAM-1) were measured using ELISA or standardized biochemical assays. Multivariate regression and receiver operating characteristic (ROC) analyses were performed. Results: Compared with medium-risk patients, individuals classified as high risk exhibited longer diabetes duration, higher body mass index, blood pressure, fasting glucose, and HbA1c levels (all p < 0.05), together with increased circulating miR-34a, inflammatory, oxidative stress, and endothelial dysfunction biomarkers, whereas SIRT1 and total antioxidant capacity were significantly reduced (all p < 0.001). These molecular alterations remained independently associated with risk after adjustment for age, sex, body mass index, smoking status, physical activity, dyslipidemia, HbA1c, and medication use. The combined biomarker model integrating miR-34a, SIRT1, hs-CRP, MDA, and VCAM-1 demonstrated excellent discriminatory performance for identifying high-risk individuals (AUC = 0.92; sensitivity = 86.4%; specificity = 85.5%). Conclusions: Cardiometabolic risk in T2DM is associated with a coordinated molecular signature characterized by miR-34a upregulation, SIRT1 suppression, systemic inflammation, oxidative stress, and endothelial dysfunction. These findings suggest that integrated biomarker profiling may complement conventional risk assessment and support future precision cardiometabolic strategies.