Hypoglycemia, mineralocorticoid receptor and autonomic control

描述（由申请人提供）：血糖控制是糖尿病管理的基石，因为血糖控制可以减少糖尿病并发症的发生和进展。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做出适当反应的能力——这种疾病被称为低血糖相关的自主神经衰竭，从而增加了严重低血糖及其后果的易感性。最近，在一项针对心血管疾病事件高风险的2型糖尿病患者的多中心临床试验中，观察到高强度治疗肢体（目标HbA1c值<6%）死亡率增加。此外，在重症监护环境下的一项多中心研究表明，随机分配到高度强化血糖控制组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间接后果的关注。因为有证据表明心血管自主神经损伤与糖尿病和心肌梗死后人群死亡率增加相关，并且可能导致死亡率增加，我们假设先前的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：(i)心脏迷走神经压力反射敏感性（ii）对短暂药物诱导的低血压应激的交感反应（iii）对使用下体负压的梯度模拟直立应激的交感反应。我们还发现，低血糖可增加循环醛固酮水平（醛固酮可降低心血管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神经变化。该建议的具体目的是确定矿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血管自主神经功能衰减；(2)正常血糖受试者暴露于低血糖后心脏交感神经功能衰减；(3)低血糖期间心血管压力反射功能衰减。因此，广泛的长期目标是：(1)了解低血糖对心血管自主神经的影响；（二）确定所涉及的机制；（三）研究改善不良后果的治疗方法；(4)因此可以安全有效地严格控制糖尿病患者和危重病人的血糖。

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.