title: Studies to investigate the role of free radicals and low density lipoprotein oxidation in the development of atherosclerosis in human subjects with diabetes mellitus
Creators: name: Britton, Mary Elizabeth
Publisher: name: University of Glasgow
Year: 1994
Subjects: subject: Physiology.

description: The oxidation of low density lipoprotein (LDL) by free radicals (FR) may be one of the early events in the production of atheroma. I have taken several approaches to test the overall hypothesis that more FR oxidation of LDL occurs in diabetes explaining its associated excess risk of atherosclerosis. Before embarking on the body of the work a methodological problem was first clarified. Diene conjugated fatty acids (DCFA) are one of the products of FR attack on lipids, and are used as markers of FR activity however dietary fat also contains DCFA. Therefore a study was designed to test the hypothesis that diet is an important source of DCFA in human serum and tissues, thereby questioning the use of DCFA as a marker of FR activity. The results suggest that diabetes per se is not associated with a lower TRAP but that an interaction may exist between diabetes and smoking which would help explain the even greater risk that smoking poses to diabetics and suggests that smoking diabetics would be more vulnerable to FR damage in circumstances of increased FR load such as following ischaemic episodes. Many explanations for the lack of correlation between peroxidisability and TRAP are discussed in the text. One possibility is that peroxidisability is influenced by the balance between lipid soluble antioxidants and the availability of oxidisable substrate and that TRAP is chiefly contributed to by water soluble antioxidants. Vitamin E is the major lipid soluble antioxidant and this balance can be represented by the ratio of the concentrations of vitamin E to cholesterol plus triglyceride termed the vitamin E status. A study was undertaken to test the hypothesis that:- individuals suffering from diabetes have lower vitamin E levels relative to levels of oxidisable lipids than do non-diabetics; or in other words, have lower vitamin E status which is in turn associated with evidence of greater lipid peroxidation in diabetes. Plasma vitamin E status and TEARS concentration were determined in thirty five diabetic and twenty nine non-diabetic subjects. Vitamin E status was not significantly different in the diabetic and non-diabetic subjects. TEARS concentrations were significantly higher in diabetics than nondiabetics but did not correlate with vitamin E status. This study confirmed reports that increased lipid peroxidation occurs in diabetes but suggest that this is little influenced by vitamin E status. Epidemiological evidence suggests an inverse correlation between dietary antioxidants and the risk of atherosclerotic disease. Ten diabetics and non-diabetics took part in a study aimed at testing the hypothesis that vitamin C and vitamin E dietary supplementation increase the TRAP and vitamin E status of plasma respectively, and reduces lipid peroxidation in diabetics and non-diabetics. In addition to the effect of vitamin supplementation upon plasma TEARS the effect on copper stimulated oxidation of LDL isolated by ultracentrifugation was also assesed. Vitamin C, 1g per day, was associated with a rise in TRAP, a reduction in vitamin E status and possibly with a delayed rise in TEARS. These findings could be explained by a pro-oxidant effect of high dose vitamin C in individuals on a normal diet containing iron. Vitamin E, 300mg per day, was associated with a rise in vitamin E status, no change in TRAP, no change in several parameters of LDL oxidation but with a fall in TEARS. Although the latter result is consistent with a reduction in FR lipid oxidation in response to vitamin E supplementation several other explanations are discussed in the text. The presence of diabetes did not alter the response to vitamin supplementation. Overall the studies in this thesis do not provide evidence for the contention that diabetes might be a state of excess FR lipid oxidation thus explaining its associated high risk of atherosclerotic disease. (Abstract shortened by ProQuest.).