Hypoglycemia, mineralocorticoid receptor and autonomic control

低血糖、盐皮质激素受体和自主控制

• 批准号: 8161121
• 负责人: ROY FREEMAN
• 金额: $ 57.11万
• 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 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8161121
• 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. PUBLIC HEALTH RELEVANCE: Recent studies reveal an increase in mortality associated with intensive glycemic control. There is evidence suggesting hypoglycemia may be implicated in this increased mortality. The goals of this proposal are to (1) determine the mechanisms of and (2) develop mechanism based therapies for hypoglycemia associated cardiovascular autonomic dysfunction.

描述（由申请人提供）：控制血糖是糖尿病管理的基石，因为血糖控制可以降低糖尿病并发症的发生率和进展。糖尿病患者实施严格的血糖控制方案导致严重医源性低血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（一种称为低血糖相关自主神经衰竭的疾病）做出适当反应的能力，从而增加严重低血糖及其后果的倾向。 最近，在一项针对心血管疾病事件高风险 2 型糖尿病患者的多中心临床试验中，在高强度治疗组（目标 HbA1c 值 <6%）中观察到死亡率增加。此外，重症监护环境中的一项多中心研究表明，随机接受高度强化血糖控制的高血糖患者死亡率增加。虽然这些研究中的死亡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的间接后果的担忧。因为有证据表明心血管自主神经损伤与糖尿病和心肌梗塞后人群的死亡率增加有关，并且可能导致其增加，所以我们假设先前的低血糖可能会损害心血管自主神经功能。在初步研究中，我们表明，先前的低血糖导致以下方面显着降低：（i）心脏迷走神经压力反射敏感性（ii）对短暂药理学诱导的低血压应激的交感神经反应，以及（iii）使用下半身对分级模拟直立应激的交感神经反应负压。我们还表明，低血糖会增加循环醛固酮水平（醛固酮的给药会降低心血管迷走神经压力反射敏感性并降低肌肉交感神经活动反应）。 在本提案中，我们希望扩展这些研究，以开发一种基于机制的干预措施，以减轻先前低血糖引起的心血管自主变化。该提案的具体目的是确定盐皮质激素受体拮抗剂治疗是否可以预防：（1）血糖正常受试者暴露于低血糖后心脏迷走神经功能减弱，（2）正常血糖受试者暴露于低血糖后心脏交感功能减弱，以及(3) 低血糖期间心血管迷走神经压力反射功能减弱 因此，广泛的长期目标是 (1) 了解自主心血管低血糖的后果； (2) 确定所涉及的机制； (3) 开发治疗方法以改善任何不良后果； (4)从而可以对糖尿病患者和危重患者进行安全有效的严格血糖控制。 公共卫生相关性：最近的研究表明，死亡率的增加与强化血糖控制相关。有证据表明低血糖可能与死亡率增加有关。该提案的目标是（1）确定低血糖相关的心血管自主神经功能障碍的机制，以及（2）开发基于机制的治疗方法。