Retinal Neurodegeneration May Precede Microvascular Changes Characteristic of Diabetic Retinopathy in Diabetes Mellitus

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2016 Apr 27

PMID 27114552

Citations 294

Authors

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 Abramoff

Affiliations

Soon will be listed here.

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.

Citing Articles

Association of serum adiponectin and leptin levels with inner retinal thickness among individuals with or without elevated HbA1c.

Koseoglu N, Wang J, Anokye-Danso F, Amezcua Moreno J, Cha E, Fuchs F Sci Rep. 2025; 15(1):8498.

PMID: 40075217 PMC: 11904190. DOI: 10.1038/s41598-025-93562-9.

The transcription factor Jun is necessary for optic nerve regeneration in larval zebrafish.

Sarich S, Sreevidya V, Udvadia A, Svoboda K, Gutzman J PLoS One. 2025; 20(3):e0313534.

PMID: 40063628 PMC: 11892826. DOI: 10.1371/journal.pone.0313534.

Association Between Macular Ganglion Cell-Inner Plexiform Layer and Non-Proliferative Retinopathy Without Macular Edema in Type 2 Diabetes via Diabetes Duration and HbAc Link.

Vrabec R, Bulum T, Ljubic S, Tomic M Biomedicines. 2025; 13(2).

PMID: 40002811 PMC: 11853396. DOI: 10.3390/biomedicines13020398.

Quantitative Analysis of Early Retinal Changes and OCT Parameters in Diabetic Subjects with and Without Retinopathy.

Aldakhil S, Challa N, Alhoshan S, Abohaimed F, Alnasser B, Almuhawas H Diagnostics (Basel). 2025; 15(4).

PMID: 40002602 PMC: 11854782. DOI: 10.3390/diagnostics15040451.

Early detection of retinal dysfunction in type 1 diabetes without retinopathy using multifocal electroretinography.

Arias-Alvarez M, Sopena-Pinilla M, Fernandez-Espinosa G, Orduna-Hospital E, Rodriguez-Mena D, Pinilla I Sci Rep. 2025; 15(1):6379.

PMID: 39984539 PMC: 11845453. DOI: 10.1038/s41598-025-89734-2.

References

Aiello L, Avery R, Arrigg P, Keyt B, Jampel H, Shah S . Vascular endothelial growth factor in ocular fluid of patients with diabetic retinopathy and other retinal disorders. N Engl J Med. 1994; 331(22):1480-7. DOI: 10.1056/NEJM199412013312203. View

van Dijk H, Kok P, Garvin M, Sonka M, DeVries J, Michels R . Selective loss of inner retinal layer thickness in type 1 diabetic patients with minimal diabetic retinopathy. Invest Ophthalmol Vis Sci. 2009; 50(7):3404-9. PMC: 2937215. DOI: 10.1167/iovs.08-3143. View

Barber A, Lieth E, Khin S, Antonetti D, Buchanan A, Gardner T . Neural apoptosis in the retina during experimental and human diabetes. Early onset and effect of insulin. J Clin Invest. 1998; 102(4):783-91. PMC: 508941. DOI: 10.1172/JCI2425. View

Fletcher E, Phipps J, Ward M, Puthussery T, Wilkinson-Berka J . Neuronal and glial cell abnormality as predictors of progression of diabetic retinopathy. Curr Pharm Des. 2007; 13(26):2699-712. DOI: 10.2174/138161207781662920. View

Bogdanov P, Corraliza L, Villena J, Carvalho A, Garcia-Arumi J, Ramos D . The db/db mouse: a useful model for the study of diabetic retinal neurodegeneration. PLoS One. 2014; 9(5):e97302. PMC: 4023966. DOI: 10.1371/journal.pone.0097302. View

Papachristodoulou D, Heath H, Kang S . The development of retinopathy in sucrose-fed and streptozotocin-diabetic rats. Diabetologia. 1976; 12(4):367-74. DOI: 10.1007/BF00420981. View

Sim D, Keane P, Fung S, Karampelas M, Sadda S, Fruttiger M . Quantitative analysis of diabetic macular ischemia using optical coherence tomography. Invest Ophthalmol Vis Sci. 2014; 55(1):417-23. DOI: 10.1167/iovs.13-12677. View

. The relationship of glycemic exposure (HbA1c) to the risk of development and progression of retinopathy in the diabetes control and complications trial. Diabetes. 1995; 44(8):968-83. View

Barthel L, Raymond P . Improved method for obtaining 3-microns cryosections for immunocytochemistry. J Histochem Cytochem. 1990; 38(9):1383-8. DOI: 10.1177/38.9.2201738. View

10.

. Treatment techniques and clinical guidelines for photocoagulation of diabetic macular edema. Early Treatment Diabetic Retinopathy Study Report Number 2. Early Treatment Diabetic Retinopathy Study Research Group. Ophthalmology. 1987; 94(7):761-74. DOI: 10.1016/s0161-6420(87)33527-4. View

11.

van Dijk H, Verbraak F, Kok P, Stehouwer M, Garvin M, Sonka M . Early neurodegeneration in the retina of type 2 diabetic patients. Invest Ophthalmol Vis Sci. 2012; 53(6):2715-9. PMC: 3366721. DOI: 10.1167/iovs.11-8997. View

12.

Phipps J, Fletcher E, Vingrys A . Paired-flash identification of rod and cone dysfunction in the diabetic rat. Invest Ophthalmol Vis Sci. 2004; 45(12):4592-600. DOI: 10.1167/iovs.04-0842. View

13.

Verma A, Raman R, Vaitheeswaran K, Pal S, Laxmi G, Gupta M . Does neuronal damage precede vascular damage in subjects with type 2 diabetes mellitus and having no clinical diabetic retinopathy?. Ophthalmic Res. 2011; 47(4):202-7. DOI: 10.1159/000333220. View

14.

BLOODWORTH Jr J . Diabetic retinopathy. Diabetes. 1962; 11:1-22. View

15.

Antonetti D, Klein R, Gardner T . Diabetic retinopathy. N Engl J Med. 2012; 366(13):1227-39. DOI: 10.1056/NEJMra1005073. View

16.

Wilkinson C, Ferris 3rd F, Klein R, Lee P, Agardh C, Davis M . Proposed international clinical diabetic retinopathy and diabetic macular edema disease severity scales. Ophthalmology. 2003; 110(9):1677-82. DOI: 10.1016/S0161-6420(03)00475-5. View

17.

Hombrebueno J, Chen M, Penalva R, Xu H . Loss of synaptic connectivity, particularly in second order neurons is a key feature of diabetic retinal neuropathy in the Ins2Akita mouse. PLoS One. 2014; 9(5):e97970. PMC: 4029784. DOI: 10.1371/journal.pone.0097970. View

18.

Realini T, Lai M, Barber L . Impact of diabetes on glaucoma screening using frequency-doubling perimetry. Ophthalmology. 2004; 111(11):2133-6. DOI: 10.1016/j.ophtha.2004.05.024. View

19.

Imai H, Singh R, Fort P, Gardner T . Neuroprotection for diabetic retinopathy. Dev Ophthalmol. 2009; 44:56-68. DOI: 10.1159/000223946. View

20.

FRIEDENWALD J . Diabetic retinopathy. Am J Ophthalmol. 1950; 33(8):1187-99. DOI: 10.1016/0002-9394(50)90988-3. View