The importance of lipid-derived malondialdehyde in diabetes mellitus.

Malondialdehyde (MDA) is a highly toxic by-product formed in part by lipid oxidation derived free radicals. Many studies have shown that its concentration is increased considerably in diabetes mellitus. Malondialdehyde reacts both irreversibly and reversibly with proteins and phospholipids with profound effects. In particular, the collagen of the cardiovascular system is not only stiffened by cross-links mediated by malondialdehyde but then becomes increasingly resistant to remodelling. It is important in diabetes mellitus because the initial modification of collagen by sugar adducts forms a series of glycation products which then stimulate breakdown of the lipids to malondialdehyde and hence further cross-linking by malondialdehyde of the already modified collagen. Some progress is being made into the mechanisms of formation and the nature of the intermolecular cross-links induced by malondialdehyde which result in the stiffening of the collagenous tissues. Our recent studies indicate the formation of pyridyl cross-links. Malondialdehyde has been shown to react several orders of magnitude faster with the pre-existing collagen enzymic cross-links than the amino acid side-chains. Malondialdehyde modification of basic amino-acid side-chains also results in a change in properties, for example, in the charge profile of the molecule resulting in modified cell-matrix interactions. Although aspects of the biochemistry of malondialdehyde are still not fully understood its complex chemistry is being unravelled and this should lead to ways of preventing its damaging reactions, for example, through antioxidant therapy.