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.
Similar content being viewed by others
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
References
Syrovatka P, Kraml P, Potockova J et al (2009) Relationship between increased body iron stores, oxidative stress and insulin resistance in healthy men. Ann Nutr Metab 54:268–274
Beard JL (2001) Iron biology in immune function, muscle metabolism and neuronal functioning. J Nutr 131:568S–579S; discussion 580S
Houstis N, Rosen ED, Lander ES (2006) Reactive oxygen species have a causal role in multiple forms of insulin resistance. Nature 440:944–948
Fleming DJ, Jacques PF, Tucker KL et al (2001) Iron status of the free-living, elderly Framingham Heart Study cohort: an iron-replete population with a high prevalence of elevated iron stores. Am J Clin Nutr 73:638–646
Jiang R, Ma J, Ascherio A, Stampfer MJ, Willett WC, Hu FB (2004) Dietary iron intake and blood donations in relation to risk of type 2 diabetes in men: a prospective cohort study. Am J Clin Nutr 79:70–75
Lee DH, Folsom AR, Jacobs DR Jr (2004) Dietary iron intake and Type 2 diabetes incidence in postmenopausal women: the Iowa Women’s Health Study. Diabetologia 47:185–194
de Luan C, Li H, Li SJ, Zhao Z, Li X, Liu ZM (2008) Body iron stores and dietary iron intake in relation to diabetes in adults in North China. Diabetes Care 31:285–286
Haap M, Fritsche A, Mensing HJ, Haring HU, Stumvoll M (2003) Association of high serum ferritin concentration with glucose intolerance and insulin resistance in healthy people. Ann Intern Med 139:869–871
Jehn M, Clark JM, Guallar E (2004) Serum ferritin and risk of the metabolic syndrome in U.S. adults. Diabetes Care 27:2422–2428
Lee BK, Kim Y, Kim YI (2011) Association of serum ferritin with metabolic syndrome and diabetes mellitus in the South Korean general population according to the Korean National Health and Nutrition Examination Survey 2008. Metabolism 60:1416–1424
Chen J, Wildman RP, Hamm LL et al (2004) Association between inflammation and insulin resistance in U.S. nondiabetic adults: results from the Third National Health and Nutrition Examination Survey. Diabetes Care 27:2960–2965
Bozzini C, Girelli D, Olivieri O et al (2005) Prevalence of body iron excess in the metabolic syndrome. Diabetes Care 28:2061–2063
Montonen J, Boeing H, Steffen A et al (2012) Body iron stores and risk of type 2 diabetes: results from the European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam study. Diabetologia 55:2613–2621
Forouhi NG, Harding AH, Allison M et al (2007) Elevated serum ferritin levels predict new-onset type 2 diabetes: results from the EPIC-Norfolk prospective study. Diabetologia 50:949–956
Jiang R, Manson JE, Meigs JB, Ma J, Rifai N, Hu FB (2004) Body iron stores in relation to risk of type 2 diabetes in apparently healthy women. JAMA 291:711–717
Kunutsor SK, Apekey TA, Walley J, Kain K (2013) Ferritin levels and risk of type 2 diabetes mellitus: an updated systematic review and meta-analysis of prospective evidence. Diabetes Metab Res Rev 29:308–318
Park SK, Ryoo JH, Kim MG, Shin JY (2012) Association of serum ferritin and the development of metabolic syndrome in middle-aged Korean men: a 5-year follow-up study. Diabetes Care 35:2521–2526
Simcox JA, McClain DA (2013) Iron and diabetes risk. Cell Metab 17:329–341
Fernandez-Real JM, Manco M (2014) Effects of iron overload on chronic metabolic diseases. Lancet Diabetes Endocrinol 2:513–526
Haap M, Machann J, von Friedeburg C et al (2011) Insulin sensitivity and liver fat: role of iron load. J Clin Endocrinol Metab 96:E958–E961
Wlazlo N, van Greevenbroek MM, Ferreira I et al (2013) Iron metabolism is associated with adipocyte insulin resistance and plasma adiponectin: the Cohort on Diabetes and Atherosclerosis Maastricht (CODAM) study. Diabetes Care 36:309–315
Fumeron F, Pean F, Driss F et al (2006) Ferritin and transferrin are both predictive of the onset of hyperglycemia in men and women over 3 years: the data from an epidemiological study on the Insulin Resistance Syndrome (DESIR) study. Diabetes Care 29:2090–2094
Vari IS, Balkau B, Kettaneh A et al (2007) Ferritin and transferrin are associated with metabolic syndrome abnormalities and their change over time in a general population: data from an epidemiological study on the insulin resistance syndrome (DESIR). Diabetes Care 30:1795–1801
Wlazlo N, van Greevenbroek MM, Ferreira I et al (2012) Low-grade inflammation and insulin resistance independently explain substantial parts of the association between body fat and serum C3: the CODAM study. Metabolism 61:1787–1796
Du H, van der AD, van Bakel MM et al (2008) Glycemic index and glycemic load in relation to food and nutrient intake and metabolic risk factors in a Dutch population. Am J Clin Nutr 87:655–661
Swinkels DW, Fleming RE (2011) Novel observations in hereditary hemochromatosis: potential implications for clinical strategies. Haematologica 96:485–488
van Bussel BC, Ferreira I, van de Waarenburg MP et al (2013) Multiple inflammatory biomarker detection in a prospective cohort study: a cross-validation between well-established single-biomarker techniques and an electrochemiluminescence-based multi-array platform. PLoS ONE 8:e58576
Martin RF (2000) General deming regression for estimating systematic bias and its confidence interval in method-comparison studies. Clin Chem 46:100–104
Wallace TM, Levy JC, Matthews DR (2004) Use and abuse of HOMA modeling. Diabetes Care 27:1487–1495
Abdul-Ghani MA, Matsuda M, Balas B, DeFronzo RA (2007) Muscle and liver insulin resistance indexes derived from the oral glucose tolerance test. Diabetes Care 30:89–94
Vangipurapu J, Stancakova A, Kuulasmaa T et al (2011) A novel surrogate index for hepatic insulin resistance. Diabetologia 54:540–543
Vangipurapu J, Stancakova A, Pihlajamaki J et al (2011) Association of indices of liver and adipocyte insulin resistance with 19 confirmed susceptibility loci for type 2 diabetes in 6,733 non-diabetic Finnish men. Diabetologia 54:563–571
Abdul-Ghani MA, Molina-Carrion M, Jani R, Jenkinson C, Defronzo RA (2008) Adipocytes in subjects with impaired fasting glucose and impaired glucose tolerance are resistant to the anti-lipolytic effect of insulin. Acta Diabetol 45:147–150
Groop LC, Bonadonna RC, DelPrato S et al (1989) Glucose and free fatty acid metabolism in non-insulin-dependent diabetes mellitus. Evidence for multiple sites of insulin resistance. J Clin Invest 84:205–213
Wendel-Vos GC, Schuit AJ, Saris WH, Kromhout D (2003) Reproducibility and relative validity of the short questionnaire to assess health-enhancing physical activity. J Clin Epidemiol 56:1163–1169
van Bussel BC, Henry RM, Schalkwijk CG et al (2011) Fish consumption in healthy adults is associated with decreased circulating biomarkers of endothelial dysfunction and inflammation during a 6-year follow-up. J Nutr 141:1719–1725
Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D (1999) A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Modification of Diet in Renal Disease Study Group. Ann Intern Med 130:461–470
Twisk JWR (2003) Applied longitudinal data analysis for epidemiology: a practical guide. Cambridge University Press, Cambridge
Kim C, Nan B, Kong S, Harlow S (2012) Changes in Iron Measures over Menopause and Associations with Insulin Resistance. J Womens Health (Larchmt) 21:872–877
Roumen C, Feskens EJ, Jansen EH, Saris WH, Blaak EE (2008) Changes in transferrin are related to changes in insulin resistance: the SLIM study. Diabet Med 25:1478–1482
DeFronzo RA, Ferrannini E, Hendler R, Felig P, Wahren J (1983) Regulation of splanchnic and peripheral glucose uptake by insulin and hyperglycemia in man. Diabetes 32:35–45
Fargion S, Dongiovanni P, Guzzo A, Colombo S, Valenti L, Fracanzani AL (2005) Iron and insulin resistance. Aliment Pharmacol Ther 22(Suppl 2):61–63
Green A, Basile R, Rumberger JM (2006) Transferrin and iron induce insulin resistance of glucose transport in adipocytes. Metabolism 55:1042–1045
Rumberger JM, Peters T Jr, Burrington C, Green A (2004) Transferrin and iron contribute to the lipolytic effect of serum in isolated adipocytes. Diabetes 53:2535–2541
Gabrielsen JS, Gao Y, Simcox JA et al (2012) Adipocyte iron regulates adiponectin and insulin sensitivity. J Clin Invest 122:3529–3540
Dongiovanni P, Ruscica M, Benedan L et al (2011) Dietary iron overload induces visceral adipose tissue insulin resistance associated with hyper-resistinemia, and synergizes with obesity and fatty liver in inducing systemic insulin resistance. J Hepatol 54:S505
Huang J, Simcox J, Mitchell TC et al (2013) Iron regulates glucose homeostasis in liver and muscle via AMP-activated protein kinase in mice. FASEB J Off Pub Fed Am Soc Exp Biol 27:2845–2854
Cooksey RC, Jones D, Gabrielsen S et al (2010) Dietary iron restriction or iron chelation protects from diabetes and loss of beta-cell function in the obese (ob/ob lep−/−) mouse. Am J Physiol Endocrinol Metab 298:E1236–E1243
Zheng X, Jiang T, Wu H et al (2011) Hepatic iron stores are increased as assessed by magnetic resonance imaging in a Chinese population with altered glucose homeostasis. Am J Clin Nutr 94:1012–1019
Lee DH, Liu DY, Jacobs DR Jr et al (2006) Common presence of non-transferrin-bound iron among patients with type 2 diabetes. Diabetes Care 29:1090–1095
Glymour MM, Weuve J, Berkman LF, Kawachi I, Robins JM (2005) When is baseline adjustment useful in analyses of change? An example with education and cognitive change. Am J Epidemiol 162:267–278
Fernandez-Real JM, Penarroja G, Castro A, Garcia-Bragado F, Hernandez-Aguado I, Ricart W (2002) Blood letting in high-ferritin type 2 diabetes: effects on insulin sensitivity and beta-cell function. Diabetes 51:1000–1004
Valenti L, Fracanzani AL, Dongiovanni P et al (2007) Iron depletion by phlebotomy improves insulin resistance in patients with nonalcoholic fatty liver disease and hyperferritinemia: evidence from a case-control study. Am J Gastroenterol 102:1251–1258
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.
Informed consent disclosure
Informed consent was obtained from all individual participants included in the study.
Author information
Authors and Affiliations
Corresponding author
Additional information
Managed by Massimo Federici.
Electronic supplementary material
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
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
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00592-014-0646-3