Pharmacological Approach to the Restoration of Hypoglycemia Awareness

摘要： 低血糖是糖尿病日常管理中最常见的临床并发症，也是 血糖正常化的主要障碍。对于1型糖尿病(T1 DM)患者，低血糖与 自主神经衰竭(HAF)使严重低血糖的风险增加25倍或更多。一个主要组成部分 低血糖无意识是HAAF的一种症状，它涉及到对 低血糖通常会促使纠正的行为反应(例如，吃东西)。目标是 确定可以恢复低血糖意识的现有生物化合物(即重新调整现有FDA的用途- 批准的药物)，我们的实验室最近使用一种新的低血糖动物模型完成了药物筛选 没有意识到预适应的大鼠对一次胰岛素发作没有增加食物消耗 诱导性低血糖。在所有测试的药物中，多巴胺拮抗剂甲氧氯普胺持续恢复 在我们的几个动物模型中测试了低血糖意识。拟议拨款中目标1的目标是 在T1 DM的HAAF动物模型中验证我们最近的药物筛选中确定的主要药物是否可以恢复两者， 1)对低血糖的认识；2)交感肾上腺对低血糖的反应受损。利用黄金 标准的高胰岛素低血糖钳夹技术，药物验证研究被提出在两个 独立的T1 DM HAAF啮齿动物模型(包括低血糖无意识大鼠和复发大鼠 低血糖引起的交感肾上腺功能缺乏症)，以确定我们的主导药物治疗是否能逆转这些 HAAF的两个主要病理成分。在目标2中，提出了一项临床试验，以测试铅 在我们的药物筛选中发现的化合物可以恢复低血糖意识和反调节 T1 DM和HAAF受试者对低血糖的反应一项安慰剂对照的随机试验将测试 四周的甲氧氯普胺(我们的先导药物注意到在几个方面特别有效 临床前模型)将，1)降低低血糖发生率，2)改善低血糖症状识别， (3)改善交感肾上腺对低血糖的反应。将评估改进指数，1) 门诊环境：低血糖事件日记、低血糖知晓率调查问卷和连续调查 血糖监测仪，以及2)在实验室环境中使用阶梯式降血糖钳，可量化 症状意识和反调节激素反应的测量。通过继续进行 我们最近药物筛选的新结果，拟议的研究是合乎逻辑的下一步寻求 重新调整FDA批准的现有药物用于治疗1型患者低血糖相关性自主神经衰竭 糖尿病。

Abstract: Hypoglycemia is the most prevalent clinical complication in the daily management of diabetes and is the major obstacle to normalizing blood sugar. For people with Type 1 diabetes (T1DM), hypoglycemia associated autonomic failure (HAAF) increases the risk for severe hypoglycemia by a factor of 25 or more. A major component of HAAF is hypoglycemia unawareness, which involves in the loss/diminution of warning symptoms to hypoglycemia that would normally prompt a corrective behavioral response (e.g., eating food). With a goal of identifying existing biological compounds that could restore hypoglycemia awareness (ie, repurpose existing FDA- approved drugs), our laboratory recently completed a drug screen using a novel animal model of hypoglycemia unawareness in which preconditioned rats failed to increase food consumption in response to an episode of insulin induced hypoglycemia. Of all drugs tested, the dopamine antagonist metoclopramide consistently restored hypoglycemia awareness in several of our animal models tested. The goal of Aim 1 in the proposed grant is to validate in T1DM animal models of HAAF whether leading drugs identified in our recent drug screen restore both, 1) hypoglycemia awareness, and 2) the impaired sympathoadrenal response to hypoglycemia. Utilizing the gold standard hyperinsulinemic hypoglycemic clamp technique, drug validation studies are proposed in two independent T1DM rodent models of HAAF (both hypoglycemia unaware rats as well rats with recurrent hypoglycemia-induced sympathoadrenal deficiency) to determine if treatment with our leading drugs reverse these two principal pathologic components of HAAF. In Aim 2, a clinical trial is proposed to test whether the lead compound identified in our drug screen can restore both hypoglycemia awareness and the counterregulatory response to hypoglycemia in subjects with T1DM and HAAF. A placebo controlled, randomized trial will test whether four weeks of treatment with metoclopramide (our lead drug noted to particularly efficacious in several preclinical models) will, 1) reduce the incidence of hypoglycemia, 2) improve hypoglycemia symptom recognition, and 3) improve the sympathoadrenal response to hypoglycemia. Indices of improvement will be assessed, 1) in the outpatient setting with hypoglycemia event diaries, hypoglycemia awareness questionnaires, and continuous glucose monitors, and 2) in the laboratory setting with stepped hypoglycemic clamps which quantifies measurements of symptomatic awareness and counterregulatory hormone responses. By proceeding forward with the novel results from our recent drug screen, the proposed studies are the logical next step in seeking to repurpose existing FDA approved drugs to treat hypoglycemia associated autonomic failure in people with Type 1 diabetes.