Abstract
Purpose :
Recent diabetic retinopathy (DR) studies have suggested that photoreceptors (PR) are altered by diabetes, contributing to early DR pathology. While in the later stages of DR, outer nuclear layer (ONL) thinning is observed in ischemic regions lacking vascular perfusion. Here, we hypothesized that diabetic hyperglycemia increases susceptibility of the outer retina to injury and tested this using mouse models of T1DM and T2DM subjected to retinal ischemia-reperfusion (IR) injury.
Methods :
T1DM was induced in C57BL/6J mice using streptozoticin (STZ) and the BKS db/db obese mouse was used to model T2DM. Retinal IR injury was caused by elevation of intraocular pressure for 90 minutes via injection of saline into the anterior chamber at 4 weeks after STZ treatment or at 10 weeks of age for db/db mice, prior to any onset of apparent diabetic retinal pathology. Retinal neurodegeneration was evaluated by optical coherence tomography (OCT), by TUNEL staining and by measuring layer thicknesses and neuron loss in thin sections of plastic embedded retinas. Systemic treatment with a sodium-glucose co-transporter 1 and 2 (SGLT1/2) inhibitor, phloridzin, was used to test the effects of lowering hyperglycemia just prior to IR injury.
Results :
As expected, nondiabetic control mice exhibited progressive inner retinal thinning after IR injury (35% by 14 days, p<0.0001) by OCT, with no significant outer retinal layer thinning. In contrast, STZ-diabetic mice showed significant thinning of the outer retina (64%, by 14 days, p<0.0001). At 1 day after IR, retinas of diabetic mice exhibited 4.3-fold greater number of TUNEL+ cells in the ONL than injured retinas of control mice (p<0.0001). A similar OCT result was obtained in db/db mice, which also exhibited significant outer retina thinning (49%, p < 0.0001) after IR injury that was not observed in control db/+ mice. Sections showed a significant loss of PR nuclei (45%, p<0.05) and inner segment length decline (45%, p<0.0001) in db/db mice after IR injury, which did not occur in db/+ mice. In STZ-diabetic mice, pre-treatment with phloridzin significantly abrogated outer retinal layer thinning from 49% to 3% (p<0.0001).
Conclusions :
Loss of PR after IR injury shows that diabetes causes PR to become highly susceptible to ischemic insult. The ability of phloridzin pretreatment to abrogate outer retinal thinning after IR suggests that the effects of hyperglycemia are readily reversible.
This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.