Chromium(III) picolinate (CrPic3) is a chemical compound sold as a nutritional supplement to treat type 2 diabetes and promote weight loss. This bright-red coordination compound is derived from chromium(III) and picolinic acid. Small quantities of chromium are needed for glucose utilization by insulin in normal health, but deficiency is extremely rare and has only been observed in hospital patients on long-term defined diets. Chromium has been identified to regulate insulin by increasing the sensitivity of the insulin receptor. As such, chromium(III) picolinate has been used as a treatment for type 2 diabetes, although its effectiveness remains controversial due to conflicting and/or poorly carried out clinical studies. Chromium(III) picolinate has been described as a "poor [...] nutritional supplement".
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History
A study in 1989 suggested that chromium(III) picolinate may assist in weight loss and increase muscle mass which led to an increase in the usage of chromium(III) picolinate supplements, making it the second most widely used supplement behind Ca2+ supplements. A 2013 Cochrane review was unable to find "reliable evidence to inform firm decisions" to support such claims. Research has generally shown that it improves insulin sensitivity by either prolonging its activity or up-regulating the production of mRNA to produce more insulin receptors.
Amongst the transition metals, Cr3+ is the most controversial in terms of nutritional value and toxicity. This controversy centers on whether Cr3+ provides any nutritional benefits given that Cr3+ nutritional supplements for humans form the basis of a multimillion-dollar industry with sales second behind Ca-containing products. Furthermore, this controversy is amplified by the fact that no Cr-containing biomolecules have had their structure characterized, nor has the mode of action been determined. The first experiment that led to the discovery of Cr3+ playing a role in glucose metabolism proposed that the biologically active form of the metal existed in a protein called glucose tolerance factor, however, new evidence suggests that it is simply an artifact obtained from isolation procedures. The only accepted indicator of chromium deficiency is the reversal of symptoms that occurs when chromium(III) supplementation is administered to hospital patients that were on total parenteral nutrition (which lacked chromium(III)) for an extensive period of time.
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Physicochemical properties
Chromium(III) picolinate is a pinkish-red compound and was first reported in 1917. It is poorly soluble in water, having a solubility of 600 µM in water at near neutral pH. Similar to other chromium(III) compounds, it is relatively inert and unreactive, meaning that this complex is stable at ambient conditions and high temperatures are required to decompose the compound. At lower pH levels, the complex hydrolyzes to release picolinic acid and free Cr3+.
Structure
Chromium(III) picolinate has a distorted octahedral geometry and is isostructural to cobalt (III) and manganese (III) counterparts. Chromium(III) is a hard lewis acid and as such has high affinity to the carboxylate oxygen and medium affinity to the pyridine nitrogen of picolinate. Each picolinate ligand acts as a bidentate chelating agent and neutralizes the +3 charge of Cr3+. Evidence that the Cr3+ center coordinates to the pyridine nitrogen comes from a shift in the IR spectra of a C=N vibration at 1602.4 cm-1 for free picolinic acid to 1565.9 cm-1 for chromium(III) picolinate. The bond length between Cr3+ and the nitrogen atom of the pyridine ring on picoliante ranges from 2.047 to 2.048 Å. The picolinate ligand coordinates to Cr3+ only when deprotonated and this is evident by the disappearance of IR bands ranging from 2400-2800 cm-1 (centered at 2500 cm-1) and 1443 cm-1, corresponding to the O-H stretching and bending, respectively, on the carboxyl functional group. Furthermore, this IR shift also indicates that only one oxygen atom from the carboxylate of picolinate coordinates to the Cr3+ center. The Cr-O bond length ranges from 1.949 to 1.957 Å. The crystal structure has only been recently described in 2013. Water does not coordinate to the Cr3+ center and is instead thought to hydrogen bond between other Cr(Pic)3 complexes to form a network of Cr(Pic)3 complexes.
Biochemistry of chromium(III) picolinate
Chromium has been identified as an essential nutrient in maintaining normal blood glucose levels and as such, it is proposed to interact with two naturally occurring molecules found within the body. These interactions are most likely to occur through coordination with hard ligands such as aspartate and glutamate, as Cr(III) itself is a hard metal.
Absorption and excretion of chromium(III) picolinate
Once chromium(III) picolinate is ingested and enters the stomach, acidic hydrolysis of the complex occurs when in contact with the stomach mucosa. The hydrolyzed Cr3+ is present in the hexaaqua form and polymerizes to form an insoluble Cr(III)-hydroxide-oxide (the process of olation) once it reaches the alkaline pH of the small intestine. Approximately 2% of Cr3+ is absorbed through the gut as chromium(III) picolinate via unsaturated passive transport. Although absorption is low, CrPic3 absorbs more efficiently than other organic and inorganic sources (i.e. CrCl3 and chromium nicotinate) and thus accumulate at higher concentrations in tissues. This has been one major selling point for chromium(III) picolinate over other chromium(III) supplements. Organic sources tend to absorb better as they have ligands which are more lipophilic and usually neutralize the charge of the metal, thus permitting for easier passage through the intestinal membrane.
It has also been shown that dietary factors affect Cr3+ absorption. Starch, simple sugars, oxalic acid, and some amino acids tend to increase the rate of absorption of chromium(III). This is a result of ligand chelation, converting hexaaqua Cr3+ into more lipophilic forms. In contrast, calcium, magnesium, titanium, zinc, vanadium, and iron reduce the rate of absorption. Presumably, these ions introduce new metal-ligand equilibria, thus decreasing the lipophilic ligand pool available to Cr3+. Once absorbed into the bloodstream, 80% of the Cr3+ from CrPic3 is passed along to transferrin. The exact mechanism of release is currently unknown, however, it is believed not to occur by a single electron reduction, as in the case of Fe3+, due to the high instability of Cr2+. Administered Cr3+ can be found in all tissues ranging from 10-100 ?g/kg body weight. It is excreted primarily in the urine (80%) while the rest is excreted in sweat and feces.
Binding of chromium(III) to transferrin
Transferrin, in addition to chromodulin has been identified as a major physiological chromium transport agent, although a recent study found that Cr3+ in fact disables transferrin from acting as a metal ion transport agent. While transferrin is highly specific for ferric ions, at normal conditions, only 30% of transferrin molecules are saturated with ferric ions, allowing for other metals, particularly those with a large charge to size ratio, to bind as well. The binding sites consist of a C-lobe and an N-lobe which are nearly identical in structure. Each lobe contains aspartic acid, histidine, 2 tyrosine residues and a bicarbonate ion that acts as a bidentate ligand to allow iron or other metals to bind to transferrin in a distorted octahedral geometry. Evidence supporting the binding of Cr3+ to transferrin comes from extensive clinical studies that showed a positive correlation between levels of ferritin and of fasting glucose, insulin, and glycosylated hemoglobin (Hb1Ac) levels. Furthermore, an in vivo study in rats showed that 80% of isotopically labelled Cr3+ ended up on transferrin while the rest were bound to albumin. An in vitro study showed that when chromium(III) chloride was added to isolated transferrin, the Cr3+ readily bound transferrin, owing to changes in the UV-Vis spectrum. The formation constant for Cr3+ in the C-lobe is 1.41 x 1010 M-1 and 2.04 x 105 M-1 in the N-lobe, which indicates that Cr3+ preferentially binds the C-lobe. Overall, the formation constant for chromium(III) is lower than that of the ferric ion. The bicarbonate ligand is crucial in binding Cr3+ as when bicarbonate concentrations are very low, the binding affinity is also significantly lower. Electron paramagnetic resonance (EPR) studies have shown that below pH 6, chromium(III) binds only to the N-lobe and that at near neutral pH, chromium(III) binds to the C-lobe as well. Chromium(III) can compete with the ferric ion for binding to the C-lobe when the saturation greatly exceeds 30%. As such, these effects are only seen in patients suffering from hemochromatosis, an iron-storage disease characterized by excessive iron saturation in transferrin.
Mechanism of action
Low-molecular-weight chromium-binding substance (LMWCr; also known as chromodulin) is an oligopeptide that seems to bind chromium(III) in the body. It consists of four amino acid residues; aspartate, cysteine, glutamate, and glycine, bonded with four (Cr3+) centers. It interacts with the insulin receptor, by prolonging kinase activity through stimulating the tyrosine kinase pathway, thus leading to improved glucose absorption. It has been confused with glucose tolerance factor. Despite recent efforts to characterize chromodulin, the exact structure is still relatively unknown.
Although chromodulin's exact mechanism of action on the insulin receptor is currently unknown, one commonly described mechanism is presented below. This proposed mechanism has the highest amount of agreement with various experiments involving chromodulin.
Normally, chromodulin exists in the apochromodulin form, which is free of Cr(III) ions and has minimal activity on insulin receptors. The apochromodulin is stored in insulin sensitive cells in the nucleus. When blood glucose levels rise, insulin is released into the bloodstream and binds to an external ?-subunit of the insulin receptor, a transmembrane protein. The insulin receptor consists of 2 extracellular ?-subunits and 2 transmembrane ?-subunits. As soon as insulin binds to the insulin receptor, a conformational change in the receptor occurs, causing all 3 tyrosine residues (located in the ?-subunits) to be phosphorylated. This activates the receptor and allows it to transmit the signal from insulin to the cell. As mentioned above, absorbed chromium(III) picolinate eventually gives up Cr3+ to transferrin. In turn, transferrin transports Cr3+ to insulin sensitive cells (i.e. adipocytes) where it binds to apochromodulin to form holochromodulin. Holochromodulin binds to the insulin receptor, which assists in maintaining the active conformation of the insulin receptor by prolonging the kinase activity of kinases or up-regulating the amount of insulin receptor mRNA levels, thus decreasing blood glucose levels.
Experiments were able to show that chromium(III) was capable of up-regulating insulin-stimulated insulin signal transduction via affecting downstream molecules of the IR, as evidenced by enhanced levels of tyrosine phosphorylation of IRS-1, elevated Thr308 and Ser473 phosphorylation of Akt, and increased PI3-K activity in a variety of cellular and animal models. The increased IRS-1 phosphorylation led to increased insulin receptor sensitivity while Akt and PI3-K led to enhanced GLUT4 translocation to the cell surface, thus causing greater uptake of glucose.
It has also been shown that chromium(III) can alleviate insulin resistance by reducing endoplasmic reticulum (ER) stress. ER stress is defined as an accumulation of misfolded and unfolded proteins in the ER lumen. ER stress leads to stimulation of c-Jun terminal kinase (JNK), which in turn phosphorylates the serine residue of IRS, leading to suppression of insulin signaling cascade and less glucose uptake. Experimental findings suggest that chromium inhibits ER stress and hence the suppression of insulin signaling is uplifted. The exact mechanism is unknown.
Another way that Cr(III) may prolong the insulin receptor's kinase activity is through the oxidation of a critical active site cysteine residue on protein-tyrosine phosphatase 1B (PTP1B). Normally, PTP1B dephosphorylates phosphotyrosine residues by carrying out nucleophilic attack on the phosphate group via its cysteine residue, thus inactivating the insulin receptor. This process removes the phosphate group from the tyrosine residue to form a Cys--S--PO32- group that is subsequently hydrolyzed by water to regenerate the cysteine residue, permitting for another round of action. Research has shown that chromium(III) may in fact cause irreversible inhibition of PTP1B. It is thought that Cr(III) is converted to Cr(VI) or Cr(V) (through the action of oxidoreductases) which then oxidize the thiol of the cysteine residue on PTP1B to sulfenic acid, consequently rendering it unable to attack the phosphate group on phosphotyrosine. However, this is only a plausible mechanism, and no direct evidence has been shown to support this hypothesis. When the signal cascade is turned off, holochromodulin is eliminated in urine since the formation constant is too large to remove Cr(III) directly. Experimental evidence has shown that the loss of chromodulin from cells is correlated with an increase in chromium concentrations in the urine after ingesting food rich in carbohydrates (i.e. glucose).
Health claims and debates
Some commercial organizations promote chromium(III) picolinate as an aid to body development for athletes and as a means of losing weight, but a number of studies have failed to demonstrate an effect of chromium(III) picolinate on either muscle growth or fat loss. In general, there is no good evidence that chromium(III) picolinate supplementation helps people lose weight.
Treatment of diabetes mellitus type 2
There are claims that the picolinate form of chromium supplementation aids in reducing insulin resistance, particularly in type 2 diabetics, but a meta-analysis of chromium(III) supplementation studies showed no association between chromium and glucose or insulin concentrations for non-diabetics, and inconclusive results for diabetics. This study has been challenged on the grounds that it excluded significant results. Subsequent trials gave mixed results, with one finding no effect in people with impaired glucose tolerance, but another seeing a small improvement in glucose resistance. A further study on obese adults with metabolic syndrome was published in 2009, this found no significant effect on insulin sensitivity, but increased short-term levels of insulin. The study also observed no effect on body weight or serum lipid levels.
In a review of these trials it was again concluded that chromium supplements had no effect on healthy people, but that there might be an improvement in glucose metabolism in diabetics, although the authors stated that the evidence for this effect remains weak. Although the authors of this review mentioned that chromium(III) picolinate decreases HbA1c levels (measure of plasma glucose concentration) by 0.7% (95% CI) in type 2 diabetes patients, they noted that most poor quality studies produced larger positive outcomes than higher quality studies. It has also been shown that the supplement does not alter blood glucose levels in non-diabetics. In addition, the effects exhibited by Cr(III) species have long term effects on the blood glucose levels of diabetes patients. In comparison to CrCl3, chromium(III) picolinate is more effective at lowering blood glucose levels. CrCl3 lowers blood glucose levels by 0.3 mM whereas chromium(III) picolinate lowers blood glucose levels by 0.8 mM. However, opinions differ on this conclusion--a review published in 2006 argued that these data instead supported the clinical efficacy of chromium(III) picolinate for the treatment of type 2 diabetes. In 2006, the U.S. Food and Drug Administration stated that the "relationship between chromium(III) picolinate intake and insulin resistance is highly uncertain".
Several different forms of chromium supplements are currently being tested for their effectiveness in alleviating abnormal blood glucose levels in diabetes patients. Promising supplements include chromium histidine and chromium nanoparticles. Currently, adequate data does not exist on the degree of tissue absorption of Cr(III) ions sourcing from these experimental supplements. Studies have currently quantified the level of chromium absorption through examination of urine output. Via this method, it was discovered that chromium histidine absorbs 75% more effectively into the body than chromium(III) picolinate. But this increase in effectiveness does not differ largely from the 1% absorption of Cr(III) ions via chromium(III) picolinate. Furthermore, both chromium histidine and chromium nanoparticles are proven to demonstrate a decrease in blood glucose levels in diabetes patients but the extent of action on blood glucose levels is not quantifiable by these two supplements. Further research into the understanding of the mechanics of these two supplements, in addition to the development of the regulation in chromium(III) picolinate supplementation can possibly provide promising prospects in the use of chromium supplementation for the treatment of type 2 diabetes mellitus.
Variability of studies
There was no consistency observed in clinical results relating chromium(III) picolinate to adequate treatment of type 2 diabetes. This is due to the degree of glucose intolerance of patients that participate in the clinical studies. Glucose intolerance is a gradient and the intensity is affected by ethnicity, degree of obesity, age, distribution of body fat and many other factors. In some studies, low dosages of the supplement were given, however, a suitable amount of chromium(III) picolinate must be administrated to a person before any appreciable drop in glucose levels are observed due to differing levels of insulin resistance. Another important point to mention is that diabetes is not always caused by glucose intolerance. As mentioned before, Cr(III) has been shown to only influence glucose intolerance and not insulin levels. Furthermore, the environments in which the studies were performed were not consistent. The levels of stress, diets consumed by patients and patient genetics were variable among study subjects. This is also true of the controls amongst different studies in which the subjects having diabetes were already being treated with a wide variety of antidiabetic drugs, which can reduce the effects of chromium on affecting insulin activity. This could explain why animal studies tend to yield more positive results owing to the fact that these diabetic animals were not treated with antidiabetic drugs for the control group. Also, as mentioned in the absorption and excretion section, the absorption/bioavailability of chromium(III) picolinate is influenced by the diet. Collectively, these different factors have contributed to the variability in the studies.
One major problem with many of the clinical studies done on with chromium is the lack of excellent analytical tools to measure chromium levels in the blood. A lack of any good analytical tools for measuring chromium in the blood prevents understanding the exact role of chromium in diseases such as diabetes.
Compared to the most widely and longest used type 2 diabetes treatment, metformin, chromium(III) picolinate is less effective at lower blood glucose levels over a long term. Metformin targets an insulin independent AMPK pathway within liver cells to reduce the circulation of glucose within the bloodstream with very minimal side effects. Compared to Cr(III) species, metformin performs both more consistently and effectively, lowering HbA1c by 1.12%, compared to 0.6% with chromium(III) picolinate (although data for it is weak). Thus, in comparison to the leading type II diabetes treatment, chromium(III) picolinate does not serve as an appropriate treatment for the disease.
Safety and toxicity
Initial concerns were raised that chromium(III) picolinate is more likely to cause DNA damage and mutation than other forms of trivalent chromium, but these results are also debated. These concerns were based, in part, on studies in fruit flies, where chromium(III) picolinate supplementation generates chromosomal aberrations, impedes progeny development, and causes sterility and lethal mutations.
Though chromium(III) picolinate has been used as a supplement for decades, toxicity concerns did not begin to arise until the late 1990s. By that time, it was established that other oxidation states of chromium - mainly chromium (VI) - were in fact toxic to human and acted as carcinogens through clastogenic effects. It was found that when chromium (VI) species formed under physiological conditions, they were reduced by vitamin C and glutathione to form reactive intermediate complexes. Though direct evidence has not been obtained, it is hypothesized that chromium (VI) metabolism involves the formation of a reactive Cr(V) species, which causes DNA damage before going to the Cr(III) oxidation state. From all the studies conducted on Cr(VI), researchers wanted to see if the toxicity of Cr(III) could be also concerning. Studies showing chromium(III) picolinate (CrPic3) could oxidize DNA in vitro began to emerge.
In 1995, researchers conducted an in vitro study on the toxic effects of Cr(III) picolinate on Chinese hamster ovary cells. The results showed that at concentrations of 0.050--1.0 mM, chromium(III) picolinate caused chromosomal damage. This toxicity was linked to the role of CrPic3 as a mutagen in the cells, resulting in mitochondrial damage and apoptosis. However, a similar study on the same types of ovary cells showed contradictory results (i.e. no cell toxicity). This discrepancy was solved by analyzing the experimental conditions more closely. It was found that the former study was done dissolving CrPic3 in acetone, and the latter in DMSO. DMSO acts as a radical scavenger, potentially removing any reactive oxygen species and preventing toxicity. Since then, many studies done on mammalian cells have shown that CrPic3 is indeed toxic, and most likely exerts its effect through generation of radical species which results in DNA damage. This hypothesis has been supported by numerous studies in which CrPic3 was administered in both radical scavenging solvents (methanol, DMSO) and normal solvents (acetone, water). Results consistently show that toxicity effects were only averted in radical scavenging solvents. Unlike the Cr(VI) complexes however, it was thought that these carcinogenic effects were due to picolinic acid itself, and not the metal ion.
Shortly thereafter, another study was published to assess the toxicity of Cr(III) picolinate, this time on humans. The researchers that conducted this study used previous knowledge that Cr(III) is reduced to Cr(II) by cellular reductants such as NADH or cysteine. This reduced form of Cr(II) is shown to react with H2O2 to generate radical species which in turn oxidize DNA base pairs. With this knowledge in mind, the researchers administered ten women with 400 ?m of chromium(III) picolinate a day for an eight-week period. By measuring the amount of an oxidized DNA base pair, 5-hydroxymethyl uracil using antibody titers, the group could infer the amount of DNA base pair oxidation occurring in direct relation to chromium(III) picolinate. The results of the study suggested that chromium(III) picolinate itself does not cause significant chromosomal damage in vivo.
Generally speaking, it has been shown that chromium(III) picolinate is not toxic to humans. As a matter of fact, to see the same toxicity effects as seen with Cr(VI) compounds, the user would need to ingest orders of magnitude higher concentrations of Cr(III). For most adults, chromium(III) picolinate can be taken orally in doses up 1000 mg per day. This low toxicity has general been associated with low absorbance of Cr(III) in the body through the lungs, skin and gastrointestinal tract, coupled with high excretion. Normally, 99% of chromium(III) taken can be recovered in the feces of the user. On the contrary, there have been isolated incidences of chromium(III) supplementation leading to kidney failure, however this relationship is unclear and has yet to remain tested.
Regulation of chromium(III) picolinate
In 2004, the UK Food Standards Agency advised consumers to use other forms of trivalent chromium in preference to chromium(III) picolinate until specialist advice was received from the Committee on Mutagenicity. This was due to concerns raised by the Expert Group on Vitamins and Minerals that chromium(III) picolinate might cause cancer (its genotoxicity). The committee also noted two case reports of renal failure that might have been caused by this supplement and called for further research into its safety. In December 2004, the Committee on Mutagenicity published its findings, which concluded that "overall it can be concluded that the balance of the data suggest that chromium(III) picolinate should be regarded as not being mutagenic in vitro" and that "the available in-vivo tests in mammals with chromium(III) picolinate are negative". Following these findings, the UK Food Standards Agency withdrew its advice to avoid chromium(III) picolinate, though it plans to keep its advice about chromium supplements under review.
In 2010, chromium(III) picolinate was approved by Health Canada to be used in dietary supplements. The monograph includes use in capsules, chewables (e.g. gummies, tablets), liquids, powders, strips or tablets. Approved labeling statements include: a factor in the maintenance of good health, provides support for healthy glucose metabolism, helps the body to metabolize carbohydrates and helps the body to metabolize fats.
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