TY - JOUR
T1 - Retinal neurodegeneration may precede microvascular changes characteristic of diabetic retinopathy in diabetes mellitus
AU - Sohn, Elliott H
AU - van Dijk, Hille W
AU - Jiao, Chunhua
AU - Kok, Pauline H B
AU - Jeong, Woojin
AU - Demirkaya, Nazli
AU - Garmager, Allison
AU - Wit, Ferdinand
AU - Kucukevcilioglu, Murat
AU - van Velthoven, Mirjam E J
AU - DeVries, J Hans
AU - Mullins, Robert F
AU - Kuehn, Markus H
AU - Schlingemann, Reinier Otto
AU - Sonka, Milan
AU - Verbraak, Frank D
AU - Abràmoff, Michael David
PY - 2016/5/10
Y1 - 2016/5/10
N2 - 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.
AB - 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.
KW - Adult
KW - Animals
KW - Diabetic Retinopathy/diagnosis
KW - Disease Progression
KW - Female
KW - Humans
KW - Longitudinal Studies
KW - Male
KW - Mice
KW - Mice, Inbred C57BL
KW - Microvessels/pathology
KW - Neurodegenerative Diseases/diagnosis
KW - Retinal Degeneration/diagnosis
KW - Species Specificity
U2 - 10.1073/pnas.1522014113
DO - 10.1073/pnas.1522014113
M3 - Article
C2 - 27114552
SN - 0027-8424
VL - 113
SP - E2655-64
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 19
ER -