Primary open-angle glaucoma in patients with diabetes mellitus: pathogenetic and clinical parallels of development (literature review)

Primary open-angle glaucoma as a chronic progressive neuropathy, characterized by functional and structural changes in the optic nerve, is one of the main causes of blindness and disability. With a general prevalence of 3% in the population of patients with diabetes mellitus, the risk of its development increases by 1.4 times and increases with the duration of the disease. The role of glycemia level as an important risk factor for the development and progression of the disease is shown. Similar pathogenetic mechanisms of the development of the disease define them as neurodegenerative, with determining mechanisms for the development of cellular apoptosis associated with excessive release of glutamate, the formation of reactive oxygen species, end products of glycation and oxidation of lipids, with mitochondrial disorders. The theory of “Brain diabetes” considers glaucoma to be a type 4 diabetes. In this case, the role of compensation for carbohydrate metabolism in the absence of which insulin resistance exacerbates transsynaptic neurodegeneration becomes crucial. The central theory of insulin resistance in patients with diabetes explains the mechanisms of glaucoma due to impaired trabecular outflow, vascular changes (amyloid angiopathy) and glial activation. The use of metformin and insulin reduces the risk of development and the severity of the progression of the glaucoma process. A study of the structural and angiographic parameters of optical coherence tomography showed a similar decrease in the volume of the ganglion cell complex, the average thickness of the retinal nerve fiber layer, and the peripapillary density of the capillary layer in patients with glaucoma and diabetes. Their comorbid course is accompanied by pronounced structural and functional changes due to the neurodegenerative process, which determines the variants of their progress, the risk of early progression and severe loss of visual function. Patients with glaucoma in the presence of diabetes should be closely monitored by specialists, be informed about the risks and the need for both adequate glycemic control and the monitoring of functional and structural changes in the optic nerve and retina.

1. Tham Y.C., Li X., Wong T.Y. et al. Global prevalence of glaucoma and projections of glaucoma burden through 2040: a systematic review and meta-analysis. Ophthalmology. 2014; 121(11):2081-2090. doi:10.1016/j.ophtha.2014.05.013

2. Egorov E.A., Patogenez i lechenie pervichnoi otkrytougol'noi glauko- my [Pathogenesis and treatment of primary open-angle glaucoma] [Electronic resource]. E.A. Egorov, V.N. Alekseev. Moscow: GEOTARMedia; 2017. 224 p. (In Russ.). ISBN 978-5-9704-4204-3

3. Gordon M.O., Beiser J.A., Brandt J.D., Heuer D.K. The Ocular Hyper- tension Treatment Study: baseline factors that predict the onset of pri- mary open-angle glaucoma. Arch Ophthalmol. 2002; 120(6):714-720; discussion 829-830. doi:10.1001/archopht.120.6.714

4. Varma R., Lee P.P., Goldberg I., Kotak S. An assessment of the health and economic burdens of glaucoma. Am J Ophthalmol. 2011; 152(4):515-522. doi: 10.1016/j.ajo.2011.06.004

5. Ko F., Boland M.V., Gupta P., Gadkaree S.K. et al. Diabetes, triglyceride levels, and other risk factors for glaucoma in the National Health and Nutrition Examination Survey 2005–2008. Invest Ophthalmol Vis Sci. 2016; 57:2152–2157. doi:10.1167/iovs.15-18373

6. Lin H.C., Stein J.D., Nan B., Childers D. et al. Association of geroprotective effects of metformin and risk of open-angle glaucoma in persons with diabetes mellitus. JAMA Ophthalmol. 2015; 133:915–923. doi:10.1001/jamaophthalmol.2015.1440

7. Ellis J.D., Evans J.M., Ruta D.A., Baines P.S. et al. Glaucoma incidence in an unselected cohort of diabetic patients: is diabetes mellitus a risk factor for glaucoma? DARTS/MEMO collaboration. Diabetes Audit and Research in Tayside Study. Medicines Monitoring Unit. Br J Ophthalmol. 2000; 84:1218–1224. doi:10.1136/bjo.84.11.1218

8. Goldacre M.J., Wotton C.J., Keenan T.D. Risk of selected eye diseases in people admitted to the hospital for hypertension or diabetes mellitus: record linkage tudies. Br J Ophthalmol. 2012; 96:872–876. doi:10.1136/bjophthalmol-2012-301519

9. Zhao D., Cho J., Kim M.H., Friedman D.S. et al. Diabetes, fasting glucose, and the risk of glaucoma: a meta-analysis. Ophthalmology. 2015; 122:72–78. doi:10.1016/j.ophtha.2014.07.051

10. Shakya-Vaidya S., Aryal U.R., Upadhyay M., Krettek A. Do non-communicable diseases such as hypertension and diabetes associate with primary open-angle glaucoma? Insights from a case-control study in Nepal. Glob Health Action. 2013; 6:22636. doi:10.3402/gha.v6i0.22636

11. Mitchell P., Smith W., Attebo K., Healey P.R. Prevalence of open-angle glaucoma in Australia. The Blue Mountains Eye Study. Ophthalmology. 1996; 103(10):1661-1669. doi:10.1016/s01616420(96)30449-1

12. Zhou M., Wang W., Huang W., Zhang X. Diabetes mellitus as a risk factor for open-angle glaucoma: a systematic review and meta-analysis. PLoS One. 2014; 9(8):e102972. doi:10.1371/journal.pone.010297

13. Khatri A., Shrestha J.K., Thapa M., Khatri B.K. Severity of primary openangle glaucoma in patients with hypertension and diabetes. Diabetes Metab Syndr Obes. 2018; 11:209–215. doi:10.2147/DMSO.S160978

14. Hymowitz M.B., Chang D., Feinberg E.B., Roy S. Increased intraocular pressure and hyperglycemic level in diabetic patients. PLoS One. 201622; 11(3):e0151833. doi:10.1371/journal.pone.0151833

15. Agrawal A., Ahuja1 S., Singh A., Samanta R. Influence of glycated haemoglobin levels on intraocular pressure in patients with Type–II Diabetes Mellitus. Nepal J Ophthalmol. 2019; 11(21):19-23. doi:10.3126/nepjoph.v11i1.25412

16. Luo X.Y., Tan N., Chee M.-L., Shi Y. Direct and Indirect Associations Between Diabetes and Intraocular Pressure: The Singapore Epidemiology of Eye Diseases Study. Invest Ophthalmol Vis Sci. 2018; 59:2205–2211. doi:10.1167/iovs.17-23013

17. Lee J.S., Oum B.S., Choi H.Y., Lee J.E. Differences in corneal thickness and corneal endothelium related to duration in diabetes. Eye (Lond). 2006; 20:315–318. doi:10.1038/sj.eye.6701868

18. Rehany U., Ishii Y., Lahav M., Rumelt S. Ultrastructural changes in corneas of diabetic patients: an electron-microscopy study. Cornea. 2000; 19:534–538. doi:10.1097/00003226-200007000-00026

19. Shen L., Walter S., Melles R.B., Glymour M.M. et al. Diabetes pathology and risk of primary open-angle glaucoma: evaluating causal mechanisms by using genetic information. Am J Epidemiol. 2016; 183:147– 155. doi:10.1093/aje/kwv204

20. Van Dijk H.W., Verbraak F.D., Stehouwer M., Kok P.H. 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; 51:224–228. doi:10.1016/j.visres.2010.08.024

21. Zhao Y.X., Chen X.W. Diabetes and risk of glaucoma: systematic review and a Meta-analysis of prospective cohort studies. Int J Ophthalmol. 2017; 10(9):1430-1435. doi:10.18240/ijo.2017.09.16

22. Husain S., Abdul Y., Singh S., Ahmad A. et al. Regulation of nitric oxide production by δ-opioid receptors during glaucomatous injury. PLoS One. 2014; 9:e110397. doi:10.1371/journal.pone.0110397

23. Toda N., Nakanishi-Toda M. Nitric oxide: ocular blood flow, glaucoma and diabetic retinopathy. Prog Retin Eye Res. 2007; 26:205–238. doi:10.1016/j.preteyeres.2007.01.004

24. Zheng L., Kern T.S. Role of nitric oxide, superoxide, peroxynitrite, and PARP in diabetic retinopathy. Front Biosci (Landmark Ed). 2009; 14:3974–3987. doi:10.2741/3505

25. Cavet M.E., Vittitow J.L., Impagnatiello F., Ongini E. et al. Nitric oxide (NO): an emerging target for the treatment of glaucoma. Invest Ophthalmol Vis Sci. 2014; 55:5005–5015. doi:10.1167/iovs.14-14515

26. Pacher P., Beckman J.S., Liaudet L. Nitric oxide and peroxynitrite in health and disease. Physiol Rev. 2007; 87:315–424. doi:10.1152/physrev.00029.2006

27. Ciccone M.M., Scicchitano P., Cameli M., Cecere A. et al. Endothelial function in pre-diabetes, diabetes and diabetic cardiomyopathy: a review. J Diabetes Metab. 2014; 5:364. doi:10.4172/2155-6156.1000364

28. Ochiai Y., Ochiai H. Higher concentration of transforming growth factor-beta in aqueous humor of glaucomatous eyes and diabetic eyes. Jpn J Ophthalmol. 2002; 46:249–253. doi:10.1016/s00215155(01)00523-8

29. Li A.-F., Chen A., Roy S. High glucose-induced fibronectin overexpression inhibits trabecular meswork cell permeability. Invest Ophthalmol Vis Sci. 2003; 44(ARVO):E-Abstract 1151.

30. Sato T., Roy S. Effect of high glucose on fibronectin expression and cell proliferation in trabecular meshwork cells. Invest Ophthalmol Vis Sci. 2002; 43(1):170–175.

31. Wong V.H., Bui B.V., Vingrys A.J. Clinical and experimental links between diabetes and glaucoma. Clin Exp Optom. 2011; 94:4–23. doi:10.1111/j.14440938.2010.00546.x

32. Ino-Ue M., Zhang L., Naka H., Kuriyama H. et al. Polyol metabolism of retrograde axonal transport in diabetic rat large optic nerve fiber. Invest Ophthalmol Vis Sci. 2000; 41:4055–4058.

33. Rudzinski M., Wong T.P., Saragovi H.U. Changes in retinal expression of neurotrophins and neurotrophin receptors induced by ocular hypertension. J Neurobiol. 2004; 58:341–354. doi:10.1002/neu.10293

34. Tanuj Dada. Is glaucoma a neurodegeneration caused by central insulin resistance: diabetes type 4? J Curr Glaucoma Pract. 2017; 11(3):77-79. doi:10.5005/jp-journals-10028-1228

35. Song B.J., Aiello L.P., Pasquale L.R. Presence and risk factors for glaucoma in patients with diabetes. Curr Diab Rep. 2016; 16(12):124. doi:10.1007/s11892-016-0815-6

36. Schur E.A., Melhorn S.J., Oh S.-K., Matthew L.J. Radiologic evidence that hypothalamic gliosis is associated with obesity and insulin resistance in humans. Obesity (Silver Spring). 2015; 23(11):2142-2148. doi:10.1002/oby.21248

37. Gunasekar P.G., Kanthasamy A.G., Borowitz J.L., Isom G.E. NMDA receptor activation produces concurrent generation of nitric oxide and reactive oxygen species: implication for cell death. J Neurochem. 1995; 65(5):2016-2021. doi: 10.1046/j.1471-4159.1995.65052016.x

38. Wilson G.N., Smith M.A., Inman D.M., Dengler-Crish C.M. Early cytoskeletal protein modifications precede overt structural degeneration in the DBA/2J mouse model of glaucoma. Front Neurosci. 2016; 3(10):494. doi:10.3389/fnins.2016.00494

39. Löffler K.U., Edward D.P., Tso M.O. Immunoreactivity against tau, amyloid precursor protein, and beta-amyloid in the human retina. Invest Ophthalmol Visual Sci. 1995; 36(1):24-31.

40. Zachary I. Neuroprotective role of vascular endothelial growth factor: signalling mechanisms, biological function, and therapeutic potential. Neurosignals. 2005; 14(5):207-221. doi: 10.1159/000088637

41. Rossino M.G., Dal Monte M., Casini G. Relationships between neurodegeneration and vascular damage in diabetic retinopathy. Front Neurosci. 2019; 8;13:1172. doi:10.3389/fnins.2019.01172

42. Antonetti D.A., Barber A.J., Bronson S.K., Freeman W.M. Diabetic retinopathy: seeing beyond glucose-induced microvascular disease. Diabetes. 2006; 55(9):2401-2411. doi:10.2337/db05-1635

43. Hernandez C., Simo R. Neuroprotection in diabetic retinopathy. Curr Diabet Reports. 2012; 12(4):329-337. doi:10.1007/s11892-012-0284-5

44. Simo R., Hernandez C. Novel approaches for treating diabetic retinopathy based on recent pathogenic evidence. Prog Retin Eye Res. 2015; 48:160-180. doi: 10.1016/j.preteyeres.2015.04.003

45. Hernandez C., Da Monte M., Simо R., Casini G. Neuroprotection as a therapeutic target for diabetic retinopathy. J Diabet Res. 2016:18. Article ID 9508541. doi:10.1155/2016/9508541

46. Zhang X., Wang N., Barile G.R., Bao S. Diabetic retinopathy: neuron protection as a therapeutic target. Int J Biochem Cell Biol. 2013; 45(7):1525–1529. doi:10.1016/j.biocel.2013.03.002

47. Jindal V. Neurodegeneration as a primary change and role of neuroprotection in diabetic retinopathy. Molecular Neurobiol. 2015; 51(3): 878–884. doi: 10.1007/s12035-014-8732-7

48. Barber A.J. A new view of diabetic retinopathy: a neurodegenerative disease of the eye. Prog Neuropsychopharmacol Biol Psychiatry. 2003; 27(2):283-290. doi:10.1016/S0278-5846(03)00023-X

49. Hammes H.P. Diabetic retinopathy: hyperglycaemia, oxidative stress and beyond. Diabetologia. 2018; 61:29–38. doi:10.1007/s00125-017-4435-8

50. Simo R., Stitt A.W., Gardner T.W. Neurodegeneration in diabetic retinopathy: does it really matter? Diabetologia. 2018; 61:1902–1912. doi: 10.1007/s00125-018-4692-1

51. Foxton R.H., Finkelstein A., Vijay S., Dahlmann-Noor A. VEGF-A is necessary and sufficient for retinal neuroprotection in models of experimental glaucoma. Am J Pathol. 2013; 182(4):1379-1390. doi: 10.1016/j.ajpath.2012.12.032

52. Du J., Patrie J.T., Prum B.E., Netland P.A. Effects of intravitreal antiVEGF therapy on glaucoma-like progression in susceptible eyes. J Glaucoma. 2019; 28(12):1035-1040. doi: 10.1097/IJG.0000000000001382

53. Kopić A., Biuk D., Barać J., Vinković M. Retinal nerve fiber layer thickness in glaucoma patients treated with multiple intravitreal anti-VEGF (bevacizumab) injections. Acta Clin Croat. 2017; 56(3):406-414. doi: 10.20471/acc.2017.56.03.07

54. Rud'ko A.S., Budzinskaya M.V., Andreeva I.V., Karpilova M.A. Effect of intravitreal injections of ranibizumab and aflibercept on the retinal nerve fiber layer in patients with concomitant neovascular agerelated macular degeneration and glaucoma. Vestn Oftalmol. 2019; 135(5.2):177-183. doi: 10.17116/oftalma2019135052177. (In Russ.).

55. Garcia-Martin E., Cipres M., Melchor I., Gil-Arribas L. Neurodegeneration in patients with type 2 diabetes mellitus without diabetic retinopathy. J Ophthalmol. 2019: 1825819. doi: 10.1155/2019/1825819

56. Spaide F. Measurable aspects of the retinal neurovascular unit in diabetes, glaucoma, and controls. Am J Ophthalmol. 2019; 207:395-409. doi: 10.1016/j.ajo.2019.04.035

57. Hou H., Shoji T., Zangwill L.M., Moghimi S. Progression of primary open-angle glaucoma in diabetic and nondiabetic patients. Am J Ophthalmol. 2018; 189:1-9. doi:10.1016/j.ajo.2018.02.002

58. Takis A., Alonistiotis D., Ioannou N., Kontou E. Follow-up of the retinal nerve fiber layer thickness of diabetic patients type 2, as a predisposing factor for glaucoma compared to normal subjects. Clin Ophthalmol. 201713; 11:1135-1141. doi:10.2147/OPTH.S129935

59. Kim Y.S., Kim M., Choi M.Y., Lee D.H. Metformin protects against retinal cell death in diabetic mice. Biochem Biophys Res Commun. 201721; 492(3):397-403. doi:10.1016/j.bbrc.2017.08.087

60. Abdelgadir E., Ali R., Rashid F., Bashier A. Effect of metformin on different non-diabetes related conditions, a special focus on malignant conditions: review of literature. J Clin Med Res. 2017; 9:388–395. doi.org/10.14740/jocmr2922e

61. Lin H.C., Stein J.D., Nan B., Childers D. Association of geroprotective effects of metformin and risk of open-angle glaucoma in persons with diabetes mellitus. JAMA Ophthalmol. 2015; 133(8):915-923. doi: 10.1001/jamaophthalmol.2015.1440

62. Amato F., López A., Peña-Méndez E.M., Vanhara P., Hampl A., Havel J. Artificial neural networks in medical diagnosis. J Appl Biomed. 2013; 11:47–58. doi:10.2478/v10136-012-0031-x

63. Apreutesei A.N., Tircoveanu F., Cantemir A., Bogdanici C. Predictions of ocular changes caused by diabetes in glaucoma patients. Comput Methods Programs Biomed. 2018; 154:183-190. doi: 10.1016/j.cmpb.2017.11.013