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(申请人提供)：血糖控制是糖尿病管理的基石，因为血糖控制可降低糖尿病并发症的发生率和进展。实施严格的治疗方案来控制糖尿病患者的血糖水平导致了严重医源性低血糖事件的发生率增加。不幸的是，低血糖本身损害了个体对后续低血糖做出适当反应的能力--一种称为低血糖相关自主神经衰竭的疾病，从而增加了严重低血糖及其后果的易感性。最近，在一项针对具有心血管疾病事件高危风险的2型糖尿病患者的多中心临床试验中，观察到高强度治疗(目标是糖化血红蛋白(HbA1c)为6%)的死亡率有所增加。此外，在重症监护环境下的一项多中心研究表明，随机选择高强度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，但这些研究提出了对低血糖潜在间接后果的担忧。由于有证据表明心血管自主神经损害与糖尿病和心肌梗死后人群死亡率的增加有关，并且可能导致死亡率增加，我们假设先天低血糖可能损害心血管自主神经功能。在初步研究中，我们发现先前的低血糖导致以下方面的显著降低：(1)心脏迷走神经压力反射敏感性；(2)对短暂的药物性低血压应激的交感反应；(3)对使用下体负压的分级模拟立位应激的交感反应。我们还发现，低血糖会增加循环中的醛固酮水平(给予醛固酮会降低心脏迷走神经压力感受性反射的敏感性，并降低肌肉交感神经的活性反应)。在这项建议中，我们希望扩展这些研究，以开发一种基于机制的干预，以减轻由既往低血糖引起的心血管自主神经变化。该建议的具体目的是确定使用盐皮质激素受体拮抗剂治疗是否可以预防：(1)正常血糖受试者暴露于低血糖后心脏迷走神经自主神经功能的减弱，(2)正常血糖受试者暴露于低血糖后心脏交感神经功能的减弱，以及(3)低血糖期间心脏迷走神经压力反射功能的减弱。因此，长期的广泛目标是(1)了解低血糖对自主心血管的影响；(2)确定相关机制；(3)开发治疗方法，以改善任何不利后果；以及(4)从而使患有糖尿病和危重患者的患者能够安全而有效地控制血糖。