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Rithwick Rajagopal, Gregory Bligard, Li Yin, Peter D Lukasiewicz, Clay F. Semenkovich; Functional deficits precede structural lesions in a mouse model of diabetic retinopathy induced by high-fat diet-feeding. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):4279.
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© ARVO (1962-2015); The Authors (2016-present)
Diet-induced obesity is a common contributor to human type 2 diabetes, the most common cause of diabetic retinopathy. To determine if high-fat diet-induced type 2 diabetes mellitus in mice can model retinal disease, we tested the hypothesis that diet-induced metabolic disease in mice promotes functional and structural deficits of the retina.
We induced diabetes in C57BL/6J mice by Western diet feeding (42% kcal from fat) beginning at 1 month of age. Insulin resistance in the setting of hyperglycemia was confirmed through metabolic profiling at 3, 6, and 12 months of age. Structural defects of the retinal vasculature were assessed by trypsin digest at 6 and 12 months. At each age, dark-adapted stimulus-evoked electroretinography was used to detect functional visual deficits.
As compared to chow-fed mice, high-fat diet-fed mice demonstrated significant gains in weight, adiposity, and insulin resistance beginning at 6 months of age. We found no evidence of structural deficits of the retinal vascular network until 12 months of age, when high-fat-fed mice had significantly greater numbers of atrophic capillaries and pericyte ghosts compared to chow-fed controls. Reductions in oscillatory potential amplitudes were present in diabetic mice at 12 months of age, but were not found at earlier ages. However, beginning at 6 months of age, amplitude reductions became highly correlated to the degree of insulin resistance. Furthermore, high-fat feeding produced a delay in oscillatory potential implicit times beginning at 6 months that persisted to 12 months of age.
With prolonged high-fat feeding, mice develop structural and functional deficits of the retina consistent with other animal models of diabetic retinopathy. In high-fat-fed mice, inner retinal electroretinographic defects precede detectable lesions in the retinal vasculature and are correlated with the degree of insulin resistance. These results suggest that insulin resistance and hyperglycemia, metabolic signatures characteristic of common forms of type 2 diabetes in humans, disrupt the physiology of the neural retina in a process that may initiate the development of abnormal vascular lesions representing the classic hallmark of diabetic retinopathy.
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