DIABETES ASSOCIATED BRAIN DAMAGE FOLLOWING SEVERE HYPOGLYCEMIA

描述(申请人提供)：低血糖是接受胰岛素治疗的糖尿病患者日常管理中最常见的临床并发症，低血糖仍然是糖尿病血糖管理的限制因素。对于接受胰岛素治疗的糖尿病患者，对严重低血糖可能导致“脑损伤”的担忧仍然是努力充分实现强化血糖控制相关好处的一个非常现实的障碍。在动物身上的实验表明，严重的低血糖会重复地导致大脑损伤和认知障碍。然而，在糖尿病患者中，严重低血糖的临床后果仍然是一个激烈争议的领域，因为记录认知损害程度的报告存在显著差异。以下提供的初步研究表明，这一新发现表明，血糖控制可以显着改善或恶化严重低血糖发作后的脑损伤程度。这项建议的总体假设是，与糖尿病相关的代谢紊乱会在胰岛素诱导的严重低血糖发作后恶化神经损伤的程度，强化血糖控制和特定的神经保护剂都可以有效地缓解这种类型的脑损伤及其相关的认知缺陷。这项建议寻求开发方法来预防低血糖对大脑的有害影响。本研究建议针对的具体目标是：1)确定糖尿病是否会加剧严重低血糖发作后的脑损伤和认知功能下降的程度，并探讨胰岛素作为神经保护剂缓解严重低血糖发作后脑损伤和认知障碍的可能性；2)探讨反复发生的既往低血糖是否能预适应大脑，从而保护大脑免受严重低血糖对大脑的损害；以及3)确定药物制剂在预防严重低血糖发作后脑损伤和认知功能障碍方面的有效性。 公共卫生相关性：对于接受胰岛素治疗的糖尿病患者来说，对于严重低血糖(低血糖)导致“脑损伤”的危险可能性的担忧，仍然是努力充分实现强化血糖控制相关好处的一个非常现实的障碍。为了开发预防严重低血糖引起的脑损伤和相关的记忆/学习障碍的方法，这些实验的结果有可能改变糖尿病患者的治疗模式。

DESCRIPTION (provided by applicant): Hypoglycemia is the most prevalent clinical complication in the daily management of insulin-treated people with diabetes and hypoglycemia continues to be the limiting factor in the glycemic management of diabetes. For insulin treated people with diabetes, concern regarding the hazardous potential for severe hypoglycemia to cause "brain damage" continues to be a very real barrier in striving to fully realize the benefits associated with intensive glycemic control. Experiments in animals demonstrate that severe hypoglycemia reproducibly leads to brain damage and cognitive impairments. In patients with diabetes however, the clinical consequences of severe hypoglycemia remains an area of intense controversy because there is a marked variability in reports documenting extent of cognitive damage. Preliminary studies presented below demonstrate the novel finding that glycemic control can significantly either improve or worsen the extent of brain damage following an episode of severe hypoglycemia. The overall hypothesis in this proposal is that the metabolic derangements associated with diabetes worsen the extent of neuronal damage following an episode of severe insulin-induced hypoglycemia and that both intensive glycemic control and specific neuroprotective agents can effectively mitigate against this type of brain damage and its associated cognitive deficits. This proposal seeks to develop approaches to prevent the detrimental effects of hypoglycemia on the brain. The specific aims to be addressed in this research proposal are to; 1) determine whether diabetes augments the extent of brain damage and cognitive decline following an episode of severe hypoglycemia and explore the possibility that insulin acts as a neuroprotective agent to mitigate against increased brain damage and cognitive deficits, 2) explore the possibility that recurrent antecedent hypoglycemia acts to pre-condition the brain thus protecting against the brain damaging effects of severe hypoglycemia in control and diabetic rats, and to identify the likely mediators of this protective phenomena, and 3) determine the efficacy of pharmaceutical agents in preventing brain damage and cognitive dysfunction following an episode of severe hypoglycemia. PUBLIC HEALTH RELEVANCE: For insulin treated people with diabetes, concern regarding the hazardous potential for severe low blood sugar (hypoglycemia) to cause "brain damage" continues to be a very real barrier in striving to fully realize the benefits associated with intensive glycemic control. With a goal of developing approaches to prevent severe hypoglycemia-induced brain damage and associated memory/learning deficits, the results from these experiments have the potential for a change in the treatment paradigms for people with diabetes.