Evidence of dysregulated iron homeostasis in newly diagnosed diabetics, but not in pre-diabetics
Introduction
The incidence of diabetes mellitus (DM) has been on the rise all over the world for the past few decades. There are estimated to be 463 million diabetics worldwide, the majority of whom have type 2 diabetes mellitus (T2DM).1 While changes in life-styles over the past decades (such as reduction in physical activity and excessive calorie consumption) are known to play important roles in contributing to the high incidence of the disease, several aspects of the pathogenesis of T2DM continue to remain elusive.2 One such aspect is its association with dysregulated iron homeostasis in the body.
Initial observations of increased incidence of DM in patients with hereditary hemochromatosis, and similar findings subsequently in secondary iron overload disorders (such as thalassemia), sparked interest in links between iron metabolism and DM.3,4 Since then, multiple epidemiological studies have shown that DM is associated with increased serum ferritin levels (indicative of high body iron stores).5,6 Reduction of body iron stores (by means of phlebotomy) resulted in improvements in insulin sensitivity.7 Studies have also found an association between increased body iron stores and chronic complications of DM.8
The mechanisms that underlie such associations are not clear. Hepcidin, a peptide hormone secreted by the liver, is the central regulator of systemic iron homeostasis.9 It acts by binding to ferroportin (the only known iron exporter in cells), causing its endocytosis and subsequent degradation.9 Ferroportin is expressed mainly in enterocytes, macrophages and hepatocytes.9 Hepcidin decreases absorption of iron from the intestine, iron recycling from splenic macrophages and release of iron from the liver; overall, this results in reduced circulating levels of iron.9
Hepcidin is known to be regulated by multiple factors. Increased levels of iron in blood and presence of inflammation increase its production, while anemia and hypoxia inhibit it.10 In addition, during erythropoiesis, erythroid precursors in the bone marrow secrete factors, such as erythroferrone [ERFE/Fam132b], growth differentiation factor-15 [GDF-15] and twisted gastrulation factor-1 [TWSG-1], all of which have been shown to suppress hepatic hepcidin expression.10 Transferrin receptors 1 and 2 (TFR1 and TFR2) in erythroid cells have also been reported to be involved in erythropoiesis and expression of the erythroid regulators of hepcidin.11,12
Studies that have estimated hepcidin in blood from patients with diabetes mellitus have shown variable results. Some have reported higher levels in diabetics compared to control subjects,13,14 while others have shown decreased15 or similar levels.16 The reasons for such differences are not clear. They may possibly be due to various factors that can affect hepcidin levels. For example, in patients known to be diabetic, the duration of the disease, extent of glycemic control, therapeutic interventions used (such as use of anti-diabetic drugs/insulin), and presence of chronic complications of DM, have been reported to have significant effects on hepcidin levels.17,18 The presence of inflammation and anemia has also been shown to affect hepcidin levels in such patients.10,19 Pre-menopausal females are known to have lower hepcidin levels than males.20 Hence, different proportions of males and females in these studies may also have contributed to the variations seen.
In the natural history of T2DM, pre-diabetes is an intermediate stage between normal glucose tolerance and frank diabetes mellitus. It represents a stage in which patients are at increased risk of developing DM. Studies on parameters of iron status in pre-diabetics have reported elevated serum ferritin levels and low transferrin saturation.21, 22, 23, 24, 25, 26, 27
In the present study, we attempted to address drawbacks of previous studies on links between DM and dysregulated iron homeostasis. We excluded known factors (described above) that can affect iron homeostasis, and serum hepcidin levels particularly, in diabetics. We did this by recruiting only men newly diagnosed with pre-diabetes and diabetes, and by excluding those with co-existing inflammation and anemia.
Section snippets
Methods
The protocol of the study was approved by the Institutional Review Board (IRB) of Christian Medical College (CMC), Vellore, India (IRB approval no: 9235 dated 12-1-2015) and conformed to the ethical guidelines of the Declaration of Helsinki (1975). Recruitment was carried out during the period between March 2015 and July 2016.
After obtaining informed consent, we recruited adult males (30 to 70 years old) who presented to the outpatient clinic of the Community Health and Development (CHAD)
Characteristics of participants in the study
One hundred and twenty male subjects were recruited; they included control (n = 40), pre-diabetic (n = 40) and diabetic (n = 40) individuals. The 3 groups were similar with regard to their ages, weights, BMI, waist and hip circumferences and waist-to-hip ratios (Table 1). Subjects in the control group were significantly taller than those in the other two groups.
Metabolic parameters
Fasting plasma glucose (FPG) concentrations were significantly higher in the pre-diabetics and diabetics, compared to control subjects; they
Discussion
Hepcidin is known to be the central regulator of systemic iron homeostasis.9 Changes in serum hepcidin levels have been reported in patients with diabetes mellitus.13, 14, 15, 16 Observations have, however, been variable, with studies reporting lower,15 higher13,14 or similar16 levels in diabetics, compared to non-diabetics. The diverse methodologies used in these studies may possibly account for the variable findings. The present study differs from the previous studies in several aspects.
Conclusion
Dysregulation of iron homeostasis (as indicated by significantly higher serum ferritin and hepcidin levels) was seen in patients with newly diagnosed diabetes, but not in the pre-diabetics. Such alterations were not attributable to the effect of inflammation on these parameters. Evidence of impaired beta-cell function was seen in pre-diabetics and diabetics. Positive correlations found between serum ferritin and HOMA-IR indicate that iron-related parameters and insulin resistance are factors
Funding sources
This work was supported by an Early Career Fellowship of the Wellcome Trust-DBT India Alliance (Grant ref. no. 500190/Z/11/Z) awarded to Joe Varghese, a fluid research grant of Christian Medical College, Vellore (IRB Min No. 9235, dated 12.1.2015) and an MD thesis grant (No: 3/2/May-2015/PG-Thesis-HRD-18) from the Indian Council of Medical Research, New Delhi, awarded to Padmanaban Venkatesan.
CRediT authorship contribution statement
Padmanaban Venkatesan: Investigation, Formal analysis, Visualization, Writing - Original Draft and Writing - Review & Editing. Joe Varghese: Conceptualization, Investigation, Formal analysis, Visualization, Project administration, Writing - Original Draft and Writing - Review & Editing. Arthi TS: Investigation. Jasmin Prasad: Resources. Jithu V. James and Anji Anura: Investigation. Molly Jacob: Conceptualization, Formal analysis, Supervision, Project administration, Funding acquisition, Writing
Declaration of competing interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
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- 1
Co-first authors.
- 2
Current affiliation: Department of Biochemistry, Coimbatore Medical College, Coimbatore, Tamil Nadu, India.
- 3
Affiliated to The Tamil Nadu Dr. MGR Medical University, Chennai, India.