Clinical Evidence of a Photoreceptor Origin in Diabetic Retinal Disease

Abstract

Clinical relevance: Although diabetes is associated with a classic microvascular disease of the retina, it is also increasingly being recognized as a cause of retinal neuropathy. Preclinical evidence suggests that retinal neuropathy in diabetes manifests in part as photoreceptor dysfunction, preceding the development of vascular features in experimental models. It remains unknown whether such findings are relevant to patients with diabetes.

Methods: Here, we review 4 lines of clinical evidence suggesting that diabetes-associated photoreceptor pathology is linked to the development of retinal microvascular disease.

Results: First, a major population-based investigation of susceptibility loci for diabetic retinopathy (DR) implicated a photoreceptor protein product as a protective factor. Next, electroretinography and other studies of visual function collectively show that rod and/or cone-derived abnormalities occur decades before the development of vascular features of DR. Third, protection from DR seemingly develops in patients with coincident retinitis pigmentosa, as suggested by several case series. Finally, based on anatomic features, we propose that the beneficial effect of macular laser in DR occurs via ablation of diseased photoreceptors.

Conclusions: The evidence we present is limited due to the small patient populations used in the studies we cite and due to the lack of methodologies that allow causative relationships to be inferred. Collectively, however, these clinical observations suggest that photoreceptors are involved in early diabetic retinal disease and may in fact give rise to the classic features of DR.

Financial disclosures: Proprietary or commercial disclosures may be found in the Footnotes and Disclosures at the end of this article.

Keywords: Diabetic retinopathy; Photoreceptor; Retinitis pigmentosa; Retinol binding protein 3.

Figure 1

Outer retinal defects after focal macular laser therapy. A patient with type 2 diabetes suffering from diabetic macular edema was treated with focal laser photocoagulation. A, Near-infrared en face retinal map showing baseline macular thickness. B, Repeat thickness measurements show improvement in macular volume with focal laser scars visible (white arrows). Optical coherence tomogram through the foveal center at baseline (C) and at 3 months after laser (D). E, OCT cross-sectional scan through a paracentral location inferior to the fovea, within the field of laser treatment, shows defects in the ellipsoid zone and the interdigitation zone with sparing of the external limiting membrane, retinal pigment epithelium, and the entire inner retina (red arrowhead).

Figure 2

Phenotypic similarities between panretinal photocoagulation and retinitis pigmentosa. A, Wide-field scanning laser ophthalmoscopy of a patient with proliferative diabetic retinopathy treated by panretinal photocoagulation. Laser scars are present in the periphery of the retina (arrowheads). B, Wide-field scanning laser ophthalmoscopy of a patient with retinitis pigmentosa due to a RHO c.1040C>T heterozygous polymorphism and concomitant type 2 diabetes, showing peripheral atrophy, bone spicule pigmentation, and no vascular signs of diabetic retinopathy. C, Optical coherence tomogram showing an outer retinal scar from peripheral laser photocoagulation (arrowheads). D, Optical coherence tomogram from a patient with retinitis pigmentosa showing paracentral atrophy of the outer retina (arrowheads).