Diabetic rats with endogenously high levels of retinal dopamine do not display retinal vascular hallmarks of diabetic retinopathy

Abstract

Purpose : Diabetic retinopathy is characterized by retinal and visual dysfunction in early stages and clinically-recognized retinal vascular pathology in late stages. We previously showed that Goto-Kakizaki (GK) rats, a polygenic, non-obese Type II diabetes model, exhibit hyperglycemia and delays in electroretinogram implicit times that are characteristic of the diabetic phenotype. However, GK rats did not show deficits in vascular structure or function. Here, we investigated retinal dopamine as a potential cause of this lack of vascular pathology in the GK rat.

Methods : In male and female GK rats (n = 17) and non-diabetic Wistar controls (n = 20-23), glucose tolerance tests were used to confirm hyperglycemia. Electroretinograms were performed monthly. Functional hyperemia was performed at 8 months to assess retinal vascular function. Retinas from rats euthanized at 8 and 12 months were assessed for vascular pathology. Dopamine levels were measured via HPLC in retinas from rats euthanized at 1, 2, 8, and 12 months.

Results : GK rats showed significant glucose intolerance beginning at 1 month of age (p < 0.001) and persisting to 8 months (p < 0.001). GK rats showed significant increases in a-wave, b-wave, flicker, and oscillatory potential amplitudes (p < 0.01 to p < 0.001), as well as significant delays in flicker and oscillatory potential implicit times (p < 0.05 to p < 0.001) beginning at 1 month and persisting to 8 months. 8-month-old GK rats showed no deficits in retinal vascular function and no increase in degenerate (acellular) retinal capillaries compared with nondiabetic controls. Dopamine levels were significantly higher in GK retinas vs. Wistar retinas – twice as high, on average – at 1, 2, 8, and 12 months (p < 0.001).

Conclusions : GK rats exhibited retinal function deficits by 1 month of age, but vascular pathology was not observed in the GK rat even by 12 months, a time point much later than the 6-8 month window when vascular pathology is usually observed in diabetic rats. GK rats exhibited higher than normal levels of dopamine. Given dopamine’s use as an anti-angiogenic in other diseases, it is possible that the endogenously high levels of dopamine in the GK rat are conferring protection against diabetic vascular pathology. Additionally, this data suggests that neuronal and vascular changes may not be related.

This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.