By: Jenny Lam
Most are aware that the complexity of diabetes spans past just “high blood sugar”. Diabetes often leads to numerous complications over time, such as nerve damage (neuropathy), eye problems, kidney disease, stroke, heart disease, and more. Many of these complications can be traced back to the contribution of advanced glycation end products, or more commonly referred to as AGEs. AGEs are harmful compounds formed when proteins or lipids combine with sugar in the bloodstream through glycation, a nonenzymatic attachment of sugar to proteins or lipids. Additionally, AGEs are also found in many animal-derived and processed foods, which are prone to further AGEs formation during cooking. When they accumulate in the body, they cause serious damage to one's health and play prominent roles in the development and pathogenesis of chronic diseases, such as heart disease, Alzheimer’s, liver disease, and as mentioned earlier, diabetes.
Formation of AGEs
AGEs are formed through two major pathways in the body; the Maillard pathway and the accumulation of triosephosphates. In the Maillard reaction, the carbonyl group of reducing sugar (glucose, fructose, etc.) reacts with an amino group of a membrane protein to form a Schiff base, which undergoes a series of rearrangements to form a more stable product known as amadori products. The formation of Schiff bases and amadori products are reversible reactions, but amadori products can undergo further oxidation, dehydration, and other chemical reactions to irreversibly form AGEs . In the second pathway, high intracellular sugar levels can disrupt normal metabolism of glucose, leading to the accumulation of glucose-metabolic intermediates, such as trisephosphates, which attack surrounding DNA, lipids, and proteins in the cell and form oxoaldehydes, causing AGE damage . Although one is not required to have diabetes to produce AGEs, having diabetes can increase levels of pre-AGE molecules, methyglyoxal (a precursor to AGEs), AGEs, AGE receptors, and higher sugar levels generally result in the formation of less stable glycation products [3, 4]. Examples of AGEs include pentosidine, glucosepane, and carboxymehyl-hydroxy-lysine .
How AGEs Cause Damage
AGEs cause damage by forming irreversible cross-links with proteins and other macromolecules. These cross-links, or bonds between multiple polymer chains, lead to intracellular damage, apoptosis, and contribute to diabetic complications. One such example is the cross-linking of collagen, which causes it to be structurally stiffer and more vulnerable to mechanical stimuli. The formation of AGEs on its side chains can also inhibit collagen’s ability to react with other cells and proteins . Additionally, the crosslinking of collagen can also cause vascular stiffening and accumulation of LDL in artery walls, contributing to atherosclerosis .
In addition to its harmful biological properties, AGEs can induce damage through interactions with specific cell surface receptors, with the most well-known one appropriately termed RAGE (receptor for AGEs). The binding of AGEs to RAGE activates a variety of cell signalling pathways that induce oxidative stress and activates nuclear factor kappa B (NF-κB), which controls genes leading to inflammation . Because RAGE is upregulated by NF-κB, high levels of AGEs can establish a positive feedback loop that leads to chronic inflammation and eventually causes organ damage .
AGEs and Diabetic Complications
Many diabetes’ complications involve the formation of AGEs, including diabetic neuropathy, retinopathy, and more. Although parts of the mechanism of diabetic neuropathy (nerve damage) are still unclear, it is likely that hyperglycemia-induced AGEs play a large role. The AGE-modified myelin that forms a sheath around nerve fibers are susceptible to phagocytosis (“cellular eating”) by macrophages, leading to the degeneration of the myelin sheath. The axons of peripheral nerve cells can also degenerate due to AGE modification of axonal cytoskeletal proteins such as tubulin, neurofilament, and actin and the glycation of the extracellular matrix (ECM) protein laminin can impair regenerative activity. All of these effects damage peripheral nerve cells and contribute to the progression of diabetic neuropathy .
Retinopathy, one of the leading causes of blindness and a common diabetic complication, is also accelerated by the presence of AGEs. Diabetic retinopathy is characterized by hyperglycemia-induced damage to the blood vessels of the retina, such as pathological angiogenesis (harmful growth of new blood vessels), vascular occlusion (blockage of blood vessels), and other related symptoms. The cross-linking of ECM proteins increases vascular stiffness, impairing vascular structure and function. The binding of AGEs to RAGE elicits signalling cascades that cause endothelial dysfunction (endothelial cells line blood vessels and regulate exchanges between tissues and the bloodstream), pericyte dropout (pericytes regulate blood flow and wrap around endothelial cells), and vascular inflammation, all of which damage the retina .
Natural Defense Against AGEs
The body has several natural defense mechanisms to prevent glycation, which are based on enzymatic activities that suppress glycation adducts formation and catalysis of glycated protein reparations. Enzymes, such as glyoxalase I and II, aldehyde reductase, aldose reductase, α-ketogluteraldehyde dehydrogenase, and fructosamine-3-kinase are part of the natural defense against glycation . These antiglycation agents can inhibit AGE formation in multiple ways, such as competing for the protein’s amino group where sugars bind to form AGEs or binding to the intermediates of glycation. Methylglyoxal, a byproduct of glycolysis and precursor to AGEs, is mainly detoxified by the glyoxalase system (glyoxalase I and II), converting the toxic compound into D-lactate, which gets further converted into D-pyruvate to enter the citric acid cycle (Krebs cycle) . In this case, methylglyoxal is effectively used to produce energy for the cell.
How can drugs prevent damage from AGEs?
Because of the detrimental effects of AGEs on almost every part of the body, there remains considerable interest in the therapeutic potential of anti-glycation compounds, such as RAGE blockers and drugs that prevent the formation of AGEs . RAGE blockers inhibit the interaction between AGEs and their receptors, thus preventing the intracellular signalling cascade that follows, whereas compounds that prevent AGE formation typically interfere with the Maillard reaction that forms AGEs. One such compound with therapeutic potential is benfotiamine, a prodrug derivative of thiamine. Benfotiamine increases levels of intracellular thiamine diphosphate, a cofactor used to activate the enzyme transketolase, which directs precursors of AGEs to a safe alternative pathway (pentose phosphate pathway) to prevent AGE formation . It is worth noting that benfotiamine also inhibits three of the four major biochemical pathways of hyperglycemic vascular damage, including AGE formation, PKC activation, and the hexosamine pathway . Because of its therapeutic potential and inhibitory ability, benfotiamine may be an effective option in combating the progression of many diabetic complications.
What can someone do to reduce their AGE levels?
Although many AGEs form inside the body, AGEs also appear in food; lowering one’s intake of AGE-rich foods can help protect against many diseases and decrease AGE levels in the blood and tissues up to 53%. These include meat—especially red meat— fried eggs, butter, certain types of cheese, oils, and nuts. Foods that are fried or highly processed also tend to have high levels of AGEs, so the method one uses to prepare their meal can affect AGEs consumption. A one-year study examining the effect of a low-AGE diet in 138 people with obesity revealed lower AGE levels, as well as increased insulin sensitivity, a decrease in weight, oxidative stress, and inflammation .
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