Endothelin - Mechanisms in Hypertension and Obesity

内皮素 - 高血压和肥胖的机制

• 批准号: 10057015
• 负责人: Joshua S Speed
• 金额: $ 7.1万
• 依托单位: UNIVERSITY OF MISSISSIPPI MED CTR
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-01-15 至 2021-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10057015
• 关键词: Acute; Address; Adipocytes; Adipose tissue; Affect; American; Blood Glucose; Cardiovascular Diseases; Chronic; Data; Diet; Endothelial Cells; Endothelin; Endothelin A Receptor; Endothelin B Receptor; Endothelin-1; Endothelium; Fasting; Fatty acid glycerol esters; Health; Hormones; Human; Hypertension; Impairment; In Vitro; Incidence; Individual; Insulin; Insulin Resistance; Intake; Knock-out; Knockout Mice; Lipids; Metabolic; Metabolic syndrome; Modeling; Morbidity - disease rate; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Patients; Peptides; Pharmacology; Physiological; Population; Prevalence; Production; Rattus; Receptor Activation; Receptor Inhibition; Risk Factors; Rodent; Rodent Model; Signal Pathway; Sleep Apnea Syndromes; Sodium Chloride; Sprague-Dawley Rats; Stimulus; System; Techniques; Testing; Transgenic Mice; Visceral; Visceral fat; blood glucose regulation; bosentan; cardiovascular health; cardiovascular risk factor; cohort; experimental study; fasting glucose; glucose metabolism; glucose tolerance; improved; improved functioning; in vitro testing; in vivo; insulin sensitivity; insulin signaling; insulin tolerance; lipid metabolism; mouse model; novel; overexpression; pre-clinical; receptor; receptor expression; receptor function; response; salt intake; subcutaneous

PROJECET SUMMARY Insulin resistance is a major health problem in the U.S. It precludes type II diabetes and is often present in obese patients, both being major risk factors for cardiovascular disease. Currently, mechanisms associated with insulin resistance aren't fully understood. ET-1 is a vasoactive peptide primarily released by endothelial cells that is associated with insulin resistance and increased in obese patients. ET-1 activates two receptors, ETA and ETB. We have previously shown that inhibiting ETB receptors in rodents, either genetically or pharmacologically, improves insulin tolerance and reduces fasting blood glucose. In addition, loss of ETB function reduces adiposity, suggesting the adipose tissue as a possible target for ET-1 induced alteration in insulin signaling. It has been previously shown that activation of ETB receptors on cultured adipocytes inhibits the anti-lipolytic effects of insulin. Furthermore, blockade of ETB receptors reduces fasting blood glucose in the GK rat model of type II diabetes and improves insulin sensitivity in a rodent model of sleep apnea. These data suggest that increased ET-1 observed in obese patients may promote insulin resistance via the ETB receptor. Thus, we hypothesize that activation of the ET-1/ETB receptor promotes IR and impairs glucose metabolism in adipocytes. To test this hypothesis, we will utilize both in vivo and in vitro techniques using two novel mouse models. One will allow us to over-express the ETB receptor, and another that will allow us to knockout the ETB receptor specifically in adipocytes. We will test the following specific aims: Specific aim 1: To test the hypothesis that ETB receptor activation inhibits insulin signaling in cultured adipocytes. Specific aim 2: To test the hypothesis that ETB receptor activation causes insulin resistance in vivo.

项目概要 胰岛素抵抗是美国的一个主要健康问题，它排除了 II 型糖尿病 糖尿病，并且经常出现在肥胖患者中，两者都是糖尿病的主要危险因素 心血管疾病。目前，与胰岛素相关的机制 阻力尚未完全理解。 ET-1是一种主要释放的血管活性肽 由内皮细胞产生，与胰岛素抵抗相关并增加 肥胖患者。 ET-1 激活两种受体：ETA 和 ETB。我们之前有过 研究表明，通过遗传或基因抑制啮齿类动物的 ETB 受体 药理学上，可改善胰岛素耐受性并降低空腹血糖。 此外，ETB 功能的丧失会减少肥胖，这表明脂肪组织 作为 ET-1 诱导的胰岛素信号改变的可能靶标。它一直 先前表明，培养的脂肪细胞上 ETB 受体的激活会抑制 胰岛素的抗脂肪分解作用。此外，阻断 ETB 受体 降低 II 型糖尿病 GK 大鼠模型的空腹血糖 提高睡眠呼吸暂停啮齿动物模型的胰岛素敏感性。这些数据表明 在肥胖患者中观察到的 ET-1 增加可能会促进胰岛素抵抗 通过 ETB 受体。因此，我们假设 ET-1/ETB 的激活 受体促进 IR 并损害脂肪细胞中的葡萄糖代谢。为了测试这个 假设，我们将利用两种新颖的体内和体外技术 鼠标模型。一种可以让我们过度表达 ETB 受体，另一种可以让我们过度表达 ETB 受体 这将使我们能够特异性地敲除脂肪细胞中的 ETB 受体。我们将 测试以下具体目标： 具体目标 1：检验 ETB 受体激活抑制胰岛素的假设 培养的脂肪细胞中的信号传导。 具体目标 2：检验 ETB 受体激活导致胰岛素的假设 体内抵抗力。

项目成果

Endothelin antagonism reduces hemoglobin A1c in patients with pulmonary hypertension.

内皮素拮抗作用可降低肺动脉高压患者的血红蛋白 A1c。

• 发表时间: 2022-08-01
• 影响因子: 2.1
• 作者: Stapel, Jennifer R;Speed, Joshua S;Clemmer, John S
• 通讯作者: Clemmer, John S

Loss of endothelin type B receptor function improves insulin sensitivity in rats.

内皮素 B 型受体功能丧失可提高大鼠的胰岛素敏感性。

• DOI: 10.1139/cjpp-2019-0666
• 发表时间: 2020-02-21
• 期刊: Canadian journal of physiology and pharmacology
• 影响因子: 2.1
• 作者: Osvaldo Rivera;M. Kasztan;Jermaine G. Johnston;Kelly A. Hyndman;Joshua S. Speed
• 通讯作者: Joshua S. Speed