Endogenous Aldosterone and Glucose Homeostasis

内源性醛固酮和葡萄糖稳态

• 批准号: 8731872
• 负责人: James Matthew Luther
• 金额: $ 42.25万
• 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 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8731872
• 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; Blood Pressure; 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; 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; public health relevance; 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）：预计到2025年，世界上患有糖尿病的成年人数量将增长到3.8亿。确定预防高风险个体（如代谢综合征或糖耐量受损（IGT）患者）发生糖尿病的药物可能会对健康产生重大影响。基于已发表的临床试验和我们的初步数据，我们提出，不适当升高的醛固酮通过损害胰岛素敏感性和胰岛素分泌促进人类糖尿病。靶向该系统将为预防肥胖、高血压人群的代谢并发症提供一种新的策略。血管紧张素I转换酶（ACE）抑制剂或血管紧张素II受体阻滞剂（ARB）可降低血压和心血管死亡率。在临床试验的回顾性分析中，它们还降低了2型糖尿病（T2 DM）的发病率。肾素-血管紧张素-醛固酮系统（RAAS）影响血糖控制的机制尚不清楚。我们假设ACE和ARB治疗期间醛固酮减少介导了这些有益作用。因为在长期ACE抑制剂和ARB治疗后，醛固酮浓度增加回到基线，这种“醛固酮突破”可能会降低对血糖的有益作用。抑制醛固酮合成的药物正在开发中，将提供一种阻断这种突破性反应的具体方法。我们已经发现内源性醛固酮在小鼠体内和离体灌流的胰岛细胞中损害葡萄糖刺激的胰岛素分泌。最近，我们已经确定，低钠摄入量的肾素-血管紧张素-醛固酮系统刺激减弱了健康人的胰岛素分泌（初步研究）。与正常葡萄糖耐量相比，葡萄糖耐量受损受试者的醛固酮也增加，胰岛素分泌受损（初步研究）。血浆醛固酮与急性胰岛素反应呈负相关。先前的研究表明醛固酮通过盐皮质激素受体激活对胰岛素敏感性产生不利影响。这些发现表明RAAS，特别是醛固酮，通过改变小鼠和人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RAAS损害胰岛素分泌和增加葡萄糖浓度的代谢综合征患者，我们假设，替代策略，如醛固酮合成酶抑制剂将提供一个有吸引力的治疗在不久的将来。我们预期靶向RAAS抑制将最大限度地减少饮食钠限制或利尿剂给药的不良代谢作用，并改善葡萄糖耐量。在本研究中，我们将检验内源性RAAS通过醛固酮损害外周胰岛素敏感性、肝脏胰岛素敏感性和胰岛素分泌的假设。