Characterization of retinal leukostasis and hemodynamics in insulin resistance and diabetes - Role of oxidants and protein kinase-C activation
Characterization of retinal leukostasis and hemodynamics in insulin resistance and diabetes - Role of oxidants and protein kinase-C activation
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DOI：
10.2337/diabetes.52.3.829
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发表时间：
2003-03-01
期刊：
影响因子：
7.7
通讯作者：
Bursell, SE
中科院分区：
文献类型：
--
作者：
Abiko, T;Abiko, A;Bursell, SE
白细胞停滞/单核细胞粘附到毛细血管内皮（白细胞停滞）的增加和视网膜血流量的减少可能是因果相关的，并与糖尿病视网膜病变的发病机制有关。在这项研究中，我们证明在没有糖尿病的胰岛素抵抗状态下观察到白细胞停滞的增加，而视网膜血流量的减少需要糖尿病和高血糖。用微珠模拟白细胞对视网膜毛细血管阻塞的微嵌塞研究没有影响视网膜血流。在糖尿病大鼠中，抗氧化剂α -硫辛酸治疗使白细胞淤积量正常化，但没有使视网膜血流量正常化。相比之下，用d - α -生育酚和蛋白激酶c β -异构体抑制（LY333531）治疗可防止糖尿病大鼠白细胞停滞增加和视网膜血流减少。血清羟过氧化物（一种氧化应激标志物）在糖尿病大鼠中升高，但通过抗氧化剂α -硫辛酸和d - α -生育酚治疗，以及令人惊讶的PKC β -异构体抑制，使其正常化。这些发现表明，白细胞停滞与内皮功能障碍、胰岛素抵抗和氧化应激有关，但与视网膜血流量无关，也不足以引起糖尿病样视网膜病变。此外，PKC β抑制治疗可以有效地使糖尿病或高血糖诱导的PKC β -异构体激活和氧化应激正常化。
Increases in leukostasis/monocyte adhesion to the capillary endothelium (leukostasis) and decreases in retinal blood flow may be causally associated and are implicated in the pathogenesis of diabetic retinopathy. In this study, we demonstrate that increases in leukostasis are observed in insulin-resistant states without diabetes, whereas decreases in retinal blood flow require diabetes and hyperglycemia. Microimpaction studies using beads mimicking retinal capillary obstruction by leukocytes did not affect retinal blood flow. In diabetic rats, treatment with the antioxidant alpha-lipoic acid normalized the amount of leukostasis but not retinal blood flow. In contrast, treatment with D-alpha-tocopherol and protein kinase-C beta-isoform inhibition (LY333531) prevented the increases in leukostasis and decreases in retinal blood flow in diabetic rats. Serum hydroxyperoxide, a marker of oxidative stress, was increased in diabetic rats, but normalized by treatment with antioxidants alpha-lipoic acid and D-alpha-tocopherol and, surprisingly, PKC beta-isoform inhibition. These findings suggest that leukostasis is associated with endothelial dysfunction, insulin resistance, and oxidative stress but is not related to retinal blood flow and is not sufficient to cause diabetic-like retinopathy. Moreover, treatment with PKC beta inhibition is effective to normalize diabetes or hyperglycemia-induced PKC beta-isoform activation and oxidative stress.