Low densitiy lipoprotein glycation mediated modifications in diabetic atherosclerosis

Evidence suggests a role for glycation and glycoxidative changes in damaged tissues and plasma components. LDL modified as a result of glucoxidation stress, is potentially atherogenic, and is implicated in the accelerated atherosclerosis associated with diabetic complications.;The purpose of this thesis is to investigate and establish the importance of glycoxidative changes to LDL and its role in the chemical complications associated with diabetes.;LDL was chemically modified in vitro with glyoxal (dicarbonyl aldehyde) to produce a crosslinked structure (glyoxalated) LDL. The complex produced (glyoxalated LDL) was used for the production of specific antibodies. Anti-glyoxalated LDL antibody was employed in specific and sensitive ELISA assays to measure the levels of glyoxalated LDL in human plasma. Levels of glyoxalated LDL measured in diabetics were generally up to 20% higher (n = 182, P <0.001) when compared to non-diabetics, reference and hyperlipidemic groups. An anti-glyoxalated LDL autoantibody ELISA assay was developed to assess the immunological importance of glyoxalated LDL and similar crosslinked structures in human plasma. Diabetics with poor glycaemic control demonstrated a 22% increase in anti-glyoxalated LDL autoantibodies (n = 39, P <0.0001) compared to reference groups, where less than a 3% increase was detected in hyperlipidemic non-diabetic subjects (n = 33, P <0.08). Unlike glycated haemoglobin, no significant age relationship was detected.;Although glyoxal is a common product of glucose and lipoprotein autoxidation, levels of glyoxalated LDL and anti-glyoxalated LDL autoantibodies measured in diabetics, hyperlipidemic and reference groups, suggest a direct relationship between hyperglycaemia and the presence of glyoxal mediated crosslinks on human LDL. Glyoxalated LDL measured with these specific immunochemical assays may predict the possible complications associated with diabetes better than glycated haemoglobin because it appears not to have a direct relationship with age at high concentrations observed in diabetics.