Transferrin Modifications and Lipid Peroxidation: Implications in Diabetes Mellitus

Abstract

Free iron is capable of stimulating the production of free radicals which cause oxidative damage such as lipid peroxidation. One of the most important mechanisms of antioxidant defense is thus the sequestration of iron in a redox-inactive form by transferrin. In diabetes mellitus, increased oxidative stress and lipid peroxidation contribute to chronic complications but it is not known if this is related to abnormalities in transferrin function. In this study we investigated the role of transferrin concentration and glycation. The antioxidant capacity of apotransferrin to inhibit lipid peroxidation by iron-binding decreased in a concentration-dependent manner from 89% at > or = 2 mg/ml to 42% at 0.5 mg/ml. Pre-incubation of apotransferrin with glucose for 14 days resulted in a concentration-dependent increase of glycation: 1, 5 and 13 micromol fructosamine/g transferrin at 0, 5.6 and 33.3 mmol/l glucose respectively, p < 0.001. This was accompanied by a decrease in the iron-binding antioxidant capacity of apotransferrin. In contrast, transferrin glycation by up to 33.3 mmol/l glucose did not affect chemiluminescence-quenching antioxidant capacity, which is iron-independent. Colorimetric evaluation of total iron binding capacity in the presence of an excess of iron (iron/transferrin molar ratio = 2.4) also decreased from 0.726 to 0.696 and 0.585mg/g transferrin after 0, 5.6 and 33.3 mmol/l glucose, respectively, p < 0.01. In conclusion, these results suggest that lower transferrin concentration and its glycation can, by enhancing the pro-oxidant effects of iron, contribute to the increased lipid peroxidation observed in diabetes.

Effects of in Vitro Glycation on Fe3+ Binding and Fe3+ Isoforms of Transferrin

“…This effect is in accordance with the decrease in TIBC we observed with increasing degrees of glycation (12 ). The measurement of TIBC is based on the addition of an excess of iron (iron/Tf molar ratio ϭ 2.4).…”

“…In either case, the iron is bound more loosely and is thus more redox-active. This interpretation could explain the decrease in Fe 3ϩ -binding antioxidant capacity we observed in glycated apoTf (12 ). The impairment of Tf function may have important consequences with regard to the appearance of oxidative stress in vivo in diabetes and its involvement in the pathogenesis of diabetic complications.…”

“…It is not known whether the increased lipid peroxidation observed in diabetes mellitus is associated with an impairment of Fe 3ϩ binding to the two sites on Tf. This hypothesis was suggested by our previous observation that glycation of apoTf led to a decrease in both its TIBC and in its capacity to prevent iron-induced lipid peroxidation (12 ). In the present study, we aimed to investigate how glycation of Tf affects Fe 3ϩ binding on the two sites by analyzing the Fe 3ϩ -Tf isoforms of in vitro-glycated Tf.…”

“…Because diabetes is also associated with both an increase in oxidative stress (7,8 ) and disturbances in iron metabolism (9 -11 ), it is of great interest to investigate the hypothesis that glycation of Tf can contribute to oxidative stress by impairment of its antioxidant function. In a recent study we showed that in vitro glycation of Tf decreases its Fe 3ϩ -binding capacity and makes it less effective in protecting against in vitro lipid peroxidation (12 ). Therefore, in the present study we aimed to gain more insight into the mechanisms underlying the effects of glycation on the Fe 3ϩ -binding capacity of Tf.…”

The endothelial cell receptor GRP78 is required for mucormycosis pathogenesis in diabetic mice

“…Exposure to hyperglycemia of iron-sequestering proteins, such as apotransferrin and hemoglobin, has been shown to damage the proteins and cause them to release free iron in serum (21,22). Therefore, diabetes can result in increased serum-free iron even in the absence of acidosis.…”