Rajagopal Rithwick, Bligard Gregory W, Zhang Sheng, Yin Li, Lukasiewicz Peter, Semenkovich Clay F
Department of Ophthalmology and Visual Sciences, Washington University School of Medicine in St. Louis, St. Louis, MO.
Division of Endocrinology, Metabolism, and Lipid Research, Washington University School of Medicine in St. Louis, St. Louis, MO.
Diabetes. 2016 Apr;65(4):1072-84. doi: 10.2337/db15-1255. Epub 2016 Jan 6.
Obesity predisposes to human type 2 diabetes, the most common cause of diabetic retinopathy. To determine if high-fat diet-induced diabetes in mice can model retinal disease, we weaned mice to chow or a high-fat diet and tested the hypothesis that diet-induced metabolic disease promotes retinopathy. Compared with controls, mice fed a diet providing 42% of energy as fat developed obesity-related glucose intolerance by 6 months. There was no evidence of microvascular disease until 12 months, when trypsin digests and dye leakage assays showed high fat-fed mice had greater atrophic capillaries, pericyte ghosts, and permeability than controls. However, electroretinographic dysfunction began at 6 months in high fat-fed mice, manifested by increased latencies and reduced amplitudes of oscillatory potentials compared with controls. These electroretinographic abnormalities were correlated with glucose intolerance. Unexpectedly, retinas from high fat-fed mice manifested striking induction of stress kinase and neural inflammasome activation at 3 months, before the development of systemic glucose intolerance, electroretinographic defects, or microvascular disease. These results suggest that retinal disease in the diabetic milieu may progress through inflammatory and neuroretinal stages long before the development of vascular lesions representing the classic hallmark of diabetic retinopathy, establishing a model for assessing novel interventions to treat eye disease.
肥胖易引发人类2型糖尿病，而2型糖尿病是糖尿病性视网膜病变最常见的病因。为了确定小鼠中高脂饮食诱导的糖尿病是否可模拟视网膜疾病，我们将小鼠断奶后分别喂食普通饲料或高脂饮食，并检验饮食诱导的代谢性疾病会促进视网膜病变这一假说。与对照组相比，喂食脂肪提供42%能量的饮食的小鼠在6个月时出现了与肥胖相关的葡萄糖不耐受。直到12个月时才有微血管疾病的迹象，此时胰蛋白酶消化和染料渗漏试验显示，高脂喂养的小鼠比对照组有更多萎缩的毛细血管、周细胞残影和通透性增加。然而，高脂喂养的小鼠在6个月时就开始出现视网膜电图功能障碍，与对照组相比，其振荡电位的潜伏期延长和振幅降低。这些视网膜电图异常与葡萄糖不耐受相关。出乎意料的是，高脂喂养小鼠的视网膜在3个月时就出现了应激激酶的显著诱导和神经炎性小体激活，此时全身性葡萄糖不耐受、视网膜电图缺陷或微血管疾病尚未出现。这些结果表明，糖尿病环境中的视网膜疾病可能在代表糖尿病性视网膜病变经典特征的血管病变出现之前很久就通过炎症和神经视网膜阶段进展，从而建立了一个评估治疗眼部疾病新干预措施的模型。
