Variation in Soluble Epoxide Hydrolase Activity and Human Insulin Sensitivity

项目总结 世界卫生组织估计，4.22亿成年人，即世界成年人口的8.5% 患有糖尿病。尽管有希望的新疗法的发展，以预防和治疗 糖尿病，新疗法的费用和不便，加上新的副作用， 授权我们继续开发新的战略，将治疗定向到那些面临最大风险的人 开发2型糖尿病(T2 DM)，并确定潜在的新药靶点。这项建议 阐述了环氧二十碳三烯酸(EETs)/可溶性环氧化物水解酶(SEH)的作用 人类胰岛素敏感/抵抗的途径。花生四烯酸的P450代谢物EETs是 天然的血管扩张剂和抗炎脂类。按sEH限制的水解度 EETs的活性，并减少sEH对EETs的水解，可以防止血管、心血管和 啮齿动物模型中的肾脏损伤。肥胖啮齿动物模型中sEH的表达和活性增加 还有糖尿病。对啮齿动物模型的研究进一步表明，降低sEH活性可以改善 通过增加胰岛素敏感组织中的信号或通过增强毛细血管来增强胰岛素敏感性 招聘。我们的研究小组发现，携带编码基因功能丧失变体的人类 对于sEH(EPHX2、rs751141或Arg287Gln)，降低血管阻力并增加胰岛素 敏感性，但我们还不知道胰岛素敏感性增加的机制，也没有 使用最严格的方法评估胰岛素敏感性。此外，我们还不知道 人类肥胖对sEH活性的影响。本提案的目的是测试最重要的 假设降低sEH活性的遗传或药物因素可以改善胰岛素 敏感性，增加胰岛素刺激的血管扩张，并增加组织胰岛素信号 肥胖的人。在目标1中，我们将检验功能丧失EPHX2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有关， 增强胰岛素刺激的血管扩张，并增加肌肉和脂肪组织中的胰岛素信号 肥胖。我们将评估基因对组织sEH活性和EET浓度的影响。在目标2中， 我们将检验这样一种假设，即一种新的口服生物可用的sEH特异性小分子抑制剂将 改善糖尿病前期肥胖患者的胰岛素敏感性。这种sEH的小分子抑制剂， GSK2256294已经在100多人中进行了安全测试，我们为其 使用。这些研究有望阐明eets/sEH途径在葡萄糖中的生理作用。 人体的动态平衡和胰岛素敏感性。此外，这些研究可能会导致制定战略 确定那些患T2 DM的最高风险者，以及开发新的药理 2型糖尿病的防治目标。

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.