Common Presence of Non–Transferrin-Bound Iron Among Patients With Type 2 Diabetes

Abstract

OBJECTIVE -Recently, we reported increased cardiovascular disease mortality among supplemental vitamin C users with type 2 diabetes in a prospective cohort study. Because vitamin C may cause oxidative stress in the presence of redox active iron, we hypothesized that nontransferrin-bound iron (NTBI), a form of iron susceptible to redox activity, may be present in patients with type 2 diabetes.RESEARCH DESIGN AND METHODS -We measured serum NTBI levels using highperformance liquid chromatography in 48 patients with known diabetes (at least 5 years duration since diagnosis), 49 patients with newly diagnosed diabetes, and 47 healthy control subjects (frequency matched on age and sex).RESULTS -NTBI was commonly present in diabetes: 59% in newly diagnosed diabetes and 92% in advanced diabetes. Mean NTBI values varied significantly between the three groups, with the highest values being observed in patients with known diabetes and the lowest in the control subjects (0.62 Ϯ 0.43 vs. 0.24 Ϯ 0.29 vs. 0.04 Ϯ 0.13 mol/l Fe). Serum total iron or percent transferrin saturation were very similar among the three groups, yet NTBI was strongly associated with serum total iron (r ϭ 0.74, P Ͻ 0.01) and percent transferrin saturation (r ϭ 0.70, P Ͻ 0.01) among the patients with known diabetes.CONCLUSIONS -Consistent with our hypothesis, these data demonstrate the common existence of NTBI in type 2 diabetic patients with a strong gradient with severity. Prospective cohort studies are required to clarify the clinical relevance of increased NTBI levels. Diabetes Care 29:1090 -1095, 2006R ecently, we reported that supplemental vitamin C intake in excess of 300 mg/day increased cardiovascular disease (CVD) mortality among postmenopausal women with type 2 diabetes in a prospective cohort study (1). This finding was unexpected in that it is contrary to the general belief that supplemental vitamin C intake is beneficial for patients with type 2 diabetes because they tend to have lower serum vitamin C levels (2,3). One explanation for this finding is that vitamin C may interact with redox active iron in patients with type 2 diabetes (4,5).Although the prooxidant reaction of vitamin C occurs readily in vitro, its relevance in vivo has been a matter of some controversy, the main point of contention being the availability of redox active iron in vivo (6). Levels of redox active iron are thought to be low due to their sequestration by various metal-binding proteins such as transferrin (7). It is generally believed that non-transferrin-bound iron (NTBI) possesses redox activity but only appears in serum when transferrin is fully iron saturated (8). However, recent studies have demonstrated that NTBI can be detected when transferrin is not fully saturated, leading to a revision of the original understanding that NTBI results from a simple spillover phenomenon (9 -11). Interestingly, a disturbance of iron metabolism and/or iron overload has recently been suggested as a mechanism of the pathogenesis of both diabetes and CVD complications (12,13).The ...

Correlates of Hepcidin and NTBI according to <b><i>HFE</i></b> Status in Patients Referred to a Liver Centre

“…C282Y homozygotes had significantly higher levels of serum NTBI in agreement with other studies that have shown high NTBI levels in hepcidin-deficient patients with mutations in HFE , HJV and TfR2 [16,30,31,32,33]. …”

Racial Differences in Iron Measures and Outcomes Observed during an Iron Reduction Trial in Peripheral Arterial Disease

“…61 Apotransferrin avidly binds and detoxifies redox-active iron. [62][63][64][65] Mean follow-up %TS levels remained at comparable levels in Black compared with White participants randomized to control (p=.336), but were found to be significantly lower in Black compared with White participants randomized to phlebotomy ( Table 2, p=.001). Interactions between measures of iron status (ferritin and %TS levels), and differing racial response to iron unloading require further study.…”

Serum iron concentration and plasma oxidant-antioxidant balance in patients with chronic venous insufficency

“…This means that some other indicators of iron metabolism should be evaluated in further studies and special attention should be paid on non-transferrin bound iron (NTBI), a low molecule iron complex capable of initiating ROS formation [46–52]. Elevated level of NTBI was found in pathological conditions, such as hemochromatosis, diabetes and cardiovascular diseases [47,49,50]. Some studies have demonstrated that NTBI correlates positively with high SI level [46–48].…”