Chromium(III) picolinate: Difference between revisions

| Watchedfields = changed

| verifiedrevid = 443523561

| Name = Chromium(III) picolinate

| ImageFile = Chromium_picolinate.png

| ImageSize = 200px

| ImageName = Skeletal formula of chromium(III) picolinate

| ImageFileL1 = Chromium(III) picolinate 3D ball.png

| ImageFileL1_Ref = {{chemboximage|correct|??}}

| ImageNameL1 = Ball and Stick model of chromium (III) picolinate

| ImageFileR1 = Chromium(III) picolinate 3D spacefill.png

| ImageFileR1_Ref = {{chemboximage|correct|??}}

| ImageNameR1 = Spacefill model of chromium (III) picolinate

| IUPACName = Tris(picolinate)chromium(III)

| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}

| SMILES_Comment = ionic form

| SMILES1 = c0ccc[n+]1c0C(=O)O[Cr-3]123(OC(=O)c0[n+]2cccc0)OC(=O)c0[n+]3cccc0

| SMILES1_Comment = coordination form

| CASNo_Ref = {{cascite|correct|??}}

| UNII_Ref = {{fdacite|correct|FDA}}

| UNII = S71T8B8Z6P

| MeltingPt =

'''Chromium(III) picolinate''' is a [[chemical compound]] with the formula Cr(C₅H₄N(CO₂H))₃, commonly abbreviated as CrPic_3. It is sold as a nutritional supplement to treat type 2 [[diabetes]] and promote weight loss.<ref>{{Cite journal

| last1 = Preuss | first1 = H. G.

| last2 = Echard | first2 = B.

| last3 = Perricone | first3 = N. V.

| last4 = Bagchi | first4 = D.

| last5 = Yasmin | first5 = T.

| last6 = Stohs | first6 = S. J.

| doi = 10.1016/j.jinorgbio.2008.07.012

| title = Comparing metabolic effects of six different commercial trivalent chromium compounds

| journal = Journal of Inorganic Biochemistry

| volume = 102

| issue = 11

| pages = 1986–1990

| year = 2008

| pmid = 18774175

}}</ref> This bright-red [[coordination compound]] is derived from [[chromium]](III) and [[picolinic acid]]. Trace amounts (25-35 [[Microgram|mcg]]<ref>{{cite web | url = https://www.hsph.harvard.edu/nutritionsource/chromium/ | title = The Nutrition Source: Chromium | publisher = School of Public Health, Harvard University }}</ref>) of chromium are needed for [[glucose]] utilization by [[insulin]] in normal health, but deficiency is extremely uncommon and has been observed usually in people receiving 100% of their nutrient needs intravenously, i.e., total [[parenteral nutrition]] diets.<ref>[http://www.food.gov.uk/multimedia/pdfs/reviewofchrome.pdf Review of Chromium] {{webarchive |url=https://web.archive.org/web/20120207123911/http://www.food.gov.uk/multimedia/pdfs/reviewofchrome.pdf |date=February 7, 2012 }} Expert Group on Vitamins and Minerals Review of Chromium, 12 August 2002</ref> Chromium has been identified as regulating insulin by increasing the sensitivity of the [[insulin receptor]].<ref>{{cite journal |author=Stearns DM |title=Is chromium a trace essential metal? |journal=BioFactors |volume=11 |issue=3 |pages=149–62 |year=2000 |pmid=10875302 |doi=10.1002/biof.5520110301|s2cid=19417496 }}</ref> As such, chromium(III) picolinate has been proposed as a treatment for type 2 [[diabetes]], although its effectiveness remains controversial due to conflicting evidence from human trials.<ref name = Cr50yr>{{cite journal |last=Vincent |first=John |year=2010 |title=Chromium: celebrating 50 years as an essential element? |journal=Dalton Transactions |volume=39 |issue= 16|pages=3787–3794 |doi=10.1039/B920480F |pmid=20372701}}</ref>

==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 [[Dietary supplement|supplements]], resulting in it being for a while the second most widely used supplement behind calcium.<ref name=Cr50yr/> A 2013 [[Cochrane review]] was unable to find "reliable evidence to inform firm decisions" to support such claims.<ref name="ReferenceA">{{Cite journal | pmid = 24293292| year = 2013| last1 = Tian| first1 = H| journal = The Cochrane Database of Systematic Reviews| volume = 2013| issue = 11| id = CD010063| last2 = Guo| first2 = X| last3 = Wang | first3 = X| last4 = He| first4 = Z| last5 = Sun| first5 = R| last6 = Ge| first6 = S| last7 = Zhang| first7 = Z| doi = 10.1002/14651858.CD010063.pub2| title = Chromium picolinate supplementation for overweight or obese adults | pages=CD010063| pmc = 7433292}}</ref> 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 receptor]]s.{{Citation needed|date=May 2015}}

Amongst the [[transition metals]], Cr³⁺ is the most controversial in terms of nutritional value and toxicity.<ref name = Levina2008>{{cite journal |last1=Levina |first1=Aviva |last2=Lay |first2=Peter |year=2008 |title=Chemical Properties and Toxcity of Chromium (III) Nutritional Supplements |journal=Chemical Research in Toxicology |volume=21 |issue=3 |pages=563–571 |doi=10.1021/tx700385t |pmid=18237145 }}</ref> This controversy centers on whether Cr³⁺ provides any nutritional benefits.<ref name=Levina2008 /><ref name=Feng>{{cite book |last=Feng |first=Weiyue |editor1-last=Vincent |editor1-first=John |year=2007 |title=The Nutritional Biochemistry of Chromium (III) |chapter=Chapter 6 – The Transport of chromium (III) in the body: Implications for Function |chapter-url=http://survival-training.info/Library/Chemistry/Chemistry%20-%20The%20Nutritional%20Biochemistry%20of%20Chromium-III%20-%20J.%20Vincent.pdf |location=Amsterdam |publisher=Elsevier B.V |pages=121–137 |isbn=978-0444530714 |access-date=20 March 2015 }}{{Dead link|date=July 2021 |bot=InternetArchiveBot |fix-attempted=yes }}</ref> 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 ''[[Chromium deficiency#Supplementation|glucose tolerance factor]]'', however, new evidence suggests that it is simply an artifact obtained from isolation procedures.<ref name=Cr50yr /><ref name=Levina2008 /><ref name = Cefalu2004>{{cite journal |last1=Cefalu |first1=William |last2=Hu |first2=Frank |year=2004 |title=Role of Chromium in Human Health and in Diabetes |url=http://care.diabetesjournals.org/content/27/11/2741.full |journal=Diabetes Care |volume=27 |issue=11 |pages=2741–2751 |doi=10.2337/diacare.27.11.2741 |access-date=20 March 2015 |pmid=15505017|doi-access=free }}</ref><ref name=Anderson1998>{{cite journal |last=Anderson |first=Richard |year=1998 |title=Chromium, Glucose Intolerance and Diabetes |journal=Journal of the American College of Nutrition |volume=17 |issue=6 |pages=548–555 |doi=10.1080/07315724.1998.10718802 |pmid=9853533 |s2cid=19532052 }}</ref> The only accepted indicator of [[chromium deficiency]] is the reversal of symptoms that occurs when chromium(III) supplementation is administered to people on [[total parenteral nutrition]].<ref name = Vincent2004>{{cite journal |last=Vincent |first=John |year=2004 |title=Recent advances in the nutritional biochemistry of trivalent chromium |journal=Proceedings of the Nutrition Society |volume=63 |issue=1 |pages=41–47 |doi=10.1079/PNS2003315 |pmid=15070438|doi-access=free }}</ref>

==Physicochemical properties==

[[File:Chromax II.JPG|thumb|150px|Watch glass with two grams of chromium(III) picolinate]]

[[File:Chromium picolinate3.gif|thumb|Rotating video file of chromium picolinate coordination chemistry and molecular geometry]]

Chromium(III) picolinate is a pinkish-red compound and was first reported in 1917.<ref name=Cr50yr /><ref name = Vincent2001>{{cite journal |last=Vincent |first=John |year=2001 |title=The Bioinorganic Chemistry of Chromium (III) |journal=Polyhedron |volume=20 |issue= 1–2|pages=1–26 |doi= 10.1016/S0277-5387(00)00624-0}}</ref> It is poorly soluble in water, having a [[solubility]] of 600 μM in water at near neutral [[pH]].<ref name=Feng /> Similar to other chromium(III) compounds, it is relatively [[Chemically inert|inert]] and unreactive, meaning that this complex is stable at ambient conditions and [[thermal decomposition|high temperatures are required to decompose]] the compound.<ref name = Abou2014>{{cite journal |last1=Abou–Gamra |first1=Zeinab |last2=Abdel–Messih |first2=Michel |s2cid=93050541 |year=2014 |title=Correlation of thermal and spectral properties of chromium(III) picolinate complex and kinetic study of its thermal degradation |journal=Journal of Thermal Analysis and Calorimetry |volume=117 |issue=2 |pages=993–1000 |doi=10.1007/s10973-014-3768-5 }}</ref> At lower pH levels, the complex [[hydrolyzes]] to release [[picolinic acid]] and free Cr³⁺.<ref name=Feng />

===Structure===

Chromium(III) picolinate has a distorted [[octahedral geometry]] and is [[isostructural]] to [[cobalt]] (III) and [[manganese]] (III) counterparts.<ref name = Costa2003>{{cite journal |last1=Parajón–Costa |first1=Beatriz |last2=Wagner |first2=Claudia |last3=Baran |first3=Enrique |year=2003 |title=Voltammetric and Spectroscopic Study of Chromium(III)/Picolinate Complexes |journal=Zeitschrift für Anorganische und Allgemeine Chemie |volume=629 |issue=6 |pages=1085–1090 |doi=10.1002/zaac.200300050 }}</ref><ref name = Stearns1992>{{cite journal |last1=Stearns |first1=Diane |last2=Armstrong |first2=William |year=1992 |title=Mononuclear and binuclear chromium(III) picolinate complexes |journal=Inorganic Chemistry |volume=31 |issue=25 |pages=5178–5184 |doi=10.1021/ic00051a007 }}</ref> Chromium(III) is a [[HSAB theory|hard lewis acid]] and as such has [[binding affinity|high affinity]] to the [[carboxylate]] oxygen and medium affinity to the [[pyridine]] nitrogen of [[picolinic acid|picolinate]].<ref name=Costa2003 /><ref name = Hakimi>{{cite journal |last=Hakimi |first=Mohammad |year=2013 |title=Structural and Spectral Characterization of a Chromium (III) Picolinate Complex: Introducing a New Redox Reaction |url=http://kpubs.org/article/articleMain.kpubs?articleANo=JCGMDC_2013_v57n6_721 |journal= Journal of the Korean Chemical Society|volume=57 |issue=6 |pages=721–725 |doi=10.5012/jkcs.2013.57.6.721 |access-date=1 April 2015|doi-access=free }}</ref> 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 [[Infrared spectroscopy#Number of vibrational modes|vibration]] at 1602.4&nbsp;cm⁻¹ for free picolinic acid to 1565.9&nbsp;cm⁻¹ for chromium(III) picolinate.<ref name=Costa2003 /> The [[bond length]] between Cr³⁺ and the nitrogen atom of the pyridine ring on picolinate ranges from 2.047 to 2.048 [[Angstrom|Å]].<ref name = Stearns1992/> The picolinate ligand coordinates to Cr³⁺ only when [[deprotonated]] and this is evident by the disappearance of IR bands ranging from 2400 to 2800&nbsp;cm⁻¹ (centered at 2500&nbsp;cm⁻¹) and 1443&nbsp;cm⁻¹, corresponding to the O-H stretching and bending, respectively, on the carboxyl functional group.<ref name = Abou2014/><ref name=Costa2003 /> Furthermore, this IR shift also indicates that only one oxygen atom from the carboxylate of picolinate coordinates to the Cr³⁺ center.<ref name = Abou2014/><ref name=Costa2003 /><ref name = Hakimi/> The Cr-O bond length ranges from 1.949 to 1.957 [[Angstrom|Å]].<ref name = Stearns1992/> The [[crystal structure]] has only been recently described in 2013.<ref name = Hakimi/> 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.<ref name = Hakimi/>

==Biochemistry of chromium(III) picolinate==

{{See also|Chromium in glucose metabolism}}

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.<ref name=Cefalu2004 /> 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]].<ref name=Lukaski>{{cite book |last=Lukaski |first=Henry |editor1-last=Vincent |editor1-first=John |year=2007 |title=The Nutritional Biochemistry of Chromium (III) |chapter=Chapter 4{{snd}}Effects of Chromium(III) as a nutritional supplement |chapter-url=http://survival-training.info/Library/Chemistry/Chemistry%20-%20The%20Nutritional%20Biochemistry%20of%20Chromium-III%20-%20J.%20Vincent.pdf |location=Amsterdam |publisher=Elsevier B.V |pages=57–70 |isbn=978-0444530714 |access-date=20 March 2015 }}{{Dead link|date=July 2021 |bot=InternetArchiveBot |fix-attempted=yes }}</ref> 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]].<ref name = Laschinsky>{{cite journal |last1=Laschinsky |first1=Niels |last2=Kottwitz |first2=Karin |last3=Freund |first3=Barbara |last4=Dresow |first4=bernd |last5=Fischer |first5=Roland |last6=Nielsen |first6=Peter |s2cid=1533593 |year=2012 |title= Bioavailability of chromium(III)-supplements in rats and humans |journal=BioMetals |volume=25 |issue=5 |pages=1051–1060 |doi=10.1007/s10534-012-9571-5 |pmid=22814636 }}</ref> Approximately 2% of Cr³⁺ is absorbed through the gut as chromium(III) picolinate via unsaturated [[passive transport]].<ref name=Vincent2001 /> 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.<ref name=Anderson1998 /><ref name = Debski>{{cite journal |last1=Debski |first1=B. |last2=Goniewicz |first2=M. |last3=Krzyzowskal |first3=M. |last4=Lewicka |first4=A. |last5=Lewickil |first5=S. |last6=Niemcewiz |first6=M. |last7= Zdanowskil |first7=R. |year=2014 |title= The role of Chromium III in the organism and its possible use in diabetes and obesity treatment |journal=Annals of Agricultural and Environmental Medicine |volume=21 |issue=2 |pages=331–335 |doi=10.5604/1232-1966.1108599 |pmid=24959784 |doi-access=free }}<!--|access-date=20 March 2015--></ref> 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.<ref name=Debski />

It has also been shown that dietary factors affect Cr³⁺ absorption. [[Starch]], [[simple sugars]], [[oxalic acid]], and some [[amino acid]]s tend to increase the rate of absorption of chromium(III). This is a result of ligand chelation, converting hexaaqua Cr³⁺ into more lipophilic forms.<ref name=Debski /> In contrast, calcium, magnesium, titanium, zinc, vanadium, and iron reduce the rate of absorption.<ref name=Debski /> 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.<ref name=Lukaski /><ref name=Debski /><ref name = Vincent2015>{{cite journal |last=Vincent |first=John |s2cid=16895342 |year=2015 |title=Is the Pharmacological Mode of Action of Chromium (III) as a secondary messenger? |journal=Biological Trace Element Research |volume= 166|issue= 1|pages= 7–12|doi=10.1007/s12011-015-0231-9 |pmid=25595680}}</ref> The [[Transferrin#Transport Mechanism|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⁺.<ref name=Laschinsky /> Administered Cr³⁺ can be found in all tissues ranging from 10 to 100 μg/kg body weight.<ref name=Debski /> It is excreted primarily in the urine (80%) while the rest is excreted in sweat and feces.<ref name=Debski />

====Binding of chromium(III) to transferrin====

[[File:Transferrin binding sites.png|thumb|right|150px|The 2 binding sites of transferrin. When iron saturation is high, Cr³⁺ can compete with Fe³⁺ for binding to the C-lobe.<ref name=Quarles />]]

[[Transferrin]], in addition to [[chromodulin]] has been identified as a major physiological chromium transport agent,<ref name=Vincent2015 /><ref name = Vincent2012>{{cite journal |last=Vincent |first=John |year=2012 |title=The binding and transport of alternative metals by transferrin |journal=Biochimica et Biophysica Acta (BBA) - General Subjects |volume=1820 |issue=3 |pages=362–378 |doi= 10.1016/j.bbagen.2011.07.003|pmid=21782896 }}</ref> although a recent study found that Cr³⁺ in fact disables transferrin from acting as a metal ion transport agent.<ref>{{Cite journal|last1=Levina|first1=Aviva|last2=Pham|first2=T. H. Nguyen|last3=Lay|first3=Peter A.|date=2016-05-01|title=Binding of Chromium(III) to Transferrin Could be Involved in Detoxification of Dietary Chromium(III) Rather Than Transport of an Essential Trace Element|journal=Angewandte Chemie International Edition|language=en|pages=8104–8107|doi=10.1002/anie.201602996|issn=1521-3773|volume=55|issue=28|pmid=27197571|doi-access=free}}</ref> 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.<ref name=Feng /><ref name=Vincent2001 /><ref name=Quarles>{{cite journal |last1=Quarles |first1=C. |last2=Marcus |first2=R.|last3=Brumaghim |first3=Julia |s2cid=24302252 |year=2011 |title=Competitive binding of Fe³⁺, Cr³⁺, and Ni²⁺ to transferrin |journal=Journal of Biological Inorganic Chemistry |volume=16 |issue=6 |pages=913–921 |doi=10.1007/s00775-011-0792-9 |pmid=21678080 }}</ref> The binding sites consist of a C-lobe and an N-lobe which are nearly identical in structure.<ref name=Quarles /> 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]].<ref name=Vincent2015 /><ref name=Quarles /><ref name=Vincent2012 /> Evidence supporting the binding of Cr³⁺ to transferrin comes from extensive clinical studies<!-- From what the secondary source states --> that showed a positive correlation between levels of [[ferritin]] and of fasting [[glucose]], [[insulin]], and [[glycated hemoglobin]] (Hb1Ac) levels.<ref name=Feng /> 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.<ref name=Vincent2001 /><ref name=Vincent2015 /><ref name=VincentWiley>{{cite book |last=Vincent |first=John |editor1-last=Vincent |editor1-first=John |year=2012 |title=The Bioinorganic Chemistry of Chromium |chapter=Biochemical Mechanisms |location=Chichester, UK |publisher=John Wiley & Sons |pages=125–167 |doi=10.1002/9781118458891.ch6 |isbn=978-0470664827 }}</ref> 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.<ref name=Feng /><ref name=Vincent2015 /><ref name=Quarles /> Overall, the formation constant for chromium(III) is lower than that of the ferric ion.<ref name=Vincent2015 /> The bicarbonate ligand is crucial in binding Cr³⁺ as when bicarbonate concentrations are very low, the binding affinity is also significantly lower.<ref name=Vincent2015 /> [[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.<ref name=Feng /> Chromium(III) can compete with the ferric ion for binding to the C-lobe when the saturation greatly exceeds 30%.<ref name=Quarles /> As such, these effects are only seen in patients with [[hemochromatosis]], an iron-storage disease characterized by excessive iron saturation in transferrin.<ref name=VincentWiley />

==Mechanism of action==

[[File:Regulation of glycogen metabolism insulin.svg|thumb|right|This diagram shows the insulin pathway and its role in regulating blood glucose levels]]

[[Low-molecular-weight chromium-binding substance]] (LMWCr; also known as chromodulin) is an oligopeptide that seems to bind chromium(III) in the body.<ref name="pmid18769887">{{cite journal | vauthors = Viera M, Davis-McGibony CM | s2cid = 32564084 | title = Isolation and characterization of low-molecular-weight chromium-binding substance (LMWCr) from chicken liver | journal = Protein J. | volume = 27 | issue = 6 | pages = 371–375 | year = 2008 | pmid = 18769887 | doi = 10.1007/s10930-008-9146-z }}</ref> It consists of four amino acid residues; [[aspartate]], [[cysteine]], [[glutamate]], and [[glycine]], bonded with four (Cr³⁺) centers.<ref name=Feng /><ref name=Vincent2004 /><ref name = Vincent2000>{{cite journal |last=Vincent |first=John |year=2000 |title=The Biochemistry of Chromium |journal=The Journal of Nutrition |volume=130 |issue=4 |pages=715–718 |doi= 10.1093/jn/130.4.715|pmid=10736319 |doi-access=free }}</ref> It interacts with the insulin receptor, by prolonging kinase activity through stimulating the tyrosine kinase pathway, thus leading to improved glucose absorption.<ref name=Vincent2015 /><ref name="pmid11472024">{{cite journal | vauthors = Clodfelder BJ, Emamaullee J, Hepburn DD, Chakov NE, Nettles HS, Vincent JB | s2cid = 8956685 | title = The trail of chromium(III) in vivo from the blood to the urine: the roles of transferrin and chromodulin | journal = J. Biol. Inorg. Chem. | volume = 6 | issue = 5–6 | pages = 608–617 | year = 2001 | pmid = 11472024 | doi = 10.1007/s007750100238 }}</ref> It has been confused with [[glucose tolerance factor]]. Despite recent efforts to characterize chromodulin, the exact structure is still relatively unknown.<ref name="pmid8283288">{{cite journal | vauthors = Vincent JB | title = Relationship between glucose tolerance factor and low-molecular-weight chromium-binding substance | journal = J. Nutr. | volume = 124 | issue = 1 | pages = 117–9 | year = 1994 | pmid = 8283288 | doi = 10.1093/jn/124.1.117| url = http://jn.nutrition.org/content/124/1/117.full.pdf }}</ref>

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.<ref name=Levina2008 /><ref name=Vincent2001 /><ref name=Laschinsky /><ref name=VincentWiley />

Normally, chromodulin exists in the apochromodulin form, which is free of Cr(III) ions and has minimal activity on insulin receptors.<ref name=VincentWiley /> 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 α-subunit of the insulin receptor, a [[transmembrane protein]].<ref name=Vincent2000 /> The insulin receptor consists of 2 extracellular α-subunits and 2 transmembrane β-subunits.<ref name=VincentWiley /> As soon as insulin binds to the insulin receptor, a conformational change in the receptor occurs, causing all 3 [[tyrosine]] residues (located in the β-subunits) to be phosphorylated. This activates the receptor and allows it to transmit the signal from insulin to the cell.<ref name=Vincent2004 /><ref name=VincentWiley /><ref name=Vincent2000 />

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.<ref name=VincentWiley /> 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.<ref name=Vincent2004 />

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 [[Threonine|Thr308]] and [[Serine|Ser473]] [[phosphorylation]] of [[Akt]], and increased [[PI3-K]] activity in a variety of cellular and animal models.<ref name = Kitamura2008>{{cite journal |last=Kitamura |first=Masanori |year=2008 |title=Endoplasmic reticulum stress and unfolded protein response in renal pathophysiology: Janus faces |journal=American Journal of Physiology |volume=295 |issue=2 |pages=323–334 |doi=10.1152/ajprenal.00050.2008 |pmid=18367660 }}</ref> 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.<ref name=Kitamura2008 />

It has also been shown that chromium(III) can alleviate [[insulin resistance]] by reducing [[endoplasmic reticulum]] (ER) stress.<ref name=Kitamura2008 /> ER stress is defined as an accumulation of misfolded and unfolded proteins in the ER lumen.<ref name=Kitamura2008 /> 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.<ref name = Hua2012>{{cite journal |last1=Hua |first1=Yinan |last2=Clark |first2=Suzanne |last3=Ren |first3=Jun |last4=Sreejayan |first4=Nair |year=2012 |title=Molecular Mechanisms of Chromium in Alleviating Insulin Resistance |journal=Journal of Nutritional Biochemistry |volume=23 |issue=4 |pages=313–319 |doi=10.1016/j.jnutbio.2011.11.001 |pmc=3308119 |pmid=22423897}}</ref> Experimental findings suggest that chromium inhibits ER stress and hence the suppression of insulin signaling is uplifted.<ref name=Hua2012 /> The exact mechanism is unknown.<ref name=Hua2012 />

[[File:Oxidation of a Cys residue to sulfenic acid by chromium species.jpg|thumb|right|250px|Oxidation of a cysteine residue to sulfenic acid]]

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.<ref name=Tonks>{{cite journal |last=Tonks |first=Nicholas |year=2003 |title=PTP1B: From the sidelines to the front lines! |journal=FEBS Letters |volume=546 |issue=1 |pages=140–148 |doi=10.1016/S0014-5793(03)00603-3 |pmid=12829250|s2cid=21205538 |doi-access=free }}</ref> 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.<ref name=Tonks /> 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.<ref name = metaldiabeticdrugs>{{cite journal |last=Levina |first=Aviva |year=2011 |title=Metal based anti-diabetic drugs: advances and challenges|journal=Dalton Transactions |volume=40 |issue= 44|pages=11675–1686 |doi=10.1039/C1DT10380F |pmid=21750828 }}</ref> However, this is only a plausible mechanism, and no direct evidence has been shown to support this hypothesis.<ref name=Tonks />

When the signal cascade is turned off, holochromodulin is eliminated in urine since the [[formation constant]] is too large to remove Cr(III) directly.<ref name=Feng /> 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).<ref name=Vincent2000 />

===Body weight===

Chromium(III) picolinate has been marketed in the United States as an aid to body development for [[sportsperson|athlete]]s and as a means of [[weight loss|losing weight]]. Reviews have reported either no effect on either muscle growth or fat loss,<ref name="JBVincent">{{cite journal | author=Vincent J.B. | title=The potential value and toxicity of chromium picolinate as a nutritional supplement, weight loss agent and muscle development agent | journal=Sports Medicine | volume=33 | issue=3 | year=2003 | pages=213–230 | pmid=12656641 | doi=10.2165/00007256-200333030-00004 | last2=Sack | first2=DA | last3=Roffman | first3=M | last4=Finch | first4=M | last5=Komorowski | first5=JR| s2cid=9981172 }}</ref> or else a modest but statistically significant -1.1&nbsp;kg (2.4&nbsp;lb) weight loss in trials longer than 12 weeks.<ref name="ReferenceA"/> The [[European Food Safety Authority]] reviewed the literature and concluded that there was insufficient evidence to support a claim.<ref name=EFSA2010>{{Cite journal |doi = 10.2903/j.efsa.2010.1732|title = Scientific Opinion on the substantiation of health claims related to chromium and contribution to normal macronutrient metabolism (ID 260, 401, 4665, 4666, 4667), maintenance of normal blood glucose concentrations (ID 262, 4667), contribution to the maintenance or achievement of a normal body weight (ID 339, 4665, 4666), and reduction of tiredness and fatigue (ID 261) pursuant to Article 13(1) of Regulation (EC) No 1924/2006|journal = EFSA Journal|year = 2010|volume = 8|issue = 10 |doi-access=free}}</ref>

===Diabetes===

There are claims that the picolinate form of chromium supplementation aids in reducing [[insulin resistance]] and improving [[glucose metabolism]], particularly in type 2 [[diabetes|diabetics]], but reviews showed no association between chromium and glucose or insulin concentrations for non-diabetics, and inconclusive results for diabetics.<ref name="MDAlthuius">{{cite journal |vauthors=Althuis MD, Jordan NE, Ludington EA, [[Janet Wittes|Wittes JT]] | title=Glucose and insulin responses to dietary chromium supplements: a meta-analysis | journal=American Journal of Clinical Nutrition | volume=76 | issue=1 | date=1 July 2002| pages=148–155 | pmid=12081828 | doi=10.1093/ajcn/76.1.148 | doi-access=free }}</ref><ref name = Balk2007>{{cite journal |author=Balk EM, Tatsioni A, [[Alice H. Lichtenstein|Lichtenstein AH]], Lau J, Pittas AG |title=Effect of chromium supplementation on glucose metabolism and lipids: a systematic review of randomized controlled trials |journal=Diabetes Care |volume=30 |issue=8 |pages=2154–2163 |year=2007 |pmid=17519436 |url=http://care.diabetesjournals.org/cgi/pmidlookup?view=long&pmid=17519436 |doi=10.2337/dc06-0996|doi-access=free }}</ref> The authors of the second review mentioned that chromium picolinate decreased [[HbA1c]] levels by 0.7% in type 2 diabetes patients, they observed that poor quality studies produced larger positive outcomes than higher quality studies.<ref name=Balk2007 /><ref name = Suksomboon2014>{{cite journal |last1=Suksomboon |first1=N. |last2=Poolsup |first2=N. |last3=Yuwanakom |first3=A. |year=2014 |title=Systematic review and meta-analysis of the efficacy and safety of chromium supplementation in diabetes |journal=Journal of Clinical Pharmacy and Therapeutics |volume=39 |issue=3 |pages=292–306 |doi=10.1111/jcpt.12147 |pmid=24635480 |s2cid=22326435 |doi-access=free }}</ref> Two reviews concluded that chromium(III) picolinate may be more effective at lowering [[blood glucose]] levels compared to other chromium-containing dietary supplements.<ref name=Balk2007 /><ref>{{cite journal |vauthors=Broadhurst CL, Domenico P |title=Clinical studies on chromium picolinate supplementation in diabetes mellitus – a review |journal=Diabetes Technol. Ther. |volume=8 |issue=6 |pages=677–87 |date=December 2006 |pmid=17109600 |doi=10.1089/dia.2006.8.677}}</ref>

In 2005, the U.S. [[Food and Drug Administration]] (FDA) approved a qualified health claim for [[chromium picolinate]] as a dietary supplement relating to insulin resistance and risk of type 2 diabetes. Any company wishing to make such a claim must use the exact wording: "One small study suggests that chromium picolinate may reduce the risk of insulin resistance, and therefore possibly may reduce the risk of type 2 diabetes. FDA concludes, however, that the existence of such a relationship between chromium picolinate and either insulin resistance or type 2 diabetes is highly uncertain." As part of the petition review process, the FDA rejected other claims for reducing abnormally elevated blood sugar, risk of cardiovascular disease, risk of retinopathy or risk of kidney disease.<ref>[https://wayback.archive-it.org/7993/20171114183739/https://www.fda.gov/Food/IngredientsPackagingLabeling/LabelingNutrition/ucm073017.htm Qualified Health Claims: Letter of Enforcement Discretion – Chromium Picolinate and Insulin Resistance (Docket No. 2004Q-0144)] (2005) U.S. Food and Drug Administration.</ref> In 2006 the FDA added that the "relationship between chromium(III) picolinate intake and insulin resistance is highly uncertain".<ref>{{cite journal |vauthors=Trumbo PR, Ellwood KC |title=Chromium picolinate intake and risk of type 2 diabetes: an evidence-based review by the United States Food and Drug Administration |journal=Nutr. Rev. |volume=64 |issue=8 |pages=357–63 |date=August 2006 |pmid=16958312 |doi=10.1111/j.1753-4887.2006.tb00220.x|url=https://zenodo.org/record/1230786 |doi-access=free }}</ref>

===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.<ref name=Anderson1998 /> Glucose intolerance is a gradient and the intensity is affected by ethnicity, degree of obesity, age, distribution of body fat and many other factors.<ref name=Anderson1998 /> In some studies, low dosages of the supplement were given, however, a suitable amount of chromium(III) picolinate must be administered to a person before any appreciable drop in glucose levels is observed due to differing levels of insulin resistance. Another important point to mention is that diabetes is not always caused by glucose intolerance.<ref name=Anderson1998 /> 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.<ref name=Anderson1998 /> 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.<ref name="Hua2012"/> 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.<ref name=Hua2012 /> 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.

==Safety and toxicity==

Initial concerns were raised that chromium(III) picolinate is more likely to cause [[DNA repair#DNA damage|DNA damage]] and [[mutation]] than other forms of [[Valence (chemistry)|trivalent]] chromium,<ref name="SChaudhary">{{cite journal |vauthors=Chaudhary S, Pinkston J, Rabile MM, Van Horn JD | title=Unusual reactivity in a commercial chromium supplement compared to baseline DNA cleavage with synthetic chromium complexes | journal=Journal of Inorganic Biochemistry | volume=99 | issue=3 | year=2005 | pages=787–794 | pmid=15708800 | doi=10.1016/j.jinorgbio.2004.12.009}}</ref> but these results are also debated.<ref name=pmid_17512455>{{cite journal |vauthors=Hininger I, Benaraba R, Osman M, Faure H, Marie Roussel A, Anderson RA |title=Safety of trivalent chromium complexes: no evidence for DNA damage in human HaCaT keratinocytes |journal=Free Radic. Biol. Med. |volume=42 |issue=12 |pages=1759–65 |year=2007 |pmid=17512455 |doi=10.1016/j.freeradbiomed.2007.02.034|url=https://naldc-legacy.nal.usda.gov/naldc/download.xhtml?id=14276&content=PDF }}</ref> These concerns were based, in part, on studies in fruit flies, where chromium(III) picolinate supplementation generates chromosomal aberrations, impedes progeny development,<ref name=pmid_16887379>{{cite journal |vauthors=Stallings DM, Hepburn DD, Hannah M, Vincent JB, O'Donnell J |title=Nutritional supplement chromium picolinate generates chromosomal aberrations and impedes progeny development in Drosophila melanogaster |journal=Mutat. Res. |volume=610 |issue=1–2 |pages=101–13 |year=2006 |pmid=16887379 |doi=10.1016/j.mrgentox.2006.06.019}}</ref> and causes sterility and lethal mutations.<ref name=pmid_12649323>{{cite journal |vauthors=Hepburn DD, Xiao J, Bindom S, Vincent JB, O'Donnell J |title=Nutritional supplement chromium picolinate causes sterility and lethal mutations in Drosophila melanogaster |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=100 |issue=7 |pages=3766–71 |year=2003 |pmid=12649323 |doi=10.1073/pnas.0636646100 |pmc=152996|doi-access=free }}</ref>

A study was published to assess the toxicity of Cr(III) picolinate on humans.<ref name=Kato>{{cite journal |last1=Kato |first1=Ikuko |last2=Vogelman |first2=Joseph |last3=Dilman |first3=Vladimir |last4=Karkoszka |first4=Jerzy |last5=Frenkel |first5=Krystyna |last6=Durr |first6=Nancy |last7=Orentreich |first7=Norman |last8=Toniolo |first8=Paolo |s2cid=19071972 |year=1998 |title=Effect of supplementation with chromium picolinate on antibody titers to 5–hydroxymethyl uracil |journal=European Journal of Epidemiology |volume=14 |issue=6 |pages=621–626 |doi=10.1023/A:1007442203258 |pmid=9794131 }}</ref> 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]].<ref name=Kato /> This reduced form of Cr(II) is shown to react with H₂O₂ to generate [[Radical (chemistry)|radical species]] which in turn [[oxidize]] [[Base pair|DNA base pairs]].<ref name=Tsou>{{cite journal |last1=Tsou |first1=Tsui–Chun |last2=Chen |first2=Chiu–lan |last3=Liu |first3=Tsung–Yun |last4=Yang |first4=Jia-Ling |year=1996 |title= Induction of 8-hydroxydeoxyguanosine in DNA by chromium(III) plus hydrogen peroxide and its prevention by scavengers |url=http://carcin.oxfordjournals.org/content/17/1/103.full.pdf |journal=Carcinogenesis |volume=17 |issue=1 |pages=103–108 |doi= 10.1093/carcin/17.1.103|pmid=8565117 |access-date=20 March 2015|doi-access=free }}</ref><ref name=Ozawa>{{cite journal |last1=Ozawa |first1=T. |last2=Hanaki |first2=A. |year=1990 |title=Spin-trapping studies on the reactions of Cr(III) with hydrogen peroxide in the presence of biological reductants: is Cr(III) non-toxic? |journal=Biochemistry International |volume=22 |issue=2 |pages=343–352 |pmid=1965278}}<!--|access-date=20 March 2015 --></ref> With this knowledge in mind, the researchers administered ten women with 400 μg of chromium(III) picolinate a day for an eight-week period.<ref name=Kato /> By measuring the amount of an oxidized DNA base pair, 5-hydroxymethyl uracil using [[antibody titer]]s, the group could infer the amount of DNA base pair oxidation occurring in direct relation to chromium(III) picolinate.<ref name=Kato /> The results of the study suggested that chromium(III) picolinate itself does not cause significant chromosomal damage [[in vivo]].<ref name=Kato />

Generally speaking, it has been shown that chromium(III) picolinate is not toxic to humans. For most adults, it can be taken orally in doses up 1000&nbsp;μg per day.<ref name=Jeejeebhoy>{{cite journal |last=Jeejeebhoy |first=Khursheed |year=2009 |title=The Role of Chromium in Nutrition and Therapeutics and As a Potential Toxin |journal=Nutrition Reviews |volume=57 |issue=11 |pages=329–335 |doi=10.1111/j.1753-4887.1999.tb06909.x |pmid=10628183|doi-access=free }}</ref> This low toxicity has generally been associated with low absorbance of Cr(III) in the body through the [[lungs]], [[skin]] and [[gastrointestinal tract]],<ref name=Fairhurst>{{cite book |last1=Fairhurst |first1=S. |last2=Minty |first2=C. |year=1989 |title=The toxicity of chromium and inorganic chromium compounds |location=London |series= Toxicity Review; 21 |publisher=H.M.S.O |pages=1–243 |isbn=978-0118855211 }}</ref> coupled with high excretion. Normally, 99% of chromium(III) taken can be recovered in the feces of the user. There have been isolated instances of chromium(III) supplementation leading to kidney failure, however this relationship is unclear and has yet to be tested.<ref name=Wasser>{{cite journal |last1=Wasser |first1=Walter |last2=Feldman |first2=Nathaniel |last3=D'Agati |first3=Vivette |s2cid=27418296 |year=1997 |title=Chronic Renal Failure after Ingestion of Over-the-Counter Chromium Picolinate |journal=Annals of Internal Medicine |volume=126 |issue=5 |pages=410 |doi=10.7326/0003-4819-126-5-199703010-00019 |pmid=9054292 }}</ref>

==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 be [[genotoxic]] (cause cancer). The committee also noted two case reports of [[kidney failure]] that might have been caused by this supplement and called for further research into its safety.<ref>[http://www.foodstandards.gov.uk/multimedia/pdfs/vitmin2003.pdf Safe Upper Levels for Vitamins and Minerals] {{Webarchive|url=https://web.archive.org/web/20080704010728/http://www.foodstandards.gov.uk/multimedia/pdfs/vitmin2003.pdf |date=2008-07-04 }} Food Standards Agency – May 2003</ref><ref>[http://www.food.gov.uk/multimedia/pdfs/evm_chromium.pdf Risk assessment: Chromium] Expert Group on Vitamins and Minerals, 2003</ref> 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".<ref>[http://www.advisorybodies.doh.gov.uk/Com/chromium.htm Statement on the Mutagenicity of Trivalent Chromium and Chromium Picolinate ] {{Webarchive|url=https://web.archive.org/web/20080516030629/http://www.advisorybodies.doh.gov.uk/Com/chromium.htm |date=2008-05-16 }} COM/04/S3 - December 2004</ref> 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.<ref>[http://www.food.gov.uk/news/newsarchive/2004/dec/chromiumupdate Agency revises chromium picolinate advice] Food Standards Agency - 13 December 2004</ref>

In 2010, chromium(III) picolinate was approved by Health Canada to be used in dietary supplements. 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.<ref>{{cite web |url=http://webprod.hc-sc.gc.ca/nhpid-bdipsn/monoReq.do?id=65 |title=Monograph: Chromium (from Chromium picolinate) |publisher=Health Canada |date =December 9, 2009 |access-date = March 24, 2015}}</ref>

{{Reflist}}

* {{Commons category-inline}}

* [http://www.merck.com/mrkshared/mmanual/section1/chapter4/4f.jsp Merck Manual]

[[Category:Coordination complexes]]

[[Category:Chromium(III) compounds]]