Effect of Taking a Single Tablet of Iron on Insulin Secretion
Condition: Insulin Secretion
Study type: Interventional

Summary: 
      Oral supplementation with highly bioavailable forms of iron, such as ferrous sulphate, is the
      treatment of choice for iron-deficiency anemia. Iron from ferrous sulphate is efficiently
      absorbed in the duodenum, resulting in a rapid increase in transferrin saturation and
      appearance of "free iron" or non-transferrin bound iron (NTBI) in blood. NTBI is highly
      reactive and can catalyze the generation of reactive oxygen species and cause oxidative
      tissue damage.

      Human pancreatic beta cells are known to express ZIP14, a transporter that has been
      implicated in uptake of NTBI from blood. In vitro and animal studies have shown that iron
      loading in beta cells can result in impaired insulin secretion. However, there are no human
      studies that have looked at the acute effects of oral iron intake on insulin secretion.

      In this study, we plan to look at the effect of a single oral dose of ferrous sulphate on
      insulin secretion kinetics in healthy individuals. A single arm before-and-after (pre-post)
      study design will be used. Consenting individuals who meet the participation criteria will
      undergo a 75g oral glucose tolerance test (OGTT) to document baseline insulin secretion
      kinetics. One week later, OGTT will be repeated after administering a single dose of ferrous
      sulphate (120 mg of elemental iron) 2 hours prior to the test. Iron-induced change in insulin
      secretion kinetics will be documented. In addition, we will determine changes in glucose
      tolerance, insulin resistance and insulin clearance rates.
    

Detailed description: 
      Oral iron supplementation is the treatment of choice in patients with iron deficiency anemia.
      In several developing countries, including India, iron is routinely supplemented to pregnant
      women, especially during the second and third trimesters of pregnancy owing to the increased
      iron requirement for the placenta and growing fetus.

      Oral administration of iron is preferred to intravenous administration because it is
      effective, relatively cheap and safe. There are many different oral iron preparations and
      most of them contain iron in the ferrous form (ferrous sulphate, ferrous fumarate, ferrous
      gluconate, ferrous ascorbate etc.). Although it has been shown that all these preparations
      are equally effective in increasing hemoglobin levels, ferrous sulphate, being easily
      available and economical, is the most prescribed iron preparation.

      Iron is absorbed in the duodenum. Dietary iron is usually in the ferric form and must be
      reduced to the ferrous form prior to absorption. This reduction reaction is catalyzed by
      duodenal ferrireductases (such as duodenal cytochrome b) and is aided by gastric HCl and
      other reducing substances in the diet, such as vitamin C (ascorbic acid). Administration of
      iron in the ferrous form (e.g., ferrous sulphate) circumvents this step, thus making it
      readily bioavailable. Ferrous iron is transported across the luminal membrane of the
      enterocytes via divalent metal transporter-1 (DMT-1). Iron is then transported across the
      basolateral membrane (into blood) by another transporter, ferroportin. Hepcidin, a peptide
      hormone synthesized and secreted by the liver, binds to and degrades ferroportin, thus
      reducing intestinal iron absorption.

      In the blood, iron is transported bound to the plasma protein, transferrin, which binds iron
      with high affinity. Transferrin is normally saturated to about 30 to 35% of its total iron
      binding capacity, leaving a large reserve to bind additional iron. In conditions of iron
      overload, such as hemochromatosis or in patients with thalassemia, transferrin saturation can
      increase significantly. When transferrin saturation increases beyond 60% and especially as it
      approaches 80%, a small but significant amount of iron circulates in blood that is not bound
      to transferrin. This fraction, called "labile iron" or non-transferrin bound iron (NTBI), is
      highly reactive and can cause oxidative tissue damage.

      NTBI is rapidly cleared from circulation, mainly by hepatocytes. It has been shown that ZIP14
      is physiologically the most important transporter that transports NTBI into hepatocytes.
      Recently, it was shown that ZIP14 is also expressed on human pancreatic beta cells and that
      it may mediate NTBI uptake by these cells. Several in vitro and animal studies have shown
      that iron overload impairs pancreatic beta cell function. Patients with hemochromatosis are
      known to accumulate iron in the beta cells, resulting in diabetes due to decreased insulin
      secretory capacity. On the other hand, iron chelation or dietary iron restriction improves
      insulin secretion in mouse models of diabetes. Similarly, iron chelation in hemochromatosis
      and thalassemia also improved insulin secretion. These studies prove a strong link between
      increased iron and impaired beta cell function.

      It has been shown that, following a single dose of ferrous sulphate (containing 60-100 mg of
      elemental iron), transferrin saturation increases rapidly and peaks (at ~ 80%) 2 hours after
      administration. This is associated with a significant increase in NTBI, which also peaks at 2
      hours. Given that oral iron administration increases NTBI in blood and that pancreatic beta
      cells take up NTBI via ZIP14, we hypothesized that oral iron may lead to increased beta cell
      iron levels which may then cause impaired insulin secretion

      In order to test this hypothesis, we plan to conduct a quasi-experimental single arm
      before-and-after study, where insulin secretion kinetics will be determined at baseline and
      after a single dose of iron (ferrous sulphate, 120 mg elemental iron) in healthy men.

      Healthy male volunteers will be recruited from among the staff of Christian Medical College,
      Vellore after obtaining written informed consent.Participants will undergo a 75g oral glucose
      tolerance tests (OGTT) to document baseline insulin secretion kinetics. One week later, the
      OGTT will be repeated after a single dose of ferrous sulphate (120 mg of elemental iron)
      given 2 hours before the test. Serum levels of glucose, insulin, C-peptide, serum iron and
      transferrin saturation will be measured during both OGTT. The effects of iron on insulin
      secretion kinetics will be documented. In addition, we will determine if changes occur in
      glucose tolerance, insulin resistance and insulin clearance rates.
    

Intervention name(s): Ferrous sulphate
Intervention type(s): Dietary Supplement
Intervention description(s): Single dose of ferrous sulphate (120 mg of elemental iron)
Intervention model: Single Group Assignment
Intervention model description: Quasi-experimental single arm before-and-after (pre-post) study.
Masking: None (Open Label)
Primary purpose: Basic Science
Keywords: Oral iron; Insulin-Secreting Cells; Diabetes Mellitus