Advanced glycosylation end products
The effects of hyperglycemia are often irreversible and lead to progressive cell dysfunction.
One of the important mechanisms responsible for the accelerated atherosclerosis in diabetes is the nonenzymatic reaction between glucose and proteins or lipoproteins in arterial walls, collectively known as Maillard, or browning reaction.
Glucose forms chemically reversible early glycosylation products with reactive amino groups of circulating or vessel wall proteins (Schiff bases), which subsequently rearrange to form the more stable Amadori-type early glycosylation products. Equilibrium levels of Schiff-base and Amadori products (the best known of which is hemoglobin A1C) are reached in hours and weeks.
Some of the early glycosylation products on long-lived proteins (e.g. vessel wall collagen) continue to undergo complex series of chemical rearrangement to form advanced glycosylation end products (AGEs).
Once formed, AGE-protein adducts are stable and virtually irreversible. Although AGEs comprise a large number of chemical structures, carboxymethyl-lysine-protein adducts are the predominant AGEs present in vivo.
AGEs accumulate continuously on long-lived vessel wall proteins with aging and at an accelerated rate in diabetes. The degree of nonenzymatic glycation is determined mainly by the glucose concentration and time of exposure. However, another critical factor to the formation of AGEs is the tissue microenvironment redox potential. Thus, situations in which the local redox potential has been shifted to favor oxidant stress, AGEs formation increases substantially.
Hyperglycemia can increase oxidative stress through several pathways. A major mechanism appears to be the hyperglycemia-induced intracellular reactive oxygen. Under normal circumstances, free radicals are rapidly eliminated by antioxidants such as reduced glutathione, vitamin C, and vitamin E. Reduced glutathione content [58,59], as well as reduced vitamin E [60,61] have been reported in diabetic patients. Plasma and tissue levels of vitamin C are 40–50% lower in diabetic patients compared with nondiabetic subjects.
Importantly, there appears to be a tight pathogenic link between hyperglycemia-induced oxidant stress and the two hyperglycemia-dependent mechanisms of vascular damage described above, namely AGEs formation and PKC activation.
Thus, hyperglycemia simultaneously enhances both AGEs formation and oxidative stress, and the mutual facilitatory interactions between glycation and oxidation chemistry can contribute sinergistically to the formation of AGEs, oxidative stress, and diabetic complications (Figure (Figure5).5 ). Indeed, there are strong correlations between levels of glycoxidation products in skin collagen and the severity of diabetic retinal, renal, and vascular disease.