Pharmacological Approach to the Restoration of Hypoglycemia Awareness

恢复低血糖意识的药理学方法

基本信息

批准号：
9900777
负责人：
SIMON J FISHER
金额：
$ 38.13万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-04-01 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9900777
关键词：
Animal Model Awareness Biochemical Biological Blood Glucose Clinical Clinical Trials Closure by clamp Complication Defect Diabetes Mellitus Dopamine Antagonists Drug Screening Eating Event FDA approved Failure Food Goals Gold Grant Hormones Hypoglycemia Impairment Incidence Individual Insulin Insulin-Dependent Diabetes Mellitus Laboratories Lead Life Measurement Metoclopramide Outpatients Pathologic Patients Pharmaceutical Preparations Pharmacology Pharmacotherapy Placebos Pre-Clinical Model Preclinical Testing Questionnaires Rattus Recurrence Reporting Risk Rodent Model Savings Symptoms Techniques Testing Therapeutic Agents behavioral response counterregulation diabetes management diabetic diaries drug testing drug use screening experimental study food consumption glucose monitor hypoglycemia unawareness improved indexing novel pre-clinical preconditioning randomized trial response restoration validation studies

项目摘要

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.

抽象的：低血糖是糖尿病日常治疗中最普遍的临床并发症，是使血糖正常化的主要障碍。适用于1型糖尿病（T1DM），低血糖相关的患者自主衰竭（HAAF）将严重低血糖症的风险增加25倍或更多。一个主要组成部分 HAAF的低血糖不认识，涉及警告症状的损失/减轻低血糖通常会引起纠正行为反应（例如，吃食物）。目标确定可能恢复低血糖意识的现有生物学化合物（即，重新利用现有的FDA- 批准的药物），我们的实验室最近使用一种新型低血糖症的动物模型完成了药物筛查预处理大鼠因胰岛素发作而无法增加食物消耗的不认识诱发低血糖。在所有测试的药物中，多巴胺拮抗剂甲氧氯普胺始终恢复我们的几种动物模型中的低血糖意识已测试。拟议赠款中目标1的目标是在HAAF的T1DM动物模型中验证主要药物是否在我们最近的药物筛查中鉴定出来是否还原， 1）低血糖意识，以及2）肾上腺肾上腺低血糖的反应受损。利用黄金标准高胰岛素降血糖夹技术，在两个中提出了药物验证研究 HAAF的独立T1DM啮齿动物模型（低血糖不知道大鼠以及复发性的大鼠低血糖引起的交感神经缺乏症）确定我们领先药物的治疗是否逆转了这些 HAAF的两个主要病理成分。在AIM 2中，提出了一项临床试验来测试是否领导在我们的药物筛选中鉴定出的化合物可以恢复低血糖意识和反调节性 T1DM和HAAF受试者中低血糖的反应。安慰剂受控的随机试验将测试是否使用甲氧氯普胺进行四个星期的治疗（我们的铅药物在几个临床前模型），1）减少低血糖的发生率，2）改善低血糖症状识别， 3）改善了对低血糖的交感神经反应。将评估改进指数，1）低血糖事件日记，低血糖意识问卷和连续的门诊环境葡萄糖监测器和2）在实验室环境中，带有逐步降血糖夹具，可量化症状意识和反调节激素反应的测量。通过前进来自我们最近的药物屏幕的新颖结果，拟议的研究是寻求的下一步的逻辑下一步重新利用现有的FDA批准的药物来治疗1型患者的低血糖症相关的自主衰竭糖尿病。