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: 10275714
• 负责人: Kunjan R Dave
• 金额: $ 46.12万
• 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/10275714
• 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; Immunoblotting; 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; 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.

项目概要 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。脑病流行病学研究 缺血表明糖尿病会增加其发病率并加剧脑缺血的后果， 主要影响因素之一是高血糖。在临床研究中，强化抗糖尿病治疗 能够延缓糖尿病继发并发症的发生和进展。主要副作用 强化抗糖尿病治疗的关键是低血糖。复发性低血糖 (RH) 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，该项目的目标是评估 先前暴露于低血糖对中风/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低血糖加剧脑缺血损伤的机制 糖尿病（ITD）大鼠。使用血栓形成的体内模型，我们观察到先前暴露于 RH 的 ITD 大鼠 与对照组相比，出现明显更大的血栓。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。无偏的 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) 水平增加，磷脂酶 c γ-1 的成员 磷酸肌醇特异性 PLC，通过细胞内钙在血小板激活中发挥重要作用 从暴露于 RH 的 ITD 大鼠中采集的血小板中的信号传导。我们还观察到 ITD 大鼠暴露于 RH 导致明显的脑缺血后灌注不足。缺血后血小板活化可能是原因 用于脑缺血后灌注不足。鉴于这些，我们假设之前暴露于 RH 增加脑缺血的风险并加剧脑缺血后低灌注 血小板功能障碍。为了检验这一假设，我们提出以下具体目标： 目标 1：确定 增加血栓形成风险（中风风险的替代指标）所需的最低 RH 暴露频率 ITD 大鼠以及这种作用的持续时间。目标 2：评估先前接触 ITD 的机制 给予 RH 的大鼠会增加血栓形成的风险。目标 3：评估血小板功能障碍在病情加重中的作用 暴露于 RH 的 ITD 大鼠的缺血性脑损伤。我们希望这些研究能够深入了解该机制 先前暴露于 RH 会增加患者的脑缺血风险和脑缺血后损伤 糖尿病患者，以帮助降低脑缺血的风险。