Recent Advances in Nutritional Sciences: The Biochemistry of Chromium
Recent Advances in Nutritional Sciences: The Biochemistry of Chromium
Recent Advances in Nutritional Sciences: The Biochemistry of Chromium
The Biochemistry of Chromium1,2 obtained have been widely disparate among studies. Chro-
mium levels in tissues and body fluids are so low that analytical
John B. Vincent
research to measure chromium concentrations before ⬃1980
was unreliable because only chromium from sample contami-
Department of Chemistry and Coalition for Biomolecular Products, nation was being detected (3).
The University of Alabama, Tuscaloosa, AL 35487-0336
The Essentiality of Chromium(III). In the late 1950s,
ABSTRACT Chromium has been known to be a micronu- Schwarz and Mertz (4) demonstrated the existence of a new
trient for mammals for four decades, but progress in elu- dietary factor, which was absent in the diet of rats fed Torula
cidating the role of chromium has proceeded slowly. How- yeast as their sole protein source. Rats consuming the diet
ever, recent studies have shed light on a potential role of developed an inability to remove glucose efficiently from the
bloodstream, which was reversed by adding foods rich in
715
716 VINCENT
dose-response studies suggest a role for chromium as chro- lenges, have been incorporated into a proposal for the mode of
modulin in signal transduction. In the last five years, system- action of chromodulin as part of an autoamplification system for
atic examinations of the activation or inhibition of phospha- insulin signaling (Fig. 1). In response to increases in blood sugar
tase and kinase activity in rat adipocytes by chromodulin levels, insulin is released rapidly into the bloodstream. Insulin
revealed two effects, i.e., a small activation of a membrane binds to an external ␣ subunit of the transmembrane protein
phosphotyrosine phosphatase (21) and, most significantly, an insulin receptor, bringing about a conformation change of the
insulin-sensitive stimulation of insulin receptor tyrosine kinase receptor. The receptor autophosphorylates tyrosine residues on
activity (13,22). Specifically, addition of chromodulin to rat the internal portion of its  subunit, turning the receptor into an
adipocytic membranes or isolated rat insulin receptor in the active kinase (23). Chromodulin is stored in its apo-form in the
presence of 100 nmol/L insulin resulted in a concentration- cytosol (19) and nucleus (Ramirez and Vincent, unpublished
dependent stimulation of protein tyrosine kinase activity up to results) of insulin-sensitive cells. Increases in plasma insulin con-
eightfold; fitting the concentration dependence gave a disso- centrations have been found to result in a movement of chro-
ciation constant of 250 – 875 pmol/L for binding of chromodu- mium from the blood to insulin-dependent cells (24,25). This
lin to the insulin receptor. The site of activation appears to be transfer is likely mediated by the metal transport protein trans-
located at or near the kinase active site; addition of chromodu- ferrin (see below). Apochromodulin possesses a large chromic ion
sensitive to insulin; increases in insulin result in a stimulation related to patients with unexplained hepatic iron overload
of the movement of transferrin receptor from vesicles to the (characterized by a nearly constant association with diabetes)
plasma membrane (35). The receptors at the cell surface can whose transferrin-bound iron levels are greatly increased (37).
bind metal-saturated transferrin, which subsequently under- Could increased loading of transferrin with iron prevent ade-
goes endocytosis with accompanying metal release at the quate chromium binding and transfer by transferrin, resulting
acidic pH of the newly formed vesicles. On the basis of these in insulin resistance and diabetes? The hemochromatotic di-
results, a mechanism for chromium transport is proposed (Fig. abetic condition is certainly exacerbated by reduced chromium
2). Increases in insulin levels should result in increased trans- retention (38), as observed in patients with adult-onset dia-
port of transferrin, including the portion containing bound betes (36).
chromium, culminating in chromium transport from the blood One note of caution must be addressed. The most popular
to insulin-sensitive cells and ultimately chromodulin. In adult- form of chromium in dietary supplements, chromium picoli-
onset diabetics, in which blood chromium levels are reduced nate, appears to be absorbed in a different fashion from dietary
and urinary chromium losses are increased (36), this transport chromium. Chromium picolinate, Cr(pic)3, is remarkably sta-
system may be exceeding normal operation. This may be ble; it remains intact for several hours in synthetic gastric juice
(39) and days to weeks under other physiologically relevant
LITERATURE CITED
1. Mertz, W. (1993) Chromium in human nutrition: a review. J. Nutr. 123:
626 – 633.
2 Lukaski, H. C. (1999) Chromium as a supplement. Annu. Rev. Nutr. 19:
279 –301.
3. Veillon, C. & Patterson, K. Y. (1999) Analytical issues in nutritional
chromium research. J. Trace Elem. Exp. Res. 12: 99 –109.
4. Schwarz, K. & Mertz, W. (1959) Chromium(III) and glucose tolerance
factor. Arch. Biochem. Biophys. 85: 292–295.
5. Mertz, W., Roginski, E. E. & Schwarz, K. (1961) Effect of trivalent
chromium on glucose uptake by epididymal fat tissue of rats. J. Biol. Chem. 236:
318 –322.
6. Mertz, W. & Roginski, E. E. (1963) The effect of trivalent chromium on
galactose entry in rat epididymal rat tissue. J. Biol. Chem. 238: 868 – 872.
7. Anderson, R. A. (1995) Chromium and parenteral nutrition. Nutrition
11: 83– 86.
8. Anderson, R. A. & Kozlovsky, A. S. (1985) Chromium intake, absorp-
tion and excretion of subjects consuming self-selected diets. Am. J. Clin. Nutr. 41:
768 –771.
9. Davis, C. M. & Vincent, J. B. (1997) Chromium in carbohydrate and
lipid metabolism. J. Biol. Inorg. Chem. 2: 675– 679.
10. Vincent, J. B. (1999) Mechanisms of chromium action: low-molecular-
weight chromium-binding substance. J. Am. Coll. Nutr. 18: 6 –12.
11. Vincent, J. B. (2000) The quest for the molecular mechanism of
chromium action and its relationship to diabetes. Nutr. Rev. 58 (in press).
12. Yamamoto, A., Wada, O. & Ono, T. (1987) Isolation of a biologically
FIGURE 2 Proposed mechanism for the movement of chromium active low-molecular-mass chromium compound from rabbit liver. Eur. J. Bio-
from blood to chromodulin. In response to increases in plasma insulin chem. 165: 627– 631.
13. Davis, C. M. & Vincent, J. B. (1997) Chromium oligopeptide activates
concentrations, transferrin-receptor (Tf-R) in insensitive cells migrates
insulin receptor tyrosine kinase activity. Biochemistry 36: 4382– 4385.
from vesicles to the plasma membrane. Transferrin (pentagon), which 14. Sumrall, K. H. & Vincent, J. B. (1997) Is glucose tolerance factor an
contains two bound metal ions [in this case one chromic ion and one artifact produced by acid hydrolysis of low-molecular-weight chromium-binding
other metal cation (M)], binds to the receptor and is internalized by substance? Polyhedron 16: 4171– 4177.
endocytosis. The pH of the resulting vesicle is reduced by ATP-driven 15. Yamamoto, A., Wada, O. & Suzuki, H. (1988) Purification and proper-
proton pumps, resulting in the release of the metal ions from transferrin. ties of biologically active chromium complex from bovine colostrum. J. Nutr. 118:
39 – 45.
Chromium released from multiple transferrin molecules is sequestered 16. Wada, O., Wu, G. Y., Yamamoto, A., Manabe, S. & Ono, T. (1983)
by apochromodulin (open circle) to produce chromium-loaded chro- Purification and chromium-excretory function of low-molecular-weight, chromi-
modulin (dark circle). um-binding substances from dog liver. Environ. Res. 32: 228 –239.
718 VINCENT
17. Yamamoto, A., Wada, O. & Ono, T. (1983) Distribution and chromium- son, K. Y. & Reamer, D. C. (1982) Effect of exercise (running) on serum
binding capacity of a low-molecular-weight, chromium-binding substance in glucose, insulin, glucagon, and chromium secretion. Diabetes 31: 212–216.
mice. J. Inorg. Biochem. 22: 91–102. 30. Anderson, R. A., Polansky, M. M., Bryden, N. A., Roginski, E. E., Patter-
18. Vincent, J. B. (1994) Relationship between glucose tolerance factor son, K. Y., Veillon, C. & Glinsmann, W. (1982) Urinary chromium excretion of
and low-molecular-weight chromium-binding substance. J. Nutr. 124: 117–118. human subjects: effects of chromium supplementation and glucose loading.
19. Yamamoto, A., Wada, O. & Manabe, S. (1989) Evidence that chro- Am. J. Clin. Nutr. 36: 1184 –1193.
mium is an essential factor for biological activity of low-molecular-weight chro- 31. Anderson, R. A., Bryden, N. A., Polansky, M. M. & Reiser, S. (1990)
mium-binding substance. Biochem. Biophys. Res. Commun. 163: 189 –193. Urinary chromium excretion and insulogenic properties of carbohydrates. Am. J.
20. Yoshimoto, S., Sakamoto, K., Wakabayashi, I. & Masui, H. (1992) Ef- Clin. Nutr. 51: 864 – 868.
fect of chromium administration on glucose tolerance in stroke-prone spontane- 32. Kozlovsky, A. S., Moser, P. B., Reisner, S. & Anderson, R. A. (1986)
ously hypertensive rats with streptozotocin-induced diabetes. Metabolism 41: Effects of diets high in simple sugars on urinary chromium losses. Metabolism 35:
636 – 642. 515–518.
21. Davis, C. M., Sumrall, K. H. & Vincent, J. B. (1996) The biologically 33. Brock, J. H. (1985) Transferrins. In: Metalloproteins (Harrison, P. M.,
active form of chromium may activate a membrane phosphotyrosine phospha- ed.), vol. 2, pp. 183–262. MacMillan, London, UK.
tase (PTP). Biochemistry 35: 12963–12969. 34. Borguet, F., Cornelis, R. & Lameire, N. (1990) Speciation of chromium
22. Davis, C. M., Royer, A. C. & Vincent, J. B. (1997) Synthetic multinu- in plasma and liver tissue of endstage renal failure patients on continuous am-
clear chromium assembly activates insulin receptor kinase activity: functional bulatory peritoneal dialysis. Biol. Trace Elem. Res. 26 –27: 449 – 460.
model for low-molecular-weight chromium-binding substance. Inorg. Chem. 36: 35. Kandror, K. V. (1999) Insulin regulation of protein traffic in rat adipo-
5316 –5320. cyte cells. J. Biol. Chem. 274: 25210 –25217.