Abstract
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.
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References
Vincent JB (2013) The bioinorganic chemistry of chromium. Wiley, Chichester
EFSA Panel on Dietetic Products, Nutrition, and Allergies (2014) Scientific opinion on dietary reference values for chromium. EFSA J 12:3845
Vincent JB (2014) Is chromium pharmacologically relevant? J Trace Elem Med Biol 28:397–405
Colomer J, Means AR (2007) Physiological roles of Ca2+/CaM-dependent protein kinase cascade in health and disease. Subcell Biochem 45:169–214
Aisen P, Aasa R, Redfield AG (1969) The chromium, manganese, and cobalt complexes of transferrin. J Biol Chem 244:4628–4633
Tan AT, Woodworth RC (1969) Ultraviolet difference spectral studies of conalbumin complexes with transition metal ions. Biochemistry 8:3711–3716
Harris DC (1977) Different metal-binding properties of the two sites of human transferrin. Biochemistry 16:560–564
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 19:4072–4079
Ainscough EW, Brodie AM, Plowman JE (1979) The chromium, manganese, cobalt, and copper complexes of human lactoferrin. Inorg Chim Acta 33:149–153
Moshtaghie AA, Ani M, Bazrafshan MR (1992) Comparative binding study of aluminum and chromium to human transferrin: effect of iron. Biol Trace Elem Res 32:39–46
Ani M, Moshtaghie AA (1992) The effect of chromium on parameters related to iron metabolism. Biol Trace Elem Res 32:57–64
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 press
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 5:129–136
Vincent JB, Love S (2012) The binding and transport of alterative metals by transferrin. Biochim Biophys Acta 1820:362–378
Brock JH (1985) Transferrins. In: Harrison PM (ed) Metalloproteins, 2nd edn. Macmillan, London, pp 183–262
Clodfelder BJ, Vincent JB (2005) The time-dependent transport of chromium in adult rats from the bloodstream to the urine. J Biol Inorg Chem 10:383–393
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 98:522–533
Hopkins LL Jr, Schwarz K (1964) Chromium(III) binding to serum proteins, specifically siderophilin. Biochim Biophys Acta 90:484–491
Kornfeld S (1969) The effect of metal attachment to human transferrin on its binding to reticulocytes. Biochim Biophys Acta 194:25–33
Kandror KV (1999) Insulin regulation of protein traffic in rat adipose cells. J Biol Chem 274:25210–25217
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 3:17–23
Vincent J (2000) The biochemistry of chromium. J Nutr 130:715–718
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 139:339–345
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 36:1184–1193
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 31:212–216
Kozlovsky AS, Moser PB, Reisner S, Anderson RA (1986) Effects of diets high in simple sugars on urinary chromium losses. Metabolism 35:515–518
Anderson RA, Bryden NA, Polansky MM, Reiser S (1990) Urinary chromium excretion and insulinogenic properties of carbohydrates. Am J Clin Nutr 51:864–868
Morris BM, Blumsohn A, MacNeil S, Gray TA (1992) The trace element chromium—a role in glucose homeostasis. Am J Clin Nutr 55:989–991
Morris BM, Griffiths H, Kemp GJ (1988) Effect of glucose loading on concentrations of chromium in plasma and urine of healthy adults. Clin Chem 34:1114–1116
Vincent JB (2010) Chromium: celebrating 50 years as an essential element? Dalton Trans 39:3787–3794
Vincent JB (2000) Elucidating a biological role for chromium at a molecular level. Acc Chem Res 33:503–510
Davis CM, Vincent JB (1997) Chromium oligopeptide activates insulin receptor tyrosine kinase activity. Biochemistry 36:4382–4385
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 36:5316–5320
Davis CM, Sumrall KH, Vincent JB (1996) The biologically active form of chromium may activate a membrane phosphotyrosine phopshatase (PTP). Biochemistry 35:12963–12969
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 14:393–404
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 141:1225–1232
Yamamoto A, Wada O, Suzuki H (1988) Purification and properties of biologically active chromium complex from bovine colostrum. J Nutr 118:39–45
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 163:189–193
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):A412
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 20:857–870
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 22:937–950
Hua Y, Clark S, Ren J, Sreejayan N (2012) Molecular mechanisms of chromium in alleviating insulin resistance. J Nutr Biochem 23:313–319
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Vincent, J.B. Is the Pharmacological Mode of Action of Chromium(III) as a Second Messenger?. Biol Trace Elem Res 166, 7–12 (2015). https://doi.org/10.1007/s12011-015-0231-9
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DOI: https://doi.org/10.1007/s12011-015-0231-9
Keywords
- Chromium
- Second messenger
- Transferrin
- Insulin
- Low-molecular-weight chromium-binding substance