Diabetes and Hemochromatosis

Diabetes and Other Diseases-Emerging Associations (JJ Nolan, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Diabetes and Other Diseases-Emerging Associations

Abstract

The common form of hereditary hemochromatosis is an autosomal recessive disorder most prevalent in Caucasians that results in excessive iron storage. The clinical manifestations of hemochromatosis are protean. HFE genotype, which determines the degree of iron overload and duration of disease have profound effects on disease expression. The prevalence of diabetes in this population has likely been underestimated because of studies that include a broad range of ethnicities and associating diabetes with allele frequency in spite of the decreased risk of diabetes in heterozygotes compared with homozygotes. Loss of insulin secretory capacity is likely the primary defect contributing to development of diabetes with insulin resistance playing a secondary role. Phlebotomy can ameliorate the defects in insulin secretion if initiated early. Screening a select population of individuals with type 2 diabetes may identify patients with hemochromatosis early and substantially impact individual clinical outcomes.

Keywords

Hemochromatosis Diabetes Iron overload Glucose metabolism Prevalence Insulin secretion 

References

Papers of particular interest, published recently, have been highlighted as: • Of importance, •• Of major importance

  1. 1.••
    Pietrangelo A. Hereditary hemochromatosis: pathogenesis, diagnosis, and treatment. Gastroenterology. 2010;139(2):393–408. 408.e1-2. A comprehensive review of all clinical aspects of hemochromatosis. Google Scholar
  2. 2.
    Federer JN, Gnirke A, Thomas W, Tsuchihashi Z, Ruddy DA, Basava A, et al. A novel MHC class I-like gene is mutated in patients with hereditary haemochromatosis. Nat Genet. 1996;13(4):399–408.CrossRefGoogle Scholar
  3. 3.
    Nemeth E, Tuttle MS, Powelson J, Vaughn MB, Donovan A, Ward DM, et al. Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization. Science. 2004;306(5704):2090–3.PubMedCrossRefGoogle Scholar
  4. 4.
    Ganz T. Systemic iron homeostasis. Physiol Rev. 2013;93(4):1721–41.PubMedCrossRefGoogle Scholar
  5. 5.
    Bacon BR, Sadiq SA. Hereditary hemochromatosis: presentation and diagnosis in the 1990s. Am J Gastroenterol. 1997;92(5):784–9.PubMedGoogle Scholar
  6. 6.
    Neghina AM, Anghel A. Hemochromatosis genotypes and risk of iron overload–a meta-analysis. Ann Epidemiol. 2011;21(1):1–14.PubMedCrossRefGoogle Scholar
  7. 7.
    Beutler E, Felitti VJ, Koziol JA, Ho NJ, Gelbart T. Penetrance of 845G– > A (C282Y) HFE hereditary haemochromatosis mutation in the USA. Lancet. 2002;359(9302):211–8.PubMedCrossRefGoogle Scholar
  8. 8.
    Bulaj ZJ, Ajioka RS, Phillips JD, LaSalle BA, Jorde LB, Griffen LM, et al. Disease-related conditions in relatives of patients with hemochromatosis. N Engl J Med. 2000;343(21):1529–35.PubMedCrossRefGoogle Scholar
  9. 9.
    Allen KJ, Gurrin LC, Constantine CC, Osborne NJ, Delatycki MB, Nicoll AJ, et al. Iron-overload-related disease in HFE hereditary hemochromatosis. N Engl J Med. 2008;358:221–30.PubMedCrossRefGoogle Scholar
  10. 10.
    Lainé F, Jouannolle AM, Morcet J, Brigand A, Pouchard M, Lafraise B, et al. Phenotypic expression in detected C282Y homozygous women depends on body mass index. J Hepatol. 2005;43(6):1055–9.PubMedCrossRefGoogle Scholar
  11. 11.
    Gurrin LC, Osborne NJ, Constantine CC, McLaren CE, English DR, Gertig DM, et al. The natural history of serum iron indices for HFE C282Y homozygosity associated with hereditary hemochromatosis. Gastroenterology. 2008;135(6):1945–52.PubMedCrossRefGoogle Scholar
  12. 12.
    Niederau C, Fischer R, Pürschel A, Stremmel W, Häussinger D, Strohmeyer G. Long-term survival in patients with hereditary hemochromatosis. Gastroenterology. 1996;110(4):1107–19.PubMedCrossRefGoogle Scholar
  13. 13.
    Center for Disease Control and Prevention. Diabetes Data and Trends. 2013. Web. 15 Nov 2013. http://www.cdc.gov/diabetes/statistics/prevalence_national.htm
  14. 14.
    Acton RT, Barton JC, Passmore LV, Adams PC, Speechley MR, Dawkins FW, 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):2084–9.PubMedCrossRefGoogle Scholar
  15. 15.
    Andersen RV, Tybjaerg-Hansen A, Appleyard M, Birgens H, Nordestgaard BG. Hemochromatosis mutations in the general population: iron overload progression rate. Blood. 2004;103(8):2914–9.PubMedCrossRefGoogle Scholar
  16. 16.
    Moczulski DK, Grzeszczak W, Gawlik B. Role of hemochromatosis C282Y and H63D mutations in HFE gene in development of type 2 diabetes and diabetic nephropathy. Diabetes Care. 2001;24(7):1187–91.PubMedCrossRefGoogle Scholar
  17. 17.
    Kwan T, Leber B, Ahuja S, Carter R, Gerstein HC. Patients with type 2 diabetes have a high frequency of the C282Y mutation of the hemochromatosis gene. Clin Invest Med. 1998;21(6):251–7.PubMedGoogle Scholar
  18. 18.
    Salonen JT, Tuomainen TP, Kontula K. Role of C282Y mutation in haemochromatosis gene in development of type 2 diabetes in healthy men: prospective cohort study. BMJ. 2000;320(7251):1706–7.PubMedCentralPubMedCrossRefGoogle Scholar
  19. 19.
    Ellervik C, Mandrup-Poulsen T, Nordestgaard BG, Larsen LE, Appleyard M, Frandsen M, et al. Prevalence of hereditary haemochromatosis in late-onset type 1 diabetes mellitus: a retrospective study. Lancet. 2001;358(9291):1405–9.PubMedCrossRefGoogle Scholar
  20. 20.
    Halsall DJ, McFarlane I, Luan J, Cox TM, Wareham NJ, et al. Typical type 2 diabetes mellitus and HFE gene mutations: a population-based case - control study. Hum Mol Genet. 2003;12(12):1361–5.PubMedCrossRefGoogle Scholar
  21. 21.
    Rong Y, Bao W, Rong S, Fang M, Wang D, Yao P, et al. Hemochromatosis gene (HFE) polymorphisms and risk of type 2 diabetes mellitus: a meta-analysis. Am J Epidemiol. 2012;176(6):461–72.PubMedCrossRefGoogle Scholar
  22. 22.
    Qi L, Meigs J, Manson JE, Ma J, Hunter D, Rifai N, et al. HFE genetic variability, body iron stores, and the risk of type 2 diabetes in U.S. women. Diabetes. 2005;54(12):3567–72.PubMedCrossRefGoogle Scholar
  23. 23.•
    Hatunic M, Finucane FM, Brennan AM, Norris S, Pacini G, Nolan JJ, et al. Effect of iron overload on glucose metabolism in patients with hereditary hemochromatosis. Metabolism. 2010;59(3):380–4. Detailed assessment of glucose metabolism in individuals with HH. PubMedCrossRefGoogle Scholar
  24. 24.•
    McClain DA, Abraham D, Rogers J, Brady R, Gault P, Ajioka R, et al. High prevalence of abnormal glucose homeostasis secondary to decreased insulin secretion in individuals with hereditary haemochromatosis. Diabetologia. 2006;49(7):1661–9. Provides an estimate of the prevalence of diabetes in HH unbiased by preexisting diabetes. Evidence that insulin secretion is the primary defect causing diabetes in HH. PubMedCrossRefGoogle Scholar
  25. 25.
    Adams PC, Reboussin DM, Barton JC, McLaren CE, Eckfeldt JH, McLaren GD, et al. Hemochromatosis and iron-overload screening in a racially diverse population. N Engl J Med. 2005;352(17):1769–78.PubMedCrossRefGoogle Scholar
  26. 26.
    O'Sullivan EP, McDermott JH, Murphy MS, Sen S, Walsh CH, et al. Declining prevalence of diabetes mellitus in hereditary haemochromatosis–the result of earlier diagnosis. Diabetes Res Clin Pract. 2008;81(3):316–20.PubMedCrossRefGoogle Scholar
  27. 27.•
    Bacon BR, Adams PC, Kowdley KV, Powell LW, Tavill AS. Diagnosis and management of hemochromatosis: 2011 Practice Guideline by the American Association for the Study of Liver Diseases. Hepatology. 2011;54(1):328–43. Practice guidelines for management of hemochromatosis. Discusses screening in individuals with liver disease. PubMedCentralPubMedCrossRefGoogle Scholar
  28. 28.
    Ford ES, Cogswell ME. Diabetes and serum ferritin concentration among U.S. adults. Diabetes Care. 1999;22(12):1978–83.PubMedCrossRefGoogle Scholar
  29. 29.
    Cheung CL, Cheung TT, Lam KS, Cheung BM. High ferritin and low transferrin saturation are associated with pre-diabetes among a national representative sample of U.S. adults. Clin Nutr. 2013;32(6):1055–60.PubMedCrossRefGoogle Scholar
  30. 30.
    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):711–7.Google Scholar
  31. 31.
    Aregbesola A, Voutilainen S, Virtanen JK, Mursu J, Tuomainen TP. Body iron stores and the risk of type 2 diabetes in middle-aged men. Eur J Endocrinol. 2013;169(2):247–53.PubMedCrossRefGoogle Scholar
  32. 32.
    Zhao Z, Li S, Liu G, Yan F, Ma X, Huang Z, 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.PubMedCentralPubMedCrossRefGoogle Scholar
  33. 33.
    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):308–18.PubMedCrossRefGoogle Scholar
  34. 34.
    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):332–9.PubMedCrossRefGoogle Scholar
  35. 35.
    Afkhami-Ardekani M, Rashidi M. Iron status in women with and without gestational diabetes mellitus. J Diabetes Complicat. 2009;23(3):194–8.PubMedCrossRefGoogle Scholar
  36. 36.
    Sharifi F, Nasab NM, Zadeh HJ. Elevated serum ferritin concentrations in prediabetic subjects. Diabetes Vasc Dis Res. 2008;5(1):15–8.CrossRefGoogle Scholar
  37. 37.
    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.PubMedCentralPubMedCrossRefGoogle Scholar
  38. 38.
    Rajpathak S, Ma J, Manson J, Willett WC, Hu FB. Iron intake and the risk of type 2 diabetes in women: a prospective cohort study. Diabetes Care. 2006;29(6):1370–6.PubMedCrossRefGoogle Scholar
  39. 39.
    Lee DH, Folsom AR, Jacobs Jr DR. Dietary iron intake and Type 2 diabetes incidence in postmenopausal women: the Iowa Women's Health Study. Diabetologia. 2004;47(2):185–94.PubMedCrossRefGoogle Scholar
  40. 40.
    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):671–81.PubMedCrossRefGoogle Scholar
  41. 41.
    Borgna-Pignatti C, Rugolotto S, De Stefano P, Piga A, Di Gregorio F, Gamberini MR, et al. Survival and disease complications in thalassemia major. Ann N Y Acad Sci. 1998;850:227–31.PubMedCrossRefGoogle Scholar
  42. 42.
    Gamberini MR, De Sanctis V, Gilli G. Hypogonadism, diabetes mellitus, hypothyroidism, hypoparathyroidism: incidence and prevalence related to iron overload and chelation therapy in patients with thalassaemia major followed from 1980 to 2007 in the Ferrara Centre. Pediatr Endocrinol Rev. 2008;6 Suppl 1:158–69.PubMedGoogle Scholar
  43. 43.
    Hramiak IM, Finegood DT, Adams PC. Factors affecting glucose tolerance in hereditary hemochromatosis. Clin Invest Med. 1997;20(2):110–8.PubMedGoogle Scholar
  44. 44.
    Kishimoto M, Endo H, Hagiwara S, Miwa A, Noda M. Immunohistochemical findings in the pancreatic islets of a patient with transfusional iron overload and diabetes: case report. J Med Invest. 2010;57(3–4):345–9.PubMedCrossRefGoogle Scholar
  45. 45.•
    Cooksey RC, Jouihan HA, Ajioka RS, Hazel MW, Jones DL, Kushner JP, et al. Oxidative stress, beta-cell apoptosis, and decreased insulin secretory capacity in mouse models of hemochromatosis. Endocrinology. 2004;145(11):5305–12. Comprehensive study of glucose homeostasis and failure of insulin secretion in a mouse model of HFE hemochromatosis. PubMedCrossRefGoogle Scholar
  46. 46.
    Jouihan HA, Cobine PA, Cooksey RC, Hoagland EA, Boudina S, Abel ED, et al. Iron-mediated inhibition of mitochondrial manganese uptake mediates mitochondrial dysfunction in a mouse model of hemochromatosis. Mol Med. 2008;14(3–4):98–108.PubMedCentralPubMedGoogle Scholar
  47. 47.
    Fernández-Real JM, López-Bermejo A, Ricart W. Cross-talk between iron metabolism and diabetes. Diabetes. 2002;51(8):2348–54.PubMedCrossRefGoogle Scholar
  48. 48.
    Kubota N, Terauchi Y, Yamauchi T, Kubota T, Moroi M, Matsui J, et al. Disruption of adiponectin causes insulin resistance and neointimal formation. J Biol Chem. 2002;277(29):25863–6.PubMedCrossRefGoogle Scholar
  49. 49.
    Gabrielsen JS, Gao Y, Simcox JA, Huang J, Thorup D, Jones D, et al. Adipocyte iron regulates adiponectin and insulin sensitivity. J Clin Invest. 2012;122(10):3529–40.PubMedCentralPubMedCrossRefGoogle Scholar
  50. 50.
    Fargnoli JL, Fung TT, Olenczuk DM, Chamberland JP, Hu FB, Mantzoros CS. Adherence to healthy eating patterns is associated with higher circulating total and high-molecular-weight adiponectin and lower resistin concentrations in women from the Nurses' Health Study. Am J Clin Nutr. 2008;88(5):1213–24.PubMedGoogle Scholar
  51. 51.
    Forouhi NG, Harding AH, Allison M, Sandhu MS, Welch A, Luben R, et al. Elevated serum ferritin levels predict new-onset type 2 diabetes: results from the EPIC-Norfolk prospective study. Diabetologia. 2007;50(5):949–56.PubMedCrossRefGoogle Scholar
  52. 52.
    Mojiminiyi OA, Marouf R, Abdella NA. Body iron stores in relation to the metabolic syndrome, glycemic control and complications in female patients with type 2 diabetes. Nutr Metab Cardiovasc Dis. 2008;18(8):559–66.PubMedCrossRefGoogle Scholar
  53. 53.
    Abraham D, Rogers J, Gault P, Kushner JP, McClain DA. Increased insulin secretory capacity but decreased insulin sensitivity after correction of iron overload by phlebotomy in hereditary haemochromatosis. Diabetologia. 2006;49(11):2546–51.PubMedCrossRefGoogle Scholar
  54. 54.
    Hatunic M, Finucane FM, Norris S, Pacini G, Nolan JJ. Glucose metabolism after normalization of markers of iron overload by venesection in subjects with hereditary hemochromatosis. Metabolism. 2010;59(12):1811–5.PubMedCrossRefGoogle Scholar
  55. 55.
    Equitani F, Fernandez-Real JM, Menichella G, Koch M, Calvani M, Nobili V, et al. Bloodletting ameliorates insulin sensitivity and secretion in parallel to reducing liver iron in carriers of HFE gene mutations. Diabetes Care. 2008;31(1):3–8.PubMedCrossRefGoogle Scholar
  56. 56.
    Valenti L, Dongiovanni P, Fracanzani AL, Fargion S. Bloodletting ameliorates insulin sensitivity and secretion in parallel to reducing liver iron in carriers of HFE gene mutations: response to Equitani et al. Diabetes Care. 2008;31(3):e18.PubMedCrossRefGoogle Scholar
  57. 57.
    Peterlin B, Globocnik Petrovic M, Makuc J, Hawlina M, Petrovic D. A hemochromatosis-causing mutation C282Y is a risk factor for proliferative diabetic retinopathy in Caucasians with type 2 diabetes. J Hum Genet. 2003;48(12):646–9.PubMedCrossRefGoogle Scholar
  58. 58.
    Oliva R, Novials A, Sánchez M, Villa M, Ingelmo M, Recasens M, et al. The HFE gene is associated to an earlier age of onset and to the presence of diabetic nephropathy in diabetes mellitus type 2. Endocrine. 2004;24(2):111–4.PubMedCrossRefGoogle Scholar
  59. 59.
    Davis TM, Beilby J, Davis WA, Olynyk JK, Jeffrey GP, Rossi E, et al. Prevalence, characteristics, and prognostic significance of HFE gene mutations in type 2 diabetes: the Fremantle Diabetes Study. Diabetes Care. 2008;31(9):1795–801.PubMedCentralPubMedCrossRefGoogle Scholar
  60. 60.
    Simcox JA, McClain DA. Iron and diabetes risk. Cell Metab. 2013;17:329–41. 720.PubMedCentralPubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  1. 1.Department of Medicine, Division of EndocrinologyUniversity of UtahSalt Lake CityUSA

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