Increased cerebral ischemic injury by repeated hypoglycemic episodes in diabetes

糖尿病患者反复低血糖会加重脑缺血损伤

• 批准号: 8295685
• 负责人: Kunjan R Dave
• 金额: $ 32.31万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-03-01 至 2016-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8295685
• 关键词: 3' Untranslated Regions; ASIC channel; Accounting; Acidosis; Acute; Adverse effects; Affect; American; Binding; Binding Proteins; Binding Sites; Blood Glucose; Blood Vessels; Brain; Brain Injuries; Cerebral Ischemia; Cerebrovascular Circulation; Cerebrum; Chronic; Clinical Research; Complications of Diabetes Mellitus; Diabetes Mellitus; Drops; Epidemiologic Studies; Glucose Transporter; Goals; Health; Heart Diseases; Hippocampus (Brain); Hyperglycemia; Hypoglycemia; Incidence; Injury; Insulin; Ischemia; Lactate Transporter; Lead; Link; Messenger RNA; MicroRNAs; Microscopy; Molecular; Monocarboxylic Acid Transporters; Neurologic; Oral; Outcome; Patients; Pharmacotherapy; Photons; Play; Predisposition; Production; Protein Binding; Proteins; Rat-1; Recurrence; Reporting; Risk; Risk Factors; Role; SLC2A1 gene; Severities; Smooth Muscle Myocytes; Streptozocin; Testing; Treatment Protocols; base; diabetic; diabetic rat; experience; extracellular; glucose transport; glucose uptake; improved; insight; mRNA Stability; mortality; novel; prevent; therapeutic target; vasoconstriction

DESCRIPTION (provided by applicant): The long-term goal of this project is to improve neurological health of diabetics by decreasing the severity and incidence of cerebral ischemia in diabetics. Cerebral ischemia and heart disease are the most serious complications of diabetes, accounting for more than 84% of the mortality among diabetics. Epidemiological studies of cerebral ischemia suggest that diabetes increases both the risk of incidence and exacerbates the consequences of cerebral ischemia. Hyperglycemia is one of the contributing factors. In clinical studies, intensive anti-diabetic therapy was able to delay the onset and slow the progression of secondary complications of diabetes. The major side-effect of intensive diabetic therapy is hypoglycemia. Several reports described hypoglycemic episodes in type 1 and type 2 diabetics receiving intensive therapy. Using the streptozotocin-diabetic rat, we observed that recurrent hypoglycemia (RH) renders the insulin-treated diabetic (ITD) rat brain more sensitive to global cerebral ischemia and results in greater brain damage. Presently, we are proposing to investigate the mechanism by which RH increases ischemic damage in ITD. In preliminary studies we observed that the intra-ischemic extracellular pH drop was enhanced, and the levels of glucose transporters (GLUTs) 1 and 3 were increased in the hippocampus of ITD rats subjected to RH. We hypothesize that in the insulin-treated diabetic brain, increased glucose transporter levels following RH lead to increased intra-ischemic acidosis, sensitizing the brain towards the enhancement of cerebral ischemia-induced damage. The following specific objectives are proposed to test the central hypothesis: 1) To determine how RH increases cerebral ischemic damage in ITD rats; 2) To determine the mechanism by which the larger intra-ischemic pH drop in RH-exposed ITD rats increases cerebral ischemic damage; and 3) To determine the mechanism by which RH increases GLUT1 and GLUT3 levels in the hippocampus of ITD rats. We expect these studies to provide insight into the mechanism by which RH increases ischemic damage in diabetics. Understanding this mechanism will help improve outcome following cerebral ischemia. PUBLIC HEALTH RELEVANCE: Diabetes is a risk factor for cerebral ischemia and heart disease. A major side effect of intensive therapy for diabetics is intermittent low blood glucose levels (hypoglycemia). Our results indicate that intermittent hypoglycemic episodes preceding an ischemic attack result in increased brain damage in diabetics. We propose to determine the mechanisms by which hypoglycemic episodes cause increased susceptibility to cerebral ischemic damage in diabetics.

描述（由申请人提供）：该项目的长期目标是通过降低糖尿病患者脑缺血的严重程度和发生率来改善糖尿病患者的神经健康。脑缺血和心脏病是糖尿病最严重的并发症，占糖尿病患者死亡率的84%以上。脑缺血的流行病学研究表明，糖尿病会增加发病风险并加剧脑缺血的后果。高血糖是促成因素之一。在临床研究中，强化抗糖尿病治疗能够延缓糖尿病继发并发症的发生并减缓其进展。糖尿病强化治疗的主要副作用是低血糖。一些报告描述了接受强化治疗的 1 型和 2 型糖尿病患者的低血糖发作。使用链脲佐菌素糖尿病大鼠，我们观察到反复低血糖（RH）使胰岛素治疗的糖尿病（ITD）大鼠大脑对全脑缺血更加敏感，并导致更大的脑损伤。目前，我们打算研究 RH 增加 ITD 缺血性损伤的机制。在初步研究中，我们观察到接受 RH 的 ITD 大鼠的缺血内细胞外 pH 值下降增强，并且海马中葡萄糖转运蛋白 (GLUT) 1 和 3 的水平增加。我们假设，在接受胰岛素治疗的糖尿病大脑中，RH 后葡萄糖转运蛋白水平增加会导致缺血性酸中毒增加，从而使大脑对脑缺血引起的损伤更加敏感。提出以下具体目标来检验中心假设：1）确定 RH 如何增加 ITD 大鼠的脑缺血损伤； 2) 确定暴露于RH的ITD大鼠缺血区内较大pH值下降增加脑缺血损伤的机制； 3) 确定RH增加ITD大鼠海马GLUT1和GLUT3水平的机制。我们期望这些研究能够深入了解 RH 增加糖尿病患者缺血性损伤的机制。了解这一机制将有助于改善脑缺血后的预后。 公共卫生相关性：糖尿病是脑缺血和心脏病的危险因素。糖尿病患者强化治疗的一个主要副作用是间歇性低血糖水平（低血糖）。我们的研究结果表明，缺血性发作前的间歇性低血糖发作会导致糖尿病患者的脑损伤增加。我们建议确定低血糖发作导致糖尿病患者脑缺血损伤易感性增加的机制。