Exp Clin Endocrinol Diabetes 2017; 125(01): 12-20
DOI: 10.1055/s-0042-118175
Article
© Georg Thieme Verlag KG Stuttgart · New York

Serum Ferritin, Insulin Resistance, and β-cell Dysfunction: A Prospective Study in Normoglycemic Japanese Men

Koshi Nakamura
1   Department of Public Health, Hokkaido University Graduate School of Medicine, Sapporo, Japan
,
Masaru Sakurai
3   Department of Social and Environmental Medicine, Kanazawa Medical University, Uchinada, Japan
,
Yuko Morikawa
4   School of Nursing, Kanazawa Medical University, Uchinada, Japan
,
Shin-ya Nagasawa
2   Department of Epidemiology and Public Health, Kanazawa Medical University, Uchinada, Japan
,
Katsuyuki Miura
5   Department of Public Health, and Center for Epidemiologic Research in Asia, Shiga University of Medical Science, Otsu, Japan
,
Masao Ishizaki
3   Department of Social and Environmental Medicine, Kanazawa Medical University, Uchinada, Japan
,
Teruhiko Kido
6   School of Health Sciences, College of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Japan
,
Yuchi Naruse
7   Department of Social Walfare, Toyama College of Welfare Science, Imizu, Japan
,
Motoko Nakashima
4   School of Nursing, Kanazawa Medical University, Uchinada, Japan
,
Kazuhiro Nogawa
8   Department of Occupational and Environmental Medicine, Graduate School of Medicine, Chiba University, Chiba, Japan
,
Yasushi Suwazono
8   Department of Occupational and Environmental Medicine, Graduate School of Medicine, Chiba University, Chiba, Japan
,
Hideaki Nakagawa
9   Medical Research Institute, Kanazawa Medical University, Uchinada, Japan
› Author Affiliations
Further Information

Publication History

received 12 April 2016
revised 12 April 2016

accepted 23 September 2016

Publication Date:
17 October 2016 (online)

Abstract

Objectives: The present cohort study investigated the relationship between serum ferritin levels and indices of insulin resistance and β-cell dysfunction in a normoglycemic population without iron overload disorders.

Methods: The study participants included 575 normoglycemic Japanese men aged 35–57 years with serum ferritin levels of 400 μg/L or less. Insulin resistance and β-cell dysfunction were estimated at baseline and after 3 years by the homeostasis model assessments of insulin resistance and β-cell function (HOMA-IR and HOMA-β, respectively). To compare the subsequent changes in HOMA-IR and HOMA-β over a 3-year follow-up period among 3 groups based on tertiles of baseline serum ferritin levels (4.9–87.1, 87.2–140.5, and 140.6–396.8 μg/L), the geometric mean HOMA-IR and HOMA-β values at year 3 were calculated for each group using analysis of covariance, incorporating the respective log-transformed parameters at baseline in addition to age, body mass index and major confounding factors.

Results: The multivariate-adjusted geometric mean HOMA-IR at year 3 was significantly higher in those in the highest and middle serum ferritin tertiles (1.24 and 1.22, respectively), compared with the lowest tertile (1.07) (p=0.009). When the total study participants were stratified by median body mass index (22.72 kg/m2), similar positive relationships were observed between serum ferritin levels and HOMA-IR for both obese and non-obese participants. However, the adjusted geometric mean HOMA-β at year 3 was similar among the 3 serum ferritin groups.

Conclusions: Elevated serum ferritin levels predicted a subsequent increase in HOMA-IR in normoglycemic Japanese men without iron overload disorders.

 
  • References

  • 1 Ponka P, Beaumont C, Richardson DR. Function and regulation of transferrin and ferritin. Semin Hematol 1998; 35: 35-54
  • 2 Salonen JT, Tuomainen TP, Nyyssönen K et al. Relation between iron stores and non-insulin dependent diabetes in men: case-control study. BMJ 1998; 317: 727
  • 3 Jiang R, Manson JE, Meigs JB et al. Body iron stores in relation to risk of type 2 diabetes in apparently healthy women. JAMA 2004; 291: 711-717
  • 4 Fumeron F, Péan F, Driss F et al. Insulin Resistance Syndrome (DESIR) Study Group . 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: 2090-2094
  • 5 Halliwell B, Gutteridge JM. Role of free radicals and catalytic metal ions in human disease: an overview. Methods Enzymol 1990; 186: 1-85
  • 6 Meneghini R. Iron homeostasis, oxidative stress, and DNA damage. Free Radic Biol Med 1997; 23: 783-792
  • 7 Houstis N, Rosen ED, Lander ES. Reactive oxygen species have a causal role in multiple forms of insulin resistance. Nature 2006; 440: 944-948
  • 8 Meigs JB, Larson MG, Fox CS et al. Association of oxidative stress, insulin resistance, and diabetes risk phenotypes: the Framingham Offspring Study. Diabetes Care 2007; 30: 2529-2535
  • 9 Syrovatka P, Kraml P, Potockova J et al. Relationship between increased body iron stores, oxidative stress and insulin resistance in healthy men. Ann Nutr Metab 2009; 54: 268-274
  • 10 Cooksey RC, Jouihan HA, Ajioka RS et al. Oxidative stress, beta-cell apoptosis, and decreased insulin secretory capacity in mouse models of hemochromatosis. Endocrinology 2004; 145: 5305-5312
  • 11 Rahier J, Loozen S, Goebbels RM et al. The haemochromatotic human pancreas: a quantitative immunohistochemical and ultrastructural study. Diabetologia 1987; 30: 5-12
  • 12 Niederau C, Berger M, Stremmel W et al. Hyperinsulinaemia in non-cirrhotic haemochromatosis: impaired hepatic insulin degradation?. Diabetologia 1984; 26: 441-444
  • 13 Green A, Basile R, Rumberger JM. Transferrin and iron induce insulin resistance of glucose transport in adipocytes. Metabolism 2006; 55: 1042-1045
  • 14 Katz LD, Glickman MG, Rapoport S et al. Splanchnic and peripheral disposal of oral glucose in man. Diabetes 1983; 32: 675-679
  • 15 Jehn M, Clark JM, Guallar E. Serum ferritin and risk of the metabolic syndrome in U.S. adults. Diabetes Care 2004; 27: 2422-2428
  • 16 Vari IS, Balkau B, Kettaneh A et al. DESIR Study Group . 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 2007; 30: 1795-1801
  • 17 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: 1416-1424
  • 18 Aregbesola A, Virtanen JK, Voutilainen S et al. Serum ferritin and glucose homeostasis: change in the association by glycaemic state. Diabetes Metab Res Rev 2015; 31: 507-514
  • 19 Wlazlo N, van Greevenbroek MM, 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 2015; 52: 337-348
  • 20 Park SK, Choi WJ, Oh CM et al. Clinical significance of serum ferritin level as an independent predictor of insulin resistance in Korean men. Diabetes Res Clin Pract 2015; 107: 187-193
  • 21 Chen KW, Boyko EJ, Bergstrom RW et al. Earlier appearance of impaired insulin secretion than of visceral adiposity in the pathogenesis of NIDDM. 5-Year follow-up of initially nondiabetic Japanese-American men. Diabetes Care 1995; 18: 747-753
  • 22 Yoshinaga H, Kosaka K. Heterogeneous relationship of early insulin response and fasting insulin level with development of non-insulin-dependent diabetes mellitus in non-diabetic Japanese subjects with or without obesity. Diabetes Res Clin Pract 1999; 44: 129-136
  • 23 Sakurai M, Nakamura K, Miura K et al. Association between a serum thyroid-stimulating hormone concentration within the normal range and indices of obesity in Japanese men and women. Intern Med 2014; 53: 669-674
  • 24 Nakamura K, Sakurai M, Miura K et al. Overall sleep status and high sensitivity C-reactive protein: a prospective study in Japanese factory workers. J Sleep Res 2014; 23: 717-727
  • 25 Rushton DH, Dover R, Sainsbury AW et al. Why should women have lower reference limits for haemoglobin and ferritin concentrations than men?. BMJ 2001; 322: 1355-1357
  • 26 Expert Committee on the Diagnosis and Classification of Diabetes Mellitus . Follow-up report on the diagnosis of diabetes mellitus. Diabetes Care 2003; 26: 3160-3167
  • 27 International Expert Committee . International Expert Committee report on the role of the A1C assay in the diagnosis of diabetes. Diabetes Care 2009; 32: 1327-1334
  • 28 Witte DL, Crosby WH, Edwards CQ et al. Practice guideline development task force of the College of American Pathologists. Hereditary hemochromatosis. Clin Chim Acta 1996; 245: 139-200
  • 29 Pearson TA, Mensah GA, Alexander RW et al. Centers for Disease Control and Prevention; American Heart Association . Markers of inflammation and cardiovascular disease: application to clinical and public health practice: A statement for healthcare professionals from the Centers for Disease Control and Prevention and the American Heart Association. Circulation 2003; 107: 499-511
  • 30 Pratt DS, Kaplan MM. Evaluation of abnormal liver-enzyme results in asymptomatic patients. N Engl J Med 2000; 342: 1266-1271
  • 31 Matthews DR, Hosker JP, Rudenski AS et al. Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 1985; 28: 412-419
  • 32 Kashiwagi A, Kasuga M, Araki E et al. Committee on the Standardization of Diabetes Mellitus-Related Laboratory Testing of Japan Diabetes Society . International clinical harmonization of glycated hemoglobin in Japan: From Japan Diabetes Society to National Glycohemoglobin Standardization Program values. Diabetol Int 2012; 3: 8-10
  • 33 Hoelzel W, Weykamp C, Jeppsson JO et al. IFCC Working Group on HbA1c Standardization . Wiedmeyer HMIFCC reference system for measurement of hemoglobin A1c in human blood and the national standardization schemes in the United States, Japan, and Sweden: a method-comparison study. Clin Chem 2004; 50: 166-174
  • 34 Ludvik B, Nolan JJ, Baloga J et al. Effect of obesity on insulin resistance in normal subjects and patients with NIDDM. Diabetes 1995; 44: 1121-1125
  • 35 Wallace TM, Levy JC, Matthews DR. Use and abuse of HOMA modeling. Diabetes Care 2004; 27: 1487-1495
  • 36 Wilson JG, Lindquist JH, Grambow SC et al. Potential role of increased iron stores in diabetes. Am J Med Sci 2003; 325: 332-339
  • 37 Marchesini G, Brizi M, Morselli-Labate AM et al. Association of nonalcoholic fatty liver disease with insulin resistance. Am J Med 1999; 107: 450-455
  • 38 Tran TN, Eubanks SK, Schaffer KJ et al. Secretion of ferritin by rat hepatoma cells and its regulation by inflammatory cytokines and iron. Blood 1997; 90: 4979-4986
  • 39 Thorand B, Löwel H, Schneider A et al. C-reactive protein as a predictor for incident diabetes mellitus among middle-aged men: results from the MONICA Augsburg cohort study, 1984–1998. Arch Intern Med 2003; 163: 93-99
  • 40 Cade JE, Moreton JA, O’Hara B et al. Diet and genetic factors associated with iron status in middle-aged women. Am J Clin Nutr 2005; 82: 813-820
  • 41 Nanri A, Shimazu T, Takachi R et al. Japan Public Health Center-based Prospective Study Group . Dietary patterns and type 2 diabetes in Japanese men and women: the Japan Public Health Center-based Prospective Study. Eur J Clin Nutr 2013; 67: 18-24