Molecular Biomarkers Nano-Imaging Laboratory, Department of Radiology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
Oncopathology Research Center, Iran University of Medical Sciences, Tehran, Iran.
FASEB J. 2021 Jun;35(6):e21593. doi: 10.1096/fj.202100353R.
Diabetes is a major risk factor for cataract, the leading cause of blindness worldwide. There is an unmet need for a realistic model of diabetic cataract for mechanistic and longitudinal studies, as existing models do not reflect key aspects of the complex human disease. Here, we introduce and characterize diabetic cataract in the Nile grass rat (NGR, Arvicanthis niloticus), an established model of metabolic syndrome and type 2 diabetes (T2D). We conducted a longitudinal study of cataract in over 88 NGRs in their non-diabetic, pre-diabetic, and diabetic stages of metabolism. Oral glucose tolerance test (OGTT) results distinguished the metabolic stages. Diverse cataract types were observed in the course of diabetes, including cortical, posterior subcapsular (PSC), and anterior subcapsular (ASC), all of which succeeded a characteristic dotted ring stage in all animals. The onset ages of diabetes and cataract were 44 ± 3 vs 29 ± 1 (P < .001) and 66 ± 5 vs 58 ± 6 (not significant) weeks in females and males, respectively. Histological analysis revealed fiber disorganization, vacuolar structures, and cellular proliferation and migration in cataractous lenses. The lens epithelial cells (LECs) in non-diabetic young NGRs expressed the stress marker GRP78, as did LECs and migrated cells in the lenses of diabetic animals. Elucidating mechanisms underlying LEC proliferation and migration will be clinically valuable in prevention and treatment of posterior capsule opacification, a dreaded complication of cataract surgery. Marked changes in N-cadherin expression emphasized a role for LEC integrity in cataractogenesis. Apoptotic cells were dispersed in the equatorial areas in early cataractogenesis. Our study reveals diverse cataract types that spontaneously develop in the diabetic NGR, and which uniquely mirror the cataract and its chronic course of development in individuals with diabetes. We provide mechanistic insights into early stages of diabetic cataract. These unique characteristics make NGR highly suited for mechanistic studies, especially in the context of metabolism, diabetes, and aging.
糖尿病是白内障的一个主要危险因素，白内障是全球致盲的主要原因。目前需要有一种现实的糖尿病性白内障模型，用于进行机制和纵向研究，因为现有的模型无法反映这种复杂人类疾病的关键方面。在这里，我们引入并描述了尼罗草鼠（NGR，Arvicanthis niloticus）的糖尿病性白内障，NGR 是代谢综合征和 2 型糖尿病（T2D）的一种既定模型。我们对超过 88 只处于非糖尿病、糖尿病前期和糖尿病代谢阶段的 NGR 进行了白内障的纵向研究。口服葡萄糖耐量试验（OGTT）结果区分了代谢阶段。在糖尿病的过程中观察到了多种白内障类型，包括皮质性、后囊下（PSC）和前囊下（ASC），所有这些类型都在所有动物中经历了一个特征性的点状环阶段。雌性和雄性动物的糖尿病和白内障发病年龄分别为 44 ± 3 周和 29 ± 1 周（P < 0.001）和 66 ± 5 周和 58 ± 6 周（无显著差异）。组织学分析显示白内障晶状体中的纤维组织紊乱、空泡结构以及细胞增殖和迁移。非糖尿病年轻 NGR 的晶状体上皮细胞（LEC）表达应激标志物 GRP78，糖尿病动物晶状体中的 LEC 和迁移细胞也是如此。阐明 LEC 增殖和迁移的机制在预防和治疗白内障手术后令人担忧的后囊混浊方面具有重要的临床价值。N-钙黏蛋白表达的显著变化强调了 LEC 完整性在白内障形成中的作用。凋亡细胞在白内障早期形成时散布在赤道区。我们的研究揭示了 NGR 中自发形成的多种白内障类型，这些类型独特地反映了个体糖尿病患者的白内障及其慢性发展过程。我们提供了糖尿病性白内障早期阶段的机制见解。这些独特的特征使 NGR 非常适合进行机制研究，特别是在代谢、糖尿病和衰老的背景下。
