Aldosterone and Glucose Metabolism

醛固酮和葡萄糖代谢

基本信息

批准号：
7681138
负责人：
James Matthew Luther
金额：
$ 17.24万
依托单位：
VANDERBILT UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-09-01 至 2013-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7681138
关键词：
Adult Affect Aldosterone Aldosterone Synthase Angiotensins Atherosclerosis Attenuated Basic Science Blood Glucose Blood Pressure Body mass index Cardiovascular system Central obesity Chymosin Clinical Clinical Trials Data Development Diabetes Mellitus Dyslipidemias Enzyme Inhibition Epidemic Event Fasting Fatty Acids Fibrinolysis Glucose Health Human Hyperglycemia Hypertension Incidence Individual Inflammation Infusion procedures Insulin Insulin Resistance Interruption Laboratories Measures Metabolic syndrome Mineralocorticoid Receptor Mus Non-Insulin-Dependent Diabetes Mellitus Obesity Overweight Patients Peptidyl-Dipeptidase A Potassium Process Protocols documentation Receptor, Angiotensin, Type 1 Regulation Renin-Angiotensin-Aldosterone System Research Research Personnel Risk Study Subject System Testing United States base blood glucose regulation cardiovascular risk factor clinically relevant experience fasting glucose glucose metabolism high risk improved insulin secretion offspring prevent programs receptor treatment effect

项目摘要

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.

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来衡量的葡萄糖稳态受损，伴随肥胖和代谢综合征，最终产生高血糖和明显的糖尿病。弗雷明汉（Framingham）后代研究最近表明，基底醛固酮浓度预测了代谢综合征的发展，这与心血管风险增加有关。我们已经观察到，在醛固酮合酶缺陷型（AS - / - ）小鼠中，空腹葡萄糖浓度降低，并且AS AS - / - 小鼠通过独立于钾的机制表现出增强的葡萄糖刺激的胰岛素分泌。该建议检验了一个中心假设，即醛固酮通过矿物皮质激素受体（MR）依赖性机制减弱了人类中的胰岛素分泌。申请人将与经验丰富的临床和基础科学研究人员合作，以在调节肾素 - 血管紧张素 - 醛固酮系统和糖尿病领域的调节方面获得专业知识，同时研究以下三个特定目标：具体目标1检验假说，即外源性醛固酮通过减弱葡萄糖刺激的胰岛素分泌而增加了人类的空腹葡萄糖浓度。特定目标2检验了内源性醛固酮会增加空腹葡萄糖并通过MR依赖性机制减少代谢综合征个体的胰岛素分泌的假设。特定目标3检验了MR拮抗作用和血管紧张素II型受体（AT1）拮抗作用的假设将对空腹血糖和胰岛素分泌产生协同的有益作用。我们将利用先前开发的方案进行醛固酮输注和高血糖夹，以评估醛固酮对正常受试者中胰岛素分泌的影响。然后，我们将研究具有糖尿病高风险的代谢综合征的受试者，以类似地评估MR和AT1拮抗作用的治疗作用。这些研究将立即具有临床相关性，以防止代谢综合征患者的糖尿病发展。