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

Elliott H Sohn, Hille W van Dijk, Chunhua Jiao, Pauline H B Kok, Woojin Jeong, Nazli Demirkaya, Allison Garmager, Ferdinand Wit, Murat Kucukevcilioglu, Mirjam E J van Velthoven, J Hans DeVries, Robert F Mullins, Markus H Kuehn, Reinier Otto Schlingemann, Milan Sonka, Frank D Verbraak, Michael David Abràmoff

Research output: Contribution to journalArticleResearchpeer-review


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.

Original languageEnglish
Pages (from-to)E2655-64
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number19
Publication statusPublished - 10 May 2016


  • Adult
  • Animals
  • Diabetic Retinopathy/diagnosis
  • Disease Progression
  • Female
  • Humans
  • Longitudinal Studies
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Microvessels/pathology
  • Neurodegenerative Diseases/diagnosis
  • Retinal Degeneration/diagnosis
  • Species Specificity


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