High-Fat Diet-Induced Retinal Dysfunction
High-Fat Diet-Induced Retinal Dysfunction
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DOI：
10.1167/iovs.14-16143
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发表时间：
2015-04-01
影响因子：
4.4
通讯作者：
Ko, Gladys Y. -P.
中科院分区：
文献类型：
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作者：
Chang, Richard Cheng-An;Shi, Liheng;Ko, Gladys Y. -P.
目的。本研究旨在探讨肥胖诱导的糖尿病前期/早期糖尿病对视网膜的影响，为2型糖尿病相关性糖尿病视网膜病变(DR)的发病机制提供新的证据。在12周的HFD喂养方案结束时，评估小鼠的血糖和胰岛素耐量，并用视网膜电信号(ERG)记录视网膜光反应。免疫印迹和免疫组织化学染色检测HFD和对照视网膜之间钙稳态调节元件的变化，以及来自DR患者和适龄对照的未染色的人视网膜切片。结果：与对照组相比，HFD小鼠的暗视和明视ERG减少。HFD视网膜细胞信号转导、钙稳态和糖代谢相关分子如磷酸化蛋白激酶B、葡萄糖转运蛋白4、L型电压门控性钙通道、质膜钙ATPase等均显著减少。在DR患者的视网膜切片中，PAKT、PMCA和L-VGCC也观察到了类似的变化。结论肥胖引起的高血糖和糖尿病前期/早期糖尿病对视网膜光敏感度和健康造成不利影响。糖尿病早期视网膜电信号成分的减少反映了视网膜光反应的神经元活性降低，这可能是由于神经元钙信号的减少所致。由于PI3K-AKT在调节钙稳态和神经存活方面具有重要作用，因此在糖尿病早期或糖尿病前期维持适当的PI3K-AKT信号可能是预防DR的新策略。
PURPOSE. The purpose of this study was to investigate the impact of obesity-induced prediabetes/early diabetes on the retina to provide new evidence on the pathogenesis of type 2 diabetes-associated diabetic retinopathy (DR).METHODS. A high-fat diet (HFD)-induced obesity mouse model (male C57BL/6J) was used in this study. At the end of the 12-week HFD feeding regimen, mice were evaluated for glucose and insulin tolerance, and retinal light responses were recorded by electroretinogram (ERG). Western immunoblot and immunohistochemical staining were used to determine changes in elements regulating calcium homeostasis between HFD and control retinas, as well as unstained human retinal sections from DR patients and age-appropriate controls.RESULTS. Compared to the control, the scotopic and photopic ERGs from HFD mice were decreased. There were significant decreases in molecules related to cell signaling, calcium homeostasis, and glucose metabolism from HFD retinas, including phosphorylated protein kinase B (pAKT), glucose transporter 4, L-type voltage-gated calcium channel (L-VGCC), and plasma membrane calcium ATPase (PMCA). Similar changes for pAKT, PMCA, and L-VGCC were also observed in human retinal sections from DR patients.CONCLUSIONS. Obesity-induced hyperglycemic and prediabetic/early diabetic conditions caused detrimental impacts on retinal light sensitivities and health. The decrease of the ERG components in early diabetes reflects the decreased neuronal activity of retinal light responses, which may be caused by a decrease in neuronal calcium signaling. Since PI3K-AKT is important in regulating calcium homeostasis and neural survival, maintaining proper PI3K-AKT signaling in early diabetes or at the prediabetic stage might be a new strategy for DR prevention.