Nonenzymatic glycosylation and the pathogenesis of diabetic complications

Glucose chemically attaches to proteins and nucleic acids without the aid of enzymes. Initially, chemically reversible Schiff base and Amadori product adducts form in proportion to glucose concentration. Equilibrium is reached after several weeks, however, and further accumulation of these early nonenzymatic glycosylation products does not continue beyond that time. Subsequent reactions of the Amadori product slowly give rise to nonequilibrium advanced glycosylation end-products which continue to accumulate indefinitely on longer-lived molecules. Excessive formation of both types of nonenzymatic glycosylation product appears to be the common biochemical link between chronic hyperglycemia and a number of pathophysiologic processes potentially involved in the development of long-term diabetic complications. The major biological effects of excessive nonenzymatic glycosylation include: inactivation of enzymes; inhibition of regulatory molecule binding; crosslinking of glycosylated proteins and trapping of soluble proteins by glycosylated extracellular matrix (both may progress in the absence of glucose); decreased susceptibility to proteolysis; abnormalities of nucleic acid function; altered macromolecular recognition and endocytosis; and increased immunogenicity.