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。中风和心脏病最为严重 糖尿病并发症，占死亡率的84%以上。脑卒中的流行病学研究 缺血提示糖尿病增加其发病率并加重脑缺血的后果， 其中一个主要的影响因素是高血糖症。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生和缓慢进展。主要副作用 是低血糖症。复发性低血糖（RH）发作在以下人群中很常见： 接受强化治疗的1型和2型患者。因此，本项目的目标是评估 既往暴露于低血糖对卒中/血栓形成风险的影响，描述潜在机制，以及 了解使用胰岛素治疗的低血糖加重脑缺血损伤的机制 糖尿病（ITD）大鼠。使用体内血栓形成模型，我们观察到先前暴露于RH的ITD大鼠 与对照组相比，血栓明显更大。我们还观察到暴露于RH的血小板 ITD大鼠对聚集刺激更敏感。无偏RNA-seq分析，随后的实时PCR， 和免疫印迹实验表明，磷脂酶c γ-1（PLCγ1）的水平增加， 磷酸肌醇特异性PLC，通过细胞内钙离子在血小板活化中起重要作用 信号，从RH暴露的ITD大鼠中采集的血小板中。我们还观察到ITD大鼠暴露于RH 导致明显的脑缺血后低灌注。缺血后血小板活化可能是 用于脑缺血后灌注不足。鉴于此，我们假设先前暴露于RH 增加脑缺血的风险并加剧脑缺血后灌注不足， 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 增加血栓形成风险所需的RH暴露的最低频率（卒中风险的替代品） ITD大鼠以及这种影响的持续时间。目的2：评价既往暴露于ITD的机制 大鼠RH增加血栓形成的风险。目的3：评价血小板功能障碍在急性心肌梗死中的作用。 RH暴露ITD大鼠的缺血性脑损伤。我们希望这些研究能够提供对机制的深入了解 预先暴露于RH会增加患者脑缺血风险和脑缺血后损伤 以帮助降低他们患脑缺血的风险。