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Iron metabolism is prospectively associated with insulin resistance and glucose intolerance over a 7-year follow-up period: the CODAM study

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Abstract

Objectives

Several markers of iron metabolism have been associated with insulin resistance (IR) and type 2 diabetes mellitus in cross-sectional studies. However, prospective data on these associations are scarce, and it is currently unclear in which tissues iron metabolism may contribute to IR. Therefore, we investigated whether markers of iron metabolism were associated with IR in muscle, liver, and adipocytes, and with glucose intolerance over a 7-year follow-up period.

Design and methods

Serum ferritin, transferrin, total iron, non-transferrin-bound iron, and transferrin saturation were determined at baseline of a prospective cohort study in 509 individuals (60 % men, age 59 ± 6.9 years, body mass index 28.5 ± 4.3). Both at baseline and after a 7-year follow-up (n = 386), measures of glucose, insulin (during glucose tolerance tests), and non-esterified fatty acids were obtained. Using generalized estimating equations, we investigated associations between baseline iron markers and indices of muscle, liver, and adipocyte insulin resistance (adipocyte IR), as well as glucose intolerance, over the 7-year period.

Results

Over a 7-year period, baseline serum ferritin (per 10 μg/L increase) was positively associated with homeostasis model assessment insulin resistance (HOMA2-IR) [β = 0.77 % (95 % CI 0.50–1.03)], hepatic insulin resistance (hepatic IR) [β = 0.39 % (0.23–0.55)], adipocyte IR [β = 1.00 % (0.65–1.35)], and AUCglucose [β = 0.32 % (0.18–0.46)] after adjustment for several covariates, including inflammatory markers (all p < 0.001). Similarly, serum transferrin (per 0.1 g/L) was associated with HOMA2-IR [β = 2.66 % (1.55–3.78)], hepatic IR [β = 1.16 % (0.47–1.85)], adipocyte IR [β = 3.75 % (2.27–5.25)], and AUCglucose [β = 1.35 % (0.74–1.96)] over 7 years.

Conclusions

Iron metabolism and related factors may contribute to IR in muscle, liver, and adipocytes, eventually leading to impaired glucose metabolism and hyperglycaemia.

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Abbreviations

Adipocyte IR:

Adipocyte insulin resistance

AUCglucose :

Area under the curve for glucose during a 75 g oral glucose tolerance test (OGTT)

BMI:

Body mass index

CVD:

Cardiovascular disease

eGFR:

Estimated glomerular filtration rate

HH:

Hereditary haemochromatosis

hepatic IR:

Hepatic insulin resistance

HOMA2-IR:

Homeostasis model assessment insulin resistance

hs-CRP:

High-sensitivity C-reactive protein

IGM:

Impaired glucose metabolism

IL-6:

Interleukin-6

IL-8:

Interleukin-8

LGI:

Low-grade inflammation

NGM:

Normal glucose metabolism

NTBI:

Non-transferrin-bound iron

TNF-α:

Tumour necrosis factor-α

T2DM:

Type 2 diabetes mellitus

SAA:

Serum amyloid A

sICAM-1:

Soluble inter-cellular adhesion molecule-1

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Acknowledgments

Dr. I. Ferreira’s research activities are supported by a senior postdoc research grant from the Netherlands Heart Foundation (Grant # 2006T050). Part of this work was supported by Grants of the Netherlands Organisation for Scientific Research (940-35-034) and the Dutch Diabetes Research Foundation (98.901).

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical standard

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

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Informed consent was obtained from all individual participants included in the study.

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Correspondence to Nick Wlazlo.

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Wlazlo, N., van Greevenbroek, M.M.J., Ferreira, I. et al. Iron metabolism is prospectively associated with insulin resistance and glucose intolerance over a 7-year follow-up period: the CODAM study. Acta Diabetol 52, 337–348 (2015). https://doi.org/10.1007/s00592-014-0646-3

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