Association of Multiple Biomarkers of Iron Metabolism and Type 2 Diabetes: The EPIC-InterAct Study

Clara Podmore; Karina Meidtner; Matthias B Schulze; Robert A Scott; Anna Ramond; Adam S Butterworth; Emanuele Di Angelantonio; John Danesh; Larraitz Arriola; Aurelio Barricarte; Heiner Boeing; Françoise Clavel-Chapelon; Amanda J Cross; CC Dahm; Guy Fagherazzi; Paul W Franks; Diana Gavrila; Sara Grioni; Marc J Gunter; Gaelle Gusto; Paula Jakszyn; Verena Katzke; Timothy J Key; Tilman Kühn; Amalia Mattiello; Peter M Nilsson; Anja Olsen; Kim Overvad; Domenico Palli; J Ramón Quirós; Olov Rolandsson; Carlotta Sacerdote; Emilio Sánchez-Cantalejo; Nadia Slimani; Ivonne Sluijs; Annemieke M W Spijkerman; Anne Tjonneland; Rosario Tumino; Daphne L van der A; Yvonne T van der Schouw; Edith J M Feskens; Nita G Forouhi; Stephen J Sharp; Elio Riboli; Claudia Langenberg; Nicholas J Wareham

doi:10.2337/dc15-0257

Association of Multiple Biomarkers of Iron Metabolism and Type 2 Diabetes: The EPIC-InterAct Study

Clara Podmore, Karina Meidtner, Matthias B Schulze, Robert A Scott, Anna Ramond, Adam S Butterworth, Emanuele Di Angelantonio, John Danesh, Larraitz Arriola, Aurelio Barricarte, Heiner Boeing, Françoise Clavel-Chapelon, Amanda J Cross, CC Dahm, Guy Fagherazzi, Paul W Franks, Diana Gavrila, Sara Grioni, Marc J Gunter, Gaelle GustoPaula Jakszyn, Verena Katzke, Timothy J Key, Tilman Kühn, Amalia Mattiello, Peter M Nilsson, Anja Olsen, Kim Overvad, Domenico Palli, J Ramón Quirós, Olov Rolandsson, Carlotta Sacerdote, Emilio Sánchez-Cantalejo, Nadia Slimani, Ivonne Sluijs, Annemieke M W Spijkerman, Anne Tjonneland, Rosario Tumino, Daphne L van der A, Yvonne T van der Schouw, Edith J M Feskens, Nita G Forouhi, Stephen J Sharp, Elio Riboli, Claudia Langenberg, Nicholas J Wareham

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Abstract

OBJECTIVE: Observational studies show an association between ferritin and type 2 diabetes (T2D), suggesting a role of high iron stores in T2D development. However, ferritin is influenced by factors other than iron stores, which is less the case for other biomarkers of iron metabolism. We investigate associations of ferritin, transferrin saturation (TSAT), serum iron, and transferrin with T2D incidence to clarify the role of iron in the pathogenesis of T2D.

RESEARCH AND DESIGN METHODS: The European Prospective Investigation into Cancer and Nutrition-InterAct study includes 12,403 incident T2D cases and a representative subcohort of 16,154 individuals from a European cohort with 3.99 million person-years of follow-up. We studied the prospective association of ferritin, TSAT, serum iron, and transferrin with incident T2D in 11,052 cases and a random subcohort of 15,182 individuals and assessed whether these associations differed by subgroups of the population.

RESULTS: Higher levels of ferritin and transferrin were associated with a higher risk of T2D (hazard ratio [HR] [95% CI] in men and women, respectively: 1.07 [1.01-1.12] and 1.12 [1.05-1.19] per 100 μg/L higher ferritin level; 1.11 [1.00-1.24] and 1.22 [1.12-1.33] per 0.5 g/L higher transferrin level) after adjusting for age, center, BMI, physical activity, smoking status, education, hs-CRP, alanine aminotransferase, and γ-glutamyl transferase. Elevated TSAT (≥45% vs. <45%) was associated with a lower risk of T2D in women (0.68 [0.54-0.86]) but was not statistically significantly associated in men (0.90 [0.75-1.08]). Serum iron was not associated with T2D. The association of ferritin with T2D was stronger among leaner individuals (Pinteraction < 0.01).

CONCLUSIONS: The pattern of association of TSAT and transferrin with T2D suggests that the underlying relationship between iron stores and T2D is more complex than the simple link suggested by the association of ferritin with T2D.

Original language	English
Journal	Diabetes Care
Volume	39
Issue number	4
Pages (from-to)	572-581
Number of pages	10
ISSN	0149-5992
DOIs	https://doi.org/10.2337/dc15-0257
Publication status	Published - 9 Feb 2016

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Podmore, C., Meidtner, K., Schulze, M. B., Scott, R. A., Ramond, A., Butterworth, A. S., Di Angelantonio, E., Danesh, J., Arriola, L., Barricarte, A., Boeing, H., Clavel-Chapelon, F., Cross, A. J., Dahm, CC., Fagherazzi, G., Franks, P. W., Gavrila, D., Grioni, S., Gunter, M. J., ... Wareham, N. J. (2016). Association of Multiple Biomarkers of Iron Metabolism and Type 2 Diabetes: The EPIC-InterAct Study. Diabetes Care, 39(4), 572-581. https://doi.org/10.2337/dc15-0257

@article{39aa8535fdfb4ad8b792e87ff7a4d9c9,

title = "Association of Multiple Biomarkers of Iron Metabolism and Type 2 Diabetes: The EPIC-InterAct Study",

abstract = "OBJECTIVE: Observational studies show an association between ferritin and type 2 diabetes (T2D), suggesting a role of high iron stores in T2D development. However, ferritin is influenced by factors other than iron stores, which is less the case for other biomarkers of iron metabolism. We investigate associations of ferritin, transferrin saturation (TSAT), serum iron, and transferrin with T2D incidence to clarify the role of iron in the pathogenesis of T2D.RESEARCH AND DESIGN METHODS: The European Prospective Investigation into Cancer and Nutrition-InterAct study includes 12,403 incident T2D cases and a representative subcohort of 16,154 individuals from a European cohort with 3.99 million person-years of follow-up. We studied the prospective association of ferritin, TSAT, serum iron, and transferrin with incident T2D in 11,052 cases and a random subcohort of 15,182 individuals and assessed whether these associations differed by subgroups of the population.RESULTS: Higher levels of ferritin and transferrin were associated with a higher risk of T2D (hazard ratio [HR] [95% CI] in men and women, respectively: 1.07 [1.01-1.12] and 1.12 [1.05-1.19] per 100 μg/L higher ferritin level; 1.11 [1.00-1.24] and 1.22 [1.12-1.33] per 0.5 g/L higher transferrin level) after adjusting for age, center, BMI, physical activity, smoking status, education, hs-CRP, alanine aminotransferase, and γ-glutamyl transferase. Elevated TSAT (≥45% vs. <45%) was associated with a lower risk of T2D in women (0.68 [0.54-0.86]) but was not statistically significantly associated in men (0.90 [0.75-1.08]). Serum iron was not associated with T2D. The association of ferritin with T2D was stronger among leaner individuals (Pinteraction < 0.01).CONCLUSIONS: The pattern of association of TSAT and transferrin with T2D suggests that the underlying relationship between iron stores and T2D is more complex than the simple link suggested by the association of ferritin with T2D.",

author = "Clara Podmore and Karina Meidtner and Schulze, {Matthias B} and Scott, {Robert A} and Anna Ramond and Butterworth, {Adam S} and {Di Angelantonio}, Emanuele and John Danesh and Larraitz Arriola and Aurelio Barricarte and Heiner Boeing and Fran{\c c}oise Clavel-Chapelon and Cross, {Amanda J} and CC Dahm and Guy Fagherazzi and Franks, {Paul W} and Diana Gavrila and Sara Grioni and Gunter, {Marc J} and Gaelle Gusto and Paula Jakszyn and Verena Katzke and Key, {Timothy J} and Tilman K{\"u}hn and Amalia Mattiello and Nilsson, {Peter M} and Anja Olsen and Kim Overvad and Domenico Palli and Quir{\'o}s, {J Ram{\'o}n} and Olov Rolandsson and Carlotta Sacerdote and Emilio S{\'a}nchez-Cantalejo and Nadia Slimani and Ivonne Sluijs and Spijkerman, {Annemieke M W} and Anne Tjonneland and Rosario Tumino and {van der A}, {Daphne L} and {van der Schouw}, {Yvonne T} and Feskens, {Edith J M} and Forouhi, {Nita G} and Sharp, {Stephen J} and Elio Riboli and Claudia Langenberg and Wareham, {Nicholas J}",

note = "{\textcopyright} 2016 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.",

year = "2016",

month = feb,

day = "9",

doi = "10.2337/dc15-0257",

language = "English",

volume = "39",

pages = "572--581",

journal = "Diabetes Care",

issn = "0149-5992",

publisher = "American Diabetes Association",

number = "4",

}

Podmore, C, Meidtner, K, Schulze, MB, Scott, RA, Ramond, A, Butterworth, AS, Di Angelantonio, E, Danesh, J, Arriola, L, Barricarte, A, Boeing, H, Clavel-Chapelon, F, Cross, AJ, Dahm, CC, Fagherazzi, G, Franks, PW, Gavrila, D, Grioni, S, Gunter, MJ, Gusto, G, Jakszyn, P, Katzke, V, Key, TJ, Kühn, T, Mattiello, A, Nilsson, PM, Olsen, A, Overvad, K, Palli, D, Quirós, JR, Rolandsson, O, Sacerdote, C, Sánchez-Cantalejo, E, Slimani, N, Sluijs, I, Spijkerman, AMW, Tjonneland, A, Tumino, R, van der A, DL, van der Schouw, YT, Feskens, EJM, Forouhi, NG, Sharp, SJ, Riboli, E, Langenberg, C & Wareham, NJ 2016, 'Association of Multiple Biomarkers of Iron Metabolism and Type 2 Diabetes: The EPIC-InterAct Study', Diabetes Care, vol. 39, no. 4, pp. 572-581. https://doi.org/10.2337/dc15-0257

TY - JOUR

T1 - Association of Multiple Biomarkers of Iron Metabolism and Type 2 Diabetes

T2 - The EPIC-InterAct Study

AU - Podmore, Clara

AU - Meidtner, Karina

AU - Schulze, Matthias B

AU - Scott, Robert A

AU - Ramond, Anna

AU - Butterworth, Adam S

AU - Di Angelantonio, Emanuele

AU - Danesh, John

AU - Arriola, Larraitz

AU - Barricarte, Aurelio

AU - Boeing, Heiner

AU - Clavel-Chapelon, Françoise

AU - Cross, Amanda J

AU - Dahm, CC

AU - Fagherazzi, Guy

AU - Franks, Paul W

AU - Gavrila, Diana

AU - Grioni, Sara

AU - Gunter, Marc J

AU - Gusto, Gaelle

AU - Jakszyn, Paula

AU - Katzke, Verena

AU - Key, Timothy J

AU - Kühn, Tilman

AU - Mattiello, Amalia

AU - Nilsson, Peter M

AU - Olsen, Anja

AU - Overvad, Kim

AU - Palli, Domenico

AU - Quirós, J Ramón

AU - Rolandsson, Olov

AU - Sacerdote, Carlotta

AU - Sánchez-Cantalejo, Emilio

AU - Slimani, Nadia

AU - Sluijs, Ivonne

AU - Spijkerman, Annemieke M W

AU - Tjonneland, Anne

AU - Tumino, Rosario

AU - van der A, Daphne L

AU - van der Schouw, Yvonne T

AU - Feskens, Edith J M

AU - Forouhi, Nita G

AU - Sharp, Stephen J

AU - Riboli, Elio

AU - Langenberg, Claudia

AU - Wareham, Nicholas J

PY - 2016/2/9

Y1 - 2016/2/9

N2 - OBJECTIVE: Observational studies show an association between ferritin and type 2 diabetes (T2D), suggesting a role of high iron stores in T2D development. However, ferritin is influenced by factors other than iron stores, which is less the case for other biomarkers of iron metabolism. We investigate associations of ferritin, transferrin saturation (TSAT), serum iron, and transferrin with T2D incidence to clarify the role of iron in the pathogenesis of T2D.RESEARCH AND DESIGN METHODS: The European Prospective Investigation into Cancer and Nutrition-InterAct study includes 12,403 incident T2D cases and a representative subcohort of 16,154 individuals from a European cohort with 3.99 million person-years of follow-up. We studied the prospective association of ferritin, TSAT, serum iron, and transferrin with incident T2D in 11,052 cases and a random subcohort of 15,182 individuals and assessed whether these associations differed by subgroups of the population.RESULTS: Higher levels of ferritin and transferrin were associated with a higher risk of T2D (hazard ratio [HR] [95% CI] in men and women, respectively: 1.07 [1.01-1.12] and 1.12 [1.05-1.19] per 100 μg/L higher ferritin level; 1.11 [1.00-1.24] and 1.22 [1.12-1.33] per 0.5 g/L higher transferrin level) after adjusting for age, center, BMI, physical activity, smoking status, education, hs-CRP, alanine aminotransferase, and γ-glutamyl transferase. Elevated TSAT (≥45% vs. <45%) was associated with a lower risk of T2D in women (0.68 [0.54-0.86]) but was not statistically significantly associated in men (0.90 [0.75-1.08]). Serum iron was not associated with T2D. The association of ferritin with T2D was stronger among leaner individuals (Pinteraction < 0.01).CONCLUSIONS: The pattern of association of TSAT and transferrin with T2D suggests that the underlying relationship between iron stores and T2D is more complex than the simple link suggested by the association of ferritin with T2D.

AB - OBJECTIVE: Observational studies show an association between ferritin and type 2 diabetes (T2D), suggesting a role of high iron stores in T2D development. However, ferritin is influenced by factors other than iron stores, which is less the case for other biomarkers of iron metabolism. We investigate associations of ferritin, transferrin saturation (TSAT), serum iron, and transferrin with T2D incidence to clarify the role of iron in the pathogenesis of T2D.RESEARCH AND DESIGN METHODS: The European Prospective Investigation into Cancer and Nutrition-InterAct study includes 12,403 incident T2D cases and a representative subcohort of 16,154 individuals from a European cohort with 3.99 million person-years of follow-up. We studied the prospective association of ferritin, TSAT, serum iron, and transferrin with incident T2D in 11,052 cases and a random subcohort of 15,182 individuals and assessed whether these associations differed by subgroups of the population.RESULTS: Higher levels of ferritin and transferrin were associated with a higher risk of T2D (hazard ratio [HR] [95% CI] in men and women, respectively: 1.07 [1.01-1.12] and 1.12 [1.05-1.19] per 100 μg/L higher ferritin level; 1.11 [1.00-1.24] and 1.22 [1.12-1.33] per 0.5 g/L higher transferrin level) after adjusting for age, center, BMI, physical activity, smoking status, education, hs-CRP, alanine aminotransferase, and γ-glutamyl transferase. Elevated TSAT (≥45% vs. <45%) was associated with a lower risk of T2D in women (0.68 [0.54-0.86]) but was not statistically significantly associated in men (0.90 [0.75-1.08]). Serum iron was not associated with T2D. The association of ferritin with T2D was stronger among leaner individuals (Pinteraction < 0.01).CONCLUSIONS: The pattern of association of TSAT and transferrin with T2D suggests that the underlying relationship between iron stores and T2D is more complex than the simple link suggested by the association of ferritin with T2D.

U2 - 10.2337/dc15-0257

DO - 10.2337/dc15-0257

M3 - Journal article

C2 - 26861925

SN - 0149-5992

VL - 39

SP - 572

EP - 581

JO - Diabetes Care

JF - Diabetes Care

IS - 4

ER -

Association of Multiple Biomarkers of Iron Metabolism and Type 2 Diabetes: The EPIC-InterAct Study

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