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，全球患有糖尿病的成人人数预计将增长到 3.8 亿。找到能够预防高危人群（例如患有代谢综合征或糖耐量受损 (IGT) 的人群）患糖尿病的药物可能会对健康产生重大影响。根据已发表的临床试验和我们的初步数据，我们提出，醛固酮不当升高会损害胰岛素敏感性和胰岛素分泌，从而促进人类患糖尿病。针对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，它们还可以降低 2 型糖尿病 (T2DM) 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仍不确定。我们假设 ACE 和 ARB 治疗期间醛固酮的减少介导了其中一些有益作用。由于长期 ACE 抑制剂和 ARB 治疗后醛固酮浓度会增加回到基线，因此这种“醛固酮突破”可能会减少对血糖的有益影响。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性的反应。我们发现内源性醛固酮会损害小鼠体内和体外灌注的胰岛细胞中葡萄糖刺激的胰岛素分泌。最近，我们确定低钠摄入量刺激肾素-血管紧张素-醛固酮系统会减弱健康人的胰岛素分泌（初步研究）。与正常糖耐量受损的受试者相比，醛固酮也会增加，并且胰岛素分泌受损（初步研究）。血浆醛固酮与对葡萄糖的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有害影响。这些发现表明，RAAS，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最近临床研究中 RAAS 阻断对糖耐量的不同有益影响。如果正如我们假设的那样，内源性 RAAS 会损害代谢综合征受试者的胰岛素分泌并增加葡萄糖浓度，那么醛固酮合酶抑制等替代策略将在不久的将来提供一种有吸引力的治疗方法。我们预计，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影响，并改善葡萄糖耐量。在本提案中，我们将测试以下假设：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。