Endogenous Aldosterone and Glucose Homeostasis

描述(申请人提供)：预计到2025年，全球成人糖尿病患者人数将增至3.8亿人。在高危人群中发现预防糖尿病发展的药物，如代谢综合征或糖耐量受损(IGT)患者，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，我们认为，不适当地升高的醛固酮通过损害胰岛素敏感性和胰岛素分泌而促进人类糖尿病。以该系统为靶点将为预防肥胖、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。在临床试验的回顾分析中，它们还可以降低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，在ACE和ARB治疗过程中，醛固酮的减少可能介导了其中一些有益的效果。由于延长血管紧张素转换酶抑制剂和ARB治疗后，醛固酮浓度回升至基线水平，这种“醛固酮突破”可能会降低对血糖的有益影响。抑制醛固酮合成的药物正在开发中，将提供一种特定的方法来阻止这一突破性反应。我们发现内源性醛固酮在小鼠体内和体外对周围胰岛细胞中葡萄糖刺激的胰岛素分泌都有损害作用。最近，我们已经确定，低钠摄入量的肾素-血管紧张素-醛固酮系统刺激会减弱健康人的胰岛素分泌(初步研究)。糖耐量受损的受试者与正常受试者相比，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对葡萄糖的反应呈负相关。先前的研究表明，醛固酮通过激活盐皮质激素受体而对胰岛素敏感性产生不利影响。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破坏葡萄糖稳态。我们的研究可能有助于解释最近的临床研究中RAAS阻滞剂对糖耐量的不同有益影响。如果内源性RAAS像我们假设的那样损害代谢综合征受试者的胰岛素分泌并增加血糖浓度，那么替代策略，如醛固酮合成酶抑制，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抑制将使限制饮食钠或利尿剂给药的不良代谢影响降至最低，并改善糖耐量。在这项提案中，我们将检验内源性RAAS损害人类外周胰岛素敏感性、肝脏胰岛素敏感性和通过醛固酮分泌胰岛素的假设。

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.