Hypoglycemia, Cardiovascular Autonomic Function and Type 2 Diabetes Mellitus

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，在一项多中心的临床试验中，观察到高强度治疗肢体(目标糖化血红蛋白为6%)的死亡率增加。 2型糖尿病是心血管疾病事件的高危人群。此外，在重症监护环境下进行的一项多中心研究显示，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和白介素6(IL-6)水平。醛固酮和IL-6是促炎因子，可引起血管损伤，并参与心血管疾病的病理生理过程。此外，醛固酮和IL-6都减弱了自主神经功能。在这项提案中，我们希望将这些研究扩展到2型糖尿病患者。该建议的具体目的是：(1)确定既往低血糖对正常血糖受试者心脏迷走神经压力反射和交感心血管功能的影响；(2)确定低血糖时低血糖对心血管压力反射功能的影响；(3)确定低血糖时对醛固酮和IL-6水平的影响；以及确定糖皮质激素受体在调节自主神经变化中的作用。因此，广泛的长期目标是(1)了解糖尿病患者低血糖对自主心血管的影响；(2)确定相关机制；(3)开发减轻任何不利后果的治疗方法；以及(4)从而实现安全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 i 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) th 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 and interleukin-6 (IL-6) levels. Aldosterone and IL-6 are proinflammatory, cause vascular injury and are implicated in the pathophysiology of cardiovascular disease. Furthermore, both aldosterone and IL-6 attenuate autonomic function. In this proposal, we wish to extend these studies to individuals with type 2 diabetes. The specific aims of the proposal are (1) to determine the effects of antecedent hypoglycemia on cardiovagal baroreflex and sympathetic cardiovascular function in euglycemic subjects; (2) to determine the effects of hypoglycemia on cardiovagal baroreflex function during hypoglycemia; (3) to determine the effects of hypoglycemia on aldosterone and IL-6 levels during hypoglycemia; and to determine the role of the mineralocorticoid receptor in mediating the autonomic changes. Thus, the broad long term objectives are (1) to understand the autonomic cardiovascular consequences of hypoglycemia in individuals with diabetes; (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.