Effect of oral iron supplementation on glucose tolerance in individuals with anemia

Iron, an essential trace element, has a wide variety of functions, such as the synthesis of hemoglobin and acting as a cofactor for various enzymes. Iron levels in the body are tightly controlled, as both iron excess (iron overload) and iron deficiency (ID) have deleterious effects. Iron deficiency anemia (IDA) is the major public health problem in India, and the prevalence is 57% in women of reproductive age. In India, IDA is usually treated with daily oral iron supplements containing 60 mg of elemental iron (Anemia Mukt Bharat, 2024). The rate of intestinal iron absorption increases in anemia, as hepcidin levels tend to be suppressed in IDA (Gulec et al., 2014). Hepcidin, a peptide hormone produced by the liver, acts as the central regulator of systemic iron homeostasis. It inhibits intestinal iron absorption by binding to and causing degradation of ferroportin, an iron efflux protein expressed in the enterocyte and macrophages (Nemeth et al., 2004). There is no physiological mechanism for iron excretion from the body, hence, intestinal iron absorption is tightly regulated to maintain optimal iron levels. The absorbed iron is carried by transferrin (Tf) to the target tissues, and is stored in the form of ferritin (Kenelly et al., 2018).

The amount of iron absorbed and the rate of its absorption should match the capacity of Tf, and nearly one-third of transferrin in the blood is saturated under normal physiological conditions (Geisser and Burckhardt, 2011). It has been demonstrated that when absorption surpasses the Tf capacity, Tf becomes saturated, and the absorbed iron exists in a free, unbound form  known as non-transferrin-bound iron (NTBI) (Brittenham et al., 2014). NTBI levels are usually undetectable in healthy individuals, and it appear when the transferrin saturation exceeds 70%, as seen in iron overload conditions like hereditary hemochromatosis and thalassemia (Knutson, 2019). NTBI is predominantly cleared by liver cells and other organs like the pancreas, kidneys can take up excess NTBI through divalent metal transporters (DMT-1) like ZRT/IRT-like protein 14 (ZIP14, SLC39A14) and ZIP8 (Coffey and Knutson, 2017).  NTBI is harmful, as it has an increased propensity to generate reactive oxygen species (ROS), which in turn leads to oxidative stress (Brissot et al., 2012). Increased levels of NTBI lead to beta cell dysfunction and diabetes in patients with hemochromatosis and thalassemia (Barton and Acton, 2017; Li et al., 2014).

NTBI is not just restricted to typical iron overload disorders, as it has also been detected in the blood  of anemic patients under treatment with iron supplementation (Dresow et al., 2008). This is explained by the fact that, hepcidin levels are suppressed as a physiological response to anemia, which enhances the absorption of supplemental iron (Silva and Rangel, 2022). This acute increase in NTBI exceeds the Tf capacity and leads to generation of NTBI. It has been reported previously that oral iron supplementation increases TfSat to a greater extent in those with iron deficiency (serum ferritin less than 25 ng/mL) compared to those who are iron-replete (serum ferritin more than 25 ng/mL) (Brittenham et al., 2014).  Iron taken as a supplement at a dose of 1 mg/kg body weight resulted in circulating NTBI despite the presence of unoccupied binding sites on transferrin (Dresow et al., 2008; Schümann et al., 2013).  These observations indicate that oral iron supplementation can generate detectable levels of NTBI in the circulation.

A study was done in male healthy volunteers to assess beta cell function in response to a single bolus of oral iron (120 mg of elemental iron in the form of ferrous sulfate) (Venkatesan et al., 2023). As stated earlier, IDA is treated with oral iron supplementation. In this study, it was found that a single dose of iron doubled transferrin saturation (TfSat) and serum iron levels. The study participants also showed glucose intolerance and a reduction in beta-cell function (as measured by disposition and insulinogenic indices). However, the insulin secretion kinetics were different between the participants with regards to their baseline TfSat. Participants who had low ferritin and TfSat at baseline but were not anemic showed more than a 100% increase in TfSat after a single dose of iron. They also showed a decrease in beta cell secretion compared to those who had better TfSat and ferritin at baseline. This could be explained by the fact that the amount of iron absorbed by the subject who had low iron stores would have exceeded the capacity of Tf, leading to the generation of NTBI. Excess NTBI may have accumulated in beta cells and caused a secretory defect. (Venkatesan et al., 2023). However, NTBI levels were not estimated as part of this study.

Daily iron supplementation (60 mg of elemental iron) for a month or two is the treatment of choice for IDA. Hence, in those with IDA, (i.e., low iron stores and decreased transferrin saturation), the daily iron supplementation can generate NTBI and cause beta cell secretory defects. This study attempts to determine the effect of oral iron supplementation on beta cell function and glucose tolerance.