Targeting NADPH oxidase to enhance nitric oxide bioavailability in insulin resistance

2型糖尿病（T2DM）和肥胖（发展为T2DM的主要危险因素）的人数在世界范围内已达到流行病的程度。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，尽管使用现代二级预防治疗，T2DM患者持续急性心肌梗死（AMI）或？心脏病?没有从类似的无2型糖尿病患者的死亡率改善中获益。2型糖尿病的一个主要特征是抵抗胰岛素的作用，这种激素被释放出来降低血糖，这一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。除了降低血糖外，胰岛素还被认为能刺激血管壁释放一种叫做一氧化氮（NO）的物质。一氧化氮可以防止动脉粥样硬化。最近发现T2DM患者一氧化氮含量降低。因此，这可能导致T2DM患者动脉粥样硬化加速。我们已经进行了研究，证明了胰岛素抵抗可能减少NO作用的新机制。我们已经证明，血管壁中的一种酶（NADPH氧化酶）产生一种清除一氧化氮的有害气体，在胰岛素抵抗中变得过度活跃。我们计划进行研究，检查降低NADPH氧化酶活性对不同胰岛素抵抗模型的影响。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2型糖尿病患者的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.