Advanced Glycation End Products and Retinal Vascular Lesions in Diabetes Mellitus

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Austin J Endocrinol Diabetes. 2015;2(1): 1034.

Advanced Glycation End Products and Retinal Vascular Lesions in Diabetes Mellitus

Wautier MP¹ and Wautier JL¹*

¹Faculty of medicine, University Denis Diderot Paris 7, Paris, France

*Corresponding author: Wautier JL, University Denis Diderot, 8 Avenue Leopold II, 75016 Paris, France

Received: April 10, 2015;Accepted: May 18, 2015; Published: May 29, 2015


Diabetic retinopathy is the first cause of blindness. Two types are preeminent, dial macular edema and proliferative retinopathy. One common factor which leads to retinal lesions is hyperglycemia. High glucose level is responsible for Advanced Glycation End Products (AGE) formation. AGE bind to a receptor (RAGE) which is present on different cell types. RAGE engagement by AGE is responsible for NADPH oxidase stimulation, resulting in oxygen species formation and genes NFκB dependent transcription. Consequently a series of reactions occurred inducing endothelial dysfunction: increase in vascular permeability, pericyte apoptosis associated to enhanced Vascular Endothelial Cell Growth Factor (VEGF) secretion. All these factors are involved in the development of diabetic vascular retinopathy. Laser treatment limited vascular dysfunction leakage and proliferation. Local anti-VEGF treatment, more recently introduced as a therapeutic approach, appears to be also beneficial for patients.

Keywords: Diabetes mellitus; vascular retinopathy; Glycation; VEGF; Endothelial cells; NADPH oxidase

Retinal Vascular Lesion in Diabetes Mellitus

Main reasons for loss of vision in patients with diabetes mellitus are diabetic macular edema and Proliferative Diabetic Retinopathy (PDR). Macular edema caused disruption of the inner bloodretinal barrier [1]. Diabetic maculopathy may develop in the nonproliferative and the proliferative stage of Diabetic Retinopathy (DR). DR involves both morphological and functional changes in the retinal capillaries, including basement membrane thickening, loss of pericytes, increased permeability and vascular dysfunction .The risk of PDR is higher in type 1 diabetes than in type 2, while diabetic macular edema is more commonly found in type 2 diabetes. Retinal Vein Occlusion (RVO) is an important cause of visual loss among older adults throughout the world. RVO is the second cause of visual loss from retinal vascular disease following diabetic retinopathy. The anatomic classification includes three groups: Branch Retinal Vein Occlusion (BRVO), Central Retinal Vein Occlusion (CRVO) and Hemi Retinal Vein Occlusion (HRVO). RVO was diagnosed by the presence of retinal hemorrhages and venous dilation/tortuosity with or without retinal/disc swelling in a defined venous retinal territory: diffuse for CRVO, and located within a hemi retina for HRVO or within a retinal quadrant or less for BRVO. The most frequent and less severe type of RVO, BRVO) [2] is possibly driven by a mechanical factor because it generally occurs at an arteriovenous crossing. The most rare and sight-threatening form, Central Retinal Vein Occlusion (CRVO) remains of unknown pathophysiology. However recent work demonstrated an increased adhesiveness of Red Blood Cells (RBC) due to phosphatidylserine exposure which binds to endothelial annexin V [3]. The prevalence of BRVO is 0.6% and is 0.1% for CRVO. The prevalence of BRVO is associated with hypertension (odd ratio (OR) 5.42, 95% confidence interval (CI) 2.18, 13.47, diabetes mellitus OR 2.43, 95% CI 1.04, 5.70) [4]. Central Retinal Artery Occlusion (CRAO) is analogous to an acute stroke of the eye. The incidence is estimated to be 1 in 100 000 people and accounts for 1 in 10 000 ophthalmological outpatient visits [5]. In a previous article we observed that patients were diagnosed as CRAO on the following criteria: sudden vision loss, presence of diffuse retinal pallor with delayed arterial filling during angiography, and a cherry red foveola [3]. The retinal artery can become blocked. The most common cause is an embolus alternatively there may a sudden narrowing of the vessel by hemorrhage into an atherosclerotic plaque or inflammation (giant cell arthritis.). Retinal artery occlusion is frequently associated to hypertension, dyslipidemia and metabolic syndrome. The metabolic syndrome is a cluster of the most dangerous heart attack risk factors: diabetes and raised fasting plasma glucose, abdominal obesity, high cholesterol and high blood pressure [6].


Advanced Glycation End Products (AGEs) deleterious effect

AGEs exert deleterious effect by acting directly to induce cross linking of long-lived proteins to promote vascular stiffness and interacting with receptor for AGE (RAGE) to induce intracellular signaling leading to enhanced oxidative stress and production of pro-inflammatory cytokines [7].RAGE is a member of the immunoglobulin superfamily of molecules and the gene coding for RAGE is located on chromosome six in the Major Histocompatibility Complex region. RAGE was originally described as a transmembrane multiligand receptor [8]. In diabetes mellitus AGE present on proteins or cell membranes bind to the receptor RAGE. Engagement of endothelial RAGE induced Tissue Factor (TF) production, Intercellular Cell Adhesion Molecule-1 (ICAM-1) and Vascular Cell Adhesion Molecule-1 (VCAM-1) expression. Furthermore the binding of AGE to RAGE induced IL-6, Vascular Endothelial Growth Factor (VEGF), and Macrophage Chemoattractant Protein-1 (MCP-1) release. (Figure 1). In humans increased AGE accumulation has been found in cataract lenses. Furthermore glycation of vitreal collagen fibrils producing dissociation from hyaluronan leading to gel structure destabilization associated with vitreous liquefaction and posterior vitreous detachment in diabetes [9].

Citation: Wautier MP and Wautier JL. Advanced Glycation End Products and Retinal Vascular Lesions in Diabetes Mellitus. Austin J Endocrinol Diabetes. 2015;2(1): 1034. ISSN: 2381-9200.