Hypoglycemia, Cardiovascular Autonomic Function and Type 2 Diabetes Mellitus

低血糖、心血管自主神经功能和 2 型糖尿病

基本信息

批准号：
8885877
负责人：
ROY FREEMAN
金额：
$ 70.03万
依托单位：
BETH ISRAEL DEACONESS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-08-27 至 2016-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8885877
关键词：
Address Aldosterone Antihypertensive Agents Attenuated Autonomic Dysfunction Baroreflex Blood Blood Glucose Blood Vessels Cardiac Cardiovascular Diseases Cardiovascular Physiology Cardiovascular system Complications of Diabetes Mellitus Critical Illness Data Diabetes Mellitus Disease European Event Exposure to Failure Functional disorder Future Glucose Glycosylated hemoglobin A Goals Health Human Hyperglycemia Hypoglycemia Impairment Incidence Individual Inflammatory Infusion procedures Injury Intensive Care Intensive Care Units Interleukin-6 Intervention Intervention Studies Limb structure Lower Body Negative Pressure Mediating Metabolic Mineralocorticoid Receptor Morbidity - disease rate Multi-Institutional Clinical Trial Multicenter Studies Myocardial Infarction Non-Insulin-Dependent Diabetes Mellitus Outcome Patients Placebos Population Predisposition Randomized Regimen Renin-Angiotensin-Aldosterone System Role Stress Testing Woman adverse outcome attenuation base cytokine diabetes management diabetic eplerenone glycemic control high risk improved men mortality response

项目摘要

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.

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，一项多中心临床试验发现，在高强度治疗组（目标 HbA1c 值 <6%）中，死亡率有所增加。 2 型糖尿病是心血管疾病事件的高风险人群。此外，重症监护室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，先前的低血糖会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）对短暂的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。我们还发现，低血糖会增加循环醛固酮和白细胞介素 6 (IL-6) 的水平。醛固酮和 IL-6 具有促炎作用，会导致血管损伤，并与心血管疾病的病理生理学有关。此外，醛固酮和 IL-6 都会减弱自主神经功能。在本提案中，我们希望将这些研究扩展到 2 型糖尿病患者。该提案的具体目的是（1）确定血糖正常的受试者先前发生的低血糖对心血管压力反射和交感心血管功能的影响； (2)确定低血糖对低血糖期间心血管迷走神经压力反射功能的影响； (3)测定低血糖对低血糖期间醛固酮和IL-6水平的影响；并确定盐皮质激素受体在介导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)从而实现安全有效的严格血糖控制。