3-Deoxyglucosone (3-DG) is synthesized via the Maillard reaction and the
polyol pathway, and is detoxified to
3-deoxyfructose and 2-keto-3-deoxygluconic
acid. 3-DG rapidly reacts with
protein amino groups to form
advanced glycation end products (AGEs) such as
imidazolone,
pyrraline, N'-(
carboxymethyl)lysine and
pentosidine, among which
imidazolone is the AGE most specific for 3-DG. As demonstrated by using gas chromatography-mass spectrometry or high-performance liquid chromatography, plasma 3-DG levels are markedly increased in diabetes and
uremia. Although the plasma 3-DG levels had been controversial, it was clearly demonstrated that its plasma level depends on the deproteinization method by which either free or total 3-DG, presumably bound to
proteins, is measured. In diabetes,
hyperglycemia enhances the synthesis of 3-DG via the Maillard reaction and the
polyol pathway, and thereby leads to its high plasma and erythrocyte levels. In
uremia, however, the decreased catabolism of 3-DG, which may be due to the loss of 3-DG
reductase activity in the end-stage kidneys, may lead to high plasma 3-DG level. The elevated 3-DG levels in plasma and erythrocytes may promote the formation of AGEs such as
imidazolone, as demonstrated by immunohistochemistry and immunochemistry using an anti-
imidazolone antibody. Although AGE-modified
proteins prepared in vitro exhibit a variety of
biological activities, known AGE structures have not yet been demonstrated to show any
biological activities. Because 3-DG is potent in the formation of AGEs and has some
biological activities, such as cellular toxicity, it may be more important in the development of diabetic and uremic complications than the known AGE structures. By demonstrating that treatment with an
aldose reductase inhibitor reduces the erythrocyte levels of 3-DG and AGEs, such as
imidazolone, light is shed on the mystery of how
aldose reductase inhibitors may prove beneficial in
diabetic complications. These evidences suggest that 3-DG plays a principal role in the development of diabetic and uremic complications.