Factors disturbing the oxidant-antioxidant balance in diabetes mellitus: Role of iron

The main objective of this thesis was to investigate how diabetes disturbs iron-metabolism and how this contributes to the increased oxidative stress in diabetes. Since free iron is one of the most reactive pro-oxidants in stimulating lipid-peroxidation, an important antioxidant defense is the iron sequestration by the iron-transport protein transferrin.; In vitro glycation of transferrin resulted in an impaired antioxidant capacity and thus higher levels of lipid-peroxidation in a liposomal model. This was associated with a decreased iron-binding capacity and altered iron-distribution of glycated transferrin.; To investigate the in vivo implications, we developed a method to specifically measure the glycation of transferrin and found this to be higher in diabetic patients, especially in type 1 diabetes. This was associated with worse glycaemic control but no correlation could be found with the total iron-binding capacity.; In a clinical study, we measured glycaemic-, iron-, inflammatory- and oxidative stress status in type 1 (n=40) and type 2 (n=67) diabetic compared to control subjects (n=100). The main findings include the impaired antioxidant capacity of diabetic plasma to protect against iron-induced lipid-peroxidation. This could only be partially explained by differences in transferrin, caeruloplasmin and albumin levels. However, non-transferrin-bound-iron was not elevated in diabetes but depended strongly on the serum iron concentrations.; Higher ferritin concentrations in type 2 diabetes were unrelated to inflammation and showed a reciprocal relationship with transferrin receptors, arguing in favour of elevated iron stores. Regarding oxidative stress, we observed lower antioxidant defences depending on the type diabetes and only partially explained by metabolic-, inflammatory- and iron-alterations.; In a small group of iron-infused haemodialysis patients (n=11), higher baseline values of lipid-peroxidation were mainly determined by higher ferritin concentrations and peroxidation was further aggreviated by iron-infusion leading to transferrin oversaturation and the presence of reactive non-transferrin-bound-iron.; In another series of experiments, the production of oxygen radicals by differentiated monocytic U937 was able to oxidize LDL. This process was greatly enhanced in the presence of copper but inhibited by transferrin.; In conclusion, this thesis contributes to the knowledge of iron abnormalities and their involvement in the increased oxidative stress in diabetes.