Biological Trace Element Research

, Volume 189, Issue 1, pp 194–200 | Cite as

Dietary Iron Modulates Glucose and Lipid Homeostasis in Diabetic Mice

  • Wan Ma
  • Yunfei Feng
  • Li Jia
  • Shuhui Li
  • Jiahui Li
  • Zhenjie Wang
  • Xiaoyun Chen
  • Huahua DuEmail author


Imbalance of iron homeostasis has been involved in clinical courses of metabolic diseases such as type 2 diabetes mellitus, obesity, and nonalcoholic fatty liver, through mechanisms not yet fully elucidated. Herein, we evaluated the effect of dietary iron on the development of diabetic syndromes in genetically obese db/db mice. Mice (aged 7 weeks) were fed with high-iron (HI) diets (1000 mg/kg chow) or low-iron (LI) diets (12 mg/kg) for 9 weeks. HI diets increased hepatic iron threefold and led to fourfold higher mRNA levels of hepcidin. HI also induced a 60% increase in fasting glucose due to insulin resistance, as confirmed by decreased hepatic glycogen deposition eightfold and a 21% decrease of serum adiponectin level. HI-fed mice had lower visceral adipose tissue mass estimated by epididymal and inguinal fat pad, associated with iron accumulation and smaller size of adipocytes. Gene expression analysis of liver showed that HI diet upregulated gluconeogenesis and downregulated lipogenesis. These results suggested that excess dietary iron leads to reduced mass, increased fasting glucose, decreased adiponectin level, and enhancement of insulin resistance, which indicated a multifactorial role of excess iron in the development of diabetes in the setting of obesity.


Dietary iron Diabetic mice Glycolipid metabolism Type 2 diabetes mellitus Obesity 


Funding Information

This study was supported by the Natural Science Foundation of Zhejiang province of China (LR16C170001), National Natural Science Foundation of China (31572411), and Major Science and Technology Project of Zhejiang province (2015C02022).

Compliance with Ethical Standards

All experimental procedures were approved by the institutional ethics committee of Zhejiang University.

Conflict of Interest

The authors declare that they have no conflict of interest.


  1. 1.
    Gozzelino R, Arosio P (2016) Iron homeostasis in health and disease. Int J Mol Sci 17:130. CrossRefGoogle Scholar
  2. 2.
    Clark SF (2009) Iron deficiency anemia: diagnosis and management. Curr Opin Gastroenterol 25:122–128. CrossRefGoogle Scholar
  3. 3.
    Hentze MW, Muckenthaler MU, Galy B, Camaschella C (2010) Two to tango: regulation of mammalian iron metabolism. Cell 142:24–38. CrossRefGoogle Scholar
  4. 4.
    Fernández-Real JM, López-Bermejo A, Ricart W (2002) Cross-talk between iron metabolism and diabetes. Diabetes 51:2348–2354. CrossRefGoogle Scholar
  5. 5.
    Wang X, Fang X, Wang F (2015) Pleiotropic actions of iron balance in diabetes mellitus. Rev Endocr Metab Disord 16:15–23. CrossRefGoogle Scholar
  6. 6.
    Stechemesser L, Eder SK, Wagner A, Patsch W, Feldman A, Strasser M et al (2017) Metabolomic profiling identifies potential pathways involved in the interaction of iron homeostasis with glucose metabolism. Mol Metab 6:38–47. CrossRefGoogle Scholar
  7. 7.
    Altamura S, Kopf S, Schmidt J, Müdder K, da Silva AR, Nawroth P, Muckenthaler MU (2017) Uncoupled iron homeostasis in type 2 diabetes mellitus. J Mol Med (Berl) 95:1387–1398. CrossRefGoogle Scholar
  8. 8.
    Ford ES, Cogswell ME (1999) Diabetes and serum ferritin concentration among U.S. adults. Diabetes Care 22:1978–1983. CrossRefGoogle Scholar
  9. 9.
    McClain DA, Abraham D, Rogers J, Brady R, Gault P, Ajioka R, Kushner JP (2006) High prevalence of abnormal glucose homeostasis secondary to decreased insulin secretion in individuals with hereditary haemochromatosis. Diabetologia 49:1661–1669. CrossRefGoogle Scholar
  10. 10.
    Huang J, Jones D, Luo B, Sanderson M, Soto J, Abel ED et al (2011) Iron overload and diabetes risk: a shift from glucose to fatty acid oxidation and increased hepatic glucose production in a mouse model of hereditary hemochromatosis. Diabetes 60:80–87. CrossRefGoogle Scholar
  11. 11.
    Hatunic M, Finucane FM, Brennan AM, Norris S, Pacini G, Nolan JJ (2010) Effect of iron overload on glucose metabolism in patients with hereditary hemochromatosis. Metabolism 59:380–384. CrossRefGoogle Scholar
  12. 12.
    Facchini FS (1998) Effect of phlebotomy on plasma glucose and insulin concentrations. Diabetes Care 21:2190–2191. CrossRefGoogle Scholar
  13. 13.
    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 51:1000–1004. CrossRefGoogle Scholar
  14. 14.
    Cooksey RC, Jones D, Gabrielsen S, Huang J, Simcox JA, Luo B, Soesanto Y, Rienhoff H, Abel ED, McClain DA (2010) Dietary iron restriction or iron chelation protects from diabetes and loss of beta-cell function in the obese (ob/ob lep-/-) mouse. Am J Physiol Endocrinol Metab 298:1236–1243. CrossRefGoogle Scholar
  15. 15.
    Pollak Y, Mechlovich D, Amit T, Bar-Am O, Manov I, Mandel SA, Weinreb O, Meyron-Holtz EG, Iancu TC, Youdim MB (2013) Effects of novel neuroprotective and neurorestorative multifunctional drugs on iron chelation and glucose metabolism. J Neural Transm 120:37–48. CrossRefGoogle Scholar
  16. 16.
    Pinhas-Hamiel O, Newfield RS, Koren I, Agmon A, Lilos P, Phillip M (2003) Greater prevalence of iron deficiency in overweight and obese children and adolescents. Int J Obes Relat Metab Disord 27:416–418. CrossRefGoogle Scholar
  17. 17.
    Davis MR, Rendina E, Peterson SK, Lucas EA, Smith BJ, Clarke SL (2012) Enhanced expression of lipogenic genes may contribute to hyperglycemia and alterations in plasma lipids in response to dietary iron deficiency. Genes Nutr 7:415–425. CrossRefGoogle Scholar
  18. 18.
    McClung JP, Andersen NE, Tarr TN, Stahl CH, Young AJ (2008) Physical activity prevents augmented body fat accretion in moderately iron-deficient rats. J Nutr 138:1293–1297. CrossRefGoogle Scholar
  19. 19.
    Xue H, Chen D, Zhong YK, Zhou ZD, Fang SX, Li MY, Guo C (2016) Deferoxamine ameliorates hepatosteatosis via several mechanisms in ob/ob mice. Ann N Y Acad Sci 1375:52–65. CrossRefGoogle Scholar
  20. 20.
    Fernández-Real JM, Manco M (2014) Effects of iron overload on chronic metabolic diseases. Lancet Diabetes Endocrinol 2:513–526. CrossRefGoogle Scholar
  21. 21.
    Sharabi K, Tavares CD, Rines AK, Puigserver P (2015) Molecular pathophysiology of hepatic glucose production. Mol Asp Med 46:21–33. CrossRefGoogle Scholar
  22. 22.
    Wallia A, Molitch ME (2014) Insulin therapy for type 2 diabetes mellitus. Jama 311:2315–2325. CrossRefGoogle Scholar
  23. 23.
    Cummings BP, Bremer AA, Kieffer TJ, D'Alessio D, Havel PJ (2013) Investigation of the mechanisms contributing to the compensatory increase in insulin secretion during dexamethasone-induced insulin resistance in rhesus macaques. J Endocrinol 216:207–215. CrossRefGoogle Scholar
  24. 24.
    Jouihan HA, Cobine PA, Cooksey RC, Hoagland EA, Boudina S, Abel ED, Winge DR, McClain DA (2008) Iron-mediated inhibition of mitochondrial manganese uptake mediates mitochondrial dysfunction in a mouse model of hemochromatosis. Mol Med 14:98–108. CrossRefGoogle Scholar
  25. 25.
    Backe MB, Moen IW, Ellervik C, Hansen JB, Mandrup-Poulsen T (2016) Iron regulation of pancreatic beta-cell functions and oxidative stress. Annu Rev Nutr 36:241–273. CrossRefGoogle Scholar
  26. 26.
    Handa P, Morgan-Stevenson V, Maliken BD, Nelson JE, Washington S, Westerman M, Yeh MM, Kowdley KV (2016) Iron overload results in oxidative stress, immune cell activation and ballooning injury leading to nonalcoholic steatohepatitis in genetically obese mice. Am J Physiol Gastrointest Liver Physiol 310:G117–G127. CrossRefGoogle Scholar
  27. 27.
    Gabrielsen JS, Gao Y, Simcox JA, Huang J, Thorup D, Jones D et al (2012) Adipocyte iron regulates adiponectin and insulin sensitivity. J Clin Invest 122:3529–3540. CrossRefGoogle Scholar
  28. 28.
    Weyer C, Funahashi T, Tanaka S, Hotta K, Matsuzawa Y, Pratley RE, Tataranni PA (2001) Hypoadiponectinemia in obesity and type 2 diabetes: close association with insulin resistance and hyperinsulinemia. J Clin Endocrinol Metab 86:1930–1935. CrossRefGoogle Scholar
  29. 29.
    Kubota N, Terauchi Y, Yamauchi T, Kubota T, Moroi M, Matsui J et al (2002) Disruption of adiponectin causes insulin resistance and neointimal formation. J Biol Chem 277:25863–25866. CrossRefGoogle Scholar
  30. 30.
    Koch RO, Zoller H, Theuri I, Obrist P, Egg G, Strohmayer W, Vogel W, Weiss G (2003) Distribution of DMT1 within the human glandular system. Histol Histopathol 18:1095–1101. Google Scholar
  31. 31.
    Hansen JB, Tonnesen MF, Madsen AN, Hagedorn PH, Friberg J, Grunnet LG et al (2012) Divalent metal transporter 1 regulates iron-mediated ROS and pancreatic β cell fate in response to cytokines. Cell Metab 16:449–461. CrossRefGoogle Scholar
  32. 32.
    Pietrangelo A (2009) Iron in NASH, chronic liver diseases and HCC: how much iron is too much? J Hepatol 50:249–251. CrossRefGoogle Scholar
  33. 33.
    Feldman A, Aigner E, Weghuber D, Paulmichl K (2015) The potential role of iron and copper in pediatric obesity and nonalcoholic fatty liver disease. Biomed Res Int 2015(287401):1–7. CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Wan Ma
    • 1
    • 2
    • 3
  • Yunfei Feng
    • 4
  • Li Jia
    • 1
    • 2
    • 3
  • Shuhui Li
    • 1
    • 2
    • 3
  • Jiahui Li
    • 1
    • 2
    • 3
  • Zhenjie Wang
    • 1
    • 2
    • 3
  • Xiaoyun Chen
    • 1
    • 2
    • 3
  • Huahua Du
    • 1
    • 2
    • 3
    Email author
  1. 1.Key Laboratory of Animal Nutrition and Feed Science (Eastern of China), Ministry of AgricultureZhejiang UniversityHangzhouChina
  2. 2.Key Laboratory of Animal Feed and Nutrition of Zhejiang ProvinceZhejiang UniversityHangzhouChina
  3. 3.College of Animal ScienceZhejiang UniversityHangzhouChina
  4. 4.Department of Endocrinology and MetabolismThe First Affiliated Hospital of Medical School of Zhejiang UniversityHangzhouChina

Personalised recommendations