Mechanisms of Hypoglycemia-Associated Authonomic Failure

描述（由申请人提供）：1型糖尿病（T1 DM）的强化血糖控制与明确的健康益处相关。然而，对于大多数患者来说，维持接近正常的血糖水平仍然是一个难以实现的目标，这在很大程度上是由于低血糖水平（低血糖症）的风险。T1 DM患者易发生低血糖，原因是反调节反应（CR）缺陷，其特征为：1）即将发生的低血糖期间胰高血糖素释放不足; 2）低血糖或运动反复发作后，额外的低血糖相关自主神经功能衰竭（HAAF）和运动相关自主神经功能衰竭（EAAF）减弱了交感肾上腺对低血糖的反应，并降低了其他CR;和3）低血糖无意识，降低触发行为反应（例如进食）的症状的阈值。因此，T1 DM中的低血糖风险阻碍了理想的胰岛素治疗，并导致血糖控制不佳。我们的实验室已经探索了一种新的方法，通过将HAAF/EAAF的机制转化为潜在的治疗方法来调节低血糖的CR，从而提高CR。我们之前已经证明，在T1 DM患者中，HAAF可以通过阿片受体阻滞剂来预防。由于肾上腺素能激活对低血糖CR也有调节作用，因此我们假设连接阿片类和肾上腺素能系统的共同机制负责HAAF和EAAF的发展。我们的具体目标是1.检查μ-阿片受体和/或肾上腺素能受体的激活是否调节人类的HAAF，2.建立负责调节HAAF/EAAF的肾上腺素能反应的组分及其与阿片样物质系统的关联，以及3.进行初步临床试验， 慢性阿片受体阻滞剂预防T1 DM患者HAAF的疗效纠正或改善T1 DM患者的低血糖反调节和恢复低血糖意识将代表这些患者管理（包括预防发病或死亡）的巨大进步。

DESCRIPTION (provided by applicant): Intensive glucose control in type 1 diabetes mellitus (T1DM) is associated with clear health benefits. However, maintaining near-normal glycemia remains an elusive goal for most patients, in large part owing to the risk of low glucose levels (hypoglycemia). T1DM patients are susceptible to hypoglycemia due to defective counterregulatory responses (CR) characterized by: 1) deficient glucagon release during impending hypoglycemia; 2) additional hypoglycemia-associated autonomic failure (HAAF) and exercise-associated autonomic failure (EAAF) that blunt the sympathoadrenal responses to hypoglycemia following repeated episodes of hypoglycemia or exercise as well as degrading other CR; and 3) hypoglycemia unawareness, lowering the threshold for symptoms that trigger behavioral responses (e.g. eating). Thus, the risk of hypoglycemia in T1DM impedes ideal insulin treatment and leads to suboptimal glycemic control. Our lab has explored a new approach of enhancing CR by translating mechanisms responsible for HAAF/EAAF into potential therapeutics to modulate the CR to hypoglycemia. We have previously demonstrated that HAAF can be prevented in T1DM patients by opioid receptor blockade. Since adrenergic activation has also a modulatory effect on hypoglycemia CR, we thus hypothesize that a common mechanism linking opioidergic and adrenergic systems is responsible for the development of HAAF and EAAF. Our specific aims are to 1. Examine whether activation of μ-opioid receptors, and/or adrenergic receptors, regulate HAAF in humans, 2. Establish the components of the adrenergic response responsible for modulating HAAF/EAAF and their association with the opioidergic system, and 3. Perform a preliminary clinical trial to examine the efficacy of chronic opioid receptor blockade in preventing HAAF in patients with T1DM. Correction or improvement of hypoglycemia counterregulation and restoring hypoglycemia awareness in patients with T1DM would represent an enormous step forward in the management of these patients, including preventing morbidities or death.