Altered insulin signaling in retinal tissue in diabetic states
Altered insulin signaling in retinal tissue in diabetic states
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DOI：
10.1074/jbc.m401339200
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发表时间：
2004-09-03
影响因子：
4.8
通讯作者：
Kahn, CR
中科院分区：
文献类型：
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作者：
Kondo, T;Kahn, CR
1型和2型糖尿病均可导致视网膜微血管功能改变和糖尿病视网膜病变。胰岛素信号也可能在这一过程中发挥作用，内皮细胞中缺乏胰岛素受体的小鼠可以防止视网膜新生血管的形成。为了明确糖尿病在视网膜功能中的作用，我们比较了1型（链脲佐菌素）和2型糖尿病小鼠模型（ob/ob）视网膜血管中的胰岛素信号。链脲佐菌素小鼠视网膜和肝脏中胰岛素受体（IR）和胰岛素受体底物(IRS)-2蛋白磷酸化和酪氨酸磷酸化升高，而IRS-1蛋白及其磷酸化维持不变。相比之下，ob/ob小鼠肝脏IR、IRS-1和IRS-2蛋白及磷酸化水平明显下调；这些在视网膜中维持或增加。在两种小鼠中，急性胰岛素刺激在视网膜内皮细胞中产生的磷脂酰肌醇3,4,5-三磷酸增强。另一方面，两种小鼠视网膜中PDK1和Akt的蛋白水平和磷酸化水平均下降。有趣的是，p38丝裂原活化蛋白激酶和ERK1的磷酸化在两种小鼠的视网膜中对胰岛素有反应，但在肝脏中无反应。视网膜hif -1 α和血管内皮生长因子升高，内皮一氧化氮合酶降低。这些观察结果表明，在胰岛素抵抗和胰岛素缺乏的糖尿病状态下，胰岛素信号的改变，如PDK/Akt反应受损和丝裂原活化蛋白激酶反应增强，可能导致视网膜病变。此外，视网膜内皮细胞中的胰岛素信号在糖尿病中发生了不同的改变，并且与肝脏等经典靶组织中的胰岛素信号调节也存在差异。
Both type 1 and type 2 diabetes can lead to altered retinal microvascular function and diabetic retinopathy. Insulin signaling may also play a role in this process, and mice lacking insulin receptors in endothelial cells are protected from retinal neovascularization. To define the role of diabetes in retinal function, we compared insulin signaling in the retinal vasculature of mouse models of type 1 ( streptozotocin) and type 2 diabetes (ob/ob). In streptozotocin mice, in both retina and liver, insulin receptor (IR) and insulin receptor substrate (IRS)-2 protein and tyrosine phosphorylation were increased by insulin, while IRS-1 protein and its phosphorylation were maintained. By contrast, in ob/ob mice, there was marked down-regulation of IR, IRS-1, and IRS-2 protein and phosphorylation in liver; these were maintained or increased in retina. In both mice, Phosphatidylinositol 3,4,5-trisphosphate generation by acute insulin stimulation was enhanced in retinal endothelial cells. On the other hand, protein levels and phosphorylation of PDK1 and Akt were decreased in retina of both mice. Interestingly, phosphorylation of p38 mitogen-activated protein kinase and ERK1 were responsive to insulin in retina of both mice but were unresponsive in liver. HIF-1alpha and vascular endothelial growth factor were increased and endothelial nitric-oxide synthase was decreased in retina. These observations indicate that, in both insulin-resistant and insulin-deficient diabetic states, there are alterations in insulin signaling, such as impaired PDK/Akt responses and enhanced mitogen-activated protein kinases responses that could contribute to the retinopathy. Furthermore, insulin signaling in retinal endothelial cells is differentially altered in diabetes and is also differentially regulated from insulin signaling in classical target tissues such as liver.