Nonenzymatic glycation of collagen in aging and diabetes.

Considerable progress has been made in our understanding of nonenzymatic glycation of collagen, and the relationship between glycation of collagen and changes in connective tissue associated with aging and diabetes. Recent studies surveyed in this review suggest the following conclusions: 1. Collagen content of early glycation products does not appear to increase throughout the life span in normal human subjects, although small increases may occur that are linked to glycemic changes. These products are increased, relative to age-matched controls, in experimental diabetes and in diabetes mellitus in collagen from virtually all tissues analyzed. 2. Collagen content of browning products increases with aging and appears to be higher in diabetic subjects than in age-matched controls. Rates of accumulation may be accelerated in subpopulations of diabetic subjects at high risk for developing complications. 3. Increases in early glycation products do not appear to be associated with alterations in collagen solubility, thermal rupture time, or mechanical strength, nor is there an association with most diabetic complications. Alterations in these products may, however, affect conformation, ligand binding, lysyl oxidase-mediated cross-linking, and interactions between collagen and other macromolecules in the extracellular matrix. 4. Increased content of browning products is associated with many physicochemical changes in collagen as well as with long-term complications in diabetes mellitus. 5. Regulatory mechanisms have been identified in vivo that may serve to control or limit the formation of glycation products. 7. Pharmacologic agents have been identified that may be able to reduce collagen content of late glycation products. Despite the progress that has been made in this field, many areas of uncertainty and controversy exist. For example, there is not yet a consensus that the browning products associated with collagen exclusively comprise advanced Maillard products derived from nonenzymatically glycated residues. There is evidence that oxidative reactions involving lipids also play a role in generating fluorophores and chromophores that may alter properties of collagen. Thus, in the extracellular matrix collagen may be continuously modified by at least three very different processes: Maillard reactions, interactions with oxidizing lipids, and enzymatically mediated cross-linking. The interrelationships between these and possibly other posttranslational modifications remain a poorly understood area of great complexity.