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，因为血糖控制可降低糖尿病并发症的发生率和进展。在糖尿病患者中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，低血糖症本身损害了个体对随后的低血糖症（一种称为低血糖症相关的自主神经衰竭的病症）做出适当反应的能力，从而增加了严重低血糖症及其后果的易感性。 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，在高强度治疗分支（目标HbA 1c值<6%）中观察到死亡率增加。此外，一项在重症监护环境中进行的多中心研究表明，随机接受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，但这些研究引起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功能损害与糖尿病和心肌梗死后人群的死亡率增加有关，并可能导致死亡率增加，因此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）对短暂性刺激诱导的过度应激的交感神经反应和（iii）对使用下体负压的分级模拟直立性应激的交感神经反应。我们还表明，低血糖症增加循环醛固酮水平（醛固酮的管理降低心迷走神经压力反射敏感性和减少肌肉交感神经活动的反应）。 在这个建议中，我们希望扩展这些研究，以开发一种基于机制的干预措施，以减轻由前期低血糖引起的心血管自主神经变化。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）暴露于低血糖后血糖正常受试者的心迷走神经自主神经功能的衰减，（2）暴露于低血糖后血糖正常受试者的心交感神经功能的衰减，和（3）低血糖期间心迷走神经压力反射功能的衰减。因此，广泛的长期目标是（1）了解低血糖症的自主心血管后果;（2）确定所涉及的机制;（3）开发治疗以改善任何不良后果;和（4）从而允许在患有糖尿病的个体和危重患者中进行安全和有效的严格血糖控制。

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.