Hypoglycemia, mineralocorticoid receptor and autonomic control

低血糖、盐皮质激素受体和自主控制

• 批准号: 8680352
• 负责人: ROY FREEMAN
• 金额: $ 51.04万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8680352
• 关键词: Address; Adrenal Glands; Adverse effects; Aldosterone; Antihypertensive Agents; Attenuated; Autonomic Dysfunction; Baroreflex; Blood; Blood Glucose; Cardiac; Cardiovascular Diseases; Cardiovascular Physiology; Cardiovascular system; Cell Nucleus; Clinical Research; Complications of Diabetes Mellitus; Critical Illness; Data; Diabetes Mellitus; Disease; Event; Exposure to; Failure; Glycosylated hemoglobin A; Goals; Hyperglycemia; Hypoglycemia; Impairment; Incidence; Individual; Intensive Care; Intensive Care Units; Intervention; Lead; Limb structure; Lower Body Negative Pressure; Metabolic; Mineralocorticoid Receptor; Mineralocorticoids; Morbidity - disease rate; Multi-Institutional Clinical Trial; Muscle; Myocardial Infarction; Nerve; Neurons; Non-Insulin-Dependent Diabetes Mellitus; Nucleus solitarius; Patients; Population; Predisposition; Randomized; Regimen; Simulate; Steroids; Stress; Testing; Therapeutic Intervention; Woman; adverse outcome; attenuation; base; diabetes management; diabetic; eplerenone; glycemic control; high risk; improved; in vivo; intravenous administration; men; mortality; pre-clinical; prevent; response

DESCRIPTION (provided by applicant): Control of blood glucose is the cornerstone of diabetes management because glycemic control decreases the incidence and progression of diabetic complications. The implementation of rigorous regimens to control blood glucose levels in patients with diabetes mellitus has led to an increased incidence of severe iatrogenic hypoglycemic events. Unfortunately, hypoglycemia itself impairs the ability of individuals to respond appropriately to subsequent hypoglycemia - a disorder known as hypoglycemia associated autonomic failure, thus increasing the predisposition to severe hypoglycemia and its consequences. Recently an increase in mortality was observed in the highly-intensive treatment limb (targeting HbA1c values of <6%) of a multi-center clinical trial of individuals with type 2 diabetes at high risk for cardiovascular disease events. In addition, a multi-center study in the intensive care setting, demonstrated increased mortality in hyperglycemic patients randomized to highly intensive glycemic control. While the cause of the mortality in these studies could not be directly attributed to hypoglycemia, the studies raise concerns about potential indirect consequences of hypoglycemia. Because there is evidence that cardiovascular autonomic impairment is associated with, and may cause, increased mortality in diabetic and post-myocardial infarct populations, we hypothesized that antecedent hypoglycemia may impair cardiovascular autonomic function. In preliminary studies, we showed that antecedent hypoglycemia resulted in significant decreases in: (i) cardiac vagal baroreflex sensitivity (ii) the sympathetic response to a transient pharmacologically induced hypotensive stress and (iii) the sympathetic response to graded simulated orthostatic stress using lower body negative pressure. We also showed that hypoglycemia increases circulating aldosterone levels (administration of aldosterone reduces cardiovagal baroreflex sensitivity and reduces the muscle sympathetic nerve activity response). In this proposal, we wish to extend these studies to develop a mechanism based intervention to attenuate the cardiovascular autonomic changes induced by antecedent hypoglycemia. The specific aims of the proposal are to determine whether treatment with a mineralocorticoid receptor antagonist prevents: (1) attenuation of cardiovagal autonomic function in euglycemic subjects after exposure to hypoglycemia, (2) attenuation of cardiac sympathetic function in euglycemic subjects after exposure to hypoglycemia and (3) attenuation of cardiovagal baroreflex function during hypoglycemia Thus, the broad long term objectives are (1) to understand the autonomic cardiovascular consequences of hypoglycemia; (2) to determine the mechanisms involved; (3) to develop treatments to ameliorate any adverse consequences; and (4) thereby allow for safe and effective rigorous glycemic control in individuals with diabetes mellitus and critically ill patients.

描述（由申请人提供）：血糖的控制是糖尿病管理的基石，因为血糖控制降低了糖尿病并发症的发生率和进展。糖尿病患者中严格的治疗血糖水平的严格方案导致严重的医源性降糖事件的发生率增加。不幸的是，低血糖本身会损害个体对随后的低血糖的适当反应的能力 - 一种称为低血糖相关的自主教衰竭的疾病，从而增加了严重低血糖症及其后果的倾向。 最近，在高度密集型治疗的肢体（靶向HbA1c值<6％的靶向HBA1C值）的多中心临床试验中，死亡率增加了，患心血管疾病事件的高风险高风险的个体。此外，在重症监护环境中进行的一项多中心研究表明，在随机分配到高血糖患者到高度强化血糖控制的高血糖患者中的死亡率增加。尽管这些研究中死亡率的原因不能直接归因于低血糖，但这些研究引起了人们对低血糖潜在间接后果的担忧。因为有证据表明心血管自主神经障碍与糖尿病和肌关注后梗死的死亡率增加有关，并且可能导致心肌梗死的死亡率增加，所以我们假设前降血糖可能会损害心血管自治功能。在初步研究中，我们表明先决性低血糖症导致：（i）心脏迷走神经性压力反射敏感性（ii）对短暂性药理学诱导的降压应激的交感神经反应，以及（iii）使用较低体内负压对分级的模拟正静力压力的交感神经反应。我们还表明，低血糖会增加循环醛固酮水平（醛固酮的给药降低了心脏伏安的压力反射敏感性并降低了肌肉交感神经活动反应）。 在此提案中，我们希望扩展这些研究，以开发基于机制的干预措施，以减轻先决性低血糖引起的心血管自主变化。 The specific aims of the proposal are to determine whether treatment with a mineralocorticoid receptor antagonist prevents: (1) attenuation of cardiovagal autonomic function in euglycemic subjects after exposure to hypoglycemia, (2) attenuation of cardiac sympathetic function in euglycemic subjects after exposure to hypoglycemia and (3) attenuation of cardiovagal baroreflex function during低血糖因此，广泛的长期目标是（1）了解低血糖的自主性心血管后果； （2）确定所涉及的机制； （3）开发治疗方法以改善任何不利后果； （4）因此，糖尿病患者和重症患者允许安全有效的严格血糖控制。