Diabetic retinopathy: a neuropathy

Diabetic retinopathy is the main cause of blindness in the working-age population, in the Western world. Classically, it is described as a microcirculatory disease, but evidence shows that there are neurodegenerative manifestations that precede the vascular manifestations, such as nervous changes, even in the absence of a pericyte lesion, previously considered the first sign of diabetic retinopathy.(¹) Major neurodegenerative changes include apoptosis and glial activation, found in retinas of diabetic donors with no documented vascular changes prior to ophthalmic examinations.(²) Thus, the documentation of patients merely with retinography and fundoscopy may not detect early changes in diabetic retinopathy.

Neurodegeneration

The pathophysiology of diabetic retinopathy is related to the apoptosis of ganglion and amacrine and Müller cells of the retina, due to an accumulation of glutamate, which leads to a picture of neurodegeneration and reduction of the layer of nerve fibers and ganglion cells.(³)

The pathophysiology of glutamate accumulation is related to dysfunction of the glutamine-synthetase enzyme of Müller cells, which reduces its ability to oxidize glutamate and to remove retinal glutamate by the glia cells. An increase in glutamate concentration leads to cell death due to an intracellular increase in calcium. Diabetes also induces activation of microglia cells, located inside the retina, which migrate to the subretinal space and release cytokines, contributing to neuronal cell death.(⁴)

Hyperglycemia triggers glycosylation of proteins and lipids, which leads to a condition of neurodegeneration, along with ischemic changes that decrease blood supply to the nerves.

It has also been found that the flow is associated with areas of neuropathy. Neurodegenerative abnormalities in areas without vascularization, such as the cornea, proven with confocal microscopy tests in diabetic patients, characterize the independent mechanism of neurodegenerative modification of the vascular change.(⁵)

However, microcirculatory changes may be related to neurological changes, as endothelial changes in the vascular basal membrane may lead to apoptosis of the pericyte in addition to capillary occlusion of the optic nerve capillaries.(⁶)

Research on diabetic neurodegeneration may explain why proliferative diabetic retinopathy and other complications can develop in 20% of diabetic patients kept under strict metabolic control, demonstrating that there are likely other risk factors that need to be controlled.(⁷)It is important, however, to emphasize that there is a greater loss of the nerve fiber layer in highly myopic and elderly patients.(⁸)

Perspectives

Neuroprotective treatment research can be useful in the management of diabetic retinopathy. Topical use of brimonidine tartrate and somatostatin eye drops cause local vasodilation in the retina, and by increasing blood flow in the retina, can prevent the progression of diabetic retinopathy. Somatostatin is usually reduced in diabetic patients with ganglion cell damage, and may have an impact on neurodegeneration prevention, by reducing glutamate cell accumulation. It also acts by preventing neovascularization and inhibiting vascular endothelial growth factor (VEGF) production.(⁹)An ascorbic acid deficit in the vitreous of diabetic patients has been demonstrated. It is an antioxidant substance inhibiting the production of VEGF, and it is important to maintain high levels of this substance in the vitreous of diabetic patients.(¹⁰) The pigment epithelium-derived factor (PEDF) is another potent neuroprotective and antiangiogenic element that protects neurons from glutamate-mediated neurodegeneration and is diminished in diabetic retinopathy.(¹¹) Other neuroprotective factors, such as insulin, neuroprotectin D1, brain-derived neurotrophic factor, glial cell line-derived neurotrophic factor, ciliary neurotrophic factor, nerve growth factor, and adrenomedullin may also be involved in the neurodegenerative process that occurs in diabetic retinopathy, but other specific studies still need to be performed.

This could prevent more invasive treatment in the final stages of diabetic retinopathy, using intravitreous antiangiogenic injections and laser photocoagulation in the retina. In addition, the study of the retinal ganglion cell layer in diabetic patients could be a method of early control of disease progression. The confirmation of a neurodegenerative disease can instigate new perspectives of diabetes diagnosis and treatment.

CONCLUSION

Neurodegeneration can be demonstrated in studies documenting the thickness of nerve fiber and ganglion cell layers as an event preceding vascular changes in diabetic retinopathy. Advances in these studies and in the treatment with neuroprotective drugs can improve the diagnosis and treatment of diabetic retinopathy.

REFERENCES

• ¹
  Grauslund J, Green A, Sjølie AK. Prevalence and 25 year incidence of proliferative retinopathy among Danish type 1 diabetic patients. Diabetologia. 2009;52(9):1829-35.
• ²
  Carrasco E, Hernández C, de Torres I, Farrés J, Simó R. Lowered cortistatin expression is an early event in the human diabetic retina and is associated with apoptosis and glial activation. Mol Vis. 2008;14:1496-502.
• ³
  van Dijk HW, Verbraak FD, Stehouwer M, Kok PH, Garvin MK, Sonka M, et al. Association of visual function and ganglion cell layer thickness in patients with diabetes mellitus type 1 and no or minimal diabetic retinopathy. Vision Res. 2011;51(2):224-8.
• ⁴
  Zhang Y, Bhavnani BR. Glutamate-induced apoptosis in neuronal cells is mediated via caspase-dependent and independent mechanisms involving calpain and caspase-3 proteases as well as apoptosis inducing factor (AIF) and this process is inhibited by equine estrogens. BMC Neurosci. 2006;7:49.
• ⁵
  Bitirgen G, Ozkagnici A, Malik RA, Kerimoglu H. Corneal nerve fibre damage precedes diabetic retinopathy in patients with type 2 diabetes mellitus. Diabet Med. 2014;31(4):431-8.
• ⁶
  Bandello F, Tejerina AN, Vujosevic S, Varano M, Egan C, Sivaprasad S, Menon G, Massin P, Verbraak FD, Lund-Andersen H, Martinez JP, Jürgens I, Smets RM, Coriat C, Wiedemann P, Ágoas V, Querques G, Holz FG, Nunes S, Alves D, Neves C, Santos T, Ribeiro L, Cunha-Vaz J; EVICR.net. Retinal layer location of increased retinal thickness in eyes with subclinical and clinical macular edema in diabetes type 2. Ophthalmic Res. 2015;54(3):112-7.
• ⁷
  Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Research Group, Nathan DM, Zinman B, Cleary PA, Backlund JY, Genuth S, Miller R, Orchard TJ. Modern-day clinical course of type 1 diabetes mellitus after 30 years’ duration: the diabetes control and complications trial/epidemiology of diabetes interventions and complications and Pittsburgh epidemiology of diabetes complications experience (1983-2005). Arch Intern Med. 2009;169(14):1307-16.
• ⁸
  Srinivasan S, Pritchard N, Sampson GP, Edwards K, Vagenas D, Russell AW, et al. Retinal thickness profile of individuals with diabetes. Ophthalmic Physiol Opt. 2016;36(2):158-66.
• ⁹
  Grauslund J, Frydkjaer-Olsen U, Peto T, Fernández-Carneado J, Ponsati B, Hernández C, Cunha-Vaz J, Simó R; EUROCONDOR. Topical treatment with brimonidine and somatostatin causes retinal vascular dilation in patients with Early diabetic retinopathy from the EUROCONDOR. Invest Ophthalmol Vis Sci. 2019;60(6):2257-62.
• ¹⁰
  Barba I, Garcia-Ramírez M, Hernández C, Alonso MA, Masmiquel L, García-Dorado D, et al. Metabolic fingerprints of proliferative diabetic retinopathy: an 1H-NMR-based metabonomic approach using vitreous humor. Invest Ophthalmol Vis Sci. 2010;51(9):4416-21.
• ¹¹
  Shen X, Xie B, Cheng Y, Jiao Q, Zhong Y. Effect of pigment epithelium derived factor on the expression of glutamine synthetase in early phase of experimental diabetic retinopathy. Ocul Immunol Inflamm. 2011;19(4):246-54.

Publication Dates

• Publication in this collection
  21 Dec 2020
• Date of issue
  2021