Retinal neurodegeneration may precede microvascular changes characteristic of diabetic retinopathy in diabetes mellitus

TLDR

Diabetic retinopathy has long been recognized as a microvasculopathy, but retinal diabetic neuropathy, characterized by inner retinal neurodegeneration, also occurs in people with diabetes mellitus. In 45 diabetic patients with minimal retinopathy, optical coherence tomography revealed progressive inner retinal thinning (NFL 0.25 µm/y, GC/IPL 0.29 µm/y) independent of glycemic control, age, and sex, with thinner NFL in diabetic donors versus controls and no capillary density difference, findings replicated in type 1 and type 2 mouse models, indicating that retinal neurodegeneration precedes vascular changes in diabetes.

Abstract

Diabetic retinopathy (DR) has long been recognized as a microvasculopathy, but retinal diabetic neuropathy (RDN), characterized by inner retinal neurodegeneration, also occurs in people with diabetes mellitus (DM). We report that in 45 people with DM and no to minimal DR there was significant, progressive loss of the nerve fiber layer (NFL) (0.25 μm/y) and the ganglion cell (GC)/inner plexiform layer (0.29 μm/y) on optical coherence tomography analysis (OCT) over a 4-y period, independent of glycated hemoglobin, age, and sex. The NFL was significantly thinner (17.3 μm) in the eyes of six donors with DM than in the eyes of six similarly aged control donors (30.4 μm), although retinal capillary density did not differ in the two groups. We confirmed significant, progressive inner retinal thinning in streptozotocin-induced "type 1" and B6.BKS(D)-Lepr(db)/J "type 2" diabetic mouse models on OCT; immunohistochemistry in type 1 mice showed GC loss but no difference in pericyte density or acellular capillaries. The results suggest that RDN may precede the established clinical and morphometric vascular changes caused by DM and represent a paradigm shift in our understanding of ocular diabetic complications.