Advanced glycoxidation endproducts metabolism

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Steady-state serum AGE levels reflect the balance of oral intake, endogenous formation, and catabolism of AGEs. AGE catabolism is dependent on both tissue degradation and renal elimination.

Cells such as tissue macrophages can ingest and degrade AGEs via specific or nonspecific receptors (5,6,41). Mesenchymal cells such as endothelial and mesangial cells seem to participate also in AGE elimination (42). It has been postulated that insulin may accelerate macrophage scavenger receptor-mediated endocytic uptake of AGE proteins through the IRS/PI3 pathway (43). Cellular removal of AGEs is processed largely through endocytosis and further intracellular degradation resulting in the formation of low-molecular-weight AGE peptides, which are released to the extracellular space and circulation (5,41,44). These peptides undergo a variable degree of reabsorption and further catabolism in the proximal nephron and the rest is excreted in the urine. Therefore, effective AGE elimination is dependent on normal renal function (5,41,44,45). We have recently found that diabetic patients with normal renal function have a significantly lower urinary AGE excretion than healthy controls. This impaired renal AGE clearance second ary to increased tubular reabsorption of AGE peptides may be a factor in the high-serum AGE levels obeserved in these patients (46).

Other intracellular protective systems also help to limit the accumulation of reactive AGE intermediates. Methylglyoxal is first converted by glyoxalase-I to S-D-lacto-ylglutathione in the presence of reduced glutathione as an essential cofactor, and then converted to D-lactate by glyoxalase-II. The significance of such systems is supported by studies in which overexpression of glyoxalase-I prevented hyperglycemia-induced AGE formation and increased macromolecular endocytosis (47). These systems, however, could still be overwhelmed by high AGE conditions such as diabetes, renal failure, or sustained excess dietary AGE intake.

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