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

• 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
• 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

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）：血糖的控制是糖尿病管理的基石，因为血糖控制降低了糖尿病并发症的发生率和进展。糖尿病患者中严格的治疗血糖水平的严格方案导致严重的医源性降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的适当反应的能力 - 一种称为低血糖相关的自主教衰竭的疾病，从而增加了严重低血糖症及其后果的倾向。 最近，在具有高度密集型治疗的肢体（靶向<6％的HBA1C值）的多中心临床试验中，死亡率增加了 2型糖尿病患心血管疾病事件的高风险。此外，一项多中心研究I重症监护环境表明，高血糖患者的死亡率增加了，随机分配至高度强化血糖对照。尽管这些研究中死亡率的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担忧。因为有证据表明心血管自主神经障碍与糖尿病和肌关注后梗死的死亡率增加有关，并且可能导致心肌梗死的死亡率增加，所以我们假设前降血糖可能会损害心血管自治功能。在初步研究中，我们表明先决性低血糖症会显着降低：（i）对瞬态药理诱导的降压应激和（iii）对较低体内负压分级的模拟正静力压力的瞬时药理诱导的降压应激和（iii）对短暂性药理诱导的降压应激的交感神经反应。我们还表明，低血糖会增加循环醛固酮和白介素6（IL-6）水平。醛固酮和IL-6具有促炎性，引起血管损伤，并与心血管疾病的病理生理有关。此外，醛固酮和IL-6都减轻了自主功能。 在此提案中，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）确定前血糖对尤利血糖受试者中心脏伏拉加那的降压和交感神经性心血管功能的影响； （2）确定低血糖症期间低血糖症对心脏反射功能的影响； （3）确定低血糖症期间低血糖症对醛固酮和IL-6水平的影响；并确定矿物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的自主性心血管后果； （2）确定所涉及的机制； （3）开发治疗方法以改善任何不利后果； （4）因此，可以安全有效地严格的血糖控制。