Ou, Peimian; (1996) Possible mechanisms for oxidative tissue damage in diabetes mellitus and of some anti-diabetic drugs. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Diabetes mellitus and its complications are associated with oxidative stress which might be caused by hyperglycaemia and transition metals. This study examines the role of transition metals in several biochemical pathways associated with hyperglycaemia. Some experimental methods developed for measurement of the oxidation reactions are discussed: (1) intracellular hydrogen peroxide (H2O2) production in erythrocytes measured by assessing catalase inactivation in the presence of aminotriazole; (2) the Ferrous Oxidation in Xylenol orange (FOX) assay applied to measurements of transition metal (Cu2+)-catalysed lipid peroxidation associated with glycation in vitro, (3) assessment of the ability of drugs to chelate transition metal, particularly copper ion, and (4) transition metal involvement in the sorbitol pathway and activation of aldose reductase. Results of the studies presented indicate that: (1) Erythrocytes exposed to ascorbic acid, but not to glucose in the presence of AMT undergo a dose- and time-dependent inactivation of endogenous catalase which is proportional to environmental H2O2 concentrations. The production of H2O2 seems to be dependent upon the availability of transition metal chelatable by copper-complexing drugs; (2) Glucose had little effect upon peroxidation of phosphatidylcholine (PC) liposomes, by contrast with the major role of free copper ions in this process. However pre-autoxidised glucose accelerated the oxidation of lipids and lipoproteins. Furthermore, glucose modified (glycated) forms of protein and lipoprotein were more vulnerable to metal-catalysed oxidative damage compared to native forms of the proteins. (3) Therapeutic agents to prevent diabetic complications are being developed. The oxidative chemistry of aminoguanidme (AG), thioctic (lipoic) acid, and the aldose reductase inhibitors (ARIs) AL-1576, sorbinil and zopolrestat was studied. Thioctic acid and the ARIs were found to act as copper ion-chelating agents inhibiting metal-catalysed ascorbate and lipid oxidation and also increased the partition of copper ions into octanol. IV By contrast, the behaviour of AG was paradoxical. AG slowly generated H2O2 and also inhibited catalase irreversibly. It is possible that such AG-mediated inhibition of catalase might occur in vivo, with presently unpredictable consequences. If irreversible catalase inhibition by AG occurs in vivo, then this would imply that catalase is not involved in oxidative stress regulation in diabetes, or that catalase positively contributes to diabetic tissue damage. 4) An increase in oxidative stress in diabetic patients is also associated with polyol pathway metabolism. Rat lenses incubated with glucose accumulated sorbitol and there was an increase in the level of aldose reductase activity in the lenses as assessed in vitro. Exposure of a lens homogenate to H2O2 was also found to enhance the in vitro AR activity. Exposure of the lenses to glucose in the presence of metal-chelating drugs prevented AR activation. This suggests that activation of AR may be related to the oxidant production associated with metals and, possibly, glucose autoxidation; In conclusion, the experimental work reported in this thesis generally supports the idea that transition metal catalyzed oxidation contributes to the complications of diabetes. These results support the concept that transition metals may play a central role in catalysing the abnormal oxidative pathways associated with hyperglycaemia, leading to the increased oxidative stress in diabetes. Development of metal-binding antioxidant drug may be a useful strategy for treatment of the diabetic complications.

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