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S.B. Koevary, J. Nussey, T.S. Kern; Effects of High Dose Insulin Eye Drops on the Development of Diabetic Retinopathy in Rats . Invest. Ophthalmol. Vis. Sci. 2003;44(13):3892.
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Purpose: We recently reported that ocularly applied insulin accumulated in the rat retina. The objective of this study was to determine whether insulin eye drops can prevent the development of retinal acellular capillaries and pericyte ghosts in long term, uncontrolled diabetic rats. Methods: Streptozotocin induced diabetic Lewis rats received daily porcine insulin eye drops (0.75% insulin in isotonic bicarbonate buffer containing 0.5% Brij-78), which was continued for 14 months (N=8). Age-matched diabetic rats that did not receive eye drops (N=4), as well as age matched nondiabetic rats (N=8), served as controls. The retinal vasculature was isolated from these rats by trypsin digestion and evaluated for vascular histopathology. Acellular capillaries and pericyte ghosts were counted and expressed per mm2 of retina and per 1,000 capillary cells, respectively. Glycated hemoglobin values were also assessed at sacrifice. Results: Weekly body weights and blood glucose values were comparable in treated and untreated diabetic rats, as were their glycated hemoglobin levels at sacrifice (mean +/- SEM of 8.2 +/- 0.9 vs. 8.7 +/- 0.7, respectively). The +/- SEM number of acellular capillaries in control, nondiabetic rats was 5.7 +/- 2, while the numbers in control diabetic, and eye drop-treated diabetic, rats were 33.6 +/- 28 (NS vs. nondiabetic controls) and 53.1 +/- 13 (p<0.039 vs. nondiabetic control), respectively. The mean +/- SEM number of pericyte ghosts in control, nondiabetic rats was 1 +/- 0.3, while the numbers in control diabetic, and eye drop-treated diabetic, rats were 9.5 +/- 0.7 and 6.3 +/- 2.3, respectively (p<0.036 and p<0.079 vs. nondiabetic controls, respectively). The acellular capillaries in many of the retinas from eye drop-treated rats had a degenerated, thread-like appearance. These retinas also showed extensive capillary obliteration and had tangled masses of vascular cells - findings not generally seen in diabetic models. Conclusions: These data suggest that rather than preventing retinopathy, high dose insulin eye drops seemed to increase the number of acellular capillaries and to induce more extensive vascular destruction. These data suggest that topical insulin is not sufficient to prevent retinopathy. Thus, inhibition of retinopathy by agressive treatment with systemic insulin likely is due to the correction of metabolic abnormalities caused by insulin deficiency, not via a direct effect of insulin on the retina.
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