Molecular Mechanisms of Vascular Oxidative Stress in the Insulin Resistant State

胰岛素抵抗综合征(内脏脂肪综合征，综合征X)是由目前的生活方式引起的多种动脉粥样硬化危险因素在单个患者体内积聚的特征，是糖尿病和动脉粥样硬化性疾病的最主要原因。然而，该综合征的发病机制和遗传背景以及血管功能障碍的分子机制尚不清楚。在肥胖、高血压和糖尿病中发现的胰岛素抵抗状态下，内皮依赖性血管扩张受到干扰的原因也不清楚。因此，本研究对高果糖饮食诱导的大鼠胰岛素抵抗状态下血管功能障碍的分子机制进行了研究。1)胰岛素抵抗状态下内皮细胞释放氧自由基。(2)内皮型一氧化氮合酶(ENOS)活性降低和NAD(P)H氧化酶活性降低是导致这种异常的主要原因。3)eNOS活性降低的主要原因与四氢生物蝶呤(BH4)合成障碍和BH2的显著产生有关。4)与内源性高胰岛素血症不同，外源性高胰岛素血症不是血管氧化应激的原因。5)胰岛素抵抗患者的乙酰胆碱依赖性血管扩张与血浆BH4/BH2比值及血管氧化应激有关。6)高果糖诱导的胰岛素抵抗综合征与甘油三酯生物合成转录因子SREBP-I基因表达增加和脂肪酸氧化转录因子PPAR-α基因表达降低有关。

Insulin resistance syndrome (visceral fat syndrome, syndrome X) is characterized with accumulation of multiple atherogenic risk factors in single patient, which is induced by the present life style and the most significant cause of diabetes mellitus and atherosclerotic diseases. However, the pathogenetic mechanisms and genetic background as well as molecular mechanisms of vascular dysfunction in the syndrome are unknown. It is also unclear why endothelium-dependent vascular dilatation is disturbed in the insulin resistant state found in obesity, hypertension and diabetes mellitus. Thus, the present study studied molecular mechanisms of vascular dysfunction in the insulin resistance state of rats induced by high fructose diet. 1) Oxygenfree radicals were released from endothelial cells in the insulin resistance state. 2) The abnormality was induced by decreased activity of endothelial NO synthase (eNOS) and activation of NAD(P)H oxidase. 3) The main cause of decreased eNOS activity is associated with impairment of synthesis of tetrahydrobiopterine (BH4) and marked production of BH2. 4) In contrast to endogenous hyperinsulinemia, exogenous hyperinsulinemia was not a cause of vascular oxidative stress. 5) Acetylcholine-dependent vascular dilatation found in patients with insulin resistance was associated with plasma BH4/BH2 ratio as well as vascular oxidative stress. Finally, 6) High fructose-induced insulin resistance syndrome was associated with increased gene expression of SREBP-I, a transcription factor for biosynthesis of triglyceride, and decreased expression of PPAR-alpha, a transcription factor for fatty acid oxidation.