Is chromium(III) pharmacologically relevant? An update focused on studies with diabetic rodent models.

A decade ago, the author assessed the status of chromium as the trivalent ion as an essential element and as a therapeutic agent based on rodent studies for this journal. The current review was undertaken to update considerations regarding the status of chromium, focusing on studies of Cr supplementation of diabetic rodent models over the last decade. Cr can no longer be considered an essential trace element for humans. Observed effects of Cr on rodent models of insulin resistance and diabetes are best interpreted in terms of a pharmacological role for Cr. The review of studies on the effects of Cr on rat models of diabetes is updated, and the results continue to suggest Cr increases insulin sensitivity in peripheral tissues of the rodent models. The lack of effects in human studies may stem from humans receiving a comparably smaller dose than the rodent models. However, given the different responses to Cr in the rodent models, humans could potentially have different responses to Cr. Recent studies primary utilizing rodents suggest two potential complementary but also contradictory modes of action for Cr(III) at a molecular level.

What Are the Implications of Cr(III) Serving as an Inhibitor of the Beta Subunit of Mitochondrial ATP Synthase?

A recent report has shown the active site of the beta subunit of mitochondrial ATP synthase is probably the site of action of Cr(III) action, independent of the insulin signaling pathway. This works appears to answer an important question about the mode of action of Cr(III) at a molecular level when supplied in supra-nutritional levels to rodents. However, as with any good research, the research also raises several questions. The relationship between this study and the results of rodent studies of chromium supplementation and between this study and the current understanding the chromium(III) transport and detoxification system are put into perspective.

Effects of Bitter Melon and a Chromium Propionate Complex on Symptoms of Insulin Resistance and Type 2 Diabetes in Rat Models.

Trivalent chromium (Cr) and bitter melon (Momordica charantia L., BM) have been shown to independently interact with the insulin signaling pathway leading to improvements in the symptoms of insulin resistance and diabetes in some animal models and human subjects. The aim of this study was to examine whether the combination of the two nutritional supplements could potentially have additive effects on treating these conditions in high-fat-fed streptozotocin (STZ)-induced diabetic rats. The experiment was conducted with 110 male Wistar rats divided into eleven groups and fed either a control or high-fat diet for 7 weeks. Half of the rats on the high-fat diet were injected with STZ (30 mg/kg body mass) to induce diabetes. The high-fat (HF) diets were then supplemented with a combination of Cr (as chromium(III) propionate complex, Cr3: either 10 or 50 mg Cr/kg diet) and bitter melon (lyophilized whole fruit: either 10 or 50 g/kg diet) for 6 weeks. After termination of the experiment, blood and internal organs were harvested for blood biochemical, hematological, and mineral (Cr) analyses using appropriate analytical methods. It was found that neither Cr(III) nor BM was able to significantly affect blood indices in HF and diabetic rats, but BM tended to improve body mass gain, blood glucose, and LDL cholesterol values, but decreased Cr content in the liver and kidneys of the Cr-co-supplemented type 2 diabetic model of rats. Supplementary Cr(III) had no appreciable effect on glucose and lipid metabolism in high-fat-fed STZ-induced diabetic rats. Supplementary BM fruit powder had some observable effects on body mass of high-fat-fed rats; these effects seem to be dampened when BM was co-administered with Cr. Cr(III) and BM appear to act as nutritional antagonists when both administered in food, probably due to binding of Cr by the polyphenol-type compounds present in the plant material. Graphical Abstract.

Effects of chromium supplementation on body composition, human and animal health, and insulin and glucose metabolism.

PURPOSE OF REVIEW: Chromium(III) has been proposed to have a nutritional or pharmacological role in changing body composition and improving symptoms of insulin resistance, type 2 diabetes, and related conditions although the mode of action of Cr(III) at a molecular level has failed to be elucidated. This review details the current status of studies into Cr(III) supplementation. RECENT FINDINGS: Clinical trials, meta-analyses and systematic reviews have failed to demonstrate clinically significant effects from Cr(III) supplementation on body composition or symptoms of insulin resistance and related conditions in humans and farm animals. Although new Cr(III) supplements continue to appear in the scientific literature, studies have failed to elucidate the mechanism of chromium action at a molecular level. Conflicting results on a role of transferrin in Cr(III) transport and detoxification have appeared. SUMMARY: Cr(III) supplementation cannot currently be recommended in humans or farm animals. Further studies are required to probe the mechanism of Cr(III) action in increasing insulin sensitivity and glucose uptake in rodent models of insulin resistance and diabetes, with particular attention being turned to a potential role of transferrin in Cr(III) transport and detoxification.

Association of smoked cannabis with treatment resistance in schizophrenia.

Association of cannabis use with schizophrenia is a well-established finding. Its role in causation, however, is debated. Different studies have found that cannabis use impacts the outcome of schizophrenia and is associated with treatment non-adherence and a higher rate of relapses. In this paper, we investigated the impact of self-reported cannabis use on treatment response in a cohort of schizophrenia patients from Pakistan, a middle-income country. The data was collected from a psychiatric hospital in Khyber Pakhtunkhwa province of Pakistan where cannabis use is prevalent. Clinical evaluation and therapeutic response were established using the Positive and Negative Syndrome Scale (PANSS), and Clinical Global Impressions Scales-Severity (CGI-S) and Improvement (CGI-I) scale. Lack of response to adequate treatment with two trials of antipsychotics was classed as treatment resistance. We compared the treatment-resistant and treatment responsive groups for different variables including cannabis use, age at onset of illness, duration of untreated psychosis and consanguinity. We had data on 230 patients. More than ninety percent of our participants were men. The rate of treatment resistance was over 60%. Ongoing use of cannabis had an association with treatment resistance. We only included cases where treatment adherence was not a problem.

Systematic Review of the Effects of Chromium(III) on Chickens.

Chromium supplementation has been proposed to have beneficial effects in farm animals, particularly when under stress. The last two decades, in particular, have seen an emphasis on examining the effects of supplemental chromium on a variety of variables in chicks and chickens. Thus, given the recent approval of a Cr(III) compound for use in chicken feed in the United States and the recent surge in papers on the use of Cr in chicken feed, the need for a systematic review of studies utilizing chickens is extremely urgent and timely. With the exception of studies on cold-stressed laying hens, the results of studies of Cr supplementation of chickens, whether broilers or laying hens, were found to be too inconsistent for any firm conclusions to be drawn other than that Cr supplementation generally leads to accumulation of Cr in tissues. Few potential trends in terms or beneficial or deleterious effects from Cr supplementation were found regardless of strain of chicken, Cr source, Cr dose, duration of supplementation, or variable examined. Hence, in summary, no recommendation for the use of Cr as a supplement for the diet of chickens can be made at this time.

[Cr3O(O2CCH2CH3)6(H2O)3]NO3·H2O (Cr3) Toxicity Potential in Bacterial and Mammalian Cells.

Chromium(III) has generally been considered to be essential for proper carbohydrate and lipid metabolism, and, despite recent evidence to the contrary, chromium(III)-containing compounds remain one of the most popular commercial dietary supplements. Cr3, or [Cr3O(O2CCH2CH3)6(H2O)3]NO3·H2O, is a trivalent chromium compound that is a promising chromium nutritional supplement. Studies with Cr3 have indicated that it is non-toxic in developmental and short- and long-term exposure studies in rodents, but the safety of this compound to chromosomes and cells has not been explored. The current study evaluates the mutagenicity, cytotoxicity, and clastogenicity of Cr3 in bacterial and mammalian cells and compares these results with similar studies using the bestselling Cr(III) nutritional supplement, chromium picolinate (CrPic). The mutagenicity of CrPic and Cr3 was tested in Escherichia coli FX-11 and Salmonella typhimurium (TA 98 and TA 100). Cytotoxicity was measured as a decrease in plating efficiency relative to controls after treatment with Cr3 and CrPic for 24 h in CHO K1 cells. Clastogenicity was measured by counting the number of metaphases damaged and of the total number chromosomal aberrations in CHO K1 cells. Mutagenesis assays in E. coli and S. typhimurium were negative. All treatments of Cr3 produced ≥ 84% plating efficiency except 80 µg/cm2, which reduced the plating efficiency to 62%. Cr3 at any treatment level did not produce a significant increase in the number of cells with abnormal metaphases, while treatments using ≥ 40 µg/cm2 of CrPic elevated the number significantly. These data suggest that Cr3 is significantly less mutagenic in bacteria cells and less clastogenic in CHO K1 cells, while CrPic is clastogenic in CHO K1 cells.

New Evidence against Chromium as an Essential Trace Element.

Nearly 60 y ago, chromium, as the trivalent ion, was proposed to be an essential element, but the results of new studies indicate that chromium currently can only be considered pharmacologically active and not an essential element. Regardless, articles still continue to appear in the literature claiming chromium is an essential element. Chromium has been marketed as an agent to reduce body mass and develop muscle; however, such marketing claims are no longer allowed in the United States because these claims, similar to claims of essential status, are not supported by experiments. Trivalent chromium has also been proposed as a therapeutic agent to increase insulin sensitivity and affect lipid metabolism. Although effective in certain rodent models, beneficial effects in humans have not been unequivocally established. Molecular mechanisms have been proposed for the beneficial effects but have not been definitively shown to occur in animals.

Relative importance of abiotic, biotic, and disturbance drivers of plant community structure in the sagebrush steppe.

Abiotic conditions, biotic factors, and disturbances can act as filters that control community structure and composition. Understanding the relative importance of these drivers would allow us to understand and predict the causes and consequences of changes in community structure. We used long-term data (1989-2002) from the sagebrush steppe in the state of Washington, USA, to ask three questions: (1) What are the key drivers of community-level metrics of community structure? (2) Do community-level metrics and functional groups differ in magnitude or direction of response to drivers of community structure? (3) What is the relative importance of drivers of community structure? The vegetation in 2002 was expressed as seven response variables: three community-level metrics (species richness, total cover, compositional change from 1989 to 2002) and the relative abundances of four functional groups. We used a multi-model inference framework to identify a set of top models for each response metric beginning from a global model that included two abiotic drivers, six disturbances, a biotic driver (initial plant community), and interactions between the disturbance and biotic drivers. We also used a permutational relative variable importance metric to rank the influence of drivers. Moisture availability was the most important driver of species richness and of native forb cover. Fire was the most important driver of shrub cover and training area usage was important for compositional change, but disturbances, including grazing, were of secondary importance for most other variables. Biotic drivers, as represented by the initial plant communities, were the most important driver for total cover and for the relative covers of exotics and native grasses. Our results indicate that the relative importance of drivers is dependent on the choice of metric, and that drivers such as disturbance and initial plant community can interact.

Formation of oxo-centered trinuclear chromium carboxylate complexes and hydrolysis of Cr3 as established by paramagnetic (2)H NMR spectroscopy.

Paramagnetic (2)H NMR techniques have been utilized to study the mechanism of formation of the oxo-bridged trinuclear Cr(III) carboxylate assembly [Cr3O(O2CCD3)6(H2O)3](+) from [Cr(H2O)6](3+) and d4-acetic acid. These studies reveal a complex mechanism dominated by the involvement of dinuclear intermediates. The oxo-bridged trinuclear Cr(III) carboxylate assembly [Cr3O(O2CCH2CH3)6(H2O)3](+) has been suggested for use as a chromium nutritional supplement and therapeutic agent as it is readily absorbed and has been proposed to enter cells intact. The paramagnetic (2)H NMR technique has been utilized to follow the stability of this Cr(III) carboxylate assembly in biologically relevant media; its stability is consistent with the assembly being able to enter cells intact.

Urinary chromium excretion in response to an insulin challenge is not a biomarker for chromium status.

Over 50 years ago, chromium (Cr) was proposed to be an essential trace element; however, recent studies indicate that this status should be removed as the effects of Cr supplementation appear to be pharmacological rather than nutritional. The pharmacological basis for Cr's effects can explain the inability of investigators to discover a biomarker for Cr status. One potential biomarker has not been examined to date. Cr is known to be mobilized in the body in response to insulin (or insulin release in response to a glucose challenge), resulting in an increase in urinary Cr excretion. The magnitude of increase in urinary Cr loss as a function of dietary Cr intake was tested as a potential biomarker for Cr. Zucker lean rats housed in carefully controlled metal-free conditions were provided a series of purified diets containing variable Cr contents (from 16 µg/kg diet to 2,000 µg/kg) for 23 weeks. The 16 µg/kg diet contained less Cr than any diet examined to date. Urine samples were collected before and after insulin and glucose challenges (0, 2, 6, and 12 h postinjection). Urinary Cr levels were analyzed by the standard method of addition using graphite furnace atomic absorption. The rate of urinary Cr loss after a glucose or insulin challenge was found to not be dependent on the Cr content of the rats' diets. Blood iron levels of the rats were also measured to determine if the addition of Cr to the diet altered iron status. The Cr content of the diet was found to have no affect on blood iron levels. Overall, the study demonstrated that insulin-stimulated urinary Cr excretion cannot be used as a biomarker for Cr status.

Chromium: is it essential, pharmacologically relevant, or toxic?

Over fifty years ago, the element chromium (as the trivalent ion) was proposed to be an essential element for mammals with a role in maintaining proper carbohydrate and lipid metabolism. Evidence for an essential role came from dietary studies with rodents, studies on the effects of chromium on subjects on total parenteral nutrition, and studies of the absorption and transport of chromium. Over the next several decades, chromium-containing nutritional supplements became so popular for weight loss and muscle development that sales were second only to calcium among mineral supplements. However, the failure to identify the responsible biomolecules(s) that bind chromium(III) and their mode of action, particularly a postulated species named glucose tolerance factor or GTF, resulted in the status of chromium being questioned in recent years, such that the question of its being essential needs to be formally readdressed. At the same time as chromium(III)'s popularity as a nutritional supplement was growing, concerns over its safety appeared. While chromium has been conclusively shown not to have beneficial effects on body mass or composition and should be removed from the list of essential trace elements, chromium(III) compounds are generally nontoxic and have beneficial pharmacological effects in rodents models of insulin insensitivity, although human studies have not conclusively shown any beneficial effects. Mechanisms have been proposed for these pharmacological effects, but all suffer from a lack of consistent supporting evidence.

Long-term exposure to [Cr(3)O(O (2)CCH (2)CH (3)) (6)(H (2)O) (3)] (+) in Wistar rats fed normal or high-fat diets does not alter glucose metabolism.

The essentiality of chromium(III) has been the subject of much debate, particularly in healthy subjects. Chromium(III)-containing supplements are widely used for body mass loss, building of lean muscle mass, and improving glucose and lipid metabolism. [Cr(3)O(O(2)CCH(2)CH(3))(6)(H(2)O)(3)](+), Cr3, is one of the most-studied chromium nutritional supplements. The current study evaluates the effects of long-term (15 months) supplementation with Cr3 on body mass and glucose metabolism in Wistar rats on traditional and cafeteria-style (high fat, high carbohydrate) diets. Male Wistar rats were randomly assigned to one of four treatment groups: (1) control diet (milled Harlan Teklad LM-485 rodent diet), (2) control diet+1 mg Cr3/kg body mass/day, (3) a cafeteria-style (CAF) diet (high fat, high carbohydrate), or (4) CAF diet+1 mg Cr3/kg/day. Cr3 supplementation had no effect on fasting blood glucose levels or blood glucose levels in response to glucose and insulin challenges. Rats consuming the CAF+Cr3 diet tended to have a significantly higher body mass than rats consuming the CAF diet, but necropsy results showed no difference in visceral fat or body wall thickness between groups. These data suggest that long-term Cr3 supplementation does not significantly affect body mass in rats consuming a normal diet or glucose levels or metabolism in rats consuming either diet.

Comparison of tissue metal concentrations in Zucker lean, Zucker obese, and Zucker diabetic fatty rats and the effects of chromium supplementation on tissue metal concentrations.

Diabetes results in several metabolic changes, including alterations in the transport, distribution, excretion, and accumulation of metals. While changes have been examined in several rat models of insulin resistance and diabetes, the metal ion concentrations in the tissues of Zucker lean, Zucker obese (an insulin resistance and early stage diabetes model), and Zucker diabetic fatty (ZDF, a type 2 diabetes model) have not previously been examined in detail. The concentration of Cu, Zn, Fe, Mg, and Ca were examined in the liver, kidney, heart and spleen, and Cr concentration in the liver and kidney of these rats were examined. Zucker obese rats have a reduction in the concentration of Cu, Zn, Fe, Mg in the liver compared to ZDF and/or lean Zucker rats, presumably as a result of the increased fat content of the liver of the obese rats. ZDF rats have increased concentrations of kidney Cu compared to the lean rats, while kidney Ca concentrations are increased in the Zucker obese rats. Spleen Fe concentrations are decreased in Zucker obese rats compared to the lean rats. No effects on metal concentrations in the heart were observed between the lean, obese, and ZDF rats, and no effects on Cr concentrations were identified. Cr(III) complexes have previously been shown to have beneficial effects on the signs of insulin resistance in Zucker obese and ZDF rats. The effects of daily gavage administration of chromium picolinate ([Cr(pic)(3)]) (1 mg Cr/kg body mass), CrCl(3) (1 mg Cr/kg body mass), and Cr3 ([Cr(3)O(propionate)(6)(H(2)O)(3)](+)) (33 µg and 1 mg Cr/kg body mass) on metal concentrations in these tissues were examined. Treatment with CrCl(3) and Cr3, but not [Cr(pic)(3)], at 1 mg Cr/kg resulted in a statistically significant accumulation of Cr in the kidney of lean and obese but not ZDF rats but resulted in lowering the elevated levels of kidney Cu in ZDF rats, suggesting a beneficial effect on this symptom of type 2 diabetes.

The need for combined inorganic, biochemical, and nutritional studies of chromium(III).

The history of biochemical and nutritional studies of the element is unfortunately full of twists and turns, most leading to dead ends. Chromium (Cr), as the trivalent ion, has been proposed to be an essential element, a body mass and muscle development agent, and, in the form of the most popular Cr-containing nutritional supplement, to be toxic when given orally to mammals. None of these proposals, despite significant attention in the popular media, has proven to be correct. Trivalent chromium has also been proposed as a therapeutic agent to increase insulin sensitivity and affect lipid metabolism, although a molecular mechanism for such actions has not been elucidated. Greater cooperative research interactions between nutritionists, biochemists, and chemists might have avoided the earlier issues in nutritional and biochemical Cr research and is necessary to establish the potential role of Cr as a therapeutic agent at a molecular level.

Potential of chromium(III) picolinate for reproductive or developmental toxicity following exposure of male CD-1 mice prior to mating.

Chromium(III) picolinate, [Cr(pic)(3)], is a commonly used nutritional supplement in humans, which has also been approved for use in animals. Health concerns have arisen over the use of [Cr(pic)(3)]. At high [Cr(pic)(3)] doses, developmental toxicity tests in female mice have shown a higher litter incidence of split cervical arch in exposed fetuses, but this was not consistently reproducible. In the current study, male CD-1 mice were used to further assess the potential for reproductive or developmental toxicity. Four weeks prior to mating, the males were fed a diet providing 200 mg/kg/day [Cr(pic)(3)] for comparison with untreated controls. Females were not treated. Each male was mated with two females, which were sacrificed on gestation day 17, and their litters were examined for adverse effects. Mating and fertility indices were not significantly altered by treatment. Male exposure to [Cr(pic)(3)] also had no effect on prenatal mortality, fetal weight, or gross or skeletal morphology. These results suggest that paternal dietary exposure to chromium(III) picolinate has little potential for adverse reproductive effects, even at exposure levels considerably higher than expected human exposures from nutritional supplements (1 mg of Cr per day or less).

Chromium is not an essential trace element for mammals: effects of a "low-chromium" diet.

Chromium was proposed to be an essential trace element over 50 years ago and has been accepted as an essential element for over 30 years. However, the studies on which chromium's status are based are methodologically flawed. Whether chromium is an essential element has been examined for the first time in carefully controlled metal-free conditions using a series of purified diets containing various chromium contents. Male Zucker lean rats were housed in specially designed metal-free cages for 6 months and fed the AIN-93G diet with no added chromium in the mineral mix component of the diet, the standard AIN-93G diet, the standard AIN-93G diet supplemented with 200 µg Cr/kg, or the standard AIN-93G diet supplemented with 1,000 µg Cr/kg. The chromium content of the diet had no effect on body mass or food intake. Similarly, the chromium content of the diet had no effect on glucose levels in glucose tolerance or insulin tolerance tests. However, a distinct trend toward lower insulin levels under the curve after a glucose challenge was observed with increasing chromium content in the diet; rats on the supplemented AIN-93G diets had significantly lower areas (P < 0.05) than rats on the low-chromium diet. The studies reveal that a diet with as little chromium as reasonably possible had no effect on body composition, glucose metabolism, or insulin sensitivity compared with a chromium-"sufficient" diet. Together with the results of other recent studies, these results clearly indicate that chromium can no longer be considered an essential element.

Chromium: celebrating 50 years as an essential element?

Fifty years ago the element chromium was proposed to be an essential element for mammals with a role in maintaining proper carbohydrate and lipid metabolism. Over the next several decades, chromium nutritional supplements became so popular for weight loss and muscle development that sales were second only to calcium among mineral supplements. However, the failure to identify the responsible biomolecules that bind Cr and their mode of action has resulted in the status of Cr being readdressed in recent years. This review considers research on the biochemistry of Cr(III) over the last two decades and how the results have affected the current status of Cr as an essential element.

Urinary chromium loss associated with diabetes is offset by increases in absorption.

The results of the current study indicate that diabetic rats have increased urinary Cr loss as a result of their diabetes; however, this increased urinary Cr loss is offset by increased absorption of Cr. Insulin resistant, obese rats have alterations in the rates of Cr transport and distribution compared to lean rats but have similar levels of urinary Cr loss and Cr absorption. Thus, any increases in urinary Cr loss associated with insulin resistance or diabetes are offset by increased absorption. Given that dietary chromium is normally absorbed with only approximately 1% efficiency, suitable Cr exists in the diet so that a standard diet possesses sufficient chromium to allow for the increases in absorption associated with diabetes. Consequently, supplementing the diet with nutritionally relevant quantities of chromium is not anticipated to have any beneficial effects. Similarly, beneficial effects on plasma variables, such as cholesterol, triglycerides, and insulin concentrations, from supra-nutritional doses of Cr(III) complexes should not arise from alleviation of chromium deficiency. These beneficial effects must arise from pharmacological effects of high dose Cr(III) administration.