DUAL ACTIONS OF INSULIN IN THE REGULATION OF ENDOTHELIN ACTIVITY IN VIVO IN H

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 内皮功能障碍是肥胖和2型糖尿病胰岛素抵抗状态的一个特征。我们实验室的长期目标是更好地了解代谢和血管功能之间的相互作用，以改进代谢性疾病及其血管并发症的治疗。我们最近证明，内皮素-1(ET-1)的作用增加有助于肥胖和2型糖尿病患者的内皮功能障碍。因此，减少ET-1的作用以改善内皮功能可能是可取的。然而，导致ET-1活性增加的因素尚不清楚。 体外和体内的研究结果表明，胰岛素和游离脂肪酸直接调节内皮素，我们的初步数据表明，这些代谢物实际上可能有助于在人类肥胖中增加ET-1的作用。一氧化氮(NO)在体外也对ET-1发挥重要的抑制作用，因此体内NO生物活性受损也可能是ET-1活性增加的重要原因。肥胖患者胰岛素刺激NO的作用减弱，而游离脂肪酸可直接损害NO的产生。因此，胰岛素和游离脂肪酸可能通过对NO的影响直接和/或间接地影响内皮素的活性。这一区别很重要，因为减少肥胖症患者ET-1作用的治疗方法可能需要也可能不需要专门改善代谢状态。 这项应用的目的是确定游离脂肪酸、胰岛素和一氧化氮在调节肥胖和瘦人的ET-1中的作用。这一建议的主要假设是，肥胖患者循环中游离脂肪酸和胰岛素的增加直接导致了ET-1在人类肥胖中的作用增强。第二个假设是，受损的NO生物活性足以解释ET-1活性的增加。比较体内腿部血管对内皮素拮抗剂的反应，以及同时增加或减少胰岛素、FFA和/或NO的情况，将被用来评估这些因素对瘦人和肥胖者ET-1作用的影响。 这些研究使用创新的方法来研究设计，以区分代谢物本身的贡献与其对NO生物活性的影响，以及为实现NO替代而采取的方法。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Endothelial dysfunction is a feature of the insulin resistant states of obesity and type 2 diabetes mellitus. The long-term goal of our laboratory is to better understand the interactions between metabolism and vascular function in order to improve therapy of metabolic diseases and their vascular complications. We have recently demonstrated that increased endothelin-1 (ET-1) action contributes to endothelial dysfunction in obesity and type 2 diabetes. It may therefore be desirable to reduce ET-1 action in order to improve endothelial function. However, the factors which cause this increased ET-1 action are unknown. In vitro and in vivo findings suggest that insulin and free fatty acids directly regulate endothelin, and our preliminary data suggests these metabolites may in fact contribute to increased ET-1 action in human obesity. Nitric oxide (NO) also exerts important inhibitory control over ET-1 in vitro, and therefore impaired NO bioactivity in vivo may also be an important contributor to increased ET-1 action. The effect of insulin to stimulate NO is reduced in obesity, and free fatty acids can directly impair NO production. It is therefore possible that insulin and free fatty acids influence endothelin activity directly, and/or indirectly via effects on NO. This distinction is important in that therapeutic approaches to reduce ET-1 action in obesity may or may not require specifically improving the metabolic state. The objective of this application is to define the roles of free fatty acids, insulin and nitric oxide in the regulation of ET-1 in obese and lean humans. The main hypothesis of this proposal is that the increases in circulating free fatty acids and insulin seen in obesity contribute directly to increased ET-1 action in human obesity. A second hypothesis is that impaired NO bioactivity is sufficient to explain increases in ET-1 action. A comparison of in vivo leg vascular response to endothelin antagonism alone and with concurrent increases or reductions in insulin, FFA, and/or NO will be used to assess the effect of these factors on ET-1 action in lean and obese humans. These studies use innovative approaches to study design in order to distinguish contributions of metabolites themselves from their effects on NO bioactivity, and the approach taken in order to achieve NO replacement.