Nonenzymatic glycation of fibrinogen is species independent and depends only on the glucose concentration in the incubation mixture under selected in vitro conditions. An increased fibrin monomer aggregation in the presence of Ca2+ ions and a decreased proteolytic susceptibility of nonenzymatically glycated fibrinogens may favour the development of thrombophilic states. Blocking of lysine residues as well as restricted conformational changes induced by glucose attachment may be responsible for these effects. Fibrin stabilization by factor XIII is not impaired by nonenzymatic glycation of fibrinogen. Attachment of aortic endothelial cells to fibrin films from glycated fibrinogens is diminished. This phenomenon may be the result of blocked plasminogen activator binding sites in fibrin by nonenzymatic glycation. These effects may contribute in vivo to the accumulation of fibrin in those tissues most frequently affected by diabetic complications.
Complement factor 3 (C3) phenotype and allele frequencies were defined in 312 patients with Type 1 diabetes (IDDM), 256 patients with Type 2 diabetes mellitus (NIDDM), 114 apparently healthy first-degree relatives of Type 1 diabetics, in 10 families (29 members) with a familial history of Type 1 or Type 2 diabetes, and 512 controls (blood donors). All persons investigated were Europeans. There is no evidence to suggest that genes linked to C3 influence susceptibility to Type 1 and Type 2 diabetes and to their late complications. C3 levels in blood plasma were found to be slightly elevated in both types of diabetes. But the C3 concentrations varied considerably within the groups. C3 split products were demonstrable in a high percentage in the blood plasma of freshly manifested Type 1 diabetic persons as well as in Type 1 diabetics with a duration of the disease of 1 to 3 years. C3 proteolysis could also be found in plasma of Type 2 diabetics (26%).
Adhesion of bovine endothelial cells on fibronectin and collagen before and after nonenzymatic glycation in vitro has been studied. Nonenzymatic glycation of these proteins reduced their ability to bind endothelial cells. Furthermore, nonenzymatically glycated fibronectin failed to bind to normal and nonenzymatically glycated gelatin and to fibrin. So gelatin and fibrin Sepharoses can be used to separate highly glycated fibronectins from fibronectins with a low degree of nonenzymatic glucose substitution. Sodium dodecylsulfate polyacrylamide gel electrophoresis did not demonstrate a covalent cross-link between nonenzymatically glycated fibronectins. These results present further evidences for the role of nonenzymatic glycation of proteins in the development of vascular complications in long-term diabetes and of atherosclerosis.
The formation of nonenzymatic glycation products of proteins and nucleic acids appears to be a link between chronic hyperglycaemia and long-term diabetic complications and special forms of aging during normoglycaemia. The major effects of extended glycation include cross-linking of glycated proteins, attachment of soluble proteins to extracellular glycated matrices, conformational changes of proteins followed by altered functions and immunogenicity, and abnormalities in nucleic acid functions.
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