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Department of Chemistry and Coalition for Biomolecular Products, The University of Alabama, Tuscaloosa, AL 35487-0336
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONThe Essentiality of...Low-Molecular-Weight Chromium...Chromium Absorption and...REFERENCES |
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KEY WORDS: • chromium • chromodulin • low-molecular-weight chromium-binding substance • insulin receptor • transferrin
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONThe Essentiality of...Low-Molecular-Weight Chromium...Chromium Absorption and...REFERENCES |
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,2)
.
The difficulty lies in the chemistry of the biologically relevant form
of chromium, substitutionally inert Cr(III), and the low concentrations
of the element in tissues. The understanding of chromium metabolism has
been so poor that no reliable method for diagnosing chromium deficiency
exists other than observing beneficial changes during chromium
supplementation; thus, it is not readily possible to determine the
chromium status of an individual (2)
. As a result, studies
on the effects of supplementation of normal diets of healthy patients
or diabetic subjects with chromium have been inconclusive; the results
obtained have been widely disparate among studies. Chromium levels in
tissues and body fluids are so low that analytical research to measure
chromium concentrations before ~1980 was unreliable because only
chromium from sample contamination was being detected (3)
. |
The Essentiality of Chromium(III). |
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TOPABSTRACTINTRODUCTIONThe Essentiality of...Low-Molecular-Weight Chromium...Chromium Absorption and...REFERENCES |
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demonstrated the
existence of a new dietary factor, which was absent in the diet of rats
fed Torula yeast as their sole protein source. Rats
consuming the diet developed an inability to remove glucose efficiently
from the bloodstream, which was reversed by adding foods rich in
chromium or by adding synthetic inorganic chromium(III) complexes to
the diet. Subsequent studies with epididymal fat tissue from
Cr-deficient rats suggested that chromium action was dependent on
insulin (5
,6)
. Evidence for an essential role for chromium
in humans comes from patients receiving total parenteral nutrition
(7)
. Some patients have developed diabetic symptoms that
were refractory to insulin but reversed by addition of chromium.
Absorption of chromium has also been shown to be inversely proportional
to chromium intake, although at any intake level, the body absorbs
dietary chromium poorly, i.e., ~0.5–2% (8)
. Yet,
identifying and isolating the naturally occurring, biologically active
form of chromium has proved difficult (9
,10)
. |
Low-Molecular-Weight Chromium-Binding Substance/Chromodulin. |
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TOPABSTRACTINTRODUCTIONThe Essentiality of...Low-Molecular-Weight Chromium...Chromium Absorption and...REFERENCES |
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. The oligopeptide possesses a molecular
weight of ~1500 Da and is comprised of only four types of
amino acid residues, i.e., glycine, cysteine, glutamate and aspartate
(12
,13)
. Despite its small molecular weight, it binds four
equivalents of chromic ions, apparently in a tetranuclear assembly, as
necessitated by charge balance arguments. To date, the oligopeptide has
been isolated and purified from rabbit liver (12)
, porcine
kidney and kidney powder (14)
, bovine liver
(13)
and colostrum (15)
, and dog liver
(16)
; it has also been isolated from mouse and rat liver
(17)
, Thus, chromodulin appears widely distributed in
mammals. There have been no reported efforts to isolate the
oligopeptide from animals other than mammals. The most novel attribute
of chromodulin is its ability to potentiate the effects of insulin on
the conversion of glucose into carbon dioxide or lipid by isolated rat
adipocytes (9
,5
,18)
. This stimulation of insulin
activation occurs without changing the concentration of insulin
required for half-maximal activity, suggesting that chromodulin
plays an intrinsic role in the adipocytes. The stimulation is also
directly dependent on the chromium content of chromodulin
(19)
. No other naturally occurring chromium-containing
species potentiates insulin action in this manner.
Combined with studies of diet supplementation with chromium on glucose
transport by rat adipocytes (20)
, the insulin
dose-response studies suggest a role for chromium as chromodulin in
signal transduction. In the last five years, systematic examinations of
the activation or inhibition of phosphatase and kinase activity in rat
adipocytes by chromodulin revealed two effects, i.e., a small
activation of a membrane phosphotyrosine phosphatase (21)
and, most significantly, an insulin-sensitive stimulation of
insulin receptor tyrosine kinase activity (13
,22)
.
Specifically, addition of chromodulin to rat adipocytic membranes or
isolated rat insulin receptor in the presence of 100 nmol/L insulin
resulted in a concentration-dependent stimulation of protein
tyrosine kinase activity up to eightfold; fitting the concentration
dependence gave a dissociation constant of 250–875 pmol/L for binding
of chromodulin to the insulin receptor. The site of activation appears
to be located at or near the kinase active site; addition of
chromodulin to a fragment of the ß subunit of the insulin receptor
that contains the active site (but does not require insulin to be
active) resulted in a similar stimulation of kinase activity. Just as
with the studies with intact rat adipocytes, stimulation of
insulin-dependent insulin receptor kinase activity by chromodulin
is dependent on the chromium content of the oligopeptide. Titration of
the metal-free or apo-form of the oligopeptide with chromic
ions revealed that four equivalents of chromic ions are required for
maximal activity. Other transition metals that are commonly associated
with biological systems were ineffective in restoring the ability of
apochromodulin to stimulate the kinase activity, indicating that the
reconstitution is chromium specific. (Similar results have been
obtained in titration studies examining the reconstitution of
stimulation of phosphatase activity.)
Recently, these results, combined with the results of studies of
chromium homeostasis in response in glucose and insulin challenges,
have been incorporated into a proposal for the mode of action of
chromodulin as part of an autoamplification system for insulin
signaling (Fig. 1
). In response to increases in blood sugar levels, insulin is released
rapidly into the bloodstream. Insulin binds to an external 
subunit
of the transmembrane protein insulin receptor, bringing about a
conformation change of the receptor. The receptor autophosphorylates
tyrosine residues on the internal portion of its ß subunit, turning
the receptor into an active kinase (23)
. Chromodulin is
stored in its apo-form in the cytosol (19)
and nucleus
(Ramirez and Vincent, unpublished results) of insulin-sensitive
cells. Increases in plasma insulin concentrations have been found to
result in a movement of chromium from the blood to
insulin-dependent cells (24
,25)
. This transfer is
likely mediated by the metal transport protein transferrin (see below).
Apochromodulin possesses a large chromic ion binding constant
(K 
1021) (26)
such
that it should sequester chromium in response to this chromic ion flux.
The newly generated holochromodulin (i.e., Cr4-chromodulin)
can then bind to the insulin-stimulated insulin receptor, helping
to maintain its active conformation and amplifying insulin signaling.
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.
The chromic centers of chromodulin are not readily reduced by
biological reducing agents to labile chromous ions (28)
,
which could be removed more easily from the oligopeptide. This loss of
chromodulin from cells is consistent with increased urinary chromium
concentrations after carbohydrate and sugar intake
(29
30
31
32)
and with chromodulin potentially representing the
major form of chromium(III) in urine (16)
. The manner in
which apochromodulin is replaced is unknown; presumably, the
oligopeptide is synthesized as a proprotein which is modified
post-translationally to give the oligopeptide (as with insulin and
proinsulin). Similarly, nothing is known of the mechanism of regulation
of chromodulin levels; however, the potential existence of a
chromium-binding translation factor similar to the
metal-binding factors that regulate the production of other
metalloproteins (e.g., iron-responsive element binding protein) is
intriguing. |
Chromium Absorption and Transport. |
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TOPABSTRACTINTRODUCTIONThe Essentiality of...Low-Molecular-Weight Chromium...Chromium Absorption and...REFERENCES |
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. In vitro studies
of the addition of chromium sources to blood or blood plasma also
result in the loading of transferrin with Cr(III), although under these
conditions, albumin and some degradation products also bind chromium
(34)
. Thus, it has been assumed that transferrin was
involved in chromium transport, although it has never been demonstrated
in vivo. Transfer of chromium from transferrin to apoLMWCr has been
demonstrated in vitro (26)
. Recent reports on the effects
of insulin on iron transport and the relationship between
hemochromatosis and hepatic iron overload and diabetes suggest that
transferrin may actually be the major physiologic chromium transport
agent. Plasma membrane recycling of transferrin receptors is sensitive
to insulin; increases in insulin result in a stimulation of the
movement of transferrin receptor from vesicles to the plasma membrane
(35)
. The receptors at the cell surface can bind
metal-saturated transferrin, which subsequently undergoes
endocytosis with accompanying metal release at the acidic pH of the
newly formed vesicles. On the basis of these results, a mechanism for
chromium transport is proposed (Fig. 2
). Increases in insulin levels should result in increased transport of
transferrin, including the portion containing bound chromium,
culminating in chromium transport from the blood to
insulin-sensitive cells and ultimately chromodulin. In
adult-onset diabetics, in which blood chromium levels are reduced
and urinary chromium losses are increased (36)
, this
transport system may be exceeding normal operation. This may be related
to patients with unexplained hepatic iron overload (characterized by a
nearly constant association with diabetes) whose transferrin-bound
iron levels are greatly increased (37)
. Could increased
loading of transferrin with iron prevent adequate chromium binding and
transfer by transferrin, resulting in insulin resistance and diabetes?
The hemochromatotic diabetic condition is certainly exacerbated by
reduced chromium retention (38)
, as observed in patients
with adult-onset diabetes (36)
.
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and days to weeks under other physiologically relevant conditions
(40
,41)
. The complex also appears to pass unhindered
through the jejunum (39)
and probably migrates to and is
incorporated into cells in its original form. Unfortunately, the
picolinate ligands shift the redox potential of the chromic center of
the complex such that it can be reduced by biological reducing agents
such as ascorbate and thiols (40)
. The resulting chromous
complex can interact with oxygen catalytically, generating the hydroxyl
radical (26)
. In vitro studies using concentrations of
Cr(pic)3 believed to correspond to those in cells of
individuals taking the supplement for prolonged periods of time and
typical cellular concentrations of ascorbate found that significant DNA
cleavage resulted from the generated hydroxyl radical
(40)
. The release of chromium from Cr(pic)3
(required for it to serve as a source of chromium) requires reduction
of the chromium (26)
, suggesting that the deleterious
chemistry and ability of Cr(pic)3 to serve as a more
absorbable source of chromium may be inexorably linked. Studies of the
long-term effects of Cr(pic)3 usage are required to
determine the significance of this chemistry.
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FOOTNOTES |
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2 Research on chromium in the author’s laboratories is funded by NRICGP/USDA 97–35200-4259.
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REFERENCES |
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TOPABSTRACTINTRODUCTIONThe Essentiality of...Low-Molecular-Weight Chromium...Chromium Absorption and...REFERENCES |
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