Variation in Soluble Epoxide Hydrolase Activity and Human Insulin Sensitivity

项目摘要 世界卫生组织估计，4.22亿成年人或世界成年人口的8.5% 患有糖尿病尽管开发了有前途的新疗法来预防和治疗 糖尿病，新疗法的费用和不便，加上新的副作用， 要求我们继续开发新的策略，以指导那些风险最大的人的治疗。 发展2型糖尿病（T2 DM），并确定潜在的新药物靶点。这项建议 阐述了环氧二十碳三烯酸（EHF）/可溶性环氧化物水解酶（sEH）的作用 胰岛素敏感性/抵抗的途径。花生四烯酸的P450代谢产物E14， 公认的天然存在的血管扩张剂和抗炎脂质。水解（sEH限度） 降低雌二醇的活性，减少雌二醇被sEH水解，可预防血管、心血管和 啮齿动物模型中的肾损伤。在肥胖的啮齿动物模型中sEH的表达和活性增加 和糖尿病在啮齿动物模型中的研究进一步表明，降低sEH的活性可以改善 通过增加胰岛素敏感组织中的信号传导或通过增强毛细血管 招聘我们的研究小组发现，携带一种功能丧失的基因编码变体的人， 对于sEH（EPHX 2、rs751141或Arg 287 Gln），血管阻力降低，胰岛素水平升高， 敏感性，但我们还不知道增加胰岛素敏感性的机制， 使用最严格的方法评估胰岛素敏感性。此外，我们不知道 人肥胖对sEH活性影响。本提案的目的是测试总体的 降低sEH活性遗传或药理学因素改善胰岛素分泌的假说 敏感性，增加胰岛素刺激的血管舒张，并增加组织胰岛素信号传导， 肥胖的人在目标1中，我们将检验功能丧失的EPHX 2变体是 与使用高胰岛素-正常血糖钳夹测量的胰岛素敏感性增加相关， 增强胰岛素刺激的血管舒张，并增加肌肉和脂肪组织中的胰岛素信号， 肥胖我们将评估基因型对组织sEH活性和EET浓度的影响。在目标2中， 我们将检验一种新的口服生物可利用的sEH特异性小分子抑制剂将 改善糖尿病前期肥胖个体胰岛素敏感性。这种sEH的小分子抑制剂， GSK 2256294已经在100多人中进行了安全测试，我们持有其IND 使用.这些研究有望阐明EkB/sEH通路在葡萄糖代谢中的生理作用。 体内平衡和胰岛素敏感性。此外，这些研究可能会导致战略， 确定发展为T2 DM的最高风险人群，以及开发新的药理学 预防和治疗T2 DM的目标。

PROJECT SUMMARY The World Health Organization estimates that 422 million adults or 8.5% of the world’s adult population has diabetes. Despite the development of promising new treatments for the prevention and treatment of diabetes, the expense and inconvenience of newer therapies, coupled with new side effect profiles, mandate that we continue to develop novel strategies to direct therapies to those at greatest risk of developing type 2 diabetes mellitus (T2DM) and to identify potential new drug targets. This proposal addresses the contribution of the epoxyeicosatrienoic acids (EETs)/ soluble epoxide hydrolase (sEH) pathway to insulin sensitivity/resistance in humans. The EETs, P450 metabolites of arachidonic acid, are well-established naturally occurring vasodilators and anti-inflammatory lipids. Hydrolysis by sEH limits the activity of EETs, and reducing the hydrolysis of EETs by sEH prevents vascular, cardiovascular, and renal injury in rodent models. Expression and activity of sEH are increased in rodent models of obesity and diabetes. Studies in rodent models further suggest that decreasing the activity of sEH improves insulin sensitivity either by increasing signaling in insulin-sensitive tissues or by enhancing capillary recruitment. Our group has found that humans who carry a loss-of-function variant of the gene encoding for sEH (EPHX2, rs751141 or Arg287Gln) have decreased vascular resistance and increased insulin sensitivity, but we do not yet know the mechanism for increased insulin sensitivity and have not assessed insulin sensitivity using the most rigorous methods. In addition, we do not know the effect of human obesity on sEH activity. The purpose of the present proposal is to test the overarching hypothesis that genetic or pharmacological factors that decrease sEH activity improve insulin sensitivity, increase insulin-stimulated vasodilation, and increase tissue insulin signaling in obese individuals. In Aim 1, we will test the hypothesis that the loss-of-function EPHX2 variant is associated with increased insulin sensitivity measured using hyperinsulinemic-euglycemic clamp, enhanced insulin-stimulated vasodilation, and increased insulin-signaling in muscle and adipose tissue in obesity. We will assess the effect of genotype on tissue sEH activity and EET concentrations. In Aim 2, we will test the hypothesis that a novel orally bioavailable specific small molecule inhibitor of sEH will improve insulin sensitivity in obese individuals with prediabetes. This small molecule inhibitor of sEH, GSK2256294, has already been tested safely in over one hundred people and we hold an IND for its use. These studies promise to elucidate the physiological role of the EETs/sEH pathway in glucose homeostasis and insulin sensitivity in humans. Moreover, these studies could lead to strategies to identify those at highest risk of developing T2DM, as well as to the development of new pharmacological targets for the prevention and treatment of T2DM.