HYPOGLYCEMIA AND AUTONOMIC NERVOUS SYSTEM FUNCTION

糖尿病控制和并发症试验和英国前瞻性糖尿病研究 已经明确证明，改善血糖控制可以降低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，这限制了糖尿病的血糖管理。 近期发生的医源性低血糖损害了神经系统和自主神经对后续低血糖的反应-一种称为低血糖相关自主神经功能衰竭的疾病-从而增加了重度低血糖的易感性。目前尚不清楚前期低血糖是否对自主神经系统功能有更广泛的影响。自主神经功能受损与糖尿病患者死亡率和发病率增加有关。如果低血糖引起全身性自主神经功能障碍，则可能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相关的自主神经功能衰竭的机制。这些研究验证了一个假设，即前期低血糖不仅损害了对后续低血糖的反调节反应，而且损害了心血管自主神经功能 在非低血糖人群中。这些研究将检查心血管自主神经功能的标志物，当受损时，与糖尿病患者发病率和死亡率增加相关。此外，我们假设，前期低血糖导致血清皮质醇的上升，皮质醇激活糖皮质激素受体介导的低血糖相关的自主神经功能衰竭的发展。 该提案的具体目的是评估先前的正常和低血糖后心血管功能的自主控制。此外，我们将确定是否给予糖皮质激素受体拮抗剂，米非司酮，在前期低血糖改善自主神经和神经内分泌反应，随后在健康的男性和女性低血糖。 因此，该提案的广泛的长期目标是充分了解这些机制， 低血糖相关的自主神经功能衰竭的后果，最终目标是找到一种有效的治疗方法。

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.