Diabetic Retinopathy - Pathology

Advanced Glycation End products (AGEs) - updated: 15 March 2008

Advanced glycation and retinal pathology during diabetes

Pharmacol Rep. 2005;57 Suppl:156-68

Stitt AW, Curtis TM.

Of all microvascular complications of diabetes mellitus, retinopathy remains the most common. This disease presents major therapeutic problems for the ophthalmologist and despite many decades of intense research it still constitutes a major cause of blindness in the Western world. This review outlines the pathological characteristics of diabetic retinopathy and proposes a link between disease progression with the formation and accumulation of advanced glycation endproducts (AGEs). AGEs form in vivo from the reaction of glucose and/or alpha-oxaloaldehydes leading to chemical modifications on the amino groups of proteins, lipids and DNA. These heterogenous adducts can modify the structure and function of proteins and lead to intra-molecular and intermolecular cross-link formation. As reported in a range of clinical investigations and determined by mechanistic in vitro and in vivo studies, AGEs accumulate in the diabetic retina where they may be effectors of retinal vascular and neural cell dysfunction. Evidence now points towards a pathogenic role for advanced glycation in the initiation and progression of diabetic retinopathy and this review will examine the current state of knowledge of AGE-related pathology in the retina at a cellular and molecular level. It will also describe how ongoing pharmaceutical strategies to inhibit AGE formation and thereby attenuate their pathogenic influence during chronic hyperglycemia may play a significant role in the treatment of diabetic retinopathy.

Publication Types:

• Review

The role of advanced glycation in the pathogenesis of diabetic retinopathy

Exp Mol Pathol. 2003 Aug;75(1):95-108

Stitt AW.

Retinopathy is one of the commonest microvascular complications of diabetes and is still the prevailing cause of registerable blindness in the working population of developed countries. The clinicopathology of microvascular lesions and the dysregulation of an array of biochemical pathways in the diabetic retina have been extensively studied, although the relative contribution of various biochemical sequelae of hyperglycaemia remains ill- defined. There is little doubt that the pathogenesis of this diabetic complication is highly complex and there is a pressing need to establish new therapeutic regimens that can effectively prevent or retard the initiation and progression of retinal microvascular cell dysfunction and death which is characteristic of the vasodegenerative stages of diabetic retinopathy. Among the several pathogenic mechanisms that may contribute to diabetic retinopathy are the formation and accumulation of advanced glycation endproducts (AGEs). AGEs can form on the amino groups of proteins, lipids, and DNA through a number of complex pathways, including nonenzymatic glycation by glucose and reaction with metabolic intermediates and reactive dicarbonyl intermediates. These reactions not only modify the structure and function of proteins, but also cause intramolecular and intermolecular cross-link formation. AGEs are known to accumulate in the diabetic retina where they may have important effects on retinal vascular cell function in vitro and in vivo. Evidence now points toward a pathogenic role for advanced glycation in the initiation and progression of diabetic retinopathy. This review will examine the basis of AGE-related pathology in the diabetic retina at cellular and molecular levels. It will also outline how recent strategies to inhibit AGE formation or limit their pathogenic influence during chronic diabetes may have an important role to play in the treatment of retinopathy.

Publication Types:

• Review

Advanced glycation and advanced lipoxidation: possible role in initiation and progression of diabetic retinopathy

Curr Pharm Des. 2004;10(27):3349-60

Stitt AW, Frizzell N, Thorpe SR.

Diabetic retinopathy remains the most common microvascular complication suffered by diabetic patients and is the leading cause of registerable blindness in the working population of developed countries. The clinicopathological lesions of diabetic retinopathy have been well characterised and although a multitude of pathogenic mechanisms have been proposed, the underlying dysfunctional biochemical and molecular pathways that lead to initiation and progression of this complication remain largely unresolved. There is little doubt that the pathogenesis of diabetic retinopathy is highly complex and there is a pressing need to establish new therapeutic regimens that can effectively prevent or limit retinal microvascular cell dysfunction and death which is characteristic of the vasodegenerative stages of diabetic retinopathy. The formation and accumulation of advanced glycation endproducts (AGEs) and/or advanced lipoxidation endproducts (ALEs) are among several pathogenic mechanisms that may contribute to diabetic retinopathy. AGEs/ALEs can form on the amino groups of proteins, lipids and DNA through a number of complex pathways including non-enzymatic glycation by glucose and reaction with metabolic intermediates and reactive dicarbonyl intermediates. These reactions not only modify the structure and function of proteins, but also cause intra-molecular and intermolecular cross-link formation. AGEs/ALEs are known to accumulate in the diabetic retina where they may have important effects on retinal vascular cell function, as determined by a growing number of in vitro and in vivo studies. Evidence now points towards a pathogenic role for advanced glycation/lipoxidation in the initiation and progression of diabetic retinopathy and this review will examine the current state of knowledge of AGE/ALE-related pathology in the diabetic retina at a cellular and molecular level. It will also outline how recent pharmaceutical strategies to inhibit AGE/ALE formation or limit their pathogenic influence during chronic hyperglycaemia may play a significant role in the treatment of diabetic retinopathy.

Publication Types:

• Review

The role of advanced glycation in the pathogenesis of diabetic retinopathy

Exp Mol Pathol. 2003 Aug;75(1):95-108

Stitt AW.

Retinopathy is one of the commonest microvascular complications of diabetes and is still the prevailing cause of registerable blindness in the working population of developed countries. The clinicopathology of microvascular lesions and the dysregulation of an array of biochemical pathways in the diabetic retina have been extensively studied, although the relative contribution of various biochemical sequelae of hyperglycaemia remains ill- defined. There is little doubt that the pathogenesis of this diabetic complication is highly complex and there is a pressing need to establish new therapeutic regimens that can effectively prevent or retard the initiation and progression of retinal microvascular cell dysfunction and death which is characteristic of the vasodegenerative stages of diabetic retinopathy. Among the several pathogenic mechanisms that may contribute to diabetic retinopathy are the formation and accumulation of advanced glycation endproducts (AGEs). AGEs can form on the amino groups of proteins, lipids, and DNA through a number of complex pathways, including nonenzymatic glycation by glucose and reaction with metabolic intermediates and reactive dicarbonyl intermediates. These reactions not only modify the structure and function of proteins, but also cause intramolecular and intermolecular cross-link formation. AGEs are known to accumulate in the diabetic retina where they may have important effects on retinal vascular cell function in vitro and in vivo. Evidence now points toward a pathogenic role for advanced glycation in the initiation and progression of diabetic retinopathy. This review will examine the basis of AGE-related pathology in the diabetic retina at cellular and molecular levels. It will also outline how recent strategies to inhibit AGE formation or limit their pathogenic influence during chronic diabetes may have an important role to play in the treatment of retinopathy.

Publication Types:

• Review

The role of advanced glycation end products in retinal microvascular leukostasis

Invest Ophthalmol Vis Sci. 2003 Oct;44(10):4457-64

Moore TC, Moore JE, Kaji Y, Frizzell N, Usui T, Poulaki V, Campbell IL, Stitt AW, Gardiner TA, Archer DB, Adamis AP.

PURPOSE. A critical event in the pathogenesis of diabetic retinopathy is the inappropriate adherence of leukocytes to the retinal capillaries. Advanced glycation end-products (AGEs) are known to play a role in chronic inflammatory processes, and the authors postulated that these adducts may play a role in promoting pathogenic increases in proinflammatory pathways within the retinal microvasculature. METHODS. Retinal microvascular endothelial cells (RMECs) were treated with glycoaldehyde-modified albumin (AGE-Alb) or unmodified albumin (Alb). NFkappaB DNA binding was measured by electromobility shift assay (EMSA) and quantified with an ELISA. In addition, the effect of AGEs on leukocyte adhesion to endothelial cell monolayers was investigated. Further studies were performed in an attempt to confirm that this was AGE-induced adhesion by co-incubation of AGE-treated cells with soluble receptor for AGE (sRAGE). Parallel in vivo studies of nondiabetic mice assessed the effect of intraperitoneal delivery of AGE-Alb on ICAM-1 mRNA expression, NFkappaB DNA-binding activity, leukostasis, and blood-retinal barrier breakdown. RESULTS. Treatment with AGE-Alb significantly enhanced the DNA-binding activity of NFkappaB (P = 0.0045) in retinal endothelial cells (RMECs) and increased the adhesion of leukocytes to RMEC monolayers (P = 0.04). The latter was significantly reduced by co-incubation with sRAGE (P < 0.01). Mice infused with AGE-Alb demonstrated a 1.8-fold increase in ICAM-1 mRNA when compared with control animals (P < 0.001, n = 20) as early as 48 hours, and this response remained for 7 days of treatment. Quantification of retinal NFkappaB demonstrated a threefold increase with AGE-Alb infusion in comparison to control levels (AGE Alb versus Alb, 0.23 vs. 0.076, P < 0.001, n = 10 mice). AGE-Alb treatment of mice also caused a significant increase in leukostasis in the retina (AGE-Alb versus Alb, 6.89 vs. 2.53, n = 12, P < 0.05) and a statistically significant increase in breakdown of the blood-retinal barrier (AGE Alb versus Alb, 8.2 vs. 1.6 n = 10, P < 0.001). CONCLUSIONS. AGEs caused upregulation of NFkappaB in the retinal microvascular endothelium and an AGE-specific increase in leukocyte adhesion in vitro was also observed. In addition, increased leukocyte adherence in vivo was demonstrated that was accompanied by blood-retinal barrier dysfunction. These findings add further evidence to the thinking that AGEs may play an important role in the pathogenesis of diabetic retinopathy.

Advanced glycation end products increase retinal vascular endothelial growth factor expression

J Clin Invest. 1998 Mar 15;101(6):1219-24

Lu M, Kuroki M, Amano S, Tolentino M, Keough K, Kim I, Bucala R, Adamis AP.

Advanced glycation end products (AGEs) are linked with the development of diabetic retinopathy; however, the pathogenic mechanisms are poorly defined. Vascular endothelial growth factor (VEGF) levels are increased in ischemic and nonischemic diabetic retina, and VEGF is required for the development of retinal and iris neovascularization. Moreover, VEGF alone can induce much of the concomitant pathology of diabetic retinopathy. In this study, we found that AGEs increased VEGF mRNA levels in the ganglion, inner nuclear, and retinal pigment epithelial (RPE) cell layers of the rat retina. In vitro, AGEs increased VEGF mRNA and secreted protein in human RPE and bovine vascular smooth muscle cells. The AGE-induced increases in VEGF expression were dose- and time-dependent, inhibited by antioxidants, and additive with hypoxia. Use of an anti-VEGF antibody blocked the capillary endothelial cell proliferation induced by the conditioned media of AGE-treated cells. AGEs may participate in the pathogenesis

Relationship of hyperglycemia to the long-term incidence and progression of diabetic retinopathy

Arch Intern Med. 1994 Oct 10;154(19):2169-78

Klein R, Klein BE, Moss SE, Cruickshanks KJ.

BACKGROUND: The object was to examine the relationship of hyperglycemia, as measured by glycosylated hemoglobin level, to the incidence and progression of diabetic retinopathy over a 10-year period. METHODS: Patients who were younger (n = 682) and older (n = 834) than 30 years at onset of diabetes participated in baseline (1980-1982) and follow-up (1984-1986 and 1990-1992) examinations of a population-based cohort study. Glycosylated hemoglobin levels were measured by microcolumn. Retinopathy was determined from stereoscopic fundus photographs. RESULTS: Persons with glycosylated hemoglobin levels in the highest quartile at baseline were more likely to have progression of retinopathy than persons with levels in the lowest quartile (younger-onset group: relative risk [RR], 2.9; 95% confidence interval [CI], 2.3 to 3.5; older-onset group taking insulin: RR, 2.1; 95% CI, 1.6 to 2.8; and older-onset group not taking insulin: RR, 4.3; 95% CI, 3.0 to 6.2) and were more likely to develop proliferative diabetic retinopathy (younger-onset group: RR, 7.1; 95% CI, 4.6 to 11.1; older-onset group taking insulin: RR, 3.1; 95% CI, 1.5 to 6.1; and older-onset group not taking insulin: RR, 13.8; 95% CI, 4.8 to 39.5). These relations were significant (P < .005) in all groups examined, even after controlling for other risk variables. CONCLUSIONS: These data are compatible with the hypothesis that long-term control of hyperglycemia, as measured by glycosylated hemoglobin levels, is a significant risk factor for the long-term progression of diabetic retinopathy and that lower levels of glycosylated hemoglobin, even later in the course of diabetes, may modify the risk imposed by higher levels earlier in the course of disease in people with both younger- and older-onset diabetes.

Publication Types:

• Review

Publication Types:

• Review