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Ping Hu, Mohammad N Uddin, Martha Neuringer, Lauren Renner, Jonathan Stoddard, Michael E Boulton, Trevor J McGill, Tailoi Chan-Ling, Maria Grant; Evidence of Diabetic Retinopathy in a Western (high fat) diet-Induced Non-human Primate Model of Type 2 diabetes (T2D). Invest. Ophthalmol. Vis. Sci. 2018;59(9):3589.
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© ARVO (1962-2015); The Authors (2016-present)
Commonly used animal models of DR include use of diabetic mice and rats, however these are severely limited in that they do not develop advanced disease and they lack a macula. This study investigated inflammation, RPE, glial, vascular, and neuronal changes using a high fat diet (Western)-induced non-human primate model of T2D.
Thirteen eyes from rhesus monkey aged 15-17 years old were used in this study. Seven fed a Typical American Diet (TAD Primate diet, LabDiet; Western diet) for 2-4 years that induced glucose intolerance, and 6 age-matched controls were fed a standard laboratory primate diet. Retinal fundus, OCT and autofluorescence imaging were undertaken prior to sacrifice. Eyes were fixed in 4% paraformaldehyde and examined using multimarker immunohistochemistry for cluster of differentiation 31 (CD31), ionized calcium binding adaptor molecule-1 (Iba-1), glial fibrillary acidic protein (GFAP), NeuN, vimentin, aquaporin-4 (AQP4), Griffonia simplicifolia (Bandeiraea) isolectin B4 (GS Lectin), as well as trypsin digests and TEM.
Retinal imaging showed fundus changes typical of human DR including venous engorgement and tortuousity, aneurysms, macular exudates, dot and blot haemorrhages, and marked increase in fundus autofluorescence. Diabetes was associated with significant decrease in CD31+ vessel density (p < 0.05), increase in acellular capillaries (p < 0.05), increase in amoeboid microglia/macrophage density and loss of regular distribution in stratum and regular spacing typical of ramified microglia. Marked increase in lipofuscin (p < 0.05) was evident in T2D reflecting compromised outer segment clearance. Confirming our earlier report in T1D mice, we also found a marked decrease in NeuN+ neuronal density of nearly 50% in our primate model (p < 0.05). AQP4 and vimentin immunoreactivity increased (p < 0.05) along vessel walls. Furthermore, GFAP immunoreactivity was also increased in astrocytes (p < 0.05) suggestive of glial activation in T2D
This model replicates many aspects of human DR, including defects in the photoreceptor RPE complex; diabetic vascular changes including capillary dropout; inflammatory infiltration of activated microglia/macrophages, significant neuronal death in the ganglion cell and inner nuclear layers, and compounded with astrocytic & Muller glial change is water transport (AQP4).
This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.
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