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Rachael S Allen, Andrew Feola, Cara Tessia Motz, Amy Ottensmeyer, Peter M Thule, Timothy S Kern, Machelle T Pardue; Long term progression of retinal and cerebral deficits in the Goto-Kakizaki rat model of Type II diabetes. Invest. Ophthalmol. Vis. Sci. 2017;58(8):5876. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
The Goto-Kakizaki (GK) rat is a spontaneously occurring, polygenic, non-obese model of Type II diabetes that develops impaired insulin secretion at 2 weeks and fasting hyperglycemia at 4 weeks. Previously, we showed that retinal deficits in the GK rat appeared by 4 weeks and preceded cognitive and exploratory behavior deficits. Here, we followed GK and Wistar rats longitudinally for 8 months to assess long term changes in retinal and cerebral function and retinal vasculature.
In male and female GK rats and Wistar (W) controls, glucose and insulin tolerance tests (hyperglycemia and insulin resistance) were performed at 1, 2, and 8 months of age. Electroretinogram (ERG, retinal function) and Y-maze (spatial alternation for cognitive function and number of entries for exploratory behavior) were performed monthly from 1-8 months. Retinas from rats euthanized at 8 months were assessed for vascular pathology.
GK rats exhibited significant glucose intolerance and insulin resistance beginning at 1 month of age (p < 0.001 for both) and persisting to 8 months (p < 0.001 for both). GK rats showed significant increases in a-wave and b-wave amplitudes across all time points (p < 0.001 for both) and flicker amplitudes beginning at 5 months (p < 0.05), as well as significant delays in flicker implicit time beginning at 1 month (p < 0.01). GK rats also showed significant deficits in spatial alternation (p < 0.01) and exploratory behavior (p < 0.001) beginning at 6 and 2 months, respectively. Retinas from 8-month-old GK rats did not show any increase in the number of degenerate (acellular) retinal capillaries compared to that in nondiabetic controls.
GK rats exhibited retinal function deficits by 1 month of age, with cerebral function deficits appearing later, raising the question of associative pathology in human subjects. Vascular pathology was not observed in the GK rat even by 8 months. Future analysis will include optical coherence tomography (OCT, retinal structure), functional hyperemia (retinal vascular function), and assessment of vascular pathology at 12 months. The time course of retinal deficits in Type II diabetes suggests that early retinal screening in human subjects using appropriate methods, such as ERG, may facilitate clinical interventions before patients develop symptomatic DR and cognitive deficits.
This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.
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