Aldosterone and Glucose Metabolism

描述（由申请人提供）： 通过恶化的胰岛素抵抗和胰岛素分泌能力测量的葡萄糖稳态受损伴随肥胖和代谢综合征，最终产生高血糖症和显性糖尿病。最近的Frachial Offspring研究表明，基础醛固酮浓度可预测代谢综合征的发展，代谢综合征与心血管风险增加有关。我们已经观察到，空腹血糖浓度降低醛固酮脱氢酶缺陷（AS-/-）小鼠，AS-/-小鼠表现出增强葡萄糖刺激的胰岛素分泌通过钾非依赖性机制。这一提议验证了醛固酮通过盐皮质激素受体（MR）依赖性机制减弱人类胰岛素分泌的中心假设。申请人将与经验丰富的临床和基础科学研究人员合作，以获得调节肾素-血管紧张素-醛固酮系统和糖尿病领域的专业知识，同时研究以下三个具体目标： 具体目的1检验外源性醛固酮通过减弱葡萄糖刺激的胰岛素分泌而增加人类空腹血糖浓度的假设。 具体目的2检验内源性醛固酮通过MR依赖性机制增加代谢综合征患者空腹血糖和减少胰岛素分泌的假设。 具体目的3检验MR拮抗作用和血管紧张素II 1型受体（AT 1）拮抗作用对空腹血糖和胰岛素分泌产生协同有益作用的假设。 我们将利用先前开发的醛固酮输注和高血糖钳夹的方案来评估醛固酮对正常受试者胰岛素分泌的影响。然后，我们将研究患有代谢综合征的受试者，这是糖尿病的高风险群体，以类似地评估MR和AT 1拮抗剂治疗的效果。这些研究将对预防代谢综合征患者发生糖尿病具有直接的临床意义。

DESCRIPTION (provided by applicant): Impaired glucose homeostasis, as measured by worsened insulin resistance and insulin secretory capacity, accompanies obesity and the metabolic syndrome, ultimately producing hyperglycemia and overt diabetes mellitus. The Framingham Offspring Study recently demonstrated that basal aldosterone concentrations predict the development of the metabolic syndrome, which is associated with increased cardiovascular risk. We have observed that fasting glucose concentrations are decreased in aldosterone synthase-deficient (AS-/-) mice, and that AS-/- mice demonstrate enhanced glucose-stimulated insulin secretion through a potassium-independent mechanism. This proposal tests the central hypothesis that aldosterone attenuates insulin secretion in humans via a mineralocorticoid receptor (MR)-dependent mechanism. The applicant will collaborate with experienced clinical and basic science investigators to gain expertise in the regulation of the rennin-angiotensin-aldosterone system and the field of diabetes, while investigating the following three specific aims: SPECIFIC AIM 1 Test the hypothesis that exogenous aldosterone increases fasting glucose concentrations in humans by attenuating glucose-stimulated insulin secretion. SPECIFIC AIM 2 Test the hypothesis that endogenous aldosterone increases fasting glucose and decreases insulin secretion in individuals with the metabolic syndrome via an MR-dependent mechanism. SPECIFIC AIM 3 Test the hypothesis that MR antagonism and angiotensin II type-1 receptor (AT1) antagonism will cause synergistic beneficial effects on fasting blood glucose and insulin secretion. We will utilize previously-developed protocols for aldosterone infusion and hyperglycemic clamp to assess the effect of aldosterone on insulin secretion in normal subjects. We will then study subjects with the metabolic syndrome, a group at high risk for diabetes, to similarly assess the effects of treatment with MR and AT1 antagonism. These studies will have immediate clinical relevance to preventing the development of diabetes in individuals with the metabolic syndrome.