Too sweet: Problems of protein glycation in the eye

Abstract

Laboratory and epidemiological data indicate that high blood sugar levels and/or consuming high glycemia diets are linked to multiple age-related diseases, including age-related macular degeneration, cataract, Parkinson's disease, Alzheimer's disease, diabetic retinopathy, and, apparently glaucoma. High concentrations of blood sugar and perturbations of the systems that regulate blood sugar lead to the accumulation of advanced-glycation end products (AGEs). AGEs are toxic compounds that are formed from the combination of sugars and their metabolites with biomolecules in a non-enzymatic biochemical reaction called glycation. In vitro and in vivo data indicate that high sugar consumption is associated with accumulation of AGEs in a variety of human tissues. Hyperglycemia, along with an oxidative environment and limited cell proliferation in many ocular tissues, encourages formation and precludes dilution of AGEs and associated damage by cell division. These circumstances make many eye tissues vulnerable to glycation-derived damage. Here, we summarize research regarding glycation-induced ocular tissue dysfunction and its contribution to the onset and development of eye disorders. We also discuss how management of carbohydrate nutrition may provide a low-cost way to ameliorate the progression of AGEs-related diseases, including age related macular degeneration and some cataracts, as they do for cardiovascular disease and diabetes.

Keywords: Advanced glycation-end products; Age-related macular degeneration; Aging; Cataracts; Cornea; Diabetes; Diabetic retinopathy; Glycemic index; Optic nerve; Retina; Trabecular meshwork; Vitreous.

Fig. 1.. Formation of AGEs and protective modulatory systems.

AGEs can be slowly formed from high concentration of blood sugar through the Maillard reaction (non-enzymatic chemical reaction between amino groups on proteins by reducing sugars) or faster through the reaction with alpha-dicarbonyls. Reactive dicarbonyls include methylglyoxal (MGO), glyoxal, or 3deoxyglucosane (3DG). AGEs include carboxymethyl-lysine (CML), carboxyethyl-lysine (CEL), methylglyoxal-derived hydroimidazolone (MGH1), etc. Protective anti-AGEs mechanisms (highlighted in green) consist of detoxifying routes such as glyoxalase pathway and protein quality control system that include ubiquitin-proteasome system (UPS) and autophagy.

Fig. 2.. Pathophysiology of AGEs in ocular tissues.

AGEs can 1) accumulate extracellularly and alter the biochemical properties of the extracellular matrix, 2) bind to plasma membrane receptor, triggering nuclear translocation of specific transcription factors or 3) AGEs formed intracellularly induce protein-crosslinking that alter conformational structure of proteins affecting their activities. Accumulation of elevated levels of intracellular aggregates is thought to be cytotoxic.