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 .