Aldosterone and Glucose Metabolism

描述(由申请人提供)： 以胰岛素抵抗和胰岛素分泌能力恶化衡量的葡萄糖稳态受损，伴随着肥胖和代谢综合征，最终导致高血糖和明显的糖尿病。弗雷明翰后代研究最近证明，基础醛固酮浓度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。我们观察到，醛固酮合成酶缺陷(AS-/-)小鼠的空腹血糖浓度降低，AS-/-小鼠通过钾依赖机制表现出葡萄糖刺激的胰岛素分泌增加。这一建议验证了中心假设，即醛固酮通过依赖于盐皮质激素受体(MR)的机制来抑制人类胰岛素的分泌。申请者将与经验丰富的临床和基础科学研究人员合作，以获得肾素-血管紧张素-醛固酮系统调节和糖尿病领域的专业知识，同时调查以下三个具体目标： 特定目的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。 特异性目的2检验内源性醛固酮通过MR依赖机制增加代谢综合征患者的空腹血糖和减少胰岛素分泌的假设。 特异性目的3验证MR拮抗和血管紧张素II 1型受体(AT1)拮抗将对空腹血糖和胰岛素分泌产生协同有利作用的假设。 我们将利用先前开发的醛固酮输注和高血糖钳夹方法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，这是一组糖尿病的高危人群，以类似地评估MR和AT1拮抗剂治疗的效果。这些研究将对预防代谢综合征患者的糖尿病发展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.