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 这个长期目标 减少脑缺血的严重程度和发病率是最严重的 糖尿病并发症，占死亡率的84％以上。 缺血表明，糖尿病会使其发病率其其其发病率，并加剧了小脑缺血的后果， 在临床研究中，主要因素之一是高血糖。 能够延迟糖尿病的次要并发症的发作和慢速进度 强烈的抗糖尿病治疗是低血糖。 1型和2型患者接受密集疗法。 事先暴露于降低血糖的中风/血栓形成风险，划定潜在机制，并且 了解低血糖加剧脑缺血伤害伤害伤害的机制 糖尿病（ITD）大鼠。 与对照相比，我们的血栓形成明显更大。 ITD大鼠对无偏的RNA-seq分析更敏感，随后的实时PCR 免疫印迹经验表明，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，从暴露于RH的ITD大鼠中收获的血小板。 导致明显的脑缺血后灌注液。 对于脑缺血后的灌注缺陷，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。 提高血栓形成风险（中风风险的替代风险）所需的最小自由rh暴露率 ITD大鼠作为此效果的持续时间2。 大鼠增加血栓形成的风险。 RH暴露的ITD大鼠的缺血性脑损伤。 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 糖尿病以帮助降低脑缺血的风险。