Submitted Successfully!
To reward your contribution, here is a gift for you: A free trial for our video production service.
Thank you for your contribution! You can also upload a video entry or images related to this topic.
Version Summary Created by Modification Content Size Created at Operation
1 + 1704 word(s) 1704 2021-02-23 04:44:48 |
2 format change Meta information modification 1704 2021-03-01 07:44:23 |

Video Upload Options

Do you have a full video?

Confirm

Are you sure to Delete?
Cite
If you have any further questions, please contact Encyclopedia Editorial Office.
Mrugacz, M. Diabetic Retinopathy and Hyperglycaemia. Encyclopedia. Available online: https://encyclopedia.pub/entry/7498 (accessed on 23 April 2024).
Mrugacz M. Diabetic Retinopathy and Hyperglycaemia. Encyclopedia. Available at: https://encyclopedia.pub/entry/7498. Accessed April 23, 2024.
Mrugacz, Malgorzata. "Diabetic Retinopathy and Hyperglycaemia" Encyclopedia, https://encyclopedia.pub/entry/7498 (accessed April 23, 2024).
Mrugacz, M. (2021, February 23). Diabetic Retinopathy and Hyperglycaemia. In Encyclopedia. https://encyclopedia.pub/entry/7498
Mrugacz, Malgorzata. "Diabetic Retinopathy and Hyperglycaemia." Encyclopedia. Web. 23 February, 2021.
Diabetic Retinopathy and Hyperglycaemia
Edit

Diabetes mellitus (DM) has become a vital societal problem as epidemiological studies demonstrate the increasing incidence of type 1 and type 2 diabetes. Lesions observed in the retina in the course of diabetes, referred to as diabetic retinopathy (DR), are caused by vascular abnormalities and are ischemic in nature. Vascular lesions in diabetes pertain to small vessels (microangiopathy) and involve precapillary arterioles, capillaries and small veins. Pericyte loss, thickening of the basement membrane, and damage and proliferation of endothelial cells are observed. Endothelial cells (monolayer squamous epithelium) form the smooth internal vascular lining indispensable for normal blood flow. Breaking its continuity initiates blood coagulation at that site.

Diabetic Retinopathy and Hyperglycaemia

1. Introduction

Diabetes mellitus (DM) has become a major societal problem. Epidemiological studies demonstrate the increasing incidence of type 1 and 2 diabetes mellitus (T1DM and T2DM, respectively)[1][2][3][4]. It is assumed that in the coming years the number of patients with diabetes will increase [1][5][6]. In 2012, the number of people with DM was 371 million, including 25.8 million in the USA. Globally, as many as 4.7 million patients died due to DM complications for the year 2012[7].

Lesions observed in the retina with diabetes, referred to as diabetic retinopathy (DR), are caused by vascular abnormalities and are ischemic in nature. Due to its widespread prevalence, diabetic retinopathy is considered the major culprit of blindness in industrialized and middle-income countries[8]. There exists a clinical division of diabetic retinopathy into non-proliferative and proliferative retinopathy. The time of Lesion progression differs among patients and is determined by diabetes duration, glycemia, genetic predispositions and treatment methods. In the USA, it is calculated that among patients with type 2 diabetes T2DM 40.3% have DR, and 8.2% suffer from vision-threatening retinopathy [9]. In patients with type I diabetes T1DM 86% have retinopathy and 42% vision impairment due to DR[10]. Studies conducted on a group of 22,896 diabetic patients showed that 34.6% had DR, and the rising risk was associated with diabetes duration and improper blood glucose and blood pressure monitoring. Vision-threatening stages of DR involve proliferative DR and diabetic macular edema (DME). The incidence of proliferative DR and DME in the researched group totaled 6.96% and 6.81% respectively. Vision impairment related to DR is a serious global health problem.[11][12]

Although the clinical examination may confirm the retina’s normality, after a few years of DM some important histological and biochemical lesions usually appear, including adhesion of leukocytes, thickening of the basement membrane as well as loss of pericytes. Pericytes are the mural cells of blood microvessels, which have recently come into focus for modulating angiogenesis, regulating blood flow, and maintaining blood–retina barrier (BRB) integrity. Pericytes lying on the capillaries, and are surrounded by the basement membrane, they can prevent ischemia-reperfusion after thrombus clearance by constricting capillaries whereas their relaxation increases blood flow [13]. When the time of duration of diabetes increases, substantial vascular lesions are more likely to affect the retina. As the duration of diabetes increases, the probability of remarkable vascular alterations in the retinal tissue rises. Advancing dysfunctional process of endothelial cells plays a key role in the structure and pathophysiology of the retina, such as thickening of the basement membrane, loss of perivascular cells, damage to the BRB and neovascularization [14][15]. These alterations are accompanied by important biochemical processes, including formation of advanced glycation end-products, and activation of protein kinase C isoforms and the polyol and hexamine pathways. [15]. Subsequently, this contributes to oxidative stress, inflammation and vascular dysfunction. Vascular lesions in diabetes affect small vessels (microangiopathy) and involve precapillary arterioles, capillaries, and small veins. The decreasing number of pericytes, thickening of the basement membrane, and proliferation of endothelial cells are observed [16][17].

2. The Retina—Hyperglycaemia and Inflammation in the Course of Diabetes

Many years of research have shown that hyperglycaemia plays a central role in the induction of diabetic retinopathy[18][19][20] Studies conducted in non-obese diabetic mice (NOD mice) have demonstrated that the first changes on the fundus of the eye blood–retinal barrier breakdown are observed already in the first week of exposure to high glucose levels[21]. In the environment of high glucose concentration, hyperglycaemia causes cell dysfunction, retinal neurovascular impairment, structural defects and functional disorders which lead to further damage of the retinal cells [13][18][19]. The next active stage of pathological changes is associated with the inflammatory process[22][23][24]. The key factors of the inflammatory process in diabetes, first local, then systemic and chronic, are chemokines, growth factors and cytokines[25][26]. In the course of inflammation, acute-phase proteins, including C-reactive protein (CRP) are produced in response to cytokine stimulation. Under physiological conditions, the level of CRP synthesis is low, however, the production increases in inflammation and it is observed in many inflammatory diseases, including diabetes[27][28][29]. Previous studies have demonstrated the elevated blood levels of CRP in patients with T1DM and T2DM suffering from diabetic complications, such as diabetic retinopathy (DR) [18][24][25][26][27]. In patients with T1DM and retinopathy, a five-fold higher level of CRP protein was detected in the blood serum compared to the group of patients with T1DM and without diabetic retinopathy [27]. The authors conclude that the persistently elevated levels of proinflammatory cytokines and CRP in chronic diabetes result from an ongoing inflammatory process in diabetes [25][26][27]. CRP is a clinically recognized marker of inflammation, however, other proteins are also proposed as useful markers of diabetic retinopathy. For example, in patients with T2DM, interleukin 34 (IL-34) has been shown to be an additional inflammatory marker in predicting the risk of chronic diabetic complications. The IL-34 parameter was found to have better discriminate values for the risk of chronic diabetic complications than the CRP protein. Based on the order of the discriminate power, defined as the area under the curve, it was found that the AUCROC area was greater for IL-34 (AUC = 89.88%) than for CRP protein (AUC = 83.96%) [26].

In other studies, the authors attempted to demonstrate whether selected inflammatory proteins may be associated with microvascular complications in adult T1DM patients [29]. In a group of 100 subjects with T1DM, the following parameters were determined: epidermal growth factor (EGF), metalloproteinase 2 (MMP-2), growth/differentiation factor 15 (GDF-15) and interleukin 29 (IL-29). Screening was performed for microvascular complications, such as autonomic and peripheral neuropathy, diabetic nephropathy, and diabetic retinopathy. The results of multivariate logistic regression showed that an increase in the EGF concentration was a statistically significant predictor of microangiopathy (p < 0.0001). Moreover, higher levels of GDF-15 have been associated with diabetic nephropathy, peripheral neuropathy and proliferative retinopathy rather than with non-proliferative retinopathy in patients with T1DM [30].

On the other hand, in children and adolescents suffering from T1DM and diabetic retinopathy, a higher level of IL-6 was demonstrated in the blood serum[31]. The authors showed a significant gradual increase of the IL-6 serum level. This was demonstrated by comparing the values in healthy children, children with T1DM without retinal changes the organ of sight and a group of children with the symptoms of non-proliferative diabetic retinopathy [31]. Higher serum levels of IL-6 were also shown in patients with T2DM and proliferative diabetic retinopathy rather than in the group of patients with T2DM without complications[32][33]. The presence of chronic inflammatory environment in the course of diabetes increases the expression of inflammatory factors, also in the aqueous humour of the eye[22][34]. The eight following factors have been recently found in the aqueous humour of DR patients: interleukin IL-6, IL-8, IL-10, vascular endothelial growth factor (VEGF), transforming growth factor-β (TGF- β), vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), and monocyte chemoattractant protein-1 (MCP-1)[13]. The study showed that TGF-β, ICAM-1, IL-10, VEGF, and VCAM-1 may play a role in the progression of diabetic retinopathy. The authors suggest that the cytokines could be potentially used as biomarkers for predicting the progression of diabetic retinopathy and help to choose a therapeutic option and/or monitor response to treatment [22][23].

Tumour necrosis factor alpha (TNFα) exerts a significantly strong effect on the development and progression of diabetic retinopathy [35][36][37][38]. Tumour necrosis factor alpha (TNFα), also known as TNF, cachectin, or differentiation inducing factor (DIF), is a pleiotropic proinflammatory cytokine, as well as one of 22 proteins belonging to TNFα superfamily, regulating cell growth and differentiation. Apart from its participation in inflammatory processes, it plays an essential role in angiogenesis. TNFα may have an inhibiting or stimulating effect on the formation of new vessels. The resulting effect of TNFα is most probably dependent on cell exposure time and its local concentration. Using a non-obese diabetic mice (NOD mice) model, it was demonstrated that the administration of TNFα into the vitreous body of the eye causes endothelial ischemia and retinal necrosis. This finding proves TNFα role in the pathogenesis of diabetic complications[37]. On the other hand, clinical studies in the group of type 1 diabetic children showed that TNFα turned out to be the paramount tested factor [35]. Studies conducted have demonstrated a significantly higher level of serum TNFα in 76% of children with T1DM and with NPDR compared to the group of children without DR (35%), as well as compared to healthy control group, in which no serum TNFα was detected. Moreover, findings indicated that from within the proinflammatory factors tested, serum TNFα level may be an independent indicator in the prediction of NPDR development in children[35]. Other authors have also detected a high blood serum TNF level in adult patients suffering from T1DM. Authors, using a multifactorial analysis of logistic regression, have proven that TNFα was an autonomous determinant of the PDR inflammatory state marker[36]. The last study tested the level of cytokines in the vitreous body and their correlation with the inflammatory cell density in the fibrovascular membranes (FVM) in patients with proliferative diabetic retinopathy (PDR) in order to assess intraocular inflammatory states in relation to the disease activity [38]. The authors’ statistical analysis demonstrated that PDR-affected patients had significantly higher levels of monocyte chemoattractant protein-1 (MCP-1) (p = 0.003), VEGF (p = 0.009) and interleukin 8 (IL-8) (p = 0.02) in the vitreous body compared to patients with inactive PDR. Moreover, statistical methods confirmed a significantly greater number of T lymphocytes (CD3+, CD4+ and CD8+) in PDR patients compared to PDR ones. The authors suggest that a relationship between the level of cytokines (MCP-1 and IL-8) in the vitreous body and the inflammatory cell density in FVM, and differences in cytokine levels in the vitreous body between PDR and without PDR groups of patients indicate the importance of local intraocular inflammation in PDR patients [39].

References

  1. Beyloe, J.P.; Honeycutt, A.A.; Narayan, K.M.; Hoerger, T.J.; Geiss, L.S.; Chen, H.; Thompson, T.J. Projection of diabetes burden through 2050: Impact of changing demography and disease prevalence in the U.S. Diabetes Care 2001, 24, 1936–1940.
  2. Hartwig, S.; Greiser, K.H.; Medenwald, D.; Tiller, D.; Herzog, B.; Schipf, S.; Ittermann, T.; Völzke, H.; Müller, G.; Haerting, J.; et al. Association of change of anthropometric measurements with incident type 2 diabetes mellitus: A pooled analysis of the prospective population-based CARLA and SHIP Cohort Studies. Medicine (Baltimore) 2015, 94, e1394.
  3. Islam, M.S. Diabetes: From Research to Clinical Practice. Adv. Exp. Med. Biol. 2020, 1307, 1–5.
  4. Imperatore, G.; Boyle, J.P.; Thompson, T.J.; Case, D.; Dabelea, D.; Hamman, R.F.; Lawrence, J.M.; Liese, A.D.; Liu, L.L.; Mayer-Davis, E.J.; et al. Projections of type 1 and type 2 diabetes burden in the U.S. population aged <20 years through 2050: Dynamic modeling of incidence, mortality, and population growth. Diabetes Care 2012, 35, 2515–2520.
  5. World Health Organization. Prevention of Blindness from Diabetes Mellitus: Report of WHO Consultation in Geneva, Switzerland, 9–11 November 2005; World Health Organization: Geneva, Switzerland, 2006.
  6. Wild, S.; Roglic, G.; Green, A. Global prevalence of diabetes. Estimates for the year 2000 and projections for 2030. Diabetes Care 2004, 27, 1047–1053.
  7. Guariguata, L. By the numbers: New estimates from the IDF Diabetes Atlas Update for Diabetes Res. Clin. Pract. 2012, 98, 524–525.
  8. Resnikoff, S. Global Data on Visual impairment in the year 2002. Bull. World Health Org. 2004, 82, 844–851.
  9. Kempen, J.H.; O’Colmain, B.J.; Leske, M.C.; Haffner, S.M.; Klein, R.; Moss, S.E.; Taylor, H.R.; Hamman, R.F.; West, S.K.; Wang, J.J.; et al. The prevalence of diabetic retinopathy among adults in the United States. Arch. Ophthalmol. 2004, 122, 552–563.
  10. Roy, M.S.; Klein, R.; O’Colmain, B.J.; Klein, B.E.K.; Moss, S.E.; Kempen, J.H. The prevalence of diabetic retinopathy among adult type 1 diabetic persons in the United States. Arch. Ophthalmol. 2004, 122, 546–551.
  11. Yau, J.W.; Rogers, S.L.; Kawasaki, R.; Lamoureux, E.L.; Kowalski, J.W.; Bek, T.; Chen, S.-J.; Dekker, J.M.; E Fletcher, A.; Grauslund, J.; et al. Global prevalence and major risk factors of diabetic retinopathy. Diabetes Care 2012, 35, 556–564.
  12. Shin, E.S.; Sorenson, C.M.; Sheibani, N. Diabetes and retinal vascular dysfunction. J. Ophthalmic Vis. Res. 2014, 9, 362–373.
  13. Yang, S.; Zhang, J.; Chen, L.; Lamoureux, E.L.; Kowalski, J.W.; Bek, T.; Chen, S.-J.; Dekker, J.M.; Fletcher, A.; Grauslund, J.; et al. The cells involved in the pathological process of diabetic retinopathy. Biomed. Pharmacother. 2020, 132, 110818.
  14. Fu, D.; Yu, J.Y.; Yang, S.; Wu, M.; Hammad, S.M.; Connell, A.R.; Du, M.; Chen, J.; Lyons, T.J. Survival or death: A dual role for autophagy in stress-induced pericyte loss in diabetic retinopathy. Diabetologia 2016, 59, 2251–2261, doi: 10.1007/s00125-016-4058-5.
  15. Brownlee, M. The pathobiology of diabetic complications: A unifying mechanism. Diabetes 2005, 54, 1615–1625, doi:10.2337/diabetes.54.6.1615.
  16. Simó-Servat, O.; Simó, R.; Hernández, C. Circulating biomarkers of diabetic retinopathy: An overview based on physio-pathology. J. Diabetes Res. 2016, 2016, 5263798.
  17. Ahsan, H. Diabetic retinopathy—Biomolecules and multiple pathophysiology. Diabetes Metab. Syndr. 2015, 9, 51–54.
  18. Zorena, K.; Kula, M.; Malinowska, E.; Raczyńska, R.; Myśliwiec, M.; Raczyńska, K. Threshold serum concentrations of tumour necrosis factor alpha (TNFα) as a potential marker of the presence of microangiopathy in children and adoles-cents with type 1 diabetes mellitus (T1DM). Hum. Immunol. 2013, 74, 75–81.
  19. Giurdanella, G.; Lupo, G.; Gennuso, F.; Conti, F.; Furno, D.L.; Mannino, G.; Anfuso, C.D.; Drago, F.; Salomone, S.; Buco-lo, C. Activation of the VEGF-A/ERK/PLA2 axis mediates early retinal endothelial cell damage induced by high glucose: New insight from an in vitro model of diabetic retinopathy. Int J. Mol. Sci. 2020, 21, 7528.
  20. Chen, Y.L.; Rosa, R.H., Jr.; Kuo, L.; Hein, T.W. hyperglycemia augments endothelin-1-induced constriction of human retinal venules. Transl. Vis. Sci. Technol. 2020, 9, 1.
  21. Xu, Q.; Qaum, T.; Adamis, A.P. Sensitive blood-retinal barrier breakdown quantitation using Evans blue. Invest Ophthal-mol. Vis. Sci. 2001, 42, 789–794.
  22. Song, S.; Yu, X.; Zhang, P.; Dai, H. Increased levels of cytokines in the aqueous humor correlate with the severity of dia-betic retinopathy. J. Diabetes Complicat. 2020, 34, 107641.
  23. Zorena, K.; Malinowska, E.; Raczyńska, D.; Myśliwiec, M.; Raczyńska, K. Serum concentrations of transforming growth factor-Beta 1 in predicting the occurrence of diabetic retinopathy in juvenile patients with type 1 diabetes mellitus. J. Dia-betes Res. 2013, 2013, 614908.
  24. Zorena, K.; Jachimowicz-Duda, O.; Wąż, P. The cut-off value for interleukin 34 as an additional potential inflammatory biomarker for the prediction of the risk of diabetic complications. Biomarkers 2016, 21, 276–282.
  25. Luan, Y.Y.; Yao, Y.M. The Clinical significance and potential role of C-reactive protein in chronic inflammatory and neu-rodegenerative diseases. Front. Immunol. 2018, 9, 1302.
  26. Qiu, F.; Ma, X.; Shin, Y.H.; Chen, J.; Chen, Q.; Zhou, K.; Wu, W.; Liang, W.; Wu, Y.; Song, Q.; et al. Pathogenic role of human C-reactive protein in diabetic retinopathy. Clin. Sci. (London) 2020, 134, 1613–1629.
  27. Coulon, J.; Willems, D.; Dorchy, H. Increase in C-reactive protein plasma levels Turing diabetes in infants and young adults. Presse Med. 2005, 34, 89–93.
  28. Amor, S.; Peferoen, L.A.N.; Vogel, D.Y.S.; Breur, M.; van der Valk, P.; Baker, D.; van Noort, J.M. Inflammation in neuro-degenerative diseases—An update. Immunology 2014, 142, 151–166.
  29. Gasecka, A.; Siwik, D.; Gajewska, M.; Jaguszewski, M.; Mazurek, T.; Filipiak, K.J.; Postula, M.; Eyileten, C. Early bi-omarkers of neurodegenerative and neurovascular disorders in diabetes. J. Clin. Med. 2020, 9, 2807.
  30. Falkowski, B.; Rogowicz-Frontczak, A.; Szczepanek-Parulska, E.; Krygier, A.; Wrotkowska, E.; Uruska, A.; Araszkiewicz, A.; Ruchala, M.; Zozulinska-Ziolkiewicz, D. Novel biochemical markers of neurovascular complications in type 1 diabetes patients. J. Clin. Med. 2020, 9, 198.
  31. Zorena, K.; Myśliwska, J.; Myśliwiec, M.; Balcerska, A.; Lipowski, P.; Raczynska-Wozniak, D.; Raczynska, K. Inflamma-tory and angiogenic factors in children with diabetic retinopathy. Fam. Med. Prim. Care Rev. 2007, 9, 1007–1010.
  32. Chen, H.; Zhang, X.; Liao, N.; Wen, F. Increased levels of IL-6, sIL-6R, and sgp130 in the aqueous humor and serum of patients with diabetic retinopathy. Mol. Vis. 2016, 22, 1005–1014.
  33. Koleva-Georgieva, D.N.; Sivkova, N.P.; Terzieva, D. Serum inflammatory cytokines IL1beta, IL-6, TNF-alpha and VEGF have influence on the development of diabetic retinopathy. Folia Med. (Plovdiv) 2011, 53, 44–50.
  34. Cvitkovic, K.; Sesar, A.; Sesar, I.; Pusic-Sesar, A.; Pejic, R.; Kelava, T.; Sucur, A.; Cavar, I. Concentrations of selected cy-tokines and vascular endothelial growth factor in aqueous humor and serum of diabetic patients. Semin. Ophthalmol. 2020, 35, 126-133.
  35. Zorena, K.; Myśliwska, J.; Myśliwiec, M.; Balcerska, A.; Hak, Ł.; Lipowski, P.; Raczyńska, K. Serum TNF-alpha level pre-dicts nonproliferative diabetic retinopathy in children. Mediat. Inflamm. 2007, 2007, 92196.
  36. Gustavsson, C.; Agardh, E.; Bengtsson, B.; Agardh, C.-D. TNF-alpha is an independent serum marker for proliferative retinopathy in type 1 diabetic patients. J. Diabetes Complicat. 2008, 22, 309–316.
  37. Mugisho, O.O.; Rupenthal, I.D.; Squirrell, D.M.; Bould, S.J.; Danesh-Meyer, H.V.; Zhang, J.; Green, C.R.; Acosta, M.L. In-travitreal pro-inflammatory cytokines in non-obese diabetic mice: Modelling signs of diabetic retinopathy. PLoS ONE 2018, 13, e0202156.
  38. 1Khaloo, P.; Qahremani, R.; Rabizadeh, S.; Omidi, M.; Rajab, A.; Heidari, F.; Farahmand, G.; Bitaraf, M.; Mirmiranpour, H.; Esteghamati, A.; et al. Nitric oxide and TNF-α are correlates of diabetic retinopathy independent of hs-CRP and HbA1c. Endocr. 2020, 69, 536–541, doi:10.1007/s12020-020-02353-x.
  39. Urbančič, M.; Petrovič, D.; Živin, A.M.; Korošec, P.; Fležar, M.; Petrovič, M. G. Correlations between vitreous cytokine levels and inflammatory cells in fibrovascular membranes of patients with proliferative diabetic retinopathy. Mol. Vis. 2020, 26, 472–482.
More
Information
Subjects: Ophthalmology
Contributor MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register :
View Times: 390
Revisions: 2 times (View History)
Update Date: 01 Mar 2021
1000/1000