Advanced Glycoxylation End Products (AGEs) and Advanced Lipoxydation End Products (ALEs), Trigger and Biomarkers Compounds from Chronic Complications of Diabetes Mellitus and Aging

Advanced Glycoxylation End Products (AGEs) and Advanced Lipoxydation End Products (ALEs), Trigger and Biomarkers Compounds from Chronic Complications of Diabetes Mellitus and Aging

Ida Ayu Dewi Wiryanthini

wiryanthini@unud.ac.id

AGEs (Advanced Glication/Glycoxylation End products) and ALEs (Advanced Lipoxydation End products) are irreversible compounds that occur when a protein / fat / nucleic acid experiences non-enzymatic glycation by reducing sugars. If the protein is glycated by reducing sugars or its derivatives such as fructose, glucose, glyoxal, AGEs will be formed. If the glycated fat will form Advanced Lipoxidation End products (ALEs) Both of these compounds are irreversible, toxic and capable of forming cross-linking with other amino or carbonyl groups.¹ As a result, proteins such as enzymes, collagen, and receptors will be damaged and lost its function. Likewise, fatty / fatty acids that experience glycation will lose its function.

The occurrence of this compound was first raised by a French chemist and nutritionist Louis Camille Maillard, at the beginning of the 20th century. The series of reactions was later called the Maillard reaction. This reaction occurs when the protein is heated with reducing sugars, first occurs Schiff base, then Amadori products that are still reversible, and finally occurs AGEs, which are yellowish brown in color and have a pleasant, irreversible aroma. He suspects that this reaction can also occur in the body, given that protein, carbohydrates and fats are the main nutritional component for us. After years of this reaction has been examined in terms of nutrition, it can finally be proven to occur in the human body. Then began studies - research on the relationship of AGEs with the occurrence of abnormalities in humans.

AGEs can come from outside and inside the body. From outside the body is from the food we consume, especially foods that are cooked without using water, such as baking, smoking, which will cause a yellowish brown color (browning reaction), such as roast duck, roast turkey and cake, pastry that is roasted until brown yellowish. Spices like taoco (soya sauce) also contain a lot of AGEs. Some drinks such as the coca cola diet, orange juice, and lots of fructose will increase the occurrence of glycation and the formation of AGEs. In the body AGEs occur through normal metabolic processes and the aging process. ^2,3,7

The damaging properties of AGEs/ALEs occur because of their irreversibility, making it difficult to convert into other compounds that are less toxic and easily removed from the tissue. Then this compound will be buried as a toxic material in the body. Also its ability to cross-link (cross-link) with proteins or other fatty acids will cause the physiological function of amino acids / proteins and fatty acids needed by the body to be damaged. The binding of AGEs to their receptors (RAGE) will trigger the expression of NF-kβ and the formation of other compounds due to activation of subsequent signal transduction such as IDRF, PDEF and others. Besides the accumulation and formation of cross bonds, AGEs will also increase the formation of ROS (Reactive Oxygen Species) by activating the enzyme NADH oxidase, so that the formation of free radicals, especially superoxid radicals, will increase. an ROS that is most harmful to the body. Eventually oxidative stress will occur, a condition where the amount of free radicals exceeds the total amount of the body's antioxidants. At this time there is damage to DNA, proteins and cell membranes. The accumulation of AGEs in tissues or organs will accelerate the aging of cells or tissues.

Diabetes is characterized by prolonged hyperglycemia very possible this nonenzimarik glycation reaction. HbA1c is an example of the beginning of the occurrence of glycation against hemoglobin by glucose. Likewise, the complications of diabetic retinopathy, diabetic neuropathy and diabetic nephropathy are closely related to the presence of AGEs.^4,5,8 The accumulation of toxic AGEs on the retina will trigger the occurrence of peripheral cell dysfunction and is an early sign of a characteristic change from diabetic retinopathy. As a result of the binding of AGEs to the receptor (RAGE), which is an immunoglobulin molecule, and is present in the epithelium of blood vessels, in smooth muscle cells, kidney cells, and nerve tissue and in the retina, will trigger several abnormalities. AGEs in peripheral cells will stimulate the expression of VEGF (Vascular Endothelial Growth Factor), also known as vascular permeability factor. This will cause retinal hyperpermeability. Furthermore it is known that the presence of VEGF correlates with the occurrence of neovascularization activity in diabetic retinopathy. AGEs also trigger inflammation, thrombosis and angiogenesis. As a result of the changes above, diabetic retinopathy is the cause of blindness in people with Diabetes Mellitus. It is also now known that β-amyloid protein accumulation occurs in the neural network of Alzheimer's patients.^6,11

Although abnormalities due to AGEs are difficult to avoid because AGEs can come from outside the body that is from the food and drinks we consume and are also the result of metabolic processes in the body but there are still efforts to overcome the effects of accumulation of AGEs in the body. inter alia by: (1) inhibiting or reducing the formation of AGEs, (2) blocking interactions between AGEs and RAGE and the signal transduction journey below, (3) using cross link breakers such as DPTC, will reduce crosslinking that has already been occur, (4) reduce the accumulation of AGEs by using antioxidants and OAD such as methformin and acarbose.¹⁰

Aminoguanidine, a hydrazine compound, was the first AGEs inhibitor compound found. This compound will capture the α-dicarbonyl compound, thus preventing the Maillard reaction from continuing. Another compound, Amadori, is another inhibitor of the formation of AGEs. This compound also captures the dicarbonyl group which will inhibit the formation of Amadori products into AGEs. Vitamin B6 derivative, pyridoxamine is a potent post Amadori inhibitor compound and is very safe to use. Which has the ability to inhibit the upregulation of the retinal basal membrane.

A more recent and more promising discovery is PEDF (Pigment Epithelium Derived Factor), one of the superfamilli serine protease inhibitors, which inhibits apoptosis from cell peripheral peritasis and proliferation of retinal endothelial cells.11 Benfothyamine, a fat-soluble vitamin B6 derivative inhibits the formation of AGEs and activation NF-kβ in the retina turned out to be a potential compound to treat diabetic retinopathy.

Avoid the consumption of food ingredients that contain lots of AGEs / ALEs and use ingredients that prevent the formation of AGEs and use materials that can break cross-bonds and the use of antioxidants will reduce and slow down the process of tissue destruction due to AGEs.⁷

REFFERENCES

1.      Suarez. Non enzymatic browning of protein and the sorbitol pathway, Prog Clin Biol Res. 1989;304:141-62.

2.      Sakai, Experimental studies on the role of fructose in the development of diabetic complication. Kobe J Med 6. 125-36.

3.      Koschinsky. Orally observed reactive glycation products (glycotoxin) : An environmental risk factor in diabetes. Natl.Acad Sci. Vol.94, pp.6474-6479, June 1997.

4.      King. The role of glycation in the pathogenesis of diabetic polyneuropathy. J Clin Pathol 2001;54: 401-405.

5.      Stitt. An important pathological event in diabetic and age related ocular disease. Br J Opht 2002, 74; 502-512.

6.      Yamagishi. Serum / cerebrospinal fluid level of glyceraldehide – derived AGEs (Biomarker for early detection of early Alzheimer disease, Med Hypotheses) 2005;64(6):1205-7.

7.      Goldberg. Advanced Glycation End products in commonly consumed food. J Am Diet Assoc, 2004; 25: 215-217.

8.      Forbes J.M. Role of Advanced Glycation End products In Diabetic Nephropathy, J.Am.Soc.Nephrol.,2003; 14:5254-58.

9.      Marie-Paule Wautier. Activation NADPH oxidase by AGE link oxidant stress to altered gene expression via RAGE Am J Physiol Endocrinol Metab vol 280, 2001.

10.   Goldin A, Beckman JA, Schimdt AM. Advanced Glication End products : sparking the development of diabetic vascular injury. Circulation 2006; 114(6):597-605.

11.   Sho-ichi Yamagishi, Kazuo Nakamura and Tsuto Imaizumi Advanced Glycation End Produccts (AGEs) and diabetic Vascular Complications, Department of Internal Medicine, School of Medicine Kurume Japan ; Current Diabetes Riview, 2005: 93-106.