Diacylglycerol accumulation and microvascular abnormalities induced by elevated glucose levels.
Diacylglycerol accumulation and microvascular abnormalities induced by elevated glucose levels.
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葡萄糖水平升高引起的二酰甘油积累和微血管异常。
DOI：
10.1172/jci114988
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发表时间：
1991
期刊：
影响因子：
--
通讯作者：
Turk,J
中科院分区：
文献类型：
--
作者：
Wolf,BA;Williamson,JR;Easom,RA;Chang,K;Sherman,WR;Turk,J
进行本实验以检查葡萄糖诱导的1，2-二酰基-sn-甘油从头合成增加（这已在许多不同组织中观察到，包括体外暴露于升高的葡萄糖水平的视网膜毛细血管内皮细胞）和蛋白激酶C的相关活化可能在介导葡萄糖诱导的血管功能变化中起作用的假设。我们在这里报告，每天两次滴注30 mM葡萄糖超过10天的大鼠皮肤室肉芽组织模型诱导约2.7倍的二酰基甘油（DAG）水平增加（与组织暴露于5 mM葡萄糖）与显着增加血管清除白蛋白和血流量。葡萄糖诱导的DAG水平增加以及血管功能变化可通过添加3 mM丙酮酸来预防。在5 mM葡萄糖存在下，用佛波醇酯TPA药理学活化蛋白激酶C增加微血管白蛋白清除率和血流量，并且用1-单油酸甘油酯（MOG）（内源性DAG的catalytic的药理学抑制剂）观察到类似的作用。蛋白激酶C的药理学抑制剂（星形孢菌素）可大大减弱葡萄糖或MOG诱导的微血管白蛋白清除率升高（但不增加血流量）。这些发现与以下假设一致：葡萄糖浓度升高通过从头合成增加组织DAG含量，导致蛋白激酶C活化，并且这些生化事件是产生微血管白蛋白清除增加的因素之一。
The present experiments were undertaken to examine the hypothesis that glucose-induced increased de novo synthesis of 1,2-diacyl-sn-glycerol (which has been observed in a number of different tissues, including retinal capillary endothelial cells exposed to elevated glucose levels in vitro) and associated activation of protein kinase C may play a role in mediating glucose-induced vascular functional changes. We report here that twice daily instillation of 30 mM glucose over 10 d in a rat skin chamber granulation tissue model induces approximately a 2.7-fold increase in diacylglycerol (DAG) levels (versus tissues exposed to 5 mM glucose) in association with marked increases in vascular clearance of albumin and blood flow. The glucose-induced increase in DAG levels as well as the vascular functional changes are prevented by addition of 3 mM pyruvate. Pharmacological activation of protein kinase C with the phorbol ester TPA in the presence of 5 mM glucose increases microvascular albumin clearance and blood flow, and similar effects are observed with 1-monoolein (MOG), a pharmacological inhibitor of the catabolism of endogenous DAG. A pharmacological inhibitor of protein kinase C (staurosporine) greatly attenuates the rise in microvascular albumin clearance (but not the rise in blood flow) induced by glucose or by MOG. These findings are compatible with the hypothesis that elevated concentrations of glucose increase tissue DAG content via de novo synthesis, resulting in protein kinase C activation, and that these biochemical events are among the factors that generate the increased microvascular albumin clearance.