Diabetic cataract in the Nile grass rat: A longitudinal phenotypic study of pathology formation

Abstract

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.

A haplotype-resolved genome assembly of the Nile rat facilitates exploration of the genetic basis of diabetes

“…Importantly, house mouse and Norway rat are relatively resistant to diet-alone induced diabetes, modeling pre-diabetes or early-diabetes and unable to develop long-term diabetic complications [14,15]. Conversely, Nile rats on rodent chow, without chemical or genetic manipulations, recapitulate the natural progression of type 2 diabetes in humans [16] including clinically relevant diabetic complications [17][18][19]. Notably, the diurnal Nile rat has a cone-rich retina that is useful to study human retinal diseases, including diabetic retinopathy.…”

Type 2 Diabetes Mellitus: Pathogenic Features and Experimental Models in Rodents

“…Эти животные являются ценной спонтанной моделью для исследований, направленных на предотвращение диабета, вызванного пищевым рационом, и представляют собой новую систему взаимодействий между генами и рационом, влияющую на использование энергии. Эта модель позволит лучше понять подходы к профилактике и лечению СД2 и метаболического синдрома [97][98][99][100][101].…”

“…These animals are a valuable spontaneous model for research aimed at preventing diet-induced diabetes and represent a novel system of the interactions between genes and diet that affect energy use. This model will allow for a better understanding of the approaches to prevent and treat T2DM and the metabolic syndrome [ 97 , 98 , 99 , 100 , 101 ].…”

Pre-hyperglycemia immune cell trafficking underlies subclinical diabetic cataractogenesis

“…Recently, we introduced a novel diabetic cataract model in the Nile grass rat (NGR, Arvicanthis niloticus ) [ 4 ], a diurnal gerbil that naturally develops metabolic syndrome (MetS) and T2D [ 5 , 6 ]. Our study revealed spontaneous formations of diverse cataract types, including the posterior sub-capsular (PSC), cortical, nuclear, and anterior sub-capsular (ASC) cataracts, all of which temporally succeeded hyper-reflective early dot-like microlesions in the equatorial regions [ 4 ]. These early lesions reminisce of supranuclear cataracts in Alzheimer’s disease [ 7 ], or blue-dot opacities in pediatric cataract [ 8 ], and in individuals with Down syndrome [ 9 ].…”

“…However, little is known about the role of LECs and immune cells in diabetic cataract formation. We reported LEC proliferation and migration in early diabetic cataract [ 4 ]. Here, we explore a novel role for immune cells in this cellular reprogramming.…”