Skip to main content

Advertisement

Log in

Effects of Acute Dietary Iron Overload in Pigs (Sus scrofa) with Induced Type 2 Diabetes Mellitus

  • Published:
Biological Trace Element Research Aims and scope Submit manuscript

Abstract

Epidemiological studies have reported an association between high iron (Fe) levels and elevated risk of developing type 2 diabetes mellitus (T2D). It is believed that the formation of Fe-catalyzed hydroxyl radicals may contribute to the development of diabetes. Our goal was to determine the effect of a diet with a high Fe content on type 2 diabetic pigs. Four groups of piglets were studied: (1) control group, basal diet; (2) Fe group, basal diet with 3,000 ppm ferrous sulfate; (3) diabetic group (streptozotocin-induced type 2 diabetes) with basal diet; (4) diabetic/Fe group, diabetic animals/3,000 ppm ferrous sulfate. For 2 months, biochemical and hematological parameters were evaluated. Tissue samples of liver and duodenum were obtained to determine mRNA relative abundance of DMT1, ferroportin (Fpn), ferritin (Fn), hepcidin (Hpc), and transferrin receptor by qRT-PCR. Fe group presented increased levels of hematological (erythrocytes, hematocrit, and hemoglobin) and iron parameters. Diabetic/Fe group showed similar behavior as Fe group but in lesser extent. The relative abundance of different genes in the four study groups yielded a different expression pattern. DMT1 showed a lower expression in the two iron groups compared with control and diabetic animals, and Hpc showed an increased on its expression in Fe and diabetic/Fe groups. Diabetic/Fe group presents greater expression of Fn and Fpn. These results suggest that there is an interaction between Fe nutrition, inflammation, and oxidative stress in the diabetes development.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Puntarulo S (2005) Review: iron, oxidative stress and human health. Mol Asp Med 26:299–312

    Article  CAS  Google Scholar 

  2. Dymock IW, Cassar J, Pyke DA, Oakley WG, Williams R (1972) Observations on the pathogenesis, complications and treatment of diabetes in 115 cases of haemochromatosis. Am J Med 52(2):203–210

    Article  CAS  PubMed  Google Scholar 

  3. Niederau C, Fischer R, Purschel A, Stremmel W, Haussinger D, Strohmeyer G (1996) Long-term survival in patients with hereditary hemochromatosis. Gastroenterology 110(4):1107–1119

    Article  CAS  PubMed  Google Scholar 

  4. Feder JN, Gnirke A, Thomas W, Tsuchihashi Z, Ruddy DA, Basava A (1996) A novel MHC class I-like gene is mutated in patients with hereditary haemochromatosis. Nat Genet 13:399–408

    Article  CAS  PubMed  Google Scholar 

  5. Zhou XY, Tomatsu S, Fleming RE, Parkkila S, Waheed A, Jiang J, Fei Y, Brunt EM, Ruddy DA, Prass CE, Schatzman RC, O'Neill R, Britton RS, Bacon BR, Sly WS (1998) HFE gene knockout produces mouse model of hereditary hemochromatosis. Proc Natl Acad Sci U S A 95(5):2492–2497

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  6. Witte D, Crosby W, Edwards C, Fairbanks V, Mitros F (1996) Practice guideline development task force of the college of American pathologists. Hereditary Hemochromatosis. Clin Chim Acta 245:139–200

    Article  CAS  PubMed  Google Scholar 

  7. Fernández-Real JM, López-Bermejo A, Ricart W (2005) Iron stores, blood donations, and insulin sensitivity and secretion. Clin Chem 51(7):1201–1205

    Article  PubMed  Google Scholar 

  8. Fernández-Real JM, Peñarroja G, Castro A, García-Bragado F, Hernández-Aguado I, Ricart W (2002) Blood letting in high-ferritin type 2 diabetes: effects on insulin sensitivity and beta-cell function. Diabetes 51(4):1000–1004

    Article  PubMed  Google Scholar 

  9. Salonen J, Tuomainen TP, Nyyssônen K, Lakka HM, Punnonen K (1998) Relation between iron stores and non-insulin dependent diabetes in men: case–control study. BMJ 317(7160):727

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  10. Jiang R, Manson J, Meigs J, Ma J, Rifai N, Hu F (2004) Body iron stores in relation to risk of type-2 diabetes in apparently healthy women. JAMA 291(6):711–717

    Article  CAS  PubMed  Google Scholar 

  11. Jiang R, Ma J, Ascherio A, Stampfer M, Willett W, Hu F (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

    CAS  PubMed  Google Scholar 

  12. Shi Z, Hu X, Yuan PX, Meyer H, Holmboe-Ottesen G (2006) Association between serum ferritin, hemoglobin, iron intake, and diabetes in adults in Jiangsu, China. Diabetes Care 29(8):1878–1883

    Article  CAS  PubMed  Google Scholar 

  13. Choi SW, Benzie IF, Ma SW, Strain JJ, Hannigan SW (2008) Acute hyperglycemia and oxidative stress: direct cause and effect? Free Radic Biol Med 44:1217–1231

    Article  CAS  PubMed  Google Scholar 

  14. Ferrannini E (2000) Insulin resistance, iron, and the liver. Lancet 355:2181–2182

    Article  CAS  PubMed  Google Scholar 

  15. Green A, Basile R, Rumberger JM (2006) Transferrin and iron induce insulin resistance of glucose transport in adipocytes. Metabolism 55:1042–1045

    Article  CAS  PubMed  Google Scholar 

  16. Tuomainen TP, Nyyssonen K, Salonen R, Tervahauta A, Korpela H, Lakka T, Kaplan GA, Salonen JT (1997) Body iron stores are associated with serum insulin and blood glucose concentrations. Population study in 1013 eastern Finnish men. Diabetes Care 20:426–428

    Article  CAS  PubMed  Google Scholar 

  17. Rajpathak S, Crandall JP, Wylie-Rossett J, Kabbat GJ, Rohan TE, Hu FB (2009) The role of iron in type-2 diabetes. Biochim Byophys Acta 1790:671–681

    Article  CAS  Google Scholar 

  18. Wilson JG, Lindquist JH, Grambow SC, Crook ED, Maher JF (2003) Potential role of increased iron stores in diabetes. Am J Med Sci 325:332–339

    Article  PubMed  Google Scholar 

  19. Furugouri K (1972) Effect of elevated dietary levels of iron on iron store in liver, some blood constituents and phosphorus deficiency in young swine. J Anim Sci 34:573–577

    CAS  PubMed  Google Scholar 

  20. Hansen S, Trakooljul N, Liu HC, Moeser A, Spears J (2009) Iron transporters are differentially regulated by dietary iron, and modifications are associated with changes in manganese metabolism in young pigs. J Nutr 139(8):1474–1479

    Article  CAS  PubMed  Google Scholar 

  21. Hansen S, Trakooljul N, Spears J, Liu HC (2010) Age and dietary iron affect expression of genes involved in iron acquisition and homeostasis in young pigs. J Nutr 140:271–277

    Article  CAS  PubMed  Google Scholar 

  22. Koopmans S, Mroz Z, Dekker R, Corbijn H, Ackermans M, Sauerwein H (2006) Association of insulin resistance with hyperglycemia in streptozotocin-diabetic pigs: effects of metformin at isoenergetic feeding in a type-2-like diabetic pig model. Metab Clin Exp 55(7):960–971

    Article  CAS  PubMed  Google Scholar 

  23. Pfaffl MW (2001) A new mathematical model for relative quantification in real-time RT-PCR. Nucleic Acids Res 29(9):e45

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  24. Dixon J, Stoops J, Parker J, Laughlin M, Weisman G, Sturek M (1999) Dyslipidemia and vascular dysfunction in diabetic pigs fed an atherogenic diet. Arterioscler Thromb Vasc Biol 19(12):2981–2992

    Article  CAS  PubMed  Google Scholar 

  25. Gunshin H, Mackenzie B, Berger U, Gunshin Y, Romero M, Boron W, Nussberger S, Gollan J, Hediger M (1997) Cloning and characterization of a mammalian proton-coupled metal-iron transporter. Nature 388:482–488

    Article  CAS  PubMed  Google Scholar 

  26. Yeh KY, Yeh M, Watkins JA, Rodriguez-Paris J, Glass J (2000) Dietary iron induces rapid changes in rat intestinal divalent metal transporter expression. Am J Physiol Gastrointest Liver Physiol 279(5):G1070–G1079

    CAS  PubMed  Google Scholar 

  27. Gunshin H, Allerson CR, Polycarpou-Schwarz M, Rofts A, Rogers JT, Kishi F, Hentze MW, Rouault TA, Andrews NC, Hediger MA (2001) Iron-dependent regulation of the divalent metal ion transporter. FEBS Lett 509(2):309–316

    Article  CAS  PubMed  Google Scholar 

  28. Garrick MD, Dolan KG, Horbinski C, Ghio AJ, Higgins D, Porubcin M, Moore EG, Hainsworth LN, Umbreit JN, Conrad ME, Feng L, Lis A, Roth JA, Singleton S, Garrick LM (2003) DMT1: a mammalian transporter for multiple metals. Biometals 16(1):41–54

    Article  CAS  PubMed  Google Scholar 

  29. Herbison CE, Thorstensen K, Chua AC, Graham RM, Leedman P, Olynyk JK, Trinder D (2009) The role of transferrin receptor 1 and 2 in transferrin-bound iron uptake in human hepatoma cells. Am J Physiol Cell Physiol 297(6):C1567–C1575

    Article  CAS  PubMed  Google Scholar 

  30. Silva M, de Brito Magalhães CL, de Paula Oliveira R, Silva ME, Pedrosa ML (2012) Differential expression of iron metabolism proteins in diabetic and diabetic iron-supplemented rat liver. J Biochem Mol Toxicol 26(3):123–129

    Article  CAS  PubMed  Google Scholar 

  31. Hentze MW, Rouault TA, Caughman SW, Dancis A, Harford JB, Klausner RD (1987) A cis-acting element is necessary and sufficient for translational regulation of human ferritin expression in response to iron. Proc Natl Acad Sci USA 84(19):6730–6734

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  32. Han J, Day JR, Connor JR, Beard JL (2002) H and L ferritin subunit mRNA expression differs in brains of control and iron-deficient rats. J Nutr 132(9):2769–2774

    CAS  PubMed  Google Scholar 

  33. Wang W, Knovich MA, Coffman LG, Torti FM, Torti SV (2010) Serum ferritin: past, present and future. Biochim Biophys Acta 1800(8):760–769

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  34. Rogers JT (1996) Ferritin translation by interleukin-1and interleukin-6: the role of sequences upstream of the start codons of the heavy and light subunit genes. Blood 87(6):2525–2537

    CAS  PubMed  Google Scholar 

  35. Smirnov IM, Bailey K, Flowers CH, Garrigues NW, Wesselius LJ (1991) Effects of TNF-alpha and IL-1beta on iron metabolism by A549 cells and influence on cytotoxicity. Am J Physiol 277(2 Pt 1):L257–L263

    Google Scholar 

  36. Kalantar-Zadeh K, Kalantar-Zadeh K, Lee GH (2006) The fascinating but deceptive ferritin: to measure it or not to measure it in chronic kidney disease? Clin J Am Soc Nephrol 1(Suppl):S9–S18

    Article  CAS  PubMed  Google Scholar 

  37. Torti FM, Torti SV (2002) Regulation of ferritin genes and protein. Blood 99(10):3505–3516

    Article  CAS  PubMed  Google Scholar 

  38. Pang JH, Jiang MJ, Chen YL, Wang FW, Wang DL, Chu SH, Chau LY (1996) Increased ferritin gene expression in atherosclerotic lesions. J Clin Investig 97(10):2204–2212

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  39. Heller RA, Schena M, Chai A, Shalon D, Bedilion T, Gilmore J, Woolley DE, Davis RW (1997) Discovery and analysis of inflammatory disease-related genes using cDNA microarrays. Proc Natl Acad Sci USA 94(6):2150–2155

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  40. Watt R (2011) The many faces of the octahedral ferritin protein. Biometals 24:489–500

    Article  CAS  PubMed  Google Scholar 

  41. Mena NP, Esparza A, Tapia V, Valdés P, Núñez MT (2008) Hepcidin inhibits apical iron uptake in intestinal cells. Am J Physiol Gastrointest Liver Physiol 294(1):G192–G198

    Article  CAS  PubMed  Google Scholar 

  42. Ganz T (2003) Hepcidin, a key regulator of iron metabolism and mediator of anemia of inflammation. Blood 102(3):783–788

    Article  CAS  PubMed  Google Scholar 

  43. Nemeth E, Rivera S, Gabayan V, Keller C, Taudorf S, Pedersen BK, Ganz T (2004) IL-6 mediates hypoferremia of inflammation by inducing the synthesis of the iron regulatory hormone hepcidin. J Clin Investig 113(9):1271–1276

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  44. Jiang F, Sun ZZ, Tang YT, Xu C, Jiao XY (2011) Hepcidin expression and iron parameters change in type 2 diabetic patients. Diabetes Res Clin Pract 93(1):43–48

    Article  CAS  PubMed  Google Scholar 

  45. Kulaksiz H, Theilig F, Bachmann S, Gehrke SG, Rost D, Janetzko A, Cetin Y, Stremmel W (2005) The iron-regulatory peptide hormone hepcidin: expression and cellular localization in the mammalian kidney. J Endocrinol 184(2):361–370

    Article  CAS  PubMed  Google Scholar 

  46. Kulaksiz H, Fein E, Redecker P, Stremmel W, Adler G, Cetin Y (2008) Pancreatic beta-cells express hepcidin, an iron-uptake regulatory peptide. J Endocrinol 197(2):241–249

    Article  CAS  PubMed  Google Scholar 

  47. Frazier MD, Mamo LB, Ghio AJ, Turi JL (2011) Hepcidin expression in human airway epithelial cells is regulated by interferon-γ. Respir Res 12:100

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  48. Ganz T, Nemeth E (2012) Hepcidin and iron homeostasis. Biochim Biophys Acta 1823(9):1434–1443

    Article  CAS  PubMed  Google Scholar 

  49. Chung B, Chaston T, Marks J, Srai SK, Sharp PA (2009) Hepcidin decreases iron transporter expression in vivo in mouse duodenum and spleen and in vitro in THP 1 macrophages and intestinal Caco-2 cells. J Nutr 139(8):1457–1462

    Article  CAS  PubMed  Google Scholar 

  50. Khan ZA, Barbin YP, Cukiernik M, Adams PC, Chakrabarti S (2004) Heme-oxygenase-mediated iron accumulation in the liver. Can J Physiol Pharmacol 82(7):448–456

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

We thank Angelica Letelier and Amaya Oyarzún for technical assistance, and Maureen Middleton for helping with care and management of animals. This project was funded in part by (1) Comisión Nacional de Investigación Científica y Tecnológica (CONICYT)—Scholarship for Doctoral Thesis 2010; (2) Programa de Investigación Domeyko en Salud, Universidad de Chile—Scholarship Doctoral Thesis 2010; and (3) FONDECYT Grant 1110080 to MA

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to M. Arredondo.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Espinoza, A., Morales, S. & Arredondo, M. Effects of Acute Dietary Iron Overload in Pigs (Sus scrofa) with Induced Type 2 Diabetes Mellitus. Biol Trace Elem Res 158, 342–352 (2014). https://doi.org/10.1007/s12011-014-9944-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12011-014-9944-4

Keywords

Navigation