Biological Trace Element Research

, Volume 166, Issue 1, pp 7–12 | Cite as

Is the Pharmacological Mode of Action of Chromium(III) as a Second Messenger?

  • John B. VincentEmail author


Although recent studies have shown that chromium (as the trivalent ion) is not an essential trace element, it has been demonstrated to generate beneficial effects at pharmacologically relevant doses on insulin sensitivity and cholesterol levels of rodent models of insulin insensitivity, including models of type 2 diabetes. The mode of action of Cr(III) at a molecular level is still an area of active debate; however, the movement of Cr(III) in the body, particularly in response to changes in insulin concentration, suggests that Cr(III) could act as a second messenger, amplifying insulin signaling. The evidence for the pharmacological mechanism of Cr(III)’s ability to increase insulin sensitivity by acting as a second messenger is reviewed, and proposals for testing this hypothesis are described.


Chromium Second messenger Transferrin Insulin Low-molecular-weight chromium-binding substance 


  1. 1.
    Vincent JB (2013) The bioinorganic chemistry of chromium. Wiley, ChichesterGoogle Scholar
  2. 2.
    EFSA Panel on Dietetic Products, Nutrition, and Allergies (2014) Scientific opinion on dietary reference values for chromium. EFSA J 12:3845Google Scholar
  3. 3.
    Vincent JB (2014) Is chromium pharmacologically relevant? J Trace Elem Med Biol 28:397–405PubMedCrossRefGoogle Scholar
  4. 4.
    Colomer J, Means AR (2007) Physiological roles of Ca2+/CaM-dependent protein kinase cascade in health and disease. Subcell Biochem 45:169–214PubMedGoogle Scholar
  5. 5.
    Aisen P, Aasa R, Redfield AG (1969) The chromium, manganese, and cobalt complexes of transferrin. J Biol Chem 244:4628–4633PubMedGoogle Scholar
  6. 6.
    Tan AT, Woodworth RC (1969) Ultraviolet difference spectral studies of conalbumin complexes with transition metal ions. Biochemistry 8:3711–3716PubMedCrossRefGoogle Scholar
  7. 7.
    Harris DC (1977) Different metal-binding properties of the two sites of human transferrin. Biochemistry 16:560–564PubMedCrossRefGoogle Scholar
  8. 8.
    Ainscough EW, Brodie AM, Plowman JE, Bloor SJ, Sanders Loehr J, Loehr TM (1980) Studies on human lactoferrin by electron paramagnetic resonance, fluorescence, and resonance Raman spectroscopy. Biochemistry 19:4072–4079PubMedCrossRefGoogle Scholar
  9. 9.
    Ainscough EW, Brodie AM, Plowman JE (1979) The chromium, manganese, cobalt, and copper complexes of human lactoferrin. Inorg Chim Acta 33:149–153CrossRefGoogle Scholar
  10. 10.
    Moshtaghie AA, Ani M, Bazrafshan MR (1992) Comparative binding study of aluminum and chromium to human transferrin: effect of iron. Biol Trace Elem Res 32:39–46PubMedCrossRefGoogle Scholar
  11. 11.
    Ani M, Moshtaghie AA (1992) The effect of chromium on parameters related to iron metabolism. Biol Trace Elem Res 32:57–64PubMedCrossRefGoogle Scholar
  12. 12.
    Ge D, Wu K, Cruce AA, Bowman MK, Vincent JB (2015) Binding of trivalent chromium to serum transferrin is sufficiently rapid to be physiologically relevant. J Inorg Biochem, in pressGoogle Scholar
  13. 13.
    Sun Y, Ramirez J, Woski SA, Vincent JB (2000) The binding of trivalent chromium to low-molecular-weight chromium-binding substance (LMWCr) and the transfer of chromium from transferrin and Cr(pic)3 to LMWCr. J Biol Inorg Chem 5:129–136PubMedCrossRefGoogle Scholar
  14. 14.
    Vincent JB, Love S (2012) The binding and transport of alterative metals by transferrin. Biochim Biophys Acta 1820:362–378PubMedCrossRefGoogle Scholar
  15. 15.
    Brock JH (1985) Transferrins. In: Harrison PM (ed) Metalloproteins, 2nd edn. Macmillan, London, pp 183–262Google Scholar
  16. 16.
    Clodfelder BJ, Vincent JB (2005) The time-dependent transport of chromium in adult rats from the bloodstream to the urine. J Biol Inorg Chem 10:383–393PubMedCrossRefGoogle Scholar
  17. 17.
    Clodfelder BJ, Upchurch RG, Vincent JB (2004) A comparison of the insulin-sensitive transport of chromium in healthy and model diabetic rats. J Inorg Biochem 98:522–533PubMedCrossRefGoogle Scholar
  18. 18.
    Hopkins LL Jr, Schwarz K (1964) Chromium(III) binding to serum proteins, specifically siderophilin. Biochim Biophys Acta 90:484–491PubMedCrossRefGoogle Scholar
  19. 19.
    Kornfeld S (1969) The effect of metal attachment to human transferrin on its binding to reticulocytes. Biochim Biophys Acta 194:25–33PubMedCrossRefGoogle Scholar
  20. 20.
    Kandror KV (1999) Insulin regulation of protein traffic in rat adipose cells. J Biol Chem 274:25210–25217PubMedCrossRefGoogle Scholar
  21. 21.
    Sayato Y, Nakamuro K, Matsui S, Ando M (1980) Metabolic fate of chromium compounds. I. Comparative behavior of chromium in rat administered with Na2 51CrO4 and 51CrCl3. J Pharm Dyn 3:17–23CrossRefGoogle Scholar
  22. 22.
    Vincent J (2000) The biochemistry of chromium. J Nutr 130:715–718PubMedGoogle Scholar
  23. 23.
    Morris BW, MacNeil S, Stanley K, Gray TA, Fraser R (1993) The inter-relationship between insulin and chromium in hyperinsulinaemic euglycaemic clamps in healthy volunteers. J Endocrinol 139:339–345PubMedCrossRefGoogle Scholar
  24. 24.
    Anderson RA, Polansky MM, Bryden NA, Roginski EE, Patterson KY, Veillon C, Glinsmann W (1982) Urinary chromium excretion of human subjects: effects of chromium supplementation and glucose loading. Am J Clin Nutr 36:1184–1193PubMedGoogle Scholar
  25. 25.
    Anderson RA, Polansky MM, Bryden NA, Roginski EE, Patterson KY, Reamer DC (1982) Effect of exercise (running) on serum glucose, insulin, glucagons, and chromium excretion. Diabetes 31:212–216PubMedCrossRefGoogle Scholar
  26. 26.
    Kozlovsky AS, Moser PB, Reisner S, Anderson RA (1986) Effects of diets high in simple sugars on urinary chromium losses. Metabolism 35:515–518PubMedCrossRefGoogle Scholar
  27. 27.
    Anderson RA, Bryden NA, Polansky MM, Reiser S (1990) Urinary chromium excretion and insulinogenic properties of carbohydrates. Am J Clin Nutr 51:864–868PubMedGoogle Scholar
  28. 28.
    Morris BM, Blumsohn A, MacNeil S, Gray TA (1992) The trace element chromium—a role in glucose homeostasis. Am J Clin Nutr 55:989–991PubMedGoogle Scholar
  29. 29.
    Morris BM, Griffiths H, Kemp GJ (1988) Effect of glucose loading on concentrations of chromium in plasma and urine of healthy adults. Clin Chem 34:1114–1116PubMedGoogle Scholar
  30. 30.
    Vincent JB (2010) Chromium: celebrating 50 years as an essential element? Dalton Trans 39:3787–3794PubMedCrossRefGoogle Scholar
  31. 31.
    Vincent JB (2000) Elucidating a biological role for chromium at a molecular level. Acc Chem Res 33:503–510PubMedCrossRefGoogle Scholar
  32. 32.
    Davis CM, Vincent JB (1997) Chromium oligopeptide activates insulin receptor tyrosine kinase activity. Biochemistry 36:4382–4385PubMedCrossRefGoogle Scholar
  33. 33.
    Davis CM, Royer AC, Vincent JB (1997) Synthetic multinuclear chromium assembly activates insulin receptor tyrosine kinase activity: functional model for low-molecular-weight chromium-binding substance. Inorg Chem 36:5316–5320CrossRefGoogle Scholar
  34. 34.
    Davis CM, Sumrall KH, Vincent JB (1996) The biologically active form of chromium may activate a membrane phosphotyrosine phopshatase (PTP). Biochemistry 35:12963–12969PubMedCrossRefGoogle Scholar
  35. 35.
    Goldstein BJ, Zhu L, Hager R, Zilbering A, Sun Y, Vincent JB (2001) Enhancement of post-receptor insulin signaling by trivalent chromium in hepatoma cells is associated with differential inhibition of specific protein-tyrosine phosphatases. J Trace Elem Exp Med 14:393–404CrossRefGoogle Scholar
  36. 36.
    Chen Y, Watson HM, Gao J, Halder Sinha S, Cassady CJ, Vincent JB (2011) Characterizing the organic component of low-molecular-weight chromium-binding substance and its binding of chromium. J Nutr 141:1225–1232PubMedCentralPubMedCrossRefGoogle Scholar
  37. 37.
    Yamamoto A, Wada O, Suzuki H (1988) Purification and properties of biologically active chromium complex from bovine colostrum. J Nutr 118:39–45PubMedGoogle Scholar
  38. 38.
    Yamamoto A, Wada O, Manabe S (1989) Evidence that chromium is an essential factor for biological activity of low-molecular-weight Cr-binding substance. Biochem Biophys Res Commun 163:189–193PubMedCrossRefGoogle Scholar
  39. 39.
    Panzhinskiy E, Ren J, Vincent JB, Sreejayan N (2012) A novel endogenous chromium binding peptide augments glucose uptake and insulin signaling in myotubes. Diabetes 61(1):A412Google Scholar
  40. 40.
    Chen G, Liu P, Pattar GR, Tackett L, Bhonagiri P, Strawbridge AB, Elmendorf JS (2006) Chromium activates glucose transporter 4 trafficking and enhances insulin-stimulated glucose transport in 3T3-L1 adipocytes via a cholesterol-dependent mechanism. Mol Endocrinol 20:857–870PubMedCrossRefGoogle Scholar
  41. 41.
    Horvath EM, Tackett L, McCarthy AM, Raman P, Brozinick JT, Elmendorf JS (2008) Antidiabetogenic effects of chromium mitigate hyperinsulinemia-induced cellular insulin resistance via correction of plasma membrane cholesterol imbalance. Mol Endocrinol 22:937–950PubMedCentralPubMedCrossRefGoogle Scholar
  42. 42.
    Hua Y, Clark S, Ren J, Sreejayan N (2012) Molecular mechanisms of chromium in alleviating insulin resistance. J Nutr Biochem 23:313–319PubMedCentralPubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  1. 1.Department of ChemistryThe University of AlabamaTuscaloosaUSA

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