Review Article
Association of iron indices and type 2 diabetes: a meta-analysis of observational studies
Ester Orban,
Sigrid Schwab,
Barbara Thorand,
Cornelia Huth,
Ester Orban
Institute of Epidemiology II, Helmholtz Zentrum München – German Research Center for Environmental Health, Neuherberg, Germany
German Center for Diabetes Research (DZD), Neuherberg, Germany
Search for more papers by this authorSigrid Schwab
Institute of Epidemiology II, Helmholtz Zentrum München – German Research Center for Environmental Health, Neuherberg, Germany
Search for more papers by this authorBarbara Thorand
Institute of Epidemiology II, Helmholtz Zentrum München – German Research Center for Environmental Health, Neuherberg, Germany
German Center for Diabetes Research (DZD), Neuherberg, Germany
Search for more papers by this authorCorresponding Author
Cornelia Huth
Institute of Epidemiology II, Helmholtz Zentrum München – German Research Center for Environmental Health, Neuherberg, Germany
German Center for Diabetes Research (DZD), Neuherberg, Germany
Correspondence to: Cornelia Huth, Institute of Epidemiology II, Helmholtz Zentrum München – German Research Center for Environmental Health, Ingolstaedter Landstraße 1, DE-85764 Neuherberg, Germany.
E-mail: [email protected]
Search for more papers by this authorEster Orban,
Sigrid Schwab,
Barbara Thorand,
Cornelia Huth,
Ester Orban
Institute of Epidemiology II, Helmholtz Zentrum München – German Research Center for Environmental Health, Neuherberg, Germany
German Center for Diabetes Research (DZD), Neuherberg, Germany
Search for more papers by this authorSigrid Schwab
Institute of Epidemiology II, Helmholtz Zentrum München – German Research Center for Environmental Health, Neuherberg, Germany
Search for more papers by this authorBarbara Thorand
Institute of Epidemiology II, Helmholtz Zentrum München – German Research Center for Environmental Health, Neuherberg, Germany
German Center for Diabetes Research (DZD), Neuherberg, Germany
Search for more papers by this authorCorresponding Author
Cornelia Huth
Institute of Epidemiology II, Helmholtz Zentrum München – German Research Center for Environmental Health, Neuherberg, Germany
German Center for Diabetes Research (DZD), Neuherberg, Germany
Correspondence to: Cornelia Huth, Institute of Epidemiology II, Helmholtz Zentrum München – German Research Center for Environmental Health, Ingolstaedter Landstraße 1, DE-85764 Neuherberg, Germany.
E-mail: [email protected]
Search for more papers by this authorSummary
The literature on the role of body iron status in the development of type 2 diabetes (T2D) in humans is inconsistent. We aimed to assess the association between iron indices and T2D by a meta-analysis of previously published studies. A systematic literature search was conducted in PubMed and EMBASE. Observational studies on the association of ferritin (when controlled for age and sex), transferrin saturation, soluble transferrin receptor and transferrin with T2D were included. Pooled association estimates were calculated using a random effects model. Forty-six eligible studies were identified. The pooled multivariable adjusted relative risks of T2D in the highest versus lowest quartile of ferritin levels were significantly elevated in both cross-sectional as well as prospective studies and after restriction to inflammation-adjusted studies [overall: 1.67 (95%CI 1.41-1.99)]. The mean difference indicated 43.54 ng/mL (95%CI 28.14-58.94) higher ferritin levels in type 2 diabetic individuals. The relative risk for a transferrin saturation ≥50% was 1.59 (95%CI 1.28-1.97), the mean difference was −1.92% [95%CI −2.99-(−0.85)]. Study-specific results of soluble transferrin receptor and transferrin levels were extremely heterogeneous. Ferritin and clinically elevated transferrin saturation were strongly associated with an increased risk of T2D, overall and in prospective studies. Ferritin was also significantly associated after multivariable adjustment including inflammation. Thus, the current evidence hints at a causal effect; however, publication bias and unmeasured confounding cannot be excluded. Copyright © 2013 John Wiley & Sons, Ltd.
Supporting Information
| Filename | Description |
|---|---|
| dmrr2506-sup-0001-documentS1.docWord document, 1 MB | Supporting info item |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
References
- 1 World Health Organization. Diabetes. Fact sheet No. 312 [article online], 2011. Available at: http://www.who.int/mediacentre/factsheets/fs312/en/. Accessed July 13, 2012.
- 2 Shaw JE, Sicree RA, Zimmet PZ. Global estimates of the prevalence of diabetes for 2010 and 2030. Diabetes Res Clin Pract 2010; 87(1): 4–14.
- 3 Rajpathak SN, Crandall JP, Wylie-Rosett J, Kabat GC, Rohan TE, Hu FB. The role of iron in type 2 diabetes in humans. Biochim Biophys Acta 2009; 1790(7): 671–681.
- 4 Fernandez-Real JM, Lopez-Bermejo A, Ricart W. Cross-talk between iron metabolism and diabetes. Diabetes 2002; 51(8): 2348–2354.
- 5 Swaminathan S, Fonseca VA, Alam MG, Shah SV. The role of iron in diabetes and its complications. Diabetes Care 2007; 30(7): 1926–1933.
- 6 Lee DH, Folsom AR, Jacobs DR Jr. Dietary iron intake and Type 2 diabetes incidence in postmenopausal women: the Iowa Women's Health Study. Diabetologia 2004; 47(2): 185–194.
- 7 Jiang R, Ma J, Ascherio A, Stampfer MJ, Willett WC, Hu FB. Dietary iron intake and blood donations in relation to risk of type 2 diabetes in men: a prospective cohort study. Am J Clin Nutr 2004; 79(1): 70–75.
- 8 Poslusna K, Ruprich J, de Vries JH, Jakubikova M, van't Veer P. Misreporting of energy and micronutrient intake estimated by food records and 24 hour recalls, control and adjustment methods in practice. Br J Nutr 2009; 101(Suppl 2): S73–S85.
- 9 Zimmermann MB. Methods to assess iron and iodine status. Br J Nutr 2008; 99(Suppl 3): S2–S9.
- 10 Cook JD, Lipschitz DA, Miles LE, Finch CA. Serum ferritin as a measure of iron stores in normal subjects. Am J Clin Nutr 1974; 27(7): 681–687.
- 11 Goodnough LT, Nemeth E, Ganz T. Detection, evaluation, and management of iron-restricted erythropoiesis. Blood, 2010; 116(23): 4754–4761.
- 12 Wish JB. Assessing iron status: beyond serum ferritin and transferrin saturation. Clin J Am Soc Nephrol 2006; 1(Suppl 1): S4–S8.
- 13 Allen J, Backstrom KR, Cooper JA, et al. Measurement of soluble transferrin receptor in serum of healthy adults. Clin Chem 1998; 44(1): 35–39.
- 14 Wilson JG, Lindquist JH, Grambow SC, Crook ED, Maher JF. Potential role of increased iron stores in diabetes. Am J Med Sci 2003; 325(6): 332–339.
- 15 Herklotz R, Huber A. Labordiagnose von Eisenstoffwechselstörungen [German]. Schweiz Med Forum 2010; 10(30-31): 500–507.
- 16 Cook JD, Baynes RD, Skikne BS. Iron deficiency and the measurement of iron status. Nutr Res Rev 1992; 5(1): 198–202.
- 17 Jehn ML, Guallar E, Clark JM, et al. A prospective study of plasma ferritin level and incident diabetes: the Atherosclerosis Risk in Communities (ARIC) Study. Am J Epidemiol 2007; 165(9): 1047–1054.
- 18 Sun L, Franco OH, Hu FB, et al. Ferritin concentrations, metabolic syndrome, and type 2 diabetes in middle-aged and elderly Chinese. J Clin Endocrinol Metab 2008; 93(12): 4690–4696.
- 19 Van Campenhout A, Van Campenhout C, Lagrou AR, et al. Impact of diabetes mellitus on the relationships between iron-, inflammatory- and oxidative stress status. Diabetes/Metabolism Research and Reviews 2006; 22(6): 444–454.
- 20 Memisogullari R, Bakan E. Levels of ceruloplasmin, transferrin, and lipid peroxidation in the serum of patients with Type 2 diabetes mellitus. J Diabetes Complications 2004; 18(4): 193–197.
- 21 Jones AF, Winkles JW, Jennings PE, Florkowski CM, Lunec J, Barnett AH. Serum antioxidant activity in diabetes mellitus. Diabetes Res 1988; 7(2): 89–92.
- 22
Habeos IG,
Psyrogiannis A,
Kyriazopoulou V,
Psilopanagiotou A,
Papavassiliou AG,
Vagenakis AG. The role of Hemochromatosis C282Y and H63D mutations in the development of type 2 diabetes mellitus in Greece. Hormones (Athens, Greece) 2003; 2(1): 55–60.
10.14310/horm.2002.1183 Google Scholar
- 23 Hughes K, Choo M, Kuperan P, Ong CN, Aw TC. Cardiovascular risk factors in non-insulin-dependent diabetics compared to non-diabetic controls: a population-based survey among Asians in Singapore. Atherosclerosis 1998; 136(1): 25–31.
- 24 Elsammak M, Refai W, Elsawaf A, Abdel-Fattah I, Abd Elatti E, Ghazal A. Elevated serum tumor necrosis factor alpha and ferritin may contribute to the insulin resistance found in HCV positive Egyptian patients. Curr Med Res Opin 2005; 21(4): 527–534.
- 25 Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. Plos Med 2009; 6(7): e1000097.
- 26 Wells GA, Shea B, O'Connell D, et al. The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses [article online]. Available at: http://www.medicine.mcgill.ca/rtamblyn/Readings%5CThe%20Newcastle%20-%20Scale%20for%20assessing%20the%20quality%20of%20nonrandomised%20studies%20in%20meta-analyses.pdf. Accessed June 01, 2012.
- 27 Schmidt CO, Kohlmann T. When to use the odds ratio or the relative risk? Int J Public Health 2008; 53(3): 165–167.
- 28 Rajpathak SN, Wylie-Rosett J, Gunter MJ, et al. Biomarkers of body iron stores and risk of developing type 2 diabetes. Diabetes Obes Metab 2009; 11(5): 472–479.
- 29 Danesh J, Collins R, Appleby P, Peto R. Association of fibrinogen, C-reactive protein, albumin, or leukocyte count with coronary heart disease: meta-analyses of prospective studies. JAMA 1998; 279(18): 1477–1482.
- 30 Higgins JP, White IR, Anzures-Cabrera J. Meta-analysis of skewed data: combining results reported on log-transformed or raw scales. Stat Med 2008; 27(29): 6072–6092.
- 31 Ganesh S, Dharmalingam M, Marcus SR. Oxidative stress in type 2 diabetes with iron deficiency in Asian Indians. J Med Biochem 2012; 31(2): 115–120.
- 32 Jiang F, Sun ZZ, Tang YT, Xu C, Jiao XY. Hepcidin expression and iron parameters change in Type 2 diabetic patients. Diabetes Res Clin Pract 2011; 93(1): 43–48.
- 33 Waheed P, Naveed AK, Farooq F. Levels of inflammatory markers and their correlation with dyslipidemia in diabetics. J Coll Physicians Surg Pak 2009; 19(4): 207–210.
- 34 Furukawa TA, Barbui C, Cipriani A, Brambilla P, Watanabe N. Imputing missing standard deviations in meta-analyses can provide accurate results. J Clin Epidemiol 2006; 59(1): 7–10.
- 35 Higgins JP, Thompson SG. Quantifying heterogeneity in a meta-analysis. Stat Med 2002; 21: 1539–1558.
- 36 Egger M, Davey Smith G, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ 1997; 315(7109): 629–634.
- 37 Shi Z, Hu X, Yuan B, Pan X, Meyer HE, Holmboe-Ottesen G. Association between serum ferritin, hemoglobin, iron intake, and diabetes in adults in Jiangsu, China. Diabetes Care 2006; 29(8): 1878–1883.
- 38 Ford ES, Cogswell ME. Diabetes and serum ferritin concentration among U.S. adults. Diabetes Care 1999; 22(12): 1978–1983.
- 39 Abou-Shousha S, Abd El-Megeed MH, Sultan HK. Interleukin-8, ferritin and soluble transferrin receptors in type II diabetes mellitus. Egypt J Immunol 2006; 13(1): 19–25.
- 40 Ellervik C, Mandrup-Poulsen T, Andersen HU, et al. Elevated transferrin saturation and risk of diabetes: three population-based studies. Diabetes Care 2011; 34(10): 2256–2258.
- 41 Acton RT, Barton JC, Passmore LV, et al. Relationships of serum ferritin, transferrin saturation, and HFE mutations and self-reported diabetes in the Hemochromatosis and Iron Overload Screening (HEIRS) study. Diabetes Care 2006; 29(9): 2084–2089.
- 42 Zhao Z, Li S, Liu G, et al. Body iron stores and heme-iron intake in relation to risk of type 2 diabetes: a systematic review and meta-analysis. PloS One 2012; 7(7): e41641.
- 43
Bao W,
Rong Y,
Rong S,
Liu L. Dietary iron intake, body iron stores, and the risk of type 2 diabetes: a systematic review and meta-analysis. BMC Med 2012; 10(119). Available at doi: 10.1186/1741-7015-10-119. 2012 October 10.
10.1186/1741‐7015‐10‐119 Google Scholar
- 44 Kunutsor SK, Apekey TA, Walley J, Kain K. Ferritin levels and risk of type 2 diabetes mellitus: an updated systematic review and meta-analysis of prospective evidence. Diabetes Metab Res Rev 2013; 29(4): 308–318.
- 45 Zacharski LR, Ornstein DL, Woloshin S, Schwartz LM. Association of age, sex, and race with body iron stores in adults: analysis of NHANES III data. Am Heart J 2000; 140(1): 98–104.
- 46 Ritchie RF, Palomaki GE, Neveux LM, Navolotskaia O, Ledue TB, Craig WY. Reference distributions for serum iron and transferrin saturation: a practical, simple, and clinically relevant approach in a large cohort. J Clin Lab Anal 2002; 16(5): 237–245.
- 47 Sterne JAC, Egger M, Moher D (eds). Chapter 10: Addressing reporting biases. In Cochrane Handbook for Systematic Reviews of Interventions, Version 5.0.1 [updated September 2008], JPT Higgins, S Green (eds). The Cochrane Collaboration, 2008. Available from www.cochrane-handbook.org.
- 48 Wolff SP. Diabetes mellitus and free radicals. Free radicals, transition metals and oxidative stress in the aetiology of diabetes mellitus and complications. Br Med Bull 1993; 49(3): 642–652.
- 49
Deeks JJ,
Higgins JPT,
Altman DG (eds). Chapter 9: Analysing data and undertaking meta-analyses. In Cochrane Handbook for Systematic Reviews of Interventions, Version 5.0.1 [updated September 2008], JPT Higgins, S Green (eds). The Cochrane Collaboration, 2008. Available from www.cochrane-handbook.org.
10.1002/9780470712184.ch9 Google Scholar
- 50 Sanderson S, Tatt ID, Higgins JP. Tools for assessing quality and susceptibility to bias in observational studies in epidemiology: a systematic review and annotated bibliography. Int J Epidemiol 2007; 36(3): 666–676.
- 51 Wiltink WF, Kruithof J, Mol C, Bos MG, van Eijk HG. Diurnal and nocturnal variations of the serum iron in normal subjects. Clin Chim Acta 1973; 49(1): 99–104.
- 52 Yang Z, Dewey KG, Lonnerdal B, et al. Comparison of plasma ferritin concentration with the ratio of plasma transferrin receptor to ferritin in estimating body iron stores: results of 4 intervention trials. Am J Clin Nutr 2008; 87(6): 1892–1898.
- 53 Jiang R, Manson JE, Meigs JB, Ma J, Rifai N, Hu FB. Body iron stores in relation to risk of type 2 diabetes in apparently healthy women. JAMA 2004; 291(6): 711–717.
- 54 Salonen JT, Tuomainen TP, Nyyssonen K, Lakka HM, Punnonen K. Relation between iron stores and non-insulin dependent diabetes in men: case-control study. BMJ 1998; 317(7160): 727.
- 55 Skikne BS, Punnonen K, Caldron PH, et al. Improved differential diagnosis of anemia of chronic disease and iron deficiency anemia: a prospective multicenter evaluation of soluble transferrin receptor and the sTfR/log ferritin index. Am J Heamatol 2011; 86(11): 923–927.
- 56 Arredondo M, Fuentes M, Jorquera D, et al. Cross-talk between body iron stores and diabetes: iron stores are associated with activity and microsatellite polymorphism of the heme oxygenase and type 2 diabetes. Biol Trace Elem Res 2011; 143(2): 625–636.
- 57 Ashourpour M, Djalali M, Djazayery A, Eshraghian MR, Taghdir M, Saedisomeolia A. Relationship between serum ferritin and inflammatory biomarkers with insulin resistance in a Persian population with type 2 diabetes and healthy people. Int J Food Sci Nutr 2010; 61(3): 316–323.
- 58 Elis A, Ferencz JR, Gilady G, Livne A, Assia EI, Lishner M. Is serum ferritin high in patients with diabetic retinopathy? A controlled study. Endocr Res 2004; 30(2): 141–147.
- 59 Fernandez-Real JM, Moreno JM, Lopez-Bermejo A, Chico B, Vendrell J, Ricart W. Circulating soluble transferrin receptor according to glucose tolerance status and insulin sensitivity. Diabetes Care 2007; 30(3): 604–608.
- 60 Hernandez C, Lecube A, Carrera A, Simo R. Soluble transferrin receptors and ferritin in Type 2 diabetic patients. Diabet Med 2004; 22(1): 97–101.
- 61 Kim C, Cheng YJ, Beckles GL. Inflammation among women with a history of gestational diabetes mellitus and diagnosed diabetes in the Third National Health and Nutrition Examination Survey. Diabetes Care 2008; 31(7): 1386–1388.
- 62 Kim CH, Kim HK, Bae SJ, Park JY, Lee KU. Association of elevated serum ferritin concentration with insulin resistance and impaired glucose metabolism in Korean men and women. Metabolism 2011; 60(3): 414–420.
- 63 Le Blanc S, Villarroel P, Candia V, et al. Type 2 diabetic patients and their offspring show altered parameters of iron status, oxidative stress and genes related to mitochondrial activity. Biometals 2012; 25: 725–735.
- 64 Lecube A, Hernandez C, Genesca J, et al. Diabetes is the main factor accounting for the high ferritin levels detected in chronic hepatitis C virus infection. Diabetes Care 2004; 27(11): 2669–2675.
- 65 Lee DH, Liu DY, Jacobs DR Jr, et al. Common presence of non-transferrin-bound iron among patients with type 2 diabetes. Diabetes Care 2006; 29(5): 1090–1095.
- 66 Lee BK, Kim Y, Kim YI. 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 2011; 60(10): 1416–1424.
- 67 Luan DC, Li H, Li SJ, Zhao Z, Li X, Liu ZM. Body iron stores and dietary iron intake in relation to diabetes in adults in North China. Diabetes Care 2008; 31(2): 285–286.
- 68
Mabayoje VO,
Akanni EO,
Arinola GO,
Hassan RO. Plasma transferrin and caeruloplasmin levels in Nigerians with diabetes mellitus. Int J Trop Med 2010; 5(1): 6–9.
10.3923/ijtmed.2010.6.9 Google Scholar
- 69 Mohan V, Snehalatha C, Bhattacharyya PK, Ramachandran A, Viswanathan M. Nutritional profile of fibrocalculous pancreatic diabetes and primary forms of diabetes seen in southern India. Diabetes Res Clin Pract 1991; 11(3): 203–207.
- 70 Mooradian AD, Kalis J, Nugent CA. The nutritional status of ambulatory elderly type II diabetic patients. Age 1990; 13(4): 87–89.
- 71 Sharma SB, Dwivedi S, Kumar N, Prabhu KM, Madan N. Studies on oxidative stress, serum iron and iron binding capacity in subjects prone to the risk of coronary artery disease. Indian Heart J 2000; 52(5): 583–586.
- 72 Skomro RP, Ludwig S, Salamon E, Kryger MH. Sleep complaints and restless legs syndrome in adult type 2 diabetics. Sleep Med 2001; 2(5): 417–422.
- 73 Smotra S, Kudyar RP. Relationship between serum ferritin and type-2 diabetes mellitus. JK Science 2008; 10(4): 170–174.
- 74 Telci A, Cakatay U, Kayali R, et al. Oxidative protein damage in plasma of type 2 diabetic patients. Horm Metab Res 2000; 32(1): 40–43.
- 75 Turnbull PJ, Sinclair AJ. Evaluation of nutritional status and its relationship with functional status in older citizens with diabetes mellitus using the mini nutritional assessment (MNA) tool – a preliminary investigation. J Nutr Health Aging 2002; 6(3): 185–189.
- 76 Zheng X, Jiang T, Wu H, et al. Hepatic iron stores are increased as assessed by magnetic resonance imaging in a Chinese population with altered glucose homeostasis. Am J Clin Nutr 2011; 94(4): 1012–1019.
- 77 Forouhi NG, Harding AH, Allison M, et al. Elevated serum ferritin levels predict new-onset type 2 diabetes: results from the EPIC-Norfolk prospective study. Diabetologia 2007; 50(5): 949–956.
- 78 Fumeron F, Pean F, Driss F, et al. 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 2006; 29(9): 2090–2094.
- 79 Le TD, Bae S, Ed Hsu C, Singh KP, Blair SN, Shang N. Effects of cardiorespiratory fitness on serum ferritin concentration and incidence of type 2 diabetes: evidence from the (ACLS). Rev Diabet Stud 2008; 5(4): 245–252.
- 80 Mainous AG 3rd, King DE, Pearson WS, Garr DR. Is an elevated serum transferrin saturation associated with the development of diabetes? J Fam Pract 2002; 51(11): 933–936.
- 81 Salomaa V, Havulinna A, Saarela O, et al. Thirty-one novel biomarkers as predictors for clinically incident diabetes. PloS One 2010; 5(4): e10100.
Citing Literature
