Cerebral ischemia and exposure to recurrent hypoglycemia in diabetes

糖尿病患者的脑缺血和反复低血糖

基本信息

批准号：
10646440
负责人：
Kunjan R Dave
金额：
$ 41.14万
依托单位：
UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
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/10646440
关键词：
Acceleration Accounting Acute American Animal Model Antidiabetic Drugs Awareness Blood Glucose Blood Platelets Blood coagulation Calcium Signaling Cardiovascular system Cerebral Ischemia 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 Ischemia 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 Induction Platelet aggregation Play Predisposition Rattus Recurrence Reporting Risk Risk Factors Role Severities Stimulus Stroke Symptoms System Testing Thrombosis Thrombus Time Western Blotting cerebral ischemic injury cerebrovascular comparison control diabetes management diabetic patient diabetic rat epidemiology study experience experimental study hazard hypoperfusion improved in vivo Model insight member mortality novel side effect small hairpin RNA stroke risk therapeutic target transcriptome sequencing

项目摘要

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改善糖尿病患者的神经系统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。大脑的流行病学研究缺血表明，糖尿病会增加其入口，并加剧脑缺血的后果，主要因素之一是高血糖。在临床研究中，强化抗糖尿病治疗能够延迟糖尿病继发并发症的发作和缓慢进展。主要的副作用强化抗糖尿病治疗是低血糖。复发性低血糖（RH）发作很常见 1型和2型患者接受强化治疗。那个项目的目的是评估事先暴露于低血糖的中风/血栓形成风险，划定潜在机制和了解胰岛素治疗的低血糖加剧脑缺血损伤的机制糖尿病（ITD）大鼠。使用体内血栓形成模型，我们观察到ITD大鼠事先暴露于RH 与对照组相比，与对照组相比，产生明显更大的血栓。我们还观察到来自RH暴露的血小板 ITD大鼠对聚集刺激更敏感。无偏的RNA-seq分析，随后的实时PCR，免疫印迹实验表明，磷脂酶Cγ-1（PLCγ1）的水平增加，这是一个成员通过细胞内钙在血小板激活中起重要作用的磷酸肌醇特异性PLC 信号传导，在从暴露于Rh的ITD大鼠中收获的血小板中。我们还观察到ITD大鼠暴露于RH 导致明显的脑缺血性灌注不足。缺血后血小板激活可能是负责用于脑外缺血性灌注不足。鉴于这些，我们假设事先暴露于RH 增加脑缺血的风险，并通过血小板功能障碍。为了检验这一假设，我们提出以下特定目的：目标1：确定提高血栓形成风险（中风风险的替代风险）所需的最小RH暴露频率 ITD大鼠以及这种作用的持续时间。目标2：评估事先暴露ITD的机制大鼠rh增加了血栓形成的风险。目标3：评估血小板功能障碍在恶化中的作用 RH暴露的ITD大鼠缺血性脑损伤。我们希望这些研究能够洞悉机制通过这种情况，患者的脑缺血风险和脑缺血后的脑缺血风险增加患有糖尿病，以帮助降低其脑缺血的风险。