National Institute of Diabetes and Digestive and Kidney Diseases, Biomedical Medical and Imaging Branch (K.Z.A., J.E., N.S., J.M., L.B., W.Q., A.M.G.), National Institutes of Health, Bethesda, MD.
Diabetes Endocrinology and Obesity Branch (K.B., A.V., S.D., A.C., M.S., L.M., S.T.C.), National Institutes of Health, Bethesda, MD.
Circ Res. 2024 Aug 30;135(6):639-650. doi: 10.1161/CIRCRESAHA.124.324272. Epub 2024 Jul 29.
Youth-onset type 2 diabetes (Y-T2D) is associated with increased risk for coronary atherosclerotic disease, but the timing of the earliest pathological features and evidence of cardiac endothelial dysfunction have not been evaluated in this population. Endothelial function magnetic resonance imaging may detect early and direct endothelial dysfunction in the absence of classical risk factors (severe hyperglycemia, hypertension, and hyperlipidemia). Using endothelial function magnetic resonance imaging, we evaluated peripheral and coronary artery structure and endothelial function in young adults with Y-T2D diagnosed ≤5 years compared with age-matched healthy peers. We isolated and characterized plasma-derived small extracellular vesicles and evaluated their effects on inflammatory and signaling biomarkers in healthy human coronary artery endothelial cells to validate the imaging findings.
Right coronary wall thickness, coronary artery flow-mediated dilation, and brachial artery flow-mediated dilation were measured at baseline and during isometric handgrip exercise using a 3.0T magnetic resonance imaging. Human coronary artery endothelial cells were treated with Y-T2D plasma-derived small extracellular vesicles. Protein expression was measured by Western blot analysis, oxidative stress was measured using the redox-sensitive probe dihydroethidium, and nitric oxide levels were measured by 4-amino-5-methylamino-2',7'-difluororescein diacetate.
Y-T2D (n=20) had higher hemoglobin A1c and high-sensitivity C-reactive protein, but similar total and LDL (low-density lipoprotein)-cholesterol compared with healthy peers (n=16). Y-T2D had greater coronary wall thickness (1.33±0.13 versus 1.22±0.13 mm; =0.04) and impaired endothelial function: lower coronary artery flow-mediated dilation (-3.1±15.5 versus 15.9±17.3%; <0.01) and brachial artery flow-mediated dilation (6.7±14.7 versus 26.4±15.2%; =0.001). Y-T2D plasma-derived small extracellular vesicles reduced phosphorylated endothelial nitric oxide synthase expression and nitric oxide levels, increased reactive oxygen species production, and elevated ICAM (intercellular adhesion molecule)-mediated inflammatory pathways in human coronary artery endothelial cells.
Coronary and brachial endothelial dysfunction was evident in Y-T2D who were within 5 years of diagnosis and did not have severe hyperglycemia or dyslipidemia. Plasma-derived small extracellular vesicles induced markers of endothelial dysfunction, which corroborated accelerated subclinical coronary atherosclerosis as an early feature in Y-T2D.
URL: https://www.clinicaltrials.gov; Unique identifier: NCT02830308 and NCT01399385.
青年起病的 2 型糖尿病（Y-T2D）与冠状动脉粥样硬化疾病的风险增加有关，但尚未在该人群中评估最早的病理学特征和心脏内皮功能障碍的证据。内皮功能磁共振成像（magnetic resonance imaging，MRI）可在无经典危险因素（严重高血糖、高血压和高脂血症）的情况下直接检测早期内皮功能障碍。我们使用内皮功能 MRI 评估了≤5 年内诊断为 Y-T2D 的年轻成年人与年龄匹配的健康同龄人的外周和冠状动脉结构以及内皮功能。我们分离并鉴定了源自血浆的小细胞外囊泡，并评估了它们对健康人冠状动脉内皮细胞中炎症和信号标志物的影响，以验证成像结果。
使用 3.0T MRI 在基线和等长握力运动期间测量右冠状动脉壁厚度、冠状动脉血流介导的扩张（flow-mediated dilation，FMD）和肱动脉血流介导的扩张。用源自 Y-T2D 的小细胞外囊泡处理人冠状动脉内皮细胞。通过 Western blot 分析测量蛋白表达，通过还原敏感探针二氢乙啶测量氧化应激，通过 4-氨基-5-甲基氨基-2'，7'-二氟荧光素二乙酸酯测量一氧化氮水平。
Y-T2D（n=20）的血红蛋白 A1c 和高敏 C 反应蛋白较高，但总胆固醇和 LDL（low-density lipoprotein）-胆固醇与健康同龄人（n=16）相似。Y-T2D 有更大的冠状动脉壁厚度（1.33±0.13 毫米 vs. 1.22±0.13 毫米；=0.04）和受损的内皮功能：更低的冠状动脉 FMD（-3.1±15.5 毫米 vs. 15.9±17.3 毫米；<0.01）和肱动脉 FMD（6.7±14.7 毫米 vs. 26.4±15.2 毫米；=0.001）。源自 Y-T2D 的小细胞外囊泡降低了磷酸化内皮型一氧化氮合酶的表达和一氧化氮水平，增加了活性氧的产生，并升高了人冠状动脉内皮细胞中细胞间黏附分子（ICAM）介导的炎症途径。
在诊断后 5 年内的 Y-T2D 中，就已经出现了冠状动脉和肱动脉内皮功能障碍，且不存在严重高血糖或血脂异常。源自血浆的小细胞外囊泡诱导了内皮功能障碍的标志物，这证实了亚临床冠状动脉粥样硬化作为 Y-T2D 的早期特征加速进展。
网址：https://www.clinicaltrials.gov；唯一标识符：NCT02830308 和 NCT01399385。
