Advanced Glycation End-Products and Diabetic Neuropathy of the Retina

Abstract

Diabetic retinopathy is a tissue-specific neurovascular impairment of the retina in patients with both type 1 and type 2 diabetes. Several pathological factors are involved in the progressive impairment of the interdependence between cells that consist of the neurovascular units (NVUs). The advanced glycation end-products (AGEs) are one of the major pathological factors that cause the impairments of neurovascular coupling in diabetic retinopathy. Although the exact mechanisms for the toxicities of the AGEs in diabetic retinopathy have not been definitively determined, the AGE-receptor of the AGE (RAGE) axis, production of reactive oxygen species, inflammatory reactions, and the activation of the cell death pathways are associated with the impairment of the NVUs in diabetic retinopathy. More specifically, neuronal cell death is an irreversible change that is directly associated with vision reduction in diabetic patients. Thus, neuroprotective therapies must be established for diabetic retinopathy. The AGEs are one of the therapeutic targets to examine to ameliorate the pathological changes in the NVUs in diabetic retinopathy. This review focuses on the basic and pathological findings of AGE-induced neurovascular abnormalities and the potential therapeutic approaches, including the use of anti-glycated drugs to protect the AGE-induced impairments of the NVUs in diabetic retinopathy.

Keywords: advanced glycation end-products; anti-glycation; apoptosis; diabetic retinopathy; neuroprotection; neurovascular unit; nutrients; oxidative stress; polyol pathway; receptor of AGEs.

Figure 1

Initial step of the Maillard reaction. In the first step, a protein reacts with an amino acid, which results in the production of a Schiff base. The Schiff base is converted into an Amadori product by the Amadori rearrangement through a protonated imine and 1,2-enaminol formation. S: reducing sugar, P: protein.

Figure 2

Hypothetical schemes of the final step of AGE formation. Carboxymethyllysine (CML) is synthesized from an Amadori compound or glyoxal [23]. Carboxyethyllysine (CEL) is made from methylglyoxal [24]. Glyoxal-derived lysine dimer (GOLD), methylglyoxal-derived lysine dimer (MOLD), and 3-DG-derived lysine dimer (DOLD) have cross-links between lysine residues and glyoxal, methylglyoxal or 3-DG [25]. Only a small percentage of AGEs in the body have been identified. Glyceraldehyde- and glycolaldehyde-derived AGEs may be synthesized faster than Amadori compound-derived AGEs and more toxic than other types of AGEs.

Figure 3

Scheme of the polyol pathway. Under normal conditions (upper figure), glucose is taken in by the retinal cells via sodium-glucose cotransporter (SGLT) or glucose transporter (GLUT). Glucose is converted to pyruvate by the metabolic glycolysis pathway. This process releases free energy to synthesize the high-energy molecule adenosine triphosphate (ATP) in the final step. In the diabetic condition, excessive uptake of glucose activates a minor cellular pathway, the polyol pathway (lower figure). The activated polyol pathway causes an increase in oxidative stress, osmotic stress, and AGE formation in diabetic retinas. G: glucose, G6P: glucose-6-phosphate, F6P: fructose-6-phosphate, GA3P: glyceraldehyde-3-P, NADP: nicotinamide adenine dinucleotide phosphate (NADP+; oxidized form, NADPH; reduced form), DAG: diacylglycerol, PKC: protein kinase C, AGEs: advanced glycation end products.

Figure 4

Hypothetic scheme of the pathophysiology of AGEs in diabetic retinas. Chronic hyperglycemia facilitates AGE production. Oxidative stress is induced by the AGE-RAGE axis, but Amadori compounds become the source of ROS production. Thus, the RAGE-independent pathways can be involved in increasing oxidative stress in diabetic retinas.