high-dose chromium(iii) supplementation has no effects on body mass and composition while altering...

High-Dose Chromium(III)Supplementation Has No Effects on Body Mass and CompositionWhile Altering Plasma Hormone and Triglycerides Concentrations

RANDALL BENNETT,1 BOBBI ADAMS,1 AMANDA FRENCH,1

YASMIN NEGGERS,2 AND JOHN B. VINCENT*,1

Departments of 1Chemistry and Coalition for BiomolecularProducts and 2Human Nutrition and Coalition for Biomolecular

Products, The University of Alabama, Tuscaloosa, AL 35487-0158

Received November 8, 2005; Accepted January 6, 2006

ABSTRACT

Chromium is generally believed to be an essential element and isoften claimed to have value as a weight loss or muscle building agent.Recent studies in humans and rats have failed to demonstrate effects onbody composition, although recent studies with pharmacological doses ofthe cation [Cr(III)3O(O2CCH2CH3)6(H2O)3]+ (or Cr3) (≤1 mg Cr/kg bodymass) in rats have noted a trend toward body mass loss and fat mass loss.Thus, the effects of large gavage doses of Cr3 (1–10 mg Cr/kg) on bodymass, organ mass, food intake, and blood plasma variables (insulin, glu-cose, leptin, cholesterol, and triglycerides) were examined over a 10-wkperiod using male Sprague–Dawley rats. No effects on body compositionwere noted, although Cr3 administration lowered (p < 0.05) plasmainsulin, leptin, and triglycerides concentrations. As Cr3 is absorbed greaterthan 10-fold better than commercially available nutritional supplements,the lack of an effect of the Cr(III) compound at these levels of administra-tion clearly indicates that Cr(III) supplements do not have an effect onbody composition at any reasonable dosage.

Index Entries: Chromium; aspartame; saccharin; insulin; leptin; cho-lesterol; Cr3; rats; body composition.

Biological Trace Element Research 53 Vol. 113, 2006

© Copyright 2006 by Humana Press Inc.All rights of any nature, whatsoever, reserved.0163-4984/(Online) 1559-0720/06/11301–0053 $30.00

* Author to whom all correspondence and reprint requests should be addressed.

INTRODUCTION

In developed countries, such as the United States, more than half ofthe adult population can be classified as overweight or obese (1). Nearly50 million Americans go on a diet each year, yet only 5% keep off theweight they lose. Obesity increases the likelihood of developing conditionssuch as type 2 diabetes, cancer, and heart disease. In the last 15 yr, nutri-tional studies have suggested that chromium (Cr) in the +3 oxidation statehas a role in insulin-dependant carbohydrate and lipid metabolism inmammals (2–4). As Cr’s role might involve potentiation of insulin signal-ing, increasing insulin sensitivity, Cr has been proposed to elicit an effecton body composition. Initial studies reported that dietary Cr supplemen-tation could potentially reduce fat mass and increase lean body mass (5–9).However, well-controlled follow-up studies were unable to support theeffect of Cr on body composition in humans (10–17). A recent comprehen-sive review (18) and recent meta-analyses (19,20) have clearly establishedthat Cr supplementation has no effect on body mass or composition ofhealthy individuals. However, Cr remains the second largest selling min-eral supplement after calcium.

Recently, gavage administration of the trinuclear chromium(III) com-plex [Cr3O(O2CCH2CH3)6(H2O)3]+ (also known as Cr3) has been shown tolower plasma insulin, total and low-density lipoprotein (LDL) cholesterol,and triglycerides levels of healthy rats (21). In association with thesechanges in blood variables, a trend toward loss of body mass with increas-ing Cr dosage and a statistically significant loss of epididymal fat at thehighest Cr3 dosage (1 mg Cr/kg body mass) was noted (21). Given thatCr3 is absorbed with 40–60 efficiency (22), over 10-fold greater than that ofcommercial chromium(III) supplements such as chromium picolinate andchromium nicotinate (23,24) and the large doses of Cr used in rat studiescompared to human studies, these observations could suggest that highdoses of Cr3 (and potentially other forms of Cr) could effect body compo-sition at high dosages.

Additionally, effects of high doses of Cr(III) compounds have beenreported to lower the concentration of the hormone leptin in blood plasmaor serum (25–27). Leptin is an adipocyte hormone that signals the brainabout the fat content of the body, resulting in changes in appetite. Sun etal. (25) found that rats on a basal or high-fat diet receiving 1, 2, or 3 mgCr/kg diet for 8 wk had lower serum leptin levels (p < 0.05) than those ofcontrols. Similarly, Wang et al. (26) have found that rats fed a high-fat dietsupplemented with 3 mg Cr/kg for 5 wk possessed lower leptin levelsthan those of controls on the high-fat diet. As blood leptin levels mightreflect fat composition with increased percent body fat leading toincreased leptin levels, lowering of leptin by Cr treatment could suggestthe existence of effects on body composition.

Herein are reported the results of a study to test whether Cr3 can havean effect on body composition at high dosages and to determine whetherCr supplementation can affect plasma leptin levels.

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Biological Trace Element Research Vol. 113, 2006

MATERIALS AND METHODS

[Cr3O(O2CCH2CH3)6(H2O)3]NO3, Cr3, and ArtificialSweeteners

The nitrate salt of the trinuclear Cr(III) cation, Cr3, was prepared asdescribed in the literature (28). The artificial sweeteners saccharin andaspartame were obtained from ACROS Organics (New Jersey, USA) andSigma Chemical Co. (St. Louis, MO, USA), respectively. All operationswere performed with doubly-deionized water unless otherwise noted andwere performed with plasticware whenever possible.

Animals

All rats were obtained from Charles River Laboratories, Inc. (Wilm-ington, MA, USA). The 5-wk-old male Sprague–Dawley rats were allowedto feed ad libitum on a commercial rat food (Harland Tekland CertifiedLM-485 Mouse/Rat Sterilizable Diet) and tap water and allowed to accli-mate to their surroundings for 1 wk before the initiation of the experi-ments. The commercial food provides a Cr-adequate diet (21). Rats wereraised in standard plastic and stainless-steel cages on a 12-h light–darkcycle. Forty-eight Sprague–Dawley rats were divided randomly into sixgroups of eight. The first group was gavaged daily with an aqueous solu-tion containing Cr3 to give a total amount of Cr equivalent to 1 mg Cr/kgbody weight. The second group received daily an aqueous solution of Cr3equivalent to 5 mg Cr/kg body mass. The third group received daily anaqueous solution of Cr3 equivalent to 10 mg Cr/kg body mass. The fourthand fifth groups were provided a 0.1% aqueous solution of aspartame orsaccharin instead of normal drinking water. The last group was gavageddaily with an equal volume of water as the Cr3-treated rats and served asthe control group. Solid food intake and body mass were monitored every4 d. The amount of water consumed by the control and the amount of arti-ficial-sweetener-treated water consumed by the fourth and fifth groupswere monitored every day. After 10 wk, the rats were sacrificed by CO2asphyxiation. The liver, kidney, heart, spleen, testes, pancreas, epididymalfat, perirenal fat, and subcutaneous fat were quickly harvested andweighed on plastic weigh boats. The University of Alabama InstitutionalAnimal Use and Care Committee approved all experiments involving rats.

Blood Chemistry

Blood (approx 1.5–2.0 mL) was collected from tail snips intopolypropylene tubes after 5 and 10 wk of administration of the[Cr3O(O2CCH2CH3)6(H2O)3]+, H2O, saccharin, and aspartame. Prior toblood collection, the rats were fasted for 12–16 h. The 0.1% aspartame andsaccharin solutions were replaced during this time with water. Immedi-ately after blood removal, 0.5 mg/mL heparin and 10 mg/mL NaF were

Cr(III) Supplements Do Not Affect Body Composition 55


added to the blood. The blood was then immediately centrifuged; theblood plasma was tested for glucose, total cholesterol, triglycerides, andhigh-density lipoprotein (HDL) cholesterol levels using diagnostic kitsfrom Pointe Scientific Inc. (Canton, MI, USA), for insulin levels using anti-body-coated kits from MP Biomedicals (Orangeburg, NY, USA), and forleptin levels using precoated microplates from R&D Systems Inc. (Min-neapolis, MN, USA). Ultraviolet (UV)–visible absorbance measurementswere made with a Hewlett-Packard 8453 spectrophotometer. Gammacounting was performed with a Packard Cobra II auto-gamma counter.

Statistical Analyses

Data were stratified by weeks of dietary Cr3 treatment or treatmentwith aspartame and saccharin into two groups (5 and 10 wk). In eachgroup of Sprague–Dawley rats, analysis of variance (ANOVA) was used totest the difference in mean concentrations of plasma variables: glucose,insulin, cholesterol, triglycerides, HDL, LDL, and leptin by four levels ofdietary Cr: control or 0, 1, 5, and 10 mg Cr/kg body mass. Differences inmean organ mass by the four dietary Cr levels were also tested byANOVA. Differences in blood variables and organ masses between controland artificial-sweetener-treated groups were evaluated using a pooled Stu-dent’s t-test. The level of significance for all analyses was set at p < 0.05.Data were analyzed using SAS software (version 9.1). Numerical values inthe tables and the text are presented as mean ± the standard deviation.

RESULTS

Body Composition and Food and Water Intake

There was not a statistically significant difference (p > 0.05) in the per-cent mass gain (average mass gain/average mass on d 1 × 100%) of thecontrol group and the treated groups throughout the 10-wk period (Fig. 1).All of the rats appeared normal throughout, and no visible differenceswere observed among any of the groups. As expected from the lack of asignificant body mass difference, the food intakes of the different groupswere also not statistically different throughout the experimental period(Fig. 2). (The decrease in food intake at d 32 resulted from the first fastingperiod before blood sampling, which occurred during this time period.)Thus, neither Cr3 nor the artificial sweeteners had any effect on body massor food intake. In contrast, saccharin treatment resulted in a distinctincrease in the amount of water consumed by the rats compared to that ofthe control, and rats receiving aspartame consumed an amount of waterequivalent to that of the control group (Fig. 3). The lack of a statistical dif-ference in body mass and food intake as a function of Cr-complex admin-istration of rats is consistent with numerous other studies (21,29–33),although these studies involved lower levels of Cr. The increase in water

56 Bennett et al.


intake with saccharin but not aspartame at 0.1% concentration is also con-sistent with previous results (34,35). The results with aspartame on bodycomposition are in contradiction to those of Beck et al. (36), who providedmale Long–Evans rats a solution of 0.1% aspartame for drinking water for14 wk. Aspartame treatment resulted in lower body masses (p < 0.05) after



Fig. 1. Percent body mass increase of male Sprague–Dawley rats adminis-tered Cr3 or artificial sweeteners. No significant differences between control andsupplemented groups were found.

Fig. 2. Food intake of male Sprague–Dawley rats administered Cr3 or artifi-cial sweeteners. No significant differences between control and supplementedgroups were found.

4 wk of treatment and an 8% loss (p < 0.02) of mass compared to those ofcontrols by the end of the experiment. Other than the use of differentstrains of rats, no explanation is apparent for the discrepancy between theresults. However, the results of Beck et al. on body mass are also not con-sistent with the work of other laboratories (37). Additionally, a review ofhuman studies using aspartame has indicated that aspartame does nothave any effect of food intake or body mass (38). The Long–Evans rats didnot have increased food intake or fluid intake compared to controls (36), inagreement with the results with the Sprague–Dawley rats.

Tissue Mass

Comparison of the tissue masses after 10 wk of treatment revealed nostatistically significant effects from any of the treatments (Table 1). A lackof any statistically significant effect of treatment of Cr3 is consistent withprevious results using lower doses of the Cr compound (21,29–33). A sta-tistically significant decrease in epididymal fat mass upon gavage treat-ment of male Sprague–Dawley rats with 1 mg Cr/kg as Cr3, but not 0.500or 0.250 mg Cr/kg, for 24 wk was observed (21). This suggested that thehighest dose of Cr3 previously examined might point toward an effect oflarge doses of the compound on fat mass. Given the variability of thisresult from experiment to experiment, this potentially important observa-tion required reproduction before any true significance could be associatedwith it. The lack of any effect in the current work suggests that the previ-ous observation was a statistical anomaly.

58 Bennett et al.


Fig. 3. Fluid intake of male Sprague–Dawley rats administered artificialsweeteners.

Similarly to Cr3, neither artificial sweetener had any effect on tissuemass. Again, this is not in agreement with the results of Beck et al. (36),who observed that Long–Evans rats receiving 0.1% aspartame-containingdrinking water had lower epididymal, subcutaneous, and perirenal fatmass than controls. The mass of the heart, liver, and spleen were notaffected by the treatment (36).

With one exception, all of the tissues appeared normal, and no visibledifferences were observed among any of the groups in the current study.The exception was the livers of the aspartame-treated rats, which pos-sessed a distinct gray color compared to the livers of the other groups.

Blood Variables

A distinct downward trend in insulin concentration was observed asa function of increased Cr dosage after 5 wk of treatment, but this effectwas not statistically significant. However, as observed previously withgavage administration of Cr3 to healthy rats (and diabetic model rats) (21),Cr3 was found to result in significant lowering of blood plasma insulinconcentrations (1, 5, and 10 mg Cr/kg) after 10 wk of treatment, and thiseffect was dependent on the Cr dosage (Table 2). Similarly, after 10 wk oftreatment, plasma triglycerides dropped as the Cr dosage was increased,again consistent with the results of earlier studies using Cr3 given intra-venously or orally (21,39,40). In contrast to previous studies with lowerdoses of Cr (21,39,40), plasma glucose levels dropped as a function of Crdosage after 5 wk of treatment, but the effect was largely ameliorated after10 wk of treatment. Cr3 had no effect on plasma HDL levels, as has beennoted previously (21,39,40). Although after 10 wk of treatment, the levels



Table 1Percentage of Relative Organ Mass (Tissue Mass/Body Mass × 100%) of Male Sprague–Dawley Rats After 10 wk of Administration of Cr3

and Artificial Sweeteners

Note: Values are means ± standard deviation; eight rats per group. No variables were sig-nificantly different between treated rats and the control group at p < 0.05.

of plasma cholesterol and LDL cholesterol appeared to drop with Cradministration, the effect is not statistically significant. This result is incontrast to earlier studies with Cr3 in which the decrease has been statisti-cally significant (39,40). Additionally, Cr3 administration led to lowerplasma leptin concentrations in a dose-dependent fashion. The lowering ofleptin levels is also consistent with previous reports using other forms ofCr (25,26). The lowering of plasma leptin levels without an appreciableeffect on body mass or fat mass indicates that the drop in leptin is not sim-ply a result of less fat being present to produce the hormone.

After 5 wk of administration in the drinking water, aspartame wasfound to lower plasma glucose, insulin, and leptin concentrations; how-ever, after 10 wk of administration, these differences were no longerobserved. However, plasma LDL cholesterol levels and triglycerides levelswere lower in the rats receiving aspartame for 10 wk. Beck et al. (36) havepreviously observed that Wistar rats receiving 0.1% aspartame in theirdrinking water possessed lower leptin levels after 14 wk of treatment; thislowering of leptin levels could be correlated with a loss of fat mass and

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Table 2Effects of the Cr3 and Artificial Sweeteners on Plasma Variables of Male

Sprague–Dawley Healthy Rats After 5 and 10 wk of Administration

Note: Values are means ± standard deviation; eight rats per group. For each variable for ratsreceiving Cr, means with different superscripts are significantly different from those of the con-trol (p < 0.05). For rats receiving the artificial sweeteners, asterisks indicate variables signifi-cantly different from those of the control (p < 0.05).

body mass. Again, the current study has failed to reproduce the results ofBeck et al. The original design of this study was to utilize the sweetener-treated rats as a positive control based on the results of Beck et al. Saccha-rin-treated rats possessed significantly lower concentrations of leptin after5 wk of treatment, but no plasma variables except triglycerides differedfrom controls after 10 wk of treatment. Consequently, the sweetenersappear to have effects at the early stage of the study, but these effects gen-erally disappear by the 10th week of treatment.

DISCUSSION

The in vivo effects of administration of Cr3 to healthy and type 1 andtype 2 diabetic model rats have previously been examined (21,39,40). (Thesynthetic cation was initially given intravenously to avoid potential differ-ences in absorption between the healthy and diabetic model rats.) After 24wk of intravenous administration (0–20 µg Cr/kg body mass) to healthymale rats, Cr3 resulted in a concentration-dependent lowering of levels offasting blood plasma LDL cholesterol, total cholesterol, triglycerides, andinsulin and of 2-h plasma insulin and glucose levels after a glucose chal-lenge (40). These results confirmed the results of previous 12-wk studyexamining the effect of the synthetic cation on healthy rats (39) and are instark contrast to those from the administration of other forms of Cr(III) tohealthy rats, which have no effects on these parameters (30). The cationhad little, if any, effect on rats with streptozotocin-induced (type 1 model)diabetes. This might have resulted from the increased variation in bloodvariables measurements for these rats compared to those of controls, suchthat insufficient power existed to observe any potential effects. However,Zucker obese rats (an early-stage type 2 diabetes model) after 24 wk ofsupplementation (20 µg/kg) had lower fasting plasma total cholesterol,triglycerides, insulin, and LDL and HDL cholesterol levels and lower 2-hplasma insulin levels after a glucose challenge. The lowering of plasmainsulin concentrations with little effect on glucose concentrations suggeststhat the supplement increases insulin sensitivity (40). No acute toxic effectswere observed for supplementation with the compound (41), and it doesnot give rise to DNA damage in in vitro studies as was observed withchromium picolinate (42).

The effects of oral (gavage) administration of the complex have alsobeen examined (21). For levels of 250, 500, or 1000 µg Cr/kg body mass,the treatment at all doses lowered fasting plasma insulin, triglycerides,total cholesterol, and LDL cholesterol levels of healthy rats while havingno effect on plasma glucose or HDL cholesterol. These levels were lowerafter 4 wk of treatment and remained lower for the next 20 wk of treat-ment. The maintenance of glucose levels with less insulin indicatesincreased insulin sensitivity. Both plasma glucose and insulin levels werelowered in 2-h glucose tolerance tests. Additionally, the healthy rats receiv-



ing the largest dose of Cr tended to possess less body mass than controlsand had approx 10% less epididymal fat; this tendency toward less bodymass [also observed in earlier studies with Cr3 (39,40)] and loss of fat sug-gested the possibility that Cr3 could potentially affect body composition atthe highest doses. In Zucker obese rats, the early-stage type 2 diabetesmodel, receiving 1000 µg Cr/kg body mass, the results were similar tothose from intravenous administration. Also in this same study, the effectsof the Cr3 on ZDF rats, a genetic model for type 2 diabetes, were alsoexamined using 1000 µg Cr/kg body mass. Again, fasting plasma insulin,triglycerides, total cholesterol and LDL cholesterol levels were all lowerwhile glucose concentrations were consistently but not statistically lower.HDL levels were lowered from their very high levels. Two-hour plasmainsulin levels were also lowered. Plasma glycated hemoglobin levels, ameasure of longer-term blood glucose status, were examined in thehealthy, Zucker obese, and ZDF rats after 4, 12, and 24 wk of treatment. Noeffect was seen for the healthy rats; however, significant effects were notedfor the diabetic models. For the ZDF rats, glycated hemoglobin was lowerafter 12 and 24 wk of treatment, reaching almost a 22% drop compared toZDF controls by wk 24; for the Zucker obese rats, glycated hemoglobinwas 27% lower at wk 24. Control studies using an intravenous injectioncontaining an amount of propionate equivalent to that received in thelargest dose used earlier have not observed similar effects (21).

The effects of Cr3 on healthy and model diabetic rats have also beenexamined by Debski and co-workers (43,44). Male Wistar rats were pro-vided a control diet or a diet containing 5 mg Cr/kg diet as the cation for10 wk. Blood plasma insulin levels were lowered 15.6% by the Cr-contain-ing diet, and glucose transport by red blood cells was increased 9.6% (43).In another study, this group utilized male Wistar rats with streptozotocin-induced diabetes. Using similar diets for 5 wk, the rats given the Cr diethad lower blood serum glucose levels (26%) and increased HDL levels(14%) (44).

The effects of Cr3 might result from the intact complex [it has beenproposed to activate the tyrosine kinase activity of insulin-stimulatedinsulin receptor (45)] or might result from Cr3 being a particularly efficientmeans by which to incorporate Cr into cells. At a nutritionally relevantlevel (3 µg Cr/kg body mass) and a pharmacologically relevant level (3mg/kg), at least 60% and 40% of the compound, respectively, is absorbedin 24 h when given by gavage administration to rats (22). This representsan approx 10-fold increase over those of chromium picolinate (marginallysoluble in water, 0.6 mM), CrCl3 (which oligimerizes in water), andchromium nicotinate [Cr(nic)2(OH), insoluble in water] (23,24). The solu-bility of the Cr3 and its stability thus allow a unique amount of the mate-rial to enter the circulatory system and tissues. During the first 24 h afterintravenous injection, the fate of 51Cr-labeled Cr3 in tissues, blood, urine,and feces has been followed (46). Remarkably, the complex is readily incor-porated into tissues and cells. The complex rapidly disappears from the

62 Bennett et al.


blood (<30 min) as radiolabeled Cr from the cation appears in tissues. Inhepatocytes, the intact cation is efficiently transported into microsomes,where its concentration reaches a maximum in approx 2 h (and corre-sponds to >90% of Cr in the cells from the injected complex); this suggeststhat the cation is actively transported into cells via endocytosis; identifica-tion of the protein(s) responsible is needed. As the complex is degraded inhepatocytes and the levels in microsomes rapidly decrease, Cr appears inthe urine as chromodulin (or a similar molecular-weight chromium-bind-ing species). The synthetic complex is degraded before or during its dis-appearance from the microsomes. Rats have also been given the 51Cr- or14C-labeled complex by intravenous injection daily for 2 wk (47). Thirtypercent of the injected Cr was lost daily as chromodulin or a similarspecies; only very small amounts are lost in the feces. The tissue and sub-cellular hepatocyte distribution of Cr after 2 wk was examined; no intactcomplex could be detected. Only approx 3% of the propionate from eachinjection of the complex was lost daily; the tissue and cellular distributionof derivatized propionate after 2 wk varied greatly from that of Cr. Thus,the active transport of Cr3 is different from the transport of all other syn-thetic forms of Cr proposed as dietary supplements; these proposed sup-plements appear to enter cells passively by diffusion. Hence, Cr3 has asignificantly greater ability to enter cells than other Cr supplements andcan bring about positive changes in carbohydrate and lipid metabolismunlike other Cr supplements.

In contrast, for example, chromium chloride and chromium picolinateat comparable oral doses (30) to previous gavage studies with Cr3 (21) notonly had no effects on body mass or body composition but also had noeffects on plasma blood variables (total cholesterol, triglycerides, and glu-cose). Given this, Cr3 might be more likely to have effects on body com-position at higher dosage than other Cr(III) compounds examined to datebecause of its effects on blood variables at the lower dosages. However,this clearly is not the case. Given that a daily dose of 10 mg Cr/kg bodymass for a rat corresponds to an average body mass human daily takingover a gram of Cr (this is far in excess of the 200 µg Cr generally takendaily in human nutritional supplements), these data in rats in which noeffects of high-dose Cr supplementation are observed on body mass orbody composition clearly indicate that no such body changes should beexpected in humans. Thus the results of this study are in accord withrecent reviews and meta-analyses (18–20) on the effects of Cr on bodycomposition in humans.

CONCLUSIONS

The results of this study using very high doses of Cr(III) as Cr3demonstrate that Cr(III) has no effect on body composition and body massin rats. These results combined with recent analyses of data on human sub-



jects taking Cr supplements suggests that no effects should be anticipatedon body mass or body composition in humans taking much lower levels ofCr supplements. Cr3 was found to result in lower leptin levels in bloodplasma after 5 and 10 wk of gavage administration at doses from 1 to 10mg Cr/kg body mass. The effects of Cr(III) compounds on plasma leptinis an area worthy of continued investigation.

ACKNOWLEDGMENT

The authors wish to thank Dontarie Stallings, James A. Neville, andthe staff of The University of Alabama Animal Care Facility for assistancewith the rat studies. A.F. was supported by the undergraduate researchcomponent of a Howard Hughes Medical Research Institute Award to TheUniversity of Alabama; B.A. was supported by the McNairs Scholars pro-gram at The University of Alabama. J.B.V. is the inventor or co-inventor offive patents on the use of Cr-oligopeptides or Cr3 as nutritional supple-ments or therapeutic agents.

REFERENCES

1. K. M. Flegal, M. D. Carrol, C. L. Ogden, and C. L. Johnson, Prevalence and trends inobesity among US adults 1999–2000, JAMA 288, 1723–1727 (2002).

2. J. B. Vincent, The bioinorganic chemistry of chromium(III), Polyhedron 20, 1–26 (2001).3. J. B. Vincent, Elucidating a biological role for chromium at a molecular level, Acc. Chem.

Res. 33, 503–510 (2000).4. H. C. Lukaski, Chromium as a supplement, Annu. Rev. Nutr. 19, 279–301 (1999).5. G. W. Evans, The effect of chromium picolinate on insulin controlled parameters in

humans, Int. J. Biosoc. Med. Res. 11, 163–180 (1989).6. G. R. Kaats, J. A. Wise, K. Blum, et al., The short-term therapeutic efficacy of treating

obesity with a plan of improved nutrition and moderate calorie restriction, Curr. Ther.Res. 51, 261–274 (1992).

7. G. R. Kaats, K. Blum, J. A. Fisher, and J. A. Adelman, Effects of chromium picolinatesupplementation on body composition: a randomized double-masked placebo-con-trolled study, Curr. Ther. Res. 57, 747–756 (1996).

8. R. Bulbulian, D. D. Pringle, and M. S. Liddy, Chromium picolinate supplementation inmale and female swimmers, Med. Sci. Sport. Exerc. 28(5 Suppl.), S111 (1996).

9. B. Bahadori, S. Wallner, H. Schneider, T. C. Wascher, and H. Topak, Effects of chromiumyeast and chromium picolinate on body composition in obese non-diabetic patients dur-ing and after a very low-calorie diet, Acta Med. Austr. 24, 185–187 (1997) (in German).

10. S. P. Clancy, P. M. Clarkson, M. E. DeCheke, et al., Effects of chromium picolinate sup-plementation on body composition, strength and urinary chromium loss in footballplayers, Int. J. Sport Nutr. 4, 142–153 (1994).

11. L. K. Trent and D. Thielding-Canel, Effects of chromium picolinate on body composi-tion, J. Sports Med. Phys. Fitness 35, 273–280 (1995).

12. H. C. Lukaski, W. Bolonchuk, W. A. Siders, and D. B. Milne, Chromium supplementa-tion and resistance training: effects on body composition, strength, and trace elementstatus of men, Am. J. Clin. Nutr. 63, 954–965 (1996).

64 Bennett et al.


13. M. A. Hallmark, T. H. Reynolds, C. A. DeSouza, C. G. Dotson, R. A. Anderson, and M.A. Rogers, Effects of chromium on resistance training on muscle strength and bodycomposition, Med. Sci. Sports Exerc. 28, 139–144 (1996).

14. W. J. Pasman, M. S. Westerperp-Plantenga, and W. H. M. Saris, The effectiveness oflong-term supplementation of carbohydrate, chromium, fibre, and caffeine on weightmaintenance, Int. J. Obes. Related Metab. Disord. 21, 1143–1151 (1997).

15. W. W. Campbell, L. J. Joseph, S. L. Davey, D. Cyr-Campbell, R. A. Anderson, and W. J.Evans, Effects of resistance training and chromium picolinate on body composition andskeletal muscle in older men, J. Appl. Physiol. 86, 29–39 (1999).

16. R. I. Press, J. Geller, and G. W. Evans, The effect of chromium picolinate on serum cho-lesterol and apolipoprotein fractions in human subjects, West. J. Med. 152, 41–45 (1990).

17. R. B. Krieder, R. Klesges, K. Harmon, et al., Effects of ingesting supplements designedto promote lean muscle tissue accretion on body composition during resistance train-ing, Int. J. Sports Nutr. 6, 234–246 (1996).

18. J. B. Vincent, The potential value and toxicity of chromium picolinate as a nutritionalsupplement, weight loss agent and muscle development agent, Sports Med. 33, 213–230(2003).

19. M. H. Pittler, C. Stevinson, and E. Ernst, Chromium picolinate for reducing bodyweight: meta-analysis of randomized trials, Int. J. Obes. 27, 522–529 (2003).

20. S. L. Nissen and R. L. Sharp, Effect of dietary supplements on lean mass and strengthgains with resistance exercise: a meta-analysis, J. Appl. Physiol. 94, 651–659 (2003).

21. B. J. Clodfelder, B. M. Gullick, H. C. Lukaski, Y. Neggers, and J. B. Vincent, Oral admin-istration of the biomimetic [Cr3O(O2CCH2CH3)6(H2O)3]+ increases insulin sensitivityand improves blood plasma variables in healthy and type 2 diabetic rats, J. Biol. Inorg.Chem. 10, 119–130 (2005).

22. B. J. Clodfelder, C. Chang, and J. B. Vincent, Absorption of the biomimetic chromiumcation triaqua-µ3-oxo-µ-hexapropionatotrichromium(III) in rats, Biol. Trace Element Res.98, 159–169 (2004).

23. K. L. Olin, D. M. Stearns, W. H. Armstrong, and C. L. Keen, Comparativeretention/absorption of 51chromium (51Cr) from 51Cr chloride, 51Cr nicotinate and 51Crpicolinate in a rat model, Trace Elements Electrolytes 11, 182–186 (1994).

24. R. A. Anderson, N. A. Bryden, M. M. Polansky, and K. Gauteschi, Dietary chromiumeffects on tissue chromium concentrations and chromium absorption in rats, J. Trace Ele-ments Exp. Med. 9, 11–25 (1996).

25. C. Sun, W. Zhang, S. Wang, and Y. Zhang, Effect of chromium gluconate on body weight,serum leptin and insulin in rats, Wei Sheng Yan Jiu 29, 370–371 (2000) (in Chinese).

26. S. Wang, C. Sun, Q. Kao, and C. Yu, Effects of chromium and fish oil on insulin resist-ance and leptin resistance in obese developing rats, Wei Sheng Yan Jiu 30, 284–286 (2001)(in Chinese).

27. B. M. Gullick, Ph.D. dissertation, The University of Alabama, Tuscaloosa (2005).28. A. Earnshaw, B. N. Figgis, and J. Lewis, Chemistry of polynuclear compounds. Part VI.

Magnetic properties of trimer chromium and iron carboxylates, J. Chem. Soc. 1656–1663(1966).

29. J. S. Striffler, J. S. Law, M. M. Polansky, S. J. Bhathena, and R. A. Anderson, Chromiumimproves insulin response to glucose in rats, Metabolism 44, 1314–1320 (1995).

30. R. A. Anderson, N. A. Bryden, and M. M. Polansky, Lack of toxicity of chromium chlo-ride and chromium picolinate in rats, J. Am. Coll. Nutr. 16, 273–279 (1997).

31. D. L. Hasten, M. Hegsted, M. J. Keenan, and G. S. Morris, Effects of various forms ofdietary chromium on growth and body composition in the rat, Nutr. Res. 17, 283–294(1997).

32. D. L. Hasten, M. Hegsted, M. J. Keenan, and G. S. Morris, Dosage effects of chromiumpicolinate on growth and body composition in the rat, Nutr. Res. 17, 1175–1186 (1997).



33. G. S. Morris, K. A. Guidry, M. Hegsted, and D. L. Hasten, Effects of dietary chromiumsupplementation on cardiac mass, metabolic enzymes, and contractile proteins, Nutr.Res. 15, 1045–1052 (1995).

34. A. Sclafani and M. Abrams, Rats show only a weak preference for the artificial sweet-ener aspartame, Physiol. Behav. 37, 253–256 (1986).

35. J. C. Smith, T. W. Castonguay, D. F. Foster, and L. M. Bloom, A detailed analysis of glu-cose and saccharin drinking in the rat, Physiol. Behav. 24, 173–176 (1980).

36. B. Beck, A. Burlet, J.-P. Max, and A. Stricker-Krongrad, Effects of long-term ingestion ofaspartame on hypothalamic neuropeptide Y, plasma leptin and body weight gain andcomposition, Physiol. Behav. 75, 41–47 (2002).

37. K. P. Porikas and H. S. Koopmans, The effect of non-nutritive sweeteners on bodyweight in rats, Appetite 11(Suppl. 1), 12–15 (1998).

38. B. J. Rolls, Effects of intense sweeteners on hunger, food intake, and body weight: areview, Am. J. Clin. Nutr. 53, 872–878 (1991).

39. Y. Sun, K. Mallya, J. Ramirez, and J. B. Vincent, The biomimetic [Cr3O(O2CCH2CH3)6(H2O)3]+ decreases plasma cholesterol and triglycerides in rats: towards chromium-containing therapeutics, J. Biol. Inorg. Chem. 4, 838–845 (1999).

40. Y. Sun, B. J. Clodfelder, A. A. Shute, T. Irvin, and J. B. Vincent, The biomimetic[Cr3O(O2CCH2CH3)6(H2O)3]+ decreases plasma insulin, cholesterol and triglycerides inhealthy and type II diabetic rats but not type I diabetic rats, J. Biol. Inorg. Chem. 7,852–862 (2002).

41. J. K. Speetjens, A. Parand, M. W. Crowder, and J. B. Vincent, Low-molecular-weightchromium-binding substance and biomimetic [Cr3O(O2CCH2CH3)6(H2O)3]+ do notcleave DNA under physiologically relevant conditions, Polyhedron 18, 2617–2624 (1999).

42. J. K. Speetjens, R. A. Collins, J. B. Vincent, and S. A. Woksi, The nutritional supplementchromium(III) tris(picolinate) cleaves DNA, Chem. Res. Toxicol. 12, 483–487 (1999).

43. B. Debski, Z. Krejpcio, T. Kuryl, R. Wokciak, and M. Lipko, Biomimetic chromium(III)complex and frutan supplementation affect insulin and membrane glucose transport inrats, J. Trace Elements Exp. Med. 17, 206–207 (2004).

44. Z. Krejpcio, B. Debski, R. Wojciak, T. Kuryl, and M. Tubacka, Biomimetic chromium(III)complex and fructan supplementation improve blood variables in STZ-induced dia-betic rats, J. Trace Elem. Exp. Med. 17, 207–208 (2004).

45. C. M. Davis, A. C. Royer, and J. B. Vincent, Synthetic multinuclear chromium assemblyactivates insulin receptor tyrosine kinase activity: functional model for low-molecular-weight chromium-binding substance, Inorg. Chem. 36, 5316–5320 (1997).

46. A. A. Shute and J. B. Vincent, The stability of the biomimetic cation triaqua-µ-oxohexa-propionatotrichromium(III) in vivo in rats, Polyhedron 20, 2241–2252 (2001).

47. A. A. Shute and J. B. Vincent, The fate of the biomimetic cation triaqua-µ-oxohexapro-pionatotrichromium(III) in rats, J. Inorg. Biochem. 89, 272–282 (2002).

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high-dose chromium(iii) supplementation has no effects on body mass and composition while altering...

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