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: 10170332
• 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/10170332
• 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; obese patients; obese person; 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% 尽管已经开发出有前景的预防和治疗糖尿病的新疗法。 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 发展 2 型糖尿病 (T2DM) 并确定潜在的新药物靶标。 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 EET（花生四烯酸的 P450 代谢物）是人类胰岛素敏感性/耐受性的途径。 sEH 限制了公认的天然血管扩张剂和抗炎脂质。 EET 的活性，并减少 sEH 对 EET 的水解，可预防血管、心血管和 肥胖啮齿动物模型中 sEH 的表达和活性增加。 啮齿动物模型的研究进一步表明，降低 sEH 的活性可以改善糖尿病。 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 我们的小组发现携带编码基因功能丧失变异的人类。 sEH（EPHX2、rs751141 或 Arg287Gln）降低了血管阻力并增加了胰岛素 敏感性，但我们还不知道增加胰岛素敏感性的机制，也没有 使用最严格的方法评估胰岛素敏感性此外，我们不知道其效果。 人类肥胖对 sEH 活性的影响 本提案的目的是测试总体情况。 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 在目标 1 中，我们将检验功能丧失的 EPHX2 变体的假设。 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 在目标 2 中，我们将评估基因型对组织 sEH 活性和 EET 浓度的影响。 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 这些研究有望阐明 EETs/sEH 途径在葡萄糖中的生理作用。 此外，这些研究可能会导致人类体内稳态和胰岛素敏感性的产生。 识别那些罹患 T2DM 风险最高的人群，以及开发新药理学 预防和治疗 T2DM 的目标。

项目成果

EET Analog Treatment Improves Insulin Signaling in a Genetic Mouse Model of Insulin Resistance.

EET 类似治疗可改善胰岛素抵抗遗传小鼠模型中的胰岛素信号传导。

• 发表时间: 2021-10-21
• 影响因子: 7.7
• 作者: Ghoshal, Kakali;Li, Xiyue;Peng, Dungeng;Falck, John R;Anugu, Raghunath Reddy;Chiusa, Manuel;Stafford, John M;Wasserman, David H;Zent, Roy;Luther, James M;Pozzi, Ambra
• 通讯作者: Pozzi, Ambra