Abstract 4372728: Adiposomal microRNAs Mediate Vascular Dysfunction in Obesity-Associated Type 2 Diabetes

Abstract

Background: Adipose tissue-derived extracellular vesicles (adiposomes) are key mediators of intercellular communication and play a critical role in metabolic disease progression, including diabetes. These vesicles carry bioactive molecules such as microRNAs (miRNAs) that regulate inflammation, vascular function, and metabolism. Our previous work showed that adiposomes from obese diabetic individuals impair endothelial function, promote vascular remodeling, and reduce microvascular flow-induced dilation, contributing to cardiovascular disease (CVD). However, the adiposomal cargo underlying these effects remains unknown. This study examines adiposomal miRNA profiles as potential contributors to the elevated CVD risk in obese diabetic patients. Methods: Adipose tissue samples were collected from obese individuals and classified into non-diabetic (n=17), pre-diabetic (n=10), and diabetic (n=14) groups based on fasting glucose and hemoglobin A1C. Adiposomes were isolated and characterized using nanoparticle tracking analysis and electron microscopy. miRNAs were extracted, sequenced, and analyzed bioinformatically. Correlations were assessed between miRNA expression and cardiometabolic measures, including (1) body fat and lean mass (DEXA), (2) glucose and lipid profiles, (3) brachial artery flow-mediated dilation, (4) flow-induced dilation in isolated arterioles, (5) echocardiographic cardiac function, and (6) inflammatory and endothelial biomarkers (IL-6, CRP, nitric oxide). Results: Diabetic and pre-diabetic groups exhibited distinct adiposomal miRNA profiles compared to non-diabetic controls. Top differentially expressed miRNAs included miR-361, miR-21, miR-130a, miR-181a, miR-10a, miR-126, miR-30e, miR-92b, miR-125a, and miR-221. Many of these miRNAs are implicated in hypertension, atherosclerosis, and cardiac hypertrophy. miR-221, miR-361, and miR-21 were upregulated 3–4 fold in diabetic subjects and significantly correlated with HbA1C and HOMA-IR. Regression analyses revealed associations between these miRNAs and BMI, fat percentage, impaired vascular dilation, and elevated LDL. Conclusion: Dysregulated adiposomal miRNA cargo may contribute to cardiometabolic dysfunction in obesity-associated diabetes. These findings highlight adiposomal miRNAs as potential mechanistic links and biomarkers for diabetes-related cardiovascular risk. Ongoing studies are investigating the downstream pathways regulated by these miRNAs.