Research Service, Louis Stokes Cleveland VA Medical Center, Cleveland, OH, USA; Department of Ophthalmic Research, Cole Eye Institute, Cleveland Clinic Foundation, Cleveland, OH, USA.
Department of Ophthalmic Research, Cole Eye Institute, Cleveland Clinic Foundation, Cleveland, OH, USA.
Exp Eye Res. 2019 Mar;180:63-74. doi: 10.1016/j.exer.2018.11.020. Epub 2018 Dec 10.
In diabetes, there are two major physiological aberrations: (i) Loss of insulin signaling due to absence of insulin (type 1 diabetes) or insulin resistance (type 2 diabetes) and (ii) increased blood glucose levels. The retina has a high proclivity to damage following diabetes, and much of the pathology seen in diabetic retinopathy has been ascribed to hyperglycemia and downstream cascades activated by increased blood glucose. However, less attention has been focused on the direct role of insulin on retinal physiology, likely due to the fact that uptake of glucose in retinal cells is not insulin-dependent. The retinal pigment epithelium (RPE) is instrumental in maintaining the structural and functional integrity of the retina. Recent studies have suggested that RPE dysfunction is a precursor of, and contributes to, the development of diabetic retinopathy. To evaluate the role of insulin on RPE cell function directly, we generated a RPE specific insulin receptor (IR) knockout (RPEIRKO) mouse using the Cre-loxP system. Using this mouse, we sought to determine the impact of insulin-mediated signaling in the RPE on retinal function under physiological control conditions as well as in streptozotocin (STZ)-induced diabetes. We demonstrate that loss of RPE-specific IR expression resulted in lower a- and b-wave electroretinogram amplitudes in diabetic mice as compared to diabetic mice that expressed IR on the RPE. Interestingly, RPEIRKO mice did not exhibit significant differences in the amplitude of the RPE-dependent electroretinogram c-wave as compared to diabetic controls. However, loss of IR-mediated signaling in the RPE reduced levels of reactive oxygen species and the expression of pro-inflammatory cytokines in the retina of diabetic mice. These results imply that IR-mediated signaling in the RPE regulates photoreceptor function and may play a role in the generation of oxidative stress and inflammation in the retina in diabetes.
在糖尿病中，存在两种主要的生理异常：（i）由于缺乏胰岛素（1 型糖尿病）或胰岛素抵抗（2 型糖尿病）而导致胰岛素信号转导丧失，以及（ii）血糖水平升高。糖尿病后视网膜容易受到损伤，糖尿病性视网膜病变中所见的许多病理学变化归因于高血糖和由血糖升高激活的下游级联反应。然而，由于视网膜细胞中葡萄糖的摄取不受胰岛素的影响，因此人们对胰岛素对视网膜生理学的直接作用关注较少。视网膜色素上皮（RPE）在维持视网膜的结构和功能完整性方面起着重要作用。最近的研究表明，RPE 功能障碍是糖尿病性视网膜病变发生和发展的前兆。为了直接评估胰岛素对 RPE 细胞功能的作用，我们使用 Cre-loxP 系统生成了一种 RPE 特异性胰岛素受体（IR）敲除（RPEIRKO）小鼠。使用这种小鼠，我们试图确定在生理对照条件下以及在链脲佐菌素（STZ）诱导的糖尿病中，胰岛素介导的 RPE 信号对视网膜功能的影响。我们证明，与在 RPE 上表达 IR 的糖尿病小鼠相比，RPE 特异性 IR 表达缺失导致糖尿病小鼠的 a-和 b-波视网膜电图幅度降低。有趣的是，与糖尿病对照相比，RPEIRKO 小鼠的 RPE 依赖性视网膜电图 c-波幅度没有显着差异。然而，RPE 中 IR 介导的信号转导丧失降低了糖尿病小鼠视网膜中活性氧和促炎细胞因子的表达水平。这些结果表明，RPE 中的 IR 介导的信号转导调节光感受器功能，并可能在糖尿病中视网膜氧化应激和炎症的产生中发挥作用。
