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的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目及 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 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，以改善代谢性疾病及其血管并发症的治疗。我们最近已经证明，增加内皮素-1（ET-1）的作用有助于肥胖和2型糖尿病的内皮功能障碍。因此，可能需要降低ET-1作用以改善内皮功能。然而，导致这种增加的ET-1作用的因素是未知的。 在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，这些代谢产物可能实际上有助于增加ET-1的行动，在人类肥胖。一氧化氮（NO）也发挥重要的抑制控制ET-1在体外，因此在体内受损的NO生物活性也可能是一个重要的贡献者增加ET-1的行动。胰岛素刺激NO的作用在肥胖症中降低，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直接影响内皮素活性，和/或通过对NO的影响间接影响内皮素活性。这种区别是重要的，因为减少肥胖症中ET-1作用的治疗方法可能需要或可能不需要特别改善代谢状态。 本申请的目的是确定游离脂肪酸、胰岛素和一氧化氮在肥胖和瘦人中ET-1调节中的作用。这一建议的主要假设是，肥胖症中所见的循环游离脂肪酸和胰岛素的增加直接导致了人类肥胖症中ET-1作用的增加。第二个假设是，受损的NO生物活性足以解释ET-1作用的增加。将使用对单独内皮素拮抗作用和同时增加或减少胰岛素、FFA和/或NO的体内腿部血管反应的比较来评估这些因素对瘦型和肥胖型人中ET-1作用的影响。 这些研究使用创新的方法进行研究设计，以区分代谢物本身对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.