Endogenous Aldosterone and Glucose Homeostasis

内源性醛固酮和葡萄糖稳态

• 批准号: 8878243
• 负责人: James Matthew Luther
• 金额: $ 37.26万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-10 至 2016-04-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8878243
• 关键词: Acute; Adrenal Cortex Hormones; Adult; Affect; Aldosterone; Aldosterone Synthase; Angiotensin II; Angiotensin II Receptor; Angiotensin-Converting Enzyme Inhibitors; Attenuated; Back; Beta Cell; Blood Glucose; Cardiovascular Diseases; Cardiovascular system; Cell physiology; Clinical; Clinical Research; Clinical Trials; Data; Development; Diabetes Mellitus; Dietary Sodium; Diuretics; Future; Glucose; Health; Hepatic; Heterogeneity; Human; Hyperglycemia; Hypertension; Incidence; Individual; Insulin; Insulin Resistance; Intake; Islet Cell; Islets of Langerhans; Link; Mediating; Metabolic; Metabolic syndrome; Mineralocorticoid Receptor; Minor; Mus; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Patients; Peptidyl-Dipeptidase A; Peripheral; Pharmaceutical Preparations; Plasma; Population; Prospective Studies; Publishing; Receptor Activation; Renin-Angiotensin-Aldosterone System; Resistant Hypertension; Risk; Sodium; Sodium-Restricted Diet; Superoxide Dismutase; System; Testing; United States; base; blood glucose regulation; blood pressure reduction; drug development; glucose production; glucose tolerance; glucose uptake; glycemic control; high risk; impaired glucose tolerance; improved; in vivo; insulin secretion; insulin sensitivity; mimetics; mortality; novel; novel strategies; preclinical study; prevent; response; tempol

DESCRIPTION (provided by applicant): The number of adults with diabetes in the world is expected to grow to 380 million by the year 2025. Identifying drugs that prevent the development of diabetes in high-risk individuals, such as those with metabolic syndrome or impaired glucose tolerance (IGT), could have a major health impact. Based on published clinical trials and our preliminary data, we propose that inappropriately elevated aldosterone promotes diabetes in humans by impairing insulin sensitivity and insulin secretion. Targeting this system will provide a novel strategy for preventing metabolic complications in an obese, hypertensive population. Angiotensin I converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs) reduce blood pressure and cardiovascular mortality. They also reduce the incidence of type 2 Diabetes Mellitus (T2DM) in retrospective analyses of clinical trials. The mechanism by which the renin-angiotensin-aldosterone system (RAAS) affects glucose control remains uncertain. We hypothesize that aldosterone reduction during ACE and ARB therapy mediates some of these beneficial effects. Because aldosterone concentrations increase back to baseline after prolonged ACE inhibitor and ARB treatment, this "aldosterone breakthrough" could reduce the beneficial effect on blood glucose. Drugs which inhibit aldosterone synthesis are in development and will provide a specific approach to block this breakthrough response. We have found that endogenous aldosterone impairs glucose-stimulated insulin secretion in vivo in mice and ex vivo in perifused pancreatic islet cells. More recently, we have determined that renin-angiotensin- aldosterone system stimulation with low sodium intake attenuates insulin secretion in healthy humans (Preliminary Studies). Aldosterone is also increased, and insulin secretion is impaired in subjects with impaired versus normal glucose tolerance (Preliminary Studies). Plasma aldosterone inversely correlated with the acute insulin response to glucose. Prior studies demonstrate a detrimental effect of aldosterone on insulin sensitivity via mineralocorticoid receptor activation. These findings suggest that the RAAS, and particularly aldosterone, impair glucose homeostasis by altering insulin secretion and insulin sensitivity in mice and in humans. Our studies may help explain the variable beneficial effect of RAAS blockade on glucose tolerance in recent clinical studies. If the endogenous RAAS impairs insulin secretion and increase glucose concentrations in subjects with metabolic syndrome as we hypothesize, alternative strategies such as aldosterone synthase inhibition will provide an attractive therapy in the near future. We anticipate that targeted RAAS inhibition will minimize the adverse metabolic effects of dietary sodium restriction or diuretic administration, and improve glucose tolerance. In this proposal we will test the hypothesis that the endogenous RAAS impairs peripheral insulin sensitivity, hepatic insulin sensitivity, and insulin secretion in humans via aldosterone.

描述（由申请人提供）：到2025年，世界上患有糖尿病的成年人的数量预计将增长到3.8亿。确定可以防止高风险个体中糖尿病发展的药物，例如具有代谢综合征或葡萄糖耐受性受损（IGT）的药物，可能会产生重大健康影响。根据已发表的临床试验和我们的初步数据，我们建议通过损害胰岛素敏感性和胰岛素分泌来促进醛固酮不适当地升高醛固酮。针对该系统将提供一种新的策略，以防止肥胖，高血压人群中的代谢并发症。血管紧张素I转化酶（ACE）抑制剂或血管紧张素II受体阻滞剂（ARB）降低了血压和心血管死亡率。它们还减少了在临床试验的回顾性分析中，2型糖尿病（T2DM）的发生率。肾素 - 血管紧张素 - 醛固酮系统（RAAS）影响葡萄糖控制的机制尚不确定。我们假设ACE期间的醛固酮减少和ARB治疗介导了其中一些有益作用。由于醛固酮浓度延长了ACE抑制剂和ARB处理后的基线，因此这种“醛固酮突破”可以减少对血糖的有益作用。抑制醛固酮合成的药物正在开发中，并将提供一种特定的方法来阻止这种突破反应。我们发现，内源性醛固酮会损害小鼠体内葡萄糖刺激的胰岛素分泌，在perifused胰岛细胞中的体内损害葡萄糖刺激的胰岛素分泌。最近，我们确定肾素 - 血管紧张素 - 醛固酮系统刺激钠摄入量低，钠摄入量低可减弱健康人的胰岛素分泌（初步研究）。醛固酮也增加，胰岛素分泌在受损与正常葡萄糖耐受性（初步研究）的受试者中受到损害。血浆醛固酮与急性胰岛素对葡萄糖的反应成反比。先前的研究表明，醛固酮通过矿物皮质激活的激活对胰岛素敏感性产生了不利影响。这些发现表明，RAA，尤其是醛固酮，通过改变小鼠和人类的胰岛素分泌和胰岛素敏感性来损害葡萄糖稳态。我们的研究可能有助于解释在最近的临床研究中，RAAS阻断对葡萄糖耐量的可变有益作用。如果内源性RAA会损害胰岛素的分泌并增加代谢综合征的受试者的葡萄糖浓度，那么我们假设的替代策略（例如醛固酮合酶抑制）将在不久的将来提供有吸引力的疗法。我们预计，靶向RAAS抑制作用将最大程度地减少饮食钠限制或利尿剂给药的不良代谢作用，并提高葡萄糖耐受性。在此提案中，我们将检验以下假设：内源性RAA会损害外周胰岛素敏感性，肝胰岛素敏感性和通过醛固酮在人类中的胰岛素分泌。