BACKGROUND 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. METHODS 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. RESULTS 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; P=0.04) and impaired endothelial function: lower coronary artery flow-mediated dilation (-3.1±15.5 versus 15.9±17.3%; P<0.01) and brachial artery flow-mediated dilation (6.7±14.7 versus 26.4±15.2%; P=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. CONCLUSIONS 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. REGISTRATION URL: https://www.clinicaltrials.gov; Unique identifier: NCT02830308 and NCT01399385.

中文翻译：

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青年发病 2 型糖尿病的内皮功能障碍：临床转化研究。


背景青年发病的 2 型糖尿病 (Y-T2D) 与冠状动脉粥样硬化疾病的风险增加相关，但尚未在该人群中评估最早病理特征的时间和心脏内皮功能障碍的证据。内皮功能磁共振成像可以在没有经典危险因素（严重高血糖、高血压和高脂血症）的情况下早期直接检测内皮功能障碍。使用内皮功能磁共振成像，我们与年龄匹配的健康同龄人相比，评估了诊断为 ≤5 岁的 Y-T2D 年轻人的外周动脉和冠状动脉结构以及内皮功能。我们分离并表征了血浆来源的小细胞外囊泡，并评估了它们对健康人冠状动脉内皮细胞中炎症和信号生物标志物的影响，以验证成像结果。方法 使用 3.0T 磁共振成像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和肱动脉血流介导的扩张。用 Y-T2D 血浆来源的小细胞外囊泡处理人冠状动脉内皮细胞。通过蛋白质印迹分析测量蛋白质表达，使用氧化还原敏感探针二氢乙锭测量氧化应激，并通过4-氨基-5-甲基氨基-2',7'-二氟树脂二乙酸酯测量一氧化氮水平。结果 与健康同龄人 (n=16) 相比，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（低密度脂蛋白）胆固醇相似。 Y-T2D 的冠状动脉壁厚度更大（1.33±0.13 对比 1.22±0.13 mm；P=0。04）和内皮功能受损：冠状动脉血流介导的扩张较低（-3.1±15.5 vs 15.9±17.3%；P<0.01）和肱动脉血流介导的扩张（6.7±14.7 vs 26.4±15.2%；P= 0.001）。 Y-T2D 血浆来源的小细胞外囊泡降低了人冠状动脉内皮细胞中磷酸化内皮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，并提高了 ICAM（细胞间粘附分子）介导的炎症途径。结论 Y-T2D 患者在诊断后 5 年内，冠状动脉和肱骨内皮功能障碍明显，且没有严重高血糖或血脂异常。血浆来源的小细胞外囊泡诱导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加速是 Y-T2D 的早期特征。注册网址：https://www.clinicaltrials.gov；唯一标识符：NCT02830308 和 NCT01399385。