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.

项目总结