AMP-activated kinase in diabetic complications

糖尿病及其相关并发症是发达国家的一个主要健康问题。 糖尿病患者患心血管疾病(CVD)的可能性是普通人群的2-4倍。一 糖尿病的特征在最近几年已经变得明显，那就是过量的氧化应激。在初步数据中 在这里，我们发现高血糖和游离脂肪酸(FFA)，I型和I型的两个特征 II型糖尿病，在血管内皮细胞中产生氧化应激。这些结果导致脂质过氧化，酪氨酸 前列环素合成酶(PGIs)硝化，降低NO生物活性，内皮型一氧化氮合酶(ENOS) 去偶联和胰岛素抵抗。我们还发现，使用AMP激活的激酶治疗 (AMPK)激活剂5-氨基-4-咪唑甲酰胺核苷(AICAR)可阻止所有这些事件 包括氧化应激增加和胰岛素抵抗的发生。这是一个基本的前提 有观点认为，AMPK的激活可以保护内皮细胞免受 通过增加线粒体解偶联蛋白(UCP)-2导致的高血糖和FFA 氧化应激与NO生物活性的增加是平行的。因此，作为这一假设的中心假设 应用，我们认为胰岛素抵抗和糖尿病的血管素质部分是由于 高血糖/游离脂肪酸诱导的氧化应激和AMPK的代偿性激活。我们的下一部分 该提案将确定AMPK激活对氧化应激、内皮功能和 胰岛素信号，利用AICAR降低细胞氧化应激和胰岛素的初步数据 增强载脂蛋白E基因敲除(KO)患者对葡萄糖和脂肪酸的抵抗力及主动脉损伤 体内的糖尿病。为了实现这一目标，我们建议进行研究1)。要确定是否激活 AMPK通过多种手段(药理学和分子生物学手段)减少氧化应激和 胰岛素抵抗并评估其作用机制，以及2)。以确定是否AMPK依赖的减少。 氧化应激和内皮功能障碍在体内糖尿病中起作用。这一功能强大的 体外和体内技术将提供新的信息，说明代谢压力如何与 糖尿病会损害血管内皮细胞。他们还应该深入了解内皮细胞是如何尝试 以保护自己免受这些压力，以及AMPK是否为糖尿病治疗的潜在靶点。

Diabetes mellitus and its associated complications are a major health problem in the developed world. Diabetics are 2- to 4-times more likely to have cardiovascular diseases (CVD) than general population. One feature of diabetes that has become apparent in recent years is excess oxidant stress. In preliminary data presented here, we have found that hyperglycemia and free fatty acids (FFA), two hallmarks of type I and type II diabetes, impart an oxidant stress in endothelial cells. These results in lipid peroxiiation, tyrosine nitration of prostacyclin synthase (PGIS), reduced NO bioactivity, endothelial nitric oxide synthase (eNOS) uncoupling, and insulin resistance. We have also found that treatment with the AMP-activated kinase (AMPK) activator, 5-amino-4-imidazole carboxamide riboside (AICAR), prevents all of these events including the increase in oxidant stress and insulin resistance from occurring. A basic premise of this proposal is that AMPK activation could protect the endothelial cell against the adverse effects of hyperglycemia and FFA by increasing mitochondrial uncoupling protein (UCP)-2 that lead to a decrease in oxidant stress in parallel with an increase in NO bioactivity. Therefore, as a central hypothesis of this application, we propose that vascular diathesis of insulin resistance and diabetes is due, in part, from a hyperglycemia/FFA-induced oxidant stress and a compensatory activation of AMPK. The next part of our proposal will determine the consequences of AMPK activation on oxidant stress, endothelial function, and insulin signaling, capitalizing on preliminary data that AICAR reduces both cellular oxidant stress and insulin resistance from glucose and fatty acids in vitro and aortic lesions in Apo-E knockout (KO) enhanced by diabetes in vivo. In order to accomplish this goal, we propose to study 1). To determine if activation of AMPK by a number of means (pharmacological and molecular biological means) reduces oxidant stress and insulin resistance and to evaluate how it works, and 2). To determine if AMPK-dependent reduction in. oxidant stress and endothelial dysfunction is operating in diabetes in vivo. This powerful combination of in vitro and in vivo techniques will provide novel information as to how the metabolic stresses associated with diabetes cause damage to the endothelium. They should also yield insights into how endothelium attempts to protect itself against these stresses and whether AMPK is a potential target for therapy for diabetes.