Cerebral ischemia and exposure to recurrent hypoglycemia in diabetes

糖尿病患者的脑缺血和反复低血糖

• 批准号: 10477358
• 负责人: Kunjan R Dave
• 金额: $ 40.76万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10477358
• 关键词: Accounting; Acute; American; Animal Model; Antidiabetic Drugs; Awareness; Blood Glucose; Blood Platelets; Blood coagulation; Calcium Signaling; Cardiovascular system; Cerebral Ischemia; Cerebrum; Clinical Research; Coagulation Process; Collaborations; Complications of Diabetes Mellitus; Development; Diabetes Mellitus; Event; Exposure to; Frequencies; Functional disorder; Goals; Harvest; Health; Heart Arrest; Heart Diseases; Hematologist; Hyperglycemia; Hypoglycemia; Impairment; Incidence; Individual; Induced Heart Arrest; Insulin; Insulin-Dependent Diabetes Mellitus; Ischemic Brain Injury; Ischemic Stroke; Literature; Masks; Megakaryocytes; Molecular; Neurologic; Non-Insulin-Dependent Diabetes Mellitus; Oral; Outcome; PLC gamma1; Pathway interactions; Patients; Perfusion; Phosphatidylinositols; Phospholipids; Platelet Activation; Platelet aggregation; Play; Predisposition; Rattus; Recurrence; Reporting; Risk; Risk Factors; Role; Severities; Stimulus; Stroke; Symptoms; System; Testing; Thrombosis; Thrombus; Time; Western Blotting; base; cerebral ischemic injury; cerebrovascular; diabetes management; diabetic; diabetic rat; epidemiology study; experience; experimental study; hazard; hypoperfusion; improved; in vivo Model; insight; member; mortality; novel; phospholipase C gamma; side effect; small hairpin RNA; stroke risk; therapeutic target; transcriptome sequencing

Project Summary The long-term goal of this project is to improve the neurological health of patients with diabetes by decreasing the severity and incidence of cerebral ischemia. Stroke and heart disease are the most serious complications of diabetes, accounting for more than 84% of the mortality. Epidemiological studies of cerebral ischemia suggest that diabetes increases its incidence and exacerbates the consequences of cerebral ischemia, with one of the main contributing factors being hyperglycemia. In clinical studies, intensive anti-diabetic therapy was able to delay the onset and slow progression of secondary complications of diabetes. The major side-effect of intensive anti-diabetic therapy is hypoglycemia. Recurrent hypoglycemia (RH) episodes are common among type 1 and type 2 patients receiving intensive therapy. Thus, the goal of this project is to evaluate the impact of prior exposure to hypoglycemia on the risk of stroke/thrombosis, delineate underlying mechanisms, and understand the mechanism by which hypoglycemia exacerbates cerebral ischemic damage using insulin-treated diabetic (ITD) rats. Using an in vivo model of thrombosis, we observed that ITD rats with prior exposure to RH develop significantly larger thrombi compared to the controls. We also observed that platelets from RH-exposed ITD rats are more sensitive to an aggregation stimulus. Unbiased RNA-seq analysis, subsequent real-time PCR, and immunoblotting experiments demonstrate increased levels of phospholipase c γ-1 (PLCγ1), a member of phosphoinositide-specific PLCs that plays an important role in platelet activation via intracellular calcium signaling, in platelets harvested from RH-exposed ITD rats. We also observed that exposure of ITD rats to RH leads to pronounced post-cerebral ischemic hypoperfusion. Post-ischemic platelet activation may be responsible for post-cerebral ischemic perfusion deficits. In view of these, we hypothesize that prior exposure to RH increases the risk of cerebral ischemia and exacerbates post-cerebral ischemia hypoperfusion by platelet dysfunction. To test this hypothesis, we propose the following specific aims: Aim 1: Determine the minimum frequency of RH exposure required to increase the risk of thrombosis (a surrogate for stroke risk) in ITD rats as well as the duration of this effect. Aim 2: Evaluate the mechanism by which prior exposure of ITD rats to RH increases the risk of thrombosis. Aim 3: Evaluate the role of platelet dysfunction in exacerbated ischemic brain damage in RH-exposed ITD rats. We expect these studies to provide insight into the mechanism by which prior exposure to RH increases cerebral ischemia risk and post-cerebral ischemic damage in patients with diabetes in order to help lower their risk of cerebral ischemia.

项目摘要 该项目的长期目标是通过以下方式改善糖尿病患者的神经健康 降低脑缺血的严重程度和发生率。中风和心脏病是最严重的 糖尿病并发症，占死亡率的84%以上。脑部疾病的流行病学研究 缺血提示糖尿病会增加其发病率，并加剧脑缺血的后果， 其中一个主要因素是高血糖。在临床研究中，强化抗糖尿病治疗 能够延缓糖尿病继发性并发症的发病和缓慢进展。主要的副作用 强化抗糖尿病治疗的关键是低血糖。复发性低血糖(RH)在以下人群中很常见 1型和2型患者接受强化治疗。因此，该项目的目标是评估 事先暴露于低血糖对中风/血栓形成风险的影响，描述潜在的机制，以及 通过胰岛素治疗了解低血糖加重脑缺血损伤的机制 糖尿病(ITD)大鼠。利用体内血栓形成模型，我们观察到既往接触RH的ITD大鼠 与对照组相比，血栓明显增大。我们还观察到暴露在RH中的血小板 ITD大鼠对聚集刺激更敏感。无偏的RNA-SEQ分析、随后的实时聚合酶链式反应 免疫印迹实验表明磷脂酶cγ-1(PLCγ1)水平增加，这是 磷脂酰肌醇特异的PLC通过细胞内钙在血小板活化中发挥重要作用 从RH暴露的ITD大鼠采集的血小板中的信号。我们还观察到，ITD大鼠暴露于RH 导致明显的脑缺血后低灌注率。脑缺血后血小板活化可能是原因之一 用于治疗脑缺血后的血流灌注缺陷。有鉴于此，我们假设先前接触RH 增加了脑缺血的风险，并加剧了脑缺血后的低灌注率 血小板功能障碍。为了验证这一假设，我们提出了以下具体目标：目标1：确定 增加血栓形成风险(中风风险的替代物)所需的RH暴露的最低频率 以及ITD大鼠这种作用的持续时间。目的2：评价ITD先天暴露的机制 大鼠向RH增加血栓形成的风险。目的3：评价急性加重期患者血小板功能障碍的作用 RH暴露ITD大鼠的缺血性脑损伤。我们希望这些研究能为我们深入了解这一机制提供帮助。 预先暴露于RH会增加患者的脑缺血风险和脑缺血后损害 患有糖尿病的人，以帮助降低他们患脑缺血的风险。