Targeting NADPH oxidase to enhance nitric oxide bioavailability in insulin resistance

患有2型糖尿病（T2DM）和肥胖（T2DM发展的主要风险因素）的人数已达到全球流行病的比例。80%的T2DM患者将死于心血管动脉粥样硬化（动脉硬化）并发症，导致死亡风险增加，相当于15岁的衰老。我们最近证明，尽管使用当代二级预防治疗的T2DM患者，持续急性心肌梗死（AMI）或？心脏病发作？没有从类似的非T2DM患者中观察到的死亡率改善中获益。2型糖尿病的一个中心特征是对胰岛素作用的抵抗，胰岛素是一种释放出来降低血糖的激素，这个过程被称为胰岛素抵抗。胰岛素抵抗已在T2DM患者的许多组织中得到证实。除了降低葡萄糖，胰岛素被认为是刺激释放的物质从血管壁称为一氧化氮（NO）。NO保护动脉免受动脉粥样硬化。最近发现，T2DM患者的NO减少。因此，这可能有助于T2DM患者中观察到的动脉粥样硬化加速。我们已经进行了研究，证明了一种新的机制，胰岛素抵抗可能会减少NO的行动。我们已经证明，血管壁中的一种酶（NADPH氧化酶）产生一种破坏性气体，清除NO，在胰岛素抵抗中变得过度活跃。我们计划在不同的胰岛素抵抗模型中研究降低NADPH氧化酶活性的效果。这项研究的结果可能会指导我们寻找新的治疗方法来预防T2DM患者的AMI。

The number of people with type 2 diabetes (T2DM) and obesity (the major risk factor for the development of T2DM) has reached epidemic proportions worldwide. 80% of people with T2DM will die from the complications of cardiovascular atherosclerosis (furring of the arteries) resulting in an increased risk of death equivalent to 15 years of aging. We recently demonstrated that despite the use of contemporary secondary prevention therapies patients with T2DM, sustaining an acute myocardial infarction (AMI) or ?heart attack? have not benefited from the improvement in mortality seen in similar patients without T2DM. A central feature of T2DM is resistance to the actions of insulin the hormone that is released to reduce blood sugar this process is known as insulin resistance. Insulin resistance has been demonstrated in many tissues of patients with T2DM. In addition to lowering glucose, insulin is thought to stimulate the release of a substance from the blood vessel wall known as nitric oxide (NO). NO protects the artery against atherosclerosis. It has recently emerged that patients with T2DM have reduced NO. This may therefore contribute to the accelerated atherosclerosis seen in patients with T2DM. We have performed studies that demonstrate a novel mechanism by which insulin resistance may reduce NO actions. We have shown that an enzyme in the blood vessel wall (NADPH oxidase) that produces a damaging gas that mops up NO becomes overactive in insulin resistance. We plan to perform studies examining the effect of reducing the activity of NADPH oxidase in different models of insulin resistance. The results of this study may guide us towards new treatments to prevent AMI in patients with T2DM.