Advanced Glycation End (AGE) Product : An Overview

Diabetes Mellitus is one of the most significant cause of morbidity and mortality all over the world. It is characterized by persistently generalized elevated plasma glucose which could cause detrimental effect intracellularly. Vascular endothelial which expressed a high level of glucose transporter 1 (GLUT) were unable to regulate intracellular glucose which make it more susceptible to damage cause by hyperglycemia. In the article "Diabetic Microvascular Complication; The Simplest Explanation on Polyol Pathway Influx", we have discussed Polyol pathway which is activated during hyperglycemia causing oxidative stress. The product of the pathway, Fructose can be phosphorylated into Fructose-3-Phosphate and then broken down into 3-Deoxyglucosone;  a powerful glycosylating agents that contribute in the formation of Advanced Glycation End (AGE) Product. 

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Diabetic Microvascular Complication; The Simplest Explanation on Polyol Pathway Influx

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Formation of the Advanced Glycation End products took place when carbonyl groups of reducing sugar (glucose, fructose) forms covalent bond with the amino groups of the plasma protein through an enzymatic process known as Maillard reaction. This reaction can be divided into 3 stages; early, intermediate and late stage.

Early Stage of Maillard Reaction

Reducing sugars such as glucose or fructose react with a free amino group of the protein to form an unstable compound called Schiff base which later rearrange to form Amadori product.

Intermediate Stage of Maillard Reaction

The Amadori product degrades to reactive carbonyl compound such as deoxyglucosone via a series of chemical reaction. Deoxyglucosone was formed by non-oxidative rearrangement and hydrolysis of Amadori products. This particular reactive carbonyl compound also formed from hydrolysis of Fructose-3-Phosphate which is formed from the Polyol pathway.

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Late stage of Maillard Reaction

Irreversible compound called AGE are formed through oxidation, dehydration and cyclization of the reactive carbonyl compound. AGE are fluorescent, insoluble compound which accumulate on long-lived protein causing impairment of the protein physiological functions.

Glycation of the protein leading to the formation of AGE are thought to be the major causes of diabetic complications such as nephropathy (problem with the kidney), neuropathy (problem with nerve) and retinopathy (problem with eyes). The formation of covalent adducts between reducing sugar and plasma protein such as albumin, fibrinogen and globulins can lead to:

• Impaired platelet activation
• Impaired fibrinolysis
• Impairment of immune system
• Increased generation of oxygen free radical

References

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•  Forbes JM, Soldatos G, Thomas MC. Below the radar: advanced glycation end products that detour "around the side". Is HbA1c not an accurate enough predictor of long term progression and glycaemic control in diabetes? Clin Biochem Rev. 2005;26:123–134
•  Fraser DA, Hansen KF. Making sense of advanced glycation end products and their relevance to diabetic complications. Inter Diabetes Monitor. 2005;17:1–7 
•  Helou C, Marier D, Jacolot P, Abdennebi-Najar L, Niquet-Léridon C, Tessier FJ, Gadonna-Widehem P. Microorganisms and Maillard reaction products: a review of the literature and recent findings. Amino Acids. (2013) 
•  Monnier VM, Nagaraj RH, Portero-Otin M, Glomb M, Elgawish AH, Sell DR, Friedlander MA. Structure of advanced Maillard reaction products and their pathological role. Nephrol Dial Transplant. 1996;11(Suppl 5):20–26