Role of advanced glycosylation products in complications of diabetes.

Glucose and other reducing sugars can react with proteins and nucleic acids, without the aid of enzymes, to form stable covalent adduct. These reactions, although studied by food chemists, have recently been found to occur in vivo. This has led to studies on the accumulation of these advanced glycosylation end products (AGE) and the role it plays in the aging of long-lived proteins and nucleic acids. In contrast to the Amadori product, which is in equilibrium with glucose, AGE is irreversibly attached to the proteins. The AGE moieties are brown, fluorescent chromophores that can cross-link proteins. We have identified and characterized two specific AGE glucose-derived cross-links in proteins 2-furoyl-4(5)-(2-furanyl)-1H-imidazole (FFI) and 1-alkyl-2-formyl-3,4-diglycosylpyrrole (AFGP). By use of a radioimmunoassay for FFI identification, it has been possible to demonstrate the presence of FFI in situ in proteins that had been exposed to glucose in vitro and in vivo. Recently, we found that reducing sugars react with amino groups on DNA nucleotides in a manner analogous to the nonenzymatic glycosylation of amino groups on proteins. The AGE-DNA formed in this manner has spectral and fluorescent properties similar to those of AGE-proteins. We have observed that formation of AGE on DNA decreases the ability of the single-stranded virus f1 to transfect Escherichia coli. When the plasmid pBR322 containing ampicillin- and tetracycline-resistant genes is incubated with reducing sugars, specific mutations are observed. These mutations have been found to be caused by insertions and deletions of the DNA. Further studies are needed for measuring the amounts of AGE-DNA and proteins linked to DNA by AGE. Potential mechanisms for repair of AGE-DNA also needs to be explored further.(ABSTRACT TRUNCATED AT 250 WORDS)