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Mechanisms of Chromium Action: Low-Molecular-Weight Chromium-Binding Substance

Department of Chemistry and Coalition for Biomolecular Products, The University of Alabama Tuscaloosa, Alabama

Address reprint requests to: John B. Vincent, Department of Chemistry and Coalition for Biomolecular Products, The University of Alabama, Tuscaloosa, AL 35487-0336

	ABSTRACT

TOP ABSTRACT INTRODUCTION BACKGROUND LOW-MOLECULAR-WEIGHT CHROMIUM... CONCLUSIONS REFERENCES

 
Chromium has long been known to be essential for proper lipid and carbohydrate metabolism in mammals, with chromium deficiency leading to symptoms associated with adult-onset diabetes and cardiovascular disease. Elucidating the structure, function, and mode of action of the biologically active form of chromium has proved enigmatic. However, a naturally-occurring oligopeptide, low-molecular-weight chromium-binding substance (LMWCr), has been found in our laboratory to activate insulin receptor kinase activity up to 7-fold with a dissociation constant of 250 picomolar in the presence of 100 nanomolar insulin, and it has been partially characterized in terms of structural and spectroscopic properties. LMWCr may function in a manner similar to that of the calcium-binding signal protein calmodulin. In other words, LMWCr is maintained in its active apo-oligopeptide form; in response to a chromium flux, LMWCr binds 4 chromic ions. The holoprotein is then capable of binding to insulin receptor (and perhaps other enzymes) activating the enzyme. Establishing a link between the nutrient chromium, LMWCr’s activation of insulin receptor kinase activity, and adult-onset diabetes and related conditions could result in a new treatment for these conditions.

Key words: chromium, low-molecular-weight chromium-binding substance, insulin receptor, kinase

Key teaching points:

• Elucidating the structure, function, and mode of action of the biologically active form of chromium has proved enigmatic.

• A naturally-occurring oligopeptide, low-molecular-weight chromium-binding substance (LMWCr) has been partially characterized in our laboratory in terms of its structural and spectroscopic properties.

• Establishing a link between the nutrient chromium, LMWCr’s activation of insulin receptor kinase activity, and adult-onset diabetes and related conditions could lead toward a new treatment for these conditions.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION BACKGROUND LOW-MOLECULAR-WEIGHT CHROMIUM... CONCLUSIONS REFERENCES

 
Molybdenum, tungsten, and the first row transition elements from vanadium to zinc have all been proposed as essential for some form of life [1–3]. Currently, for each metal with the exception of chromium, at least one (and usually many) metallobiomolecule containing an ion of that element has been well characterized in terms of its structure, biological function, and mode of action. In fact, the three-dimensional structures of biomolecules containing every metal except chromium have been determined by x-ray crystallography. The failure to determine the structure, function, and mode of action of biologically active chromium has recently led some to question the requirement for chromium. For example, a recent review article by notable bio-inorganic chemists [4] specifically indicated that chromium was not a "biological" metal. Thus, it is critical for researchers in the biochemical field to convincingly prove a role for chromium.

	BACKGROUND

TOP ABSTRACT INTRODUCTION BACKGROUND LOW-MOLECULAR-WEIGHT CHROMIUM... CONCLUSIONS REFERENCES

 
Since its "discovery" nearly 40 years ago, chromium biochemistry has proven to be an enigma. Some compounds have previously been proposed as the biologically active form of chromium. In 1957, a material isolated from an acid hydrolyzate of porcine kidney powder was found to reverse glucose intolerance in rats fed a Torula yeast-based diet; it was proposed as a new dietary agent, soon to be named glucose tolerance factor (GTF) [5]. Subsequently this diet was found to be deficient in chromium, and the isolated material from kidney powder was found to possess appreciable quantities of Cr³⁺, which proved to be the active component [6]. Porcine GTF, in in vitro assays using rat epididymal fat pads, potentiated the effects of insulin [7]. A chromium-rich material from Brewer’s yeast was also found to be active in the fat pad assays and to possess nearly identical properties to the porcine kidney powder GTF [8,9]. The ability to readily obtain significant quantities of the yeast GTF all but led to abandonment of studies on the porcine material after 1960. Hence, the abbreviation GTF currently is used usually to refer essentially exclusively to the material from yeast. Unfortunately, the isolation and characterization of this material has not proven to be reproducible in some laboratories [10–12]. The yeast GTF has been proposed to be a low molecular weight molecule that possesses an ultraviolet absorbance maximum at about 260 nm and to be comprised of Cr³⁺, glycine, glutamate, cysteine, and nicotinic acid [8]. The presence of glutathione has been proposed, but the tripeptide has never been obtained from GTF preparations; additionally, the ratios of the components of GTF have not been reported. The isolation procedure for the yeast GTF also involves an acid hydrolysis, which uses refluxing 5 N HCl for 18 h [8]. Literature on GTF research from the late 1950s until about 1980 has been exhaustively reviewed [13].

Chromium tris (picolinate) has also recently been proposed potentially to be the biologically active form of chromium [14]. This suggestion is at best impractical because of the requirements to make this complex in vivo. Significantly both GTF and the picolinate complex appear only to be readily absorbable sources of chromium, not possessing intrinsic biological activity [15–17]. Because of the presence of the picolinate ligands, the latter material has also been claimed to induce chromosome damage [18]. Also, pharmokinetic models have shown that chromium picolinate taken as a supplement in excess doses or for prolonged periods of time potentially could result in accumulation of chromium in human tissues [19]. However, a lack of toxicity of the complex has been observed in rats fed doses of chromium picolinate up to 30 mg Cr per kg body weight [20]. Literature on chromium tris (picolinate) is growing at a tremendous rate and is in desperate need of comprehensive review.

Nevertheless, medical studies would appear to indicate clearly that chromium is required for normal carbohydrate and lipid metabolism [21–27]. Chromium deficiency in humans and other mammals results in symptoms comparable to those associated with adult-onset diabetes and cardiovascular disease [26]. Improvement in glucose tolerance after supplementation of the diet with chromium has been documented many times, as well as improvements in other symptoms [27]. Recently chromium supplementation (in the form of chromium picolinate) has been found to have beneficial effects on adult-onset diabetes patients [28,29]. However, beneficial effects from the administration of chromium have not been observed in all cases; chromium apparently serves only as a nutrient and not as a therapeutic, and it may benefit only those who are marginally to overtly chromium deficient [25]. Yet the positive effects attributed to chromium presumably arise from the interaction of chromium with a specific biomolecule(s). This presumed interaction leads researchers to ask a crucial question: What is the structure, function, and mode of the biologically active form(s) of chromium at a molecular level?

	LOW-MOLECULAR-WEIGHT CHROMIUM-BINDING SUBSTANCE

TOP ABSTRACT INTRODUCTION BACKGROUND LOW-MOLECULAR-WEIGHT CHROMIUM... CONCLUSIONS REFERENCES

 
Isolation, Purification, and Physical Characterization
At present, the most viable candidate for the biologically active form of chromium is an oligopeptide, low-molecular-weight chromium-binding substance (LMWCr) [30–40]. LMWCr is found mainly in the liver of mammals, while appreciable quantities are also found in the kidney; other tissues examined to date have contained at least traces of the material [34]. LMWCr is also found in urine, where it may represent a major portion of urinary chromium [33]. Interest in LMWCr stems from its ability in a chromium-dependent manner to potentiate the ability of insulin to stimulate the metabolism of glucose by isolated rat adipocytes [30–32,37,39]. The degree of stimulation by LMWCr of the conversion of glucose into lipid and carbon dioxide is similar, and the concentration of insulin required for half maximal stimulation of glucose metabolism is independent of LMWCr concentration [16,32]. These results suggest that LMWCr functions to potentiate insulin after insulin binds to the external side of insulin receptor (ie, is intrinsic to the insulin-sensitive adipocytes) but before the pathways in glycolysis leading to conversion of glucose in lipid and into carbon dioxide diverge [16]. The LD₅₀ value for LMWCr is surprisingly small when compared to values for other forms of chromium such as chromate or chromic salts, being 134.9 mg/kg of body weight when given to mice by intraperitoneal injection [33].

This laboratory has expended much effort in developing methods to isolate an appreciable quantity of LMWCr and in characterizing the composition and spectroscopic properties of the oligopeptide [39]. Previous efforts to isolate LMWCr in other laboratories, using rabbit liver [30], dog liver [33], and cow colostrum [32], resulted in obtaining less than 1 milligram of pure material. Scaling these procedures up to obtain substantial quantities of LMWCr would require the sacrifice of large numbers of animals or the handling of unreasonably large volumes of liquid.

Because of the high concentration of LMWCr in liver and its availability in bulk, bovine liver was chosen as a source of the oligopeptide [39]. To guarantee that the material contained its full complement of chromium, an in vitro chromium-loading procedure was developed that required the addition of 3.4 mmol of chromium as dichromate per 2 liters of homogenate. In the case of rabbit liver and dog liver purifications, the animals had been injected with chromate before being killed [30,34]. As (di)chromate is a potent carcinogen, injection into a whole cow would render the meat unsuitable for consumption and make this source of liver tissue unfeasible from a financial standpoint.

Using this technique followed by a series of ethanol precipitations and chromatographic separations, approximately 30 mg of LMWCr can be isolated from 5 to 6 kg of diced liver tissue (one typical adult cow liver). When chromate is not used, only small amounts of material can be isolated; however, material is still present, indicating that it occurs naturally. This result also indicates that LMWCr is maintained almost entirely (the extent of chromium coming from the blades of the Waring blender and other similar sources not being determined) in its apo (metal free) form, as found in earlier work by Yamamoto and coworkers using mouse liver [34]. Chromic salts can also be used, but the degree of loading is not as high. The inclusion of protease inhibitors throughout the purification has no effect on the yield of LMWCr but makes purification easier, as the number of oligopeptides of similar size present is reduced; thus, LMWCr is not a proteolytic artifact. The addition of chromium is less than optimal (as it always leaves unanswered the question as to whether LMWCr is some type of artifact arising from chromium treatment), but it is absolutely necessary. As LMWCr is assayed by examining its effect on the rate of glucose metabolism by fat cells or on the activation of kinase or phosphatase enzymes (assays which are sensitive in both positive and negative fashions to a wide range of chemicals), LMWCr can only be followed through the purification procedure by analyzing for its chromium content.

Size exclusion chromatography gives a molecular mass of 1.48 kDa for bovine liver LMWCr. The oligopeptide has a chromium-to-protein ratio of approximately 4 to 1; amino acid analyses indicate that aspartate, glutamate, glycine, and cysteine are present in a 2.15:4.47:2.47:2.35 molar ratio, respectively, assuming a molecular mass of 1200 for the organic portion. No significant amounts of other amino acids were found. The composition in terms of chromium and amino acids is very similar to that of other liver LMWCrs (Table 1). No nicotinic acid has been detected in isolated LMWCr. The oligopeptides are quite active in rat adipocyte biological activity assays (biological activity is defined as the ability to potentiate insulin’s stimulation of the metabolism of glucose to give lipids or carbon dioxide by isolated rat adipocytes). The addition of 2 ng of chromium as bovine LMWCr into 200 µL of suspended adipocytes is already saturating in terms of potentiation [39].

Spectroscopic studies also indicate that LMWCr contains a multinuclear anion-bridged chromic carboxylate assembly. The ultraviolet spectrum of bovine liver LMWCr possesses one feature of uncertain origin at about 260 nm. This feature is also present in apoLMWCr, indicating it is not chromium-based. Thiolate-to-chromium (III) charge transfer bands that normally occur in this region are lacking in the spectrum of LMWCr, suggesting that cysteine does not bind to the hard metal centers in the material. The visible spectrum of LMWCr possesses 2 broad bands, typical of chromium (III) complexes (d³). The value of 10 Dq obtained from the spectrum indicates that the chromium is in a octahedral or pseudo-octahedral environment predominately to solely of oxygen-based ligands. Most importantly two shoulders are present in the spectrum at about 316 and 336 nm; these shoulders are tentatively assigned to special pair excitation transitions, based on comparison to assignments of similar bands in synthetic chromium (III) complexes [39]. These transitions are only possible for multinuclear complexes.

Paramagnetic nuclear magnetic resonance (NMR) has recently been shown to be a valuable tool to examine multinuclear chromium (III) assemblies [41–44]. Paramagnetic ¹H NMR of LMWCr has revealed the presence of a broad absorption at approximately +45 ppm. This feature is strikingly similar to the methylene or methyl proton resonances of bridging propionate or acetate ligands, respectively, bound to oxide- and hydroxide-bridged chromic assemblies (usually between +35–+45 ppm). In contrast, the shift for the protons of such ligands bound in a monodentate fashion to chromic ions is +15–+25 ppm. Given the organic composition of LMWCr, no other proton resonances are expected in this region, providing additional evidence for a multinuclear assembly in LMWCr, in addition to electronic spectra and charge balance and coordination chemistry arguments [39]. (The oligopeptide does not possess enough negative charges (deprotonated carboxylates, etc.) to compensate for the presence of 4 chromic ions; as the chromium-containing oligopeptide adheres to anion exchange columns, small anionic ligands to the chromium must be present. Cr³⁺ is essentially always found in an octahedral environment; 4 chromic centers require 24 atoms to be bound. Because of the small size of LMWCr, the protein could hardly provide enough ligands to occupy 24 sites. This suggests a need for bridging carboxylates and anionic ligands such as oxide or hydroxide.) Thus, LMWCr appears to possess a tetranuclear assembly, although the presence of 2 dinuclear assemblies cannot be ruled out with certainty [39], perhaps reminiscent of the oxo-bridged, carboxylate-bridged dinuclear iron centers of non-heme iron proteins such as ribonucleotide reductase and the oxo-bridged, carboxylate-bridged tetramanganese assembly of photosystem II.

Biological Function and Mode of Action
LMWCr appears to have role in insulin potentiation after the hormone binds to its receptor. Recent work by Yoshomoto and coworkers also suggests that the role of chromium in insulin potential occurs at or before carbohydrate transport into the cell [45]. The events in the cell between insulin binding and carbohydrate transport are primarily signal transduction events. Consequently, this laboratory examined the effect on adipocyte kinases and phosphatases. The result was that the primary function of LMWCr may be the activation of insulin receptor tyrosine kinase activity in response to insulin [35], while it appears to also activate a membrane phosphototyrosine phosphatase [36]. The addition of bovine liver LMWCr to rat adipocytic membranes in the presence of 100nM insulin results in concentration-dependent, 3.5- and 8-fold stimulation of insulin-dependent protein tyrosine kinase activity, using a fragment of gastrin and cell division kinase p34^cdc2 as substrates, respectively; no activation of kinase activity with either substrate is observed in the absence of insulin. The dependence of the activations on the concentration of LMWCr can be fit to a hyperbolic curve to give dissociation constants of approximately 875 pM. Addition of polyclonal antibodies (whose epitope corresponds to a region of insulin receptor subunits believed to be essential in the binding of insulin) to the rat adipocytic membranes results in a loss of activation of insulin receptor kinase activity. Similarly, the addition of bovine LMWCr to isolated and purified rat insulin receptor in the presence of insulin amplifies stimulation of receptor tyrosine kinase activity by approximately 7-fold with a dissociation constant of approximately 250 pM [35]. The addition of LMWCr to an isolated fragment of the ß subunit of insulin receptor (which contains the catalytic site but does not require insulin for activation) results in over a 3-fold amplification of kinase activity with a dissociation constant of 133 pM [40]. A similar effect has been noted using rat adipocytic membranes in the presence of insulin-like growth factor 1 (IGF-1), suggesting that LMWCr activates the tyrosine kinase activity of that hormone receptor as well. The IGF-1 receptor is part of a family of receptor proteins that includes insulin receptor [46].

Chromium plays a crucial role in the activation of insulin receptor kinase activity by LMWCr. ApoLMWCr is inactive in the activation of the kinase activity in adipocytic membranes. However, titration of apoLMWCr with chromic ions results in the total restoration of the ability to activate kinase activity; approximately 4 chromic ions per oligopeptide were required for maximal activity, consistent with the presence of 4 chromium per molecule for isolated holoLMWCr. The reconstitution of the activation potential of LMWCr is specific to chromium. Other transition metal ions commonly associated with biological systems are ineffective.

Similar results have been obtained for a rat adipocytic membrane tyrosine phosphatase. LMWCr was found to activate a phosphototyrosine phosphatase (PTP) similar to a membrane PTP1A’ or PTP1B [36]. It was ineffective in activating any soluble phosphatases, membrane serine/threonine phosphatases, isolated alkaline phosphatase, and isolated leukocyte-antigen-related PTP, but was found to activate the catalytic fragment of Yersinia PTP. Titration of apoLMWCr with Cr³⁺ revealed again that approximately 4 (3.89) chromium/oligopeptide is required for maximal activity; addition of other transition metal ions failed to restore the ability of apoLMWCr to activate the PTP activity. Curiously, a comparison of the sequence of Yersinia PTP with the cytoplasmic portion of insulin receptor reveals a single region of homology 7 amino acids in length, DY(FY)R(KQ)XG. While it is far too preliminary to make any conclusions, it is interesting to note that the conserved tyrosine is one of the 3 tyrosines of insulin receptor that are autophosphorylated in response to insulin.

Recently, a number of key pieces of evidence have begun to come together to start to rough out the puzzle of the biological role and function of chromium [37] (Figure 1). Blood homeostasis studies have revealed that in response to increases in blood insulin concentrations (which result from increases in blood carbohydrate levels), chromium concentrations decrease as the metal is taken up by insulin-dependent cells [47–49]. LMWCr is maintained in these insulin-dependent cells almost entirely in its metal-free apo form; the apo form has a correspondingly large chromic ion binding constant, as it can remove chromium from Cr-transferrin, a potential chromium transport agent in blood [30]. Thus, movement of chromium in response to insulin could result in the production of LMWCr in its active form possessing a multinuclear chromium assembly. The holoLMWCr is consequently primed so that, in the presence of insulin, insulin receptor tyrosine kinase is activated and membrane phosphototyrosine phosphatase activity may be activated.

View larger version (20K): [in this window] [in a new window]   Fig. 1. Proposed mechanism for the activation of insulin receptor activity by LMWCr in response to insulin. The inactive form of insulin receptor (IR) is converted to the active form by binding insulin (I). This triggers a movement of chromium from the blood into insulin-dependent cells, which in turn results in apoLMWCr (triangle) binding chromium. Finally, the holoLMWCr (square) binds to insulin receptor, further activating the receptor kinase activity. ApoLMWCr is unable to bind to receptor and activate kinase activity. When the insulin concentration drops, holoLMWCr may be released from the cell to relieve its effects. Thus, LMWCr functions on the inside of the cell and does not affect insulin. Adapted, with permission, from Davis CM, Vincent JB: Chromium in carbohydrate and lipid metabolism. J Biol Inorg Chem 2:675–679, 1997.

Little is known of the fate of LMWCr after the stress that induced insulin action is relieved and after blood insulin concentrations, for example, are reduced, and thus the proportion of activated insulin receptors as well. Presumably, if the above model for LMWCr action is correct, chromium or LMWCr must be removed from these cells to stop the activation activity. Chromium is excreted in urine in response to stresses including high sugar intake [52,53]. In particular, carbohydrates that alter circulating insulin levels also affect urinary chromium losses: as glucose tolerance decreases, the mobilization of chromium and resulting chromium loss have also been shown to decrease [54]. Overall, these studies indicate that within 90 minutes of ingestion of sugar by humans, an increase in urinary chromium loss occurs. Since LMWCr may represent the major form of Cr (III) in urine [33], LMWCr, as the holo-oligopeptide, may be removed from insulin-responsive cells to relieve its effects, after which it is ultimately excreted in the urine.

Relationship between LMWCr and Glucose Tolerance Factor?
The characterization of the composition of GTF has proved very problematic. Even a decade ago its existence as a discrete, isolable species was questioned by workers in the GTF field [21]. However, recent studies on LMWCr may have provided some solutions to the GTF mystery. Recently LMWCr has been found to occur in appreciable quantities in porcine kidney and to be concentrated in the process to prepare porcine kidney powder [38]. Also, porcine LMWCr was shown to be susceptible to acid hydrolysis (such as that used to treat Brewer’s yeast extracts in the isolation of yeast GTF), yielding lower molecular weight, chromium-containing species. Given the similarity between the composition and certain properties of LMWCr and GTF (ie, both contain chromium, cysteine, glycine, and glutamic acid and ultraviolet absorption features at about 260 nm) and the fact that GTF was first isolated from acid-hydrolyzed porcine kidney powder, it has been suggested that GTF may be an artifact resulting from the acid hydrolysis of LMWCr [38]. It should be noted that the pioneering studies in the late 1950s that identified GTF were designed and directed toward identifying a heat-stable, acid-stable vitamin or cofactor [55]. They did identify chromium as a necessary cofactor, while unfortunately destroying any proteinaceous material associated with chromium. The resultant association between GTF and LMWCr could potentially resolve some of the conflict regarding the nature of GTF, as the products of the hydrolysis of the extracts could be very sensitive to experimental conditions.

	CONCLUSIONS

TOP ABSTRACT INTRODUCTION BACKGROUND LOW-MOLECULAR-WEIGHT CHROMIUM... CONCLUSIONS REFERENCES

 
Establishing a link between the nutrient chromium and the symptoms of its deficiency at a molecular level has been a long and often controversial pursuit. A potential solution involving the ability of the oligopeptide LMWCr to potentiate insulin’s activation of insulin receptor tyrosine kinase activity appears to be the closest approach to a solution to date, yet many questions need to be answered. For example, the three-dimensional structure of LMWCr remains to be established, and its activation of insulin receptor kinase activity has only been demonstrated in vitro to date. Hopefully, further studies to test the hypothesis that LMWCr plays a crucial role in insulin signal amplification will help to establish the link between chromium and proper carbohydrate and lipid metabolism.

	ACKNOWLEDGMENTS

 
Work on LMWCr in the laboratory of J.B.V. is funded by the NRICGP/USDA 97-35200-4259.

Received October 1, 1998. Accepted November 1, 1998.

	REFERENCES

TOP ABSTRACT INTRODUCTION BACKGROUND LOW-MOLECULAR-WEIGHT CHROMIUM... CONCLUSIONS REFERENCES

 

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