Variation in Soluble Epoxide Hydrolase Activity and Human Insulin Sensitivity

可溶性环氧化物水解酶活性和人胰岛素敏感性的变化

• 批准号: 9981733
• 负责人: Nancy J. Brown
• 金额: $ 46.74万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-01 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9981733
• 关键词: Acids; Acute Renal Failure with Renal Papillary Necrosis; Address; Adherence; Adipose tissue; Adult; Affect; Agonist; Alleles; Amylases; Animals; Anti-Inflammatory Agents; Apoptosis; Arachidonic Acids; Bioavailable; Biology; Biopsy; Blood Volume; Blood capillaries; Blood flow; Body Weight decreased; CYP2C19 gene; Cardiac Surgery procedures; Cardiovascular system; Cell physiology; Clinical Research; Closure by clamp; Coupled; Cytochrome P450; Development; Diabetes Mellitus; Eicosanoids; Endothelium; Enzymes; Epoxide hydrolase; Excretory function; Exercise; Forearm; Functional disorder; Genes; Genetic; Genotype; Glucose Clamp; Human; Hydrolysis; Hypertension; Incidence; Individual; Inflammation; Injections; Injury to Kidney; Insulin; Insulin Resistance; Investigational Drugs; Islet Cell; Isotopes; Kidney; Lead; Life Style; Lipase; Lipids; Liver; Lung diseases; Measures; Metformin; Methods; Morbidity - disease rate; Mus; Muscle; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Obesity Epidemic; Oral; Pathway interactions; Patients; Pharmacology; Physiological; Plasma; Plethysmography; Population; Prediabetes syndrome; Prevention; Research; Retinal Diseases; Risk; Rodent; Rodent Model; Role; Serum; Signal Transduction; Sodium; Testing; Tissues; Variant; Vascular resistance; Vasodilation; Vasodilator Agents; World Health Organization; analog; blood glucose regulation; cardiovascular injury; diabetes risk; endothelial dysfunction; enzyme activity; gain of function; gallstone disease; genetic variant; glucagon-like peptide 1; high risk; hypertension treatment; improved; inhibitor/antagonist; insulin sensitivity; insulin sensitivity/resistance; insulin signaling; loss of function; mortality; new therapeutic target; novel; novel strategies; novel therapeutics; obesity treatment; prevent; recruit; side effect; small molecule inhibitor; targeted treatment; vascular injury

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.

项目概要 世界卫生组织估计，有 4.22 亿成年人，即世界成年人口的 8.5% 患有糖尿病。尽管开发了有前景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， 要求我们继续制定新的策略，为那些面临最大风险的人提供治疗 开发 2 型糖尿病 (T2DM) 并确定潜在的新药物靶点。这个提议 解决了环氧二十碳三烯酸 (EET)/可溶性环氧化物水解酶 (sEH) 的贡献 人类胰岛素敏感性/抵抗的途径。 EET，即花生四烯酸的 P450 代谢物，是 公认的天然血管扩张剂和抗炎脂质。 sEH 限制下的水解 EET 的活性，并减少 sEH 对 EET 的水解，可预防血管、心血管和 啮齿动物模型中的肾损伤。肥胖啮齿动物模型中 sEH 的表达和活性增加 和糖尿病。啮齿动物模型的研究进一步表明，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增强毛细血管来提高胰岛素敏感性 招聘。我们的小组发现，携带编码基因功能丧失变体的人类 对于 sEH（EPHX2、rs751141 或 Arg287Gln），血管阻力降低，胰岛素增加 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。另外，我们不知道效果如何 人类肥胖对 sEH 活性的影响。本提案的目的是测试总体方案 假设遗传或药理学因素降低 sEH 活性可改善胰岛素 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 肥胖者。在目标 1 中，我们将检验以下假设：功能丧失的 EPHX2 变体是 与使用高胰岛素正常血糖钳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传导 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， 我们将检验以下假设：一种新型口服生物可利用的 sEH 特异性小分子抑制剂将 改善患有糖尿病前期的肥胖个体的胰岛素敏感性。这种 sEH 的小分子抑制剂， GSK2256294，已经在一百多人身上进行了安全测试，我们为其持有 IND 使用。这些研究有望阐明 EETs/sEH 通路在葡萄糖中的生理作用 人类体内稳态和胰岛素敏感性。此外，这些研究可能会导致制定策略 识别那些罹患 T2DM 的风险最高的人，以及新药理的开发 预防和治疗 T2DM 的目标。