HYPOGLYCEMIA AND AUTONOMIC NERVOUS SYSTEM FUNCTION

糖尿病控制和并发症试验及英国前瞻性糖尿病研究 明确地证明，改善血糖控制可以减少糖尿病微血管并发症的发生率和进展。严格控制糖尿病患者血糖的方案的实施导致严重医源性低血糖事件的发生率增加，从而限制了糖尿病的血糖管理。 最近发生的医源性低血糖损害了神经烯：分泌和自主神经对随后低血糖的反应--一种称为低血糖相关性自主神经衰竭的疾病--从而增加了严重低血糖的易感性。目前尚不清楚先天低血糖是否对自主神经系统功能有更普遍的影响。在糖尿病患者中，自主神经功能受损与死亡率和发病率增加有关。如果低血糖导致全身性自主神经功能障碍，可能会进一步增加糖尿病相关的死亡率和发病率。本研究的目的是了解低血糖与自主神经衰竭相关的机制。建议的研究验证了这一假设，即先天低血糖不仅会损害对后续低血糖的反调节反应，还会损害心血管自主神经功能。 在非低血糖个体中。这些研究将检查心血管自主神经功能的那些标记物，当这些标记物受损时，与糖尿病患者发病率和死亡率的增加有关。此外，我们假设先天低血糖导致血清皮质醇升高，糖皮质激素受体的皮质醇激活介导了低血糖相关的自主神经衰竭的发展。 该建议的具体目的是评估先前的正常血糖和低血糖后心血管功能的自主控制。此外，我们将确定糖皮质激素受体拮抗剂米非司酮是否能改善健康男性和女性对后续低血糖的自主神经和神经内分泌反应。 因此，该提案的广泛长期目标是充分了解机制和 低血糖的后果与自主神经衰竭有关，最终目标是找到有效的治疗方法。

The Diabetes Control and Complications Trial and the United Kingdom Prospective Diabetes Study have documented unequivocally that improved glycemic control decreases the incidence and progression of microvascular complicatons of diabetes. The implementation of regimens to rigorously control blood sugar in diabetic patients has led to an increased incidence of severe iatrogenic hypoglycemic events that have limited glycemic management of diabetes mellitus. Recent antecedent iatrogenic hypoglycemia impairs the neuroende:rine and autonomic response to subsequent hypoglycemia - a disorder known as hypoglycemia associated autonomic failure - thus increasing the predisposition to severe hypoglycemia. It is not known whether antecedent hypoglycemia has more general effects on autonomic nervous system function. Impaired autonomic function is associated with increased mortality and morbidity in individuals with diabetes mellitus. If hypoglycemia induces generalized autonomic dysfunction it may further increase the mortality and morbidity associated with diabetes mellitus. The goal of this research is to understand the mechanisms of hypoglycemia associated autonomic failure. The proposed studies test the hypothesis that antecedent hypoglycemia not only impairs the counterregulatory response to subsequent hypoglycemia but also impairs cardiovascular autonomic function in non-hypoglycemic individuals. These studies will examine those markers of cardiovascular autonomic function that, when impaired, are associated with increased morbidity and mortality in patients with diabetes. Furthermore, we hypothesize that antecedent hypoglycemia causes a rise in serum cortisol and that cortisol activation of glucocorticoid receptors mediates the development of hypoglycemia associated autonomic failure. The specific aims for the proposal are to assess autonomic control of cardiovascular function following antecedent euglycemia and hypoglycemia. In addition, we will determine whether administration of a glucocorticoid receptor antagonist, mifepristone, prior to antecedent hypoglycemia improves the autonomic and neuroendocrine response to subsequent hypoglycemia in healthy men and women. Thus, the broad long term objectives of the proposal are to fully understand the mechanisms and consequences of hypoglycemia associated autonomic failure with the ultimate goal of finding an efficacious treatment.