Glucose Metabolism Is Required for Platelet Hyperactivation in a Murine Model of Type 1 Diabetes
Glucose Metabolism Is Required for Platelet Hyperactivation in a Murine Model of Type 1 Diabetes
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DOI：
10.2337/db18-0981
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发表时间：
2019-05-01
期刊：
影响因子：
7.7
通讯作者：
Abel, E. Dale
中科院分区：
文献类型：
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作者：
Fidler, Trevor P.;Marti, Alex;Abel, E. Dale
1型糖尿病（T1 DM）患者血栓形成和血小板活化增加。糖尿病患者血小板过度活化的机制尚不完全清楚。除了激素环境改变外，T1 DM还伴有高血糖症、血脂异常和炎症增加。体外血小板分析显示，正常葡萄糖降低血小板活化，而高血糖条件下增加血小板活化。因此，我们假设高血糖增加了血小板葡萄糖利用率，这增加了血小板活化，促进血栓形成。从给予链脲佐菌素（STZ）诱导T1 DM的小鼠中分离的血小板中葡萄糖摄取和糖酵解增加，与GLUT 3的诱导一致。STZ诱导的糖尿病小鼠的血小板在给予蛋白酶激活受体4肽和惊厥素后表现出活化增加。相比之下，从缺乏利用葡萄糖能力的GLUT 1和GLUT 3双敲除（DKO）小鼠中分离的血小板未能增加高血糖小鼠的激活。在胶原蛋白/肾上腺素诱导的体内血小板活化肺栓塞模型中，相对于非糖尿病对照组，糖尿病小鼠的存活率降低。相对于非糖尿病对照组，糖尿病DKO小鼠肺栓塞后的存活率增加。这些数据表明，体内血小板葡萄糖代谢增加导致T1 DM模型中血小板活化和血栓形成增加。
Patients with type 1 diabetes mellitus (T1DM) have increased thrombosis and platelet activation. The mechanisms for platelet hyperactivation in diabetes are incompletely understood. T1DM is accompanied by hyperglycemia, dyslipidemia, and increased inflammation in addition to an altered hormonal milieu. In vitro analysis of platelets revealed that normal glucose reduces platelet activation whereas hyperglycemic conditions increase platelet activation. We therefore hypothesized that hyperglycemia increases platelet glucose utilization, which increases platelet activation to promote thrombosis. Glucose uptake and glycolysis were increased in platelets isolated from mice given streptozotocin (STZ) to induce T1DM in concert with induction of GLUT3. Platelets from STZ-induced diabetic mice exhibited increased activation after administration of protease-activated receptor 4 peptide and convulxin. In contrast, platelets isolated from GLUT1 and GLUT3 double-knockout (DKO) mice, which lack the ability to use glucose, failed to increase activation in hyperglycemic mice. Diabetic mice displayed decreased survival in a collagen/epinephrine-induced pulmonary embolism model of in vivo platelet activation relative to nondiabetic controls. Survival after pulmonary embolism was increased in diabetic DKO mice relative to nondiabetic controls. These data reveal that increased platelet glucose metabolism in vivo contributes to increased platelet activation and thrombosis in a model of T1DM.