Effect of Taking a Single Tablet of Iron on Insulin Secretion

February 11, 2022 updated by: Padmanaban Venkatesan, Christian Medical College, Vellore, India

Acute Effect of a Single Dose of Oral Iron on Pancreatic Beta Cell Function in Healthy Individuals: a Quasi-experimental Single Arm Before-and-after (Pre-post) Study

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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

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.

Study Type

Interventional

Enrollment (Actual)

15

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • India
    • Tamil Nadu
      • Vellore, Tamil Nadu, India, 632002
        • Christian Medical College

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

16 years to 58 years (Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

Male

Description

Inclusion Criteria:

BMI - 18 to 30 kg/m^2

Exclusion Criteria:

  1. Known case of diabetes mellitus/pre-diabetes
  2. History of chronic inflammatory disease
  3. Anemia (detection of pallor on examination). Absence of anemia will be confirmed by hemoglobin estimation done at the time of baseline OGTT based on WHO criteria.
  4. On iron supplementation
  5. History of any gastrointestinal disorders that might affect absorption of iron/glucose

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Basic Science
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Healthy men (before-and-after (pre-post) study)
Partcipants 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.
Dietary supplement: Ferrous sulphate
Single dose of ferrous sulphate (120 mg of elemental iron)

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Change in insulin secretion kinetics
Time Frame: 2 hours from intake of 120 mg of elemental iron
Change in insulin secretion rate as determined by deconvolution of C-peptide levels in blood during an oral glucose tolerance test based on a previously published mathematical model (Van Cauter et al., 1992).
2 hours from intake of 120 mg of elemental iron
Change in disposition index
Time Frame: 2 hours from intake of 120 mg of elemental iron
Disposition index is a measure of beta-cell function which is calculated as a product of insulin sensitivity and insulin secretion during an oral glucose tolerance test
2 hours from intake of 120 mg of elemental iron
Change in insulinogenic index
Time Frame: 2 hours from intake of 120 mg of elemental iron
A measure of beta-cell function which calculates the increase in insulin secretion in response to increase in glucose concentration during an oral glucose tolerance test
2 hours from intake of 120 mg of elemental iron

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Change in glucose tolerance
Time Frame: 2 hours from intake of 120 mg of elemental iron
Glucose tolerance will be determined by calculating the area under the curve (AUC) of glucose levels during oral glucose tolerance test
2 hours from intake of 120 mg of elemental iron
Change in insulin sensitivity
Time Frame: 2 hours from intake of 120 mg of elemental iron
Insulin sensitivity which is a measure of insulin action will be calculated using the Matsuda index (Matsuda and DeFronzo, 1999)
2 hours from intake of 120 mg of elemental iron
Change in insulin clearance rate
Time Frame: 2 hours from intake of 120 mg of elemental iron
Insulin clearance rate which is a measure of rate of disappearance of insulin from the blood will be calculated as described previously (Castillo et al., 1994)
2 hours from intake of 120 mg of elemental iron

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Christian Medical College, Vellore, India

Investigators

  • Principal Investigator: Padmanaban Venkatesan, M.D., Christian Medical College, Vellore, India
  • Principal Investigator: Joe Varghese, M.D.,PhD, Christian Medical College, Vellore, India

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

October 10, 2020

Primary Completion (Actual)

September 16, 2021

Study Completion (Actual)

September 16, 2021

Study Registration Dates

First Submitted

February 5, 2022

First Submitted That Met QC Criteria

February 5, 2022

First Posted (Actual)

February 14, 2022

Study Record Updates

Last Update Posted (Actual)

March 2, 2022

Last Update Submitted That Met QC Criteria

February 11, 2022

Last Verified

February 1, 2022

More Information

Terms related to this study

Keywords

Other Study ID Numbers

  • IRB min.13294 Dt.26.08.2020

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

No

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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