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Comparative Study
. 2013 Feb 15;54(2):1370-7.
doi: 10.1167/iovs.12-10927.

Early Visual Deficits in Streptozotocin-Induced Diabetic Long Evans Rats

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Free PMC article
Comparative Study

Early Visual Deficits in Streptozotocin-Induced Diabetic Long Evans Rats

Moe H Aung et al. Invest Ophthalmol Vis Sci. .
Free PMC article

Abstract

Purpose: Although diabetic retinopathy (DR) is clinically diagnosed based on vascular pathology, diabetic patients with angiographically normal retinas have been found to exhibit subtle defects in vision. This has led to the theory that diabetes-associated metabolic abnormalities directly impair neural retinal function before the development of vasculopathy, thereby resulting in visual deficits. In this study, we sought to delineate the temporal relationship between retinal dysfunction and visual deficits in a rat model of Type 1 diabetes. Moreover, we investigated the relative contribution of retinal dysfunction versus diabetes-induced lens opacity, to the visual deficits found in early-stage DR.

Methods: Pigmented Long Evans rats were rendered diabetic with streptozotocin (STZ). Control and diabetic rats were assessed across 12 weeks of hyperglycemia for visual function with optokinetic tracking weekly visual acuity and monthly contrast sensitivity, retinal function with dark-adapted electroretinograms (monthly electroretinograms [ERGs]), and cataract formation with slit lamp exam (biweekly).

Results: Diabetic rats exhibited significantly reduced visual function and delayed ERG responses by 1 month post-STZ. Significant cataracts did not develop until 6 weeks post-STZ. Moreover, increases in lens opacity (r = -0.728) and ERG implicit times (r = -0.615 for rod-dominated response and r = -0.322 for rod/cone mixed response) showed significant correlations with reductions in visual acuity in diabetic rats.

Conclusions: STZ-induced hyperglycemia reduces visual function, affecting both visual acuity and contrast sensitivity. The data suggest that visual defects found in early-stage DR may initially involve abnormalities of the neural retina and worsen with later development of cataracts.

Conflict of interest statement

Disclosure: M.H. Aung, None; M.K. Kim, None; D.E. Olson, None; P.M. Thule, None; M.T. Pardue, None

Figures

Figure 1
Figure 1
Reduced visual function due to hyperglycemia over the 12-week study. (A) Significantly reduced visual acuity (22%) was observed in DM rats (red, n = 6) starting at 3 weeks post-STZ (P < 0.001) when compared with CTRL rats (blue, n = 6), and continued to decrease with disease duration. (B) Contrast sensitivity at 0.064 cyc/deg spatial frequency was reduced in DM rats (red, n = 6) starting at 9 weeks post-STZ (P = 0.011) when compared with CTRL rats (blue, n = 6), and worsened with disease progression. Although the deficit seemed to appear at 5 weeks post-STZ, the change was not statistically significant. Data shown are mean ± SEM. Asterisks represent significant post hoc comparisons, P < 0.05.
Figure 2
Figure 2
Cataract scores for CTRL (blue, n = 6) and DM (red, n = 6) groups over time. At 6 weeks post-STZ, DM animals had significantly higher cataract scores in comparison with CTRL rats (P < 0.001). Moreover, the cataracts worsened over the course of the study. Data shown are mean ± SEM. Asterisks represent significant post hoc comparisons, P < 0.05.
Figure 3
Figure 3
Stratification of visual acuity (A) and contrast sensitivity (B) of DM animals based on the presence or absence of cataracts. For visual acuity (A), a significant difference between the groups was found (Main Treatment Effect: P < 0.001), such that visual acuity decreased with the presence of hyperglycemia (DM-CT group) and was further reduced by the addition of cataracts (DM+CT group). These results indicate that other factor(s) besides optical opacities due to diabetes contribute to the reduction of visual function. For contrast sensitivity (B), CTRL rats have the highest thresholds among the three groups examined (Main Treatment Effect: P = 0.02). We did not observe a further reduction in contrast sensitivity of DM rats due to cataract formation. Data shown are mean ± SEM. CT, presence of cataracts.
Figure 4
Figure 4
Retinal dysfunction due to diabetes. (A, B) Representative OP waveforms to a dim-flash ([A], −1.8 log cd s/m2) or bright-flash ([B], 0.6 log cd s/m2) stimulus from a CTRL rat (blue) at 4-week time point and a DM rat (red) at 4-week, 8-week, and 12-week time points. The gray lines indicate the peak of OP1 in the CTRL rat, whereas the gray arrows indicate the peak of OP1 in the diabetic rat when delayed. (C, D) Average OP2 implicit times (± SEM) in response to dim flash (C) and bright flash (D) over the 12-week study. As early as 8 weeks post-STZ, OP2 of the DM group shows a significant delay in comparison with that of the CTRL group in response to only dim stimulus (P = 0.012). (E, F) Average OP4 implicit times (± SEM) in response to dim flash (E) and bright flash (F) over the 12-week study. OP4 of DM group in response to dim flash displays a significant delay at 4 weeks post-STZ (P = 0.037). In contrast, OP4 elicited with bright flash shows only a main treatment effect between CTRL and DM groups (Main Treatment Effect: P = 0.008). Data shown are mean ± SEM. Asterisks represent significant post hoc comparisons, P < 0.05.
Figure 5
Figure 5
Scatter plots of visual acuity value against corresponding (A) cataract score, (B) dim-flash OP4 latency, and (C) bright-flash OP4 latency for CTRL (n = 7–8) and DM (n = 5–8) rats at 4 weeks, 8 weeks, and 12 weeks postinjection. As expected, the visual acuities of our animals significantly correlate to cataract scores (Spearman Rank Order, P < 0.0001). More interestingly, changes in visual acuity also significantly correlated with OP4 implicit times elicited from rod-dominated response (Pearson Product, P < 0.0001) and mixed rod/cone response (Pearson Product, P = 0.04) conditions. The blue circle symbols represent data points for CTRL animals and the red square symbols represent data points for DM animals. CS, cataract score; IT, implicit time; r, correlation coefficient; VA, visual acuity.
Figure 6
Figure 6
Chronological summary of the functional deficits found in our study. The onsets of clinically significant vascular lesions listed were estimates based on published reports on an STZ-induced diabetic rat model.,,

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