DIABETES ASSOCIATED BRAIN DAMAGE FOLLOWING SEVERE HYPOGLYCEMIA

描述（由申请人提供）：低血糖是胰岛素治疗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，对严重低血糖造成“脑损伤”的潜在危险的担忧仍然是努力充分实现强化血糖控制相关益处的一个非常现实的障碍。动物实验表明，严重的低血糖可导致脑损伤和认知障碍。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，因为在记录认知损伤程度的报告中存在明显的差异。下面提出的初步研究表明，血糖控制可以显著改善或加重严重低血糖发作后的脑损伤程度。该建议的总体假设是，糖尿病相关的代谢紊乱加重了胰岛素诱导的严重低血糖发作后神经元损伤的程度，强化血糖控制和特异性神经保护剂可以有效减轻这种类型的脑损伤及其相关的认知缺陷。这一建议旨在发展预防低血糖对大脑有害影响的方法。在本研究计划中要解决的具体目标是：1)确定糖尿病是否会增加严重低血糖发作后脑损伤和认知能力下降的程度，并探讨胰岛素作为神经保护剂减轻脑损伤和认知缺陷的可能性；2)探讨复发性先前低血糖对大脑进行预调节的可能性，从而保护对照组和糖尿病大鼠免受严重低血糖的脑损伤影响。并确定这种保护现象的可能介质，以及3)确定药物在预防严重低血糖发作后脑损伤和认知功能障碍方面的功效。

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.