Chromium(III) picolinate is a
chemical compound
A chemical compound is a chemical substance composed of many identical molecules (or molecular entities) containing atoms from more than one chemical element held together by chemical bonds. A molecule consisting of atoms of only one element ...
with the formula Cr(C
5H
4N(CO
2H))
3, commonly abbreviated as CrPic
3. It is sold as a nutritional supplement to treat type 2
diabetes
Diabetes, also known as diabetes mellitus, is a group of metabolic disorders characterized by a high blood sugar level ( hyperglycemia) over a prolonged period of time. Symptoms often include frequent urination, increased thirst and increased ap ...
and promote weight loss. This bright-red
coordination compound
A coordination complex consists of a central atom or ion, which is usually metallic and is called the ''coordination centre'', and a surrounding array of bound molecules or ions, that are in turn known as ''ligands'' or complexing agents. Many ...
is derived from
chromium
Chromium is a chemical element with the symbol Cr and atomic number 24. It is the first element in group 6. It is a steely-grey, lustrous, hard, and brittle transition metal.
Chromium metal is valued for its high corrosion resistance and hardne ...
(III) and
picolinic acid
Picolinic acid is an organic compound with the formula C5H4N(CO2H). It is a derivative of pyridine with a carboxylic acid (COOH) substituent at the 2-position. It is an isomer of nicotinic acid and isonicotinic acid, which have the carboxyl side ...
. Large quantities of chromium are needed for
glucose
Glucose is a simple sugar with the molecular formula . Glucose is overall the most abundant monosaccharide, a subcategory of carbohydrates. Glucose is mainly made by plants and most algae during photosynthesis from water and carbon dioxide, using ...
utilization by
insulin
Insulin (, from Latin ''insula'', 'island') is a peptide hormone produced by beta cells of the pancreatic islets encoded in humans by the ''INS'' gene. It is considered to be the main anabolic hormone of the body. It regulates the metabolism o ...
in normal health, but deficiency is extremely common and has been observed in people receiving 100% of their nutrient needs intravenously, i.e., total
parenteral nutrition
Parenteral nutrition (PN) is the feeding of nutritional products to a person intravenously, bypassing the usual process of eating and digestion. The products are made by pharmaceutical compounding companies. The person receives a nutritional mix ...
diets. Chromium has been identified as regulating insulin by increasing the sensitivity of the
insulin receptor
The insulin receptor (IR) is a transmembrane receptor that is activated by insulin, IGF-I, IGF-II and belongs to the large class of receptor tyrosine kinase. Metabolically, the insulin receptor plays a key role in the regulation of glucose homeo ...
. As such, chromium(III) picolinate has been proposed as a treatment for type 2
diabetes
Diabetes, also known as diabetes mellitus, is a group of metabolic disorders characterized by a high blood sugar level ( hyperglycemia) over a prolonged period of time. Symptoms often include frequent urination, increased thirst and increased ap ...
, although its effectiveness remains controversial due to conflicting evidence from human trials.
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, resulting in it being for a while the second most widely used supplement behind calcium.
[ A 2013 ]Cochrane review
Cochrane (previously known as the Cochrane Collaboration) is a British international charitable organisation formed to organise medical research findings to facilitate evidence-based choices about health interventions involving health professi ...
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
In molecular biology, messenger ribonucleic acid (mRNA) is a single-stranded molecule of RNA that corresponds to the genetic sequence of a gene, and is read by a ribosome in the process of Protein biosynthesis, synthesizing a protein.
mRNA is ...
to produce more insulin receptor
The insulin receptor (IR) is a transmembrane receptor that is activated by insulin, IGF-I, IGF-II and belongs to the large class of receptor tyrosine kinase. Metabolically, the insulin receptor plays a key role in the regulation of glucose homeo ...
s.
Amongst the transition metals
In chemistry, a transition metal (or transition element) is a chemical element in the d-block of the periodic table (groups 3 to 12), though the elements of group 12 (and less often group 3) are sometimes excluded. They are the elements that can ...
, Cr3+ is the most controversial in terms of nutritional value and toxicity. This controversy centers on whether Cr3+ provides any nutritional benefits. 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
Chromium deficiency is described as the consequence of an insufficient dietary intake of the mineral chromium. Chromium was first proposed as an essential element for normal glucose metabolism in 1959, and was widely accepted as being such by the ...
'', however, new evidence suggests that it is simply an artifact obtained from isolation procedures. The only accepted indicator of chromium deficiency
Chromium deficiency is described as the consequence of an insufficient dietary intake of the mineral chromium. Chromium was first proposed as an essential element for normal glucose metabolism in 1959, and was widely accepted as being such by the ...
is the reversal of symptoms that occurs when chromium(III) supplementation is administered to people on total parenteral nutrition
Parenteral nutrition (PN) is the feeding of nutritional products to a person intravenously, bypassing the usual process of eating and digestion. The products are made by pharmaceutical compounding companies. The person receives a nutritional mix ...
.
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
In chemistry, solubility is the ability of a substance, the solute, to form a solution with another substance, the solvent. Insolubility is the opposite property, the inability of the solute to form such a solution.
The extent of the solubil ...
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
Hydrolysis (; ) is any chemical reaction in which a molecule of water breaks one or more chemical bonds. The term is used broadly for substitution, elimination, and solvation reactions in which water is the nucleophile.
Biological hydrolysis ...
to release picolinic acid
Picolinic acid is an organic compound with the formula C5H4N(CO2H). It is a derivative of pyridine with a carboxylic acid (COOH) substituent at the 2-position. It is an isomer of nicotinic acid and isonicotinic acid, which have the carboxyl side ...
and free Cr3+.
Structure
Chromium(III) picolinate has a distorted octahedral geometry
In chemistry, octahedral molecular geometry, also called square bipyramidal, describes the shape of compounds with six atoms or groups of atoms or ligands symmetrically arranged around a central atom, defining the vertices of an octahedron. The oc ...
and is isostructural Isostructural chemical compounds have similar chemical structures. "Isomorphous" when used in the relation to crystal structures is not synonymous: in addition to the same atomic connectivity that characterises isostructural compounds, isomorphous s ...
to cobalt
Cobalt is a chemical element with the symbol Co and atomic number 27. As with nickel, cobalt is found in the Earth's crust only in a chemically combined form, save for small deposits found in alloys of natural meteoric iron. The free element, pr ...
(III) and manganese
Manganese is a chemical element with the symbol Mn and atomic number 25. It is a hard, brittle, silvery metal, often found in minerals in combination with iron. Manganese is a transition metal with a multifaceted array of industrial alloy use ...
(III) counterparts. Chromium(III) is a hard lewis acid and as such has high affinity to the carboxylate
In organic chemistry, a carboxylate is the conjugate base of a carboxylic acid, (or ). It is an ion with negative charge.
Carboxylate salts are salts that have the general formula , where M is a metal and ''n'' is 1, 2,...; ''carboxylat ...
oxygen and medium affinity to the pyridine
Pyridine is a basic heterocyclic organic compound with the chemical formula . It is structurally related to benzene, with one methine group replaced by a nitrogen atom. It is a highly flammable, weakly alkaline, water-miscible liquid with a d ...
nitrogen of picolinate. Each picolinate ligand acts as a bidentate chelating
Chelation is a type of bonding of ions and molecules to metal ions. It involves the formation or presence of two or more separate coordinate bonds between a Denticity, polydentate (multiple bonded) ligand and a single central metal atom. These l ...
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
Infrared spectroscopy (IR spectroscopy or vibrational spectroscopy) is the measurement of the interaction of infrared radiation with matter by absorption, emission, or reflection. It is used to study and identify chemical substances or functiona ...
of a C=N vibration
Vibration is a mechanical phenomenon whereby oscillations occur about an equilibrium point. The word comes from Latin ''vibrationem'' ("shaking, brandishing"). The oscillations may be periodic function, periodic, such as the motion of a pendulum ...
at 1602.4 cm−1 for free picolinic acid to 1565.9 cm−1 for chromium(III) picolinate. The bond length
In molecular geometry, bond length or bond distance is defined as the average distance between nuclei of two bonded atoms in a molecule. It is a transferable property of a bond between atoms of fixed types, relatively independent of the rest of ...
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
Deprotonation (or dehydronation) is the removal (transfer) of a proton (or hydron, or hydrogen cation), (H+) from a Brønsted–Lowry acid in an acid–base reaction.Henry Jakubowski, Biochemistry Online Chapter 2A3, https://employees.csbsju.edu ...
and this is evident by the disappearance of IR bands ranging from 2400 to 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
In crystallography, crystal structure is a description of the ordered arrangement of atoms, ions or molecules in a crystal, crystalline material. Ordered structures occur from the intrinsic nature of the constituent particles to form symmetric pat ...
has only been recently described in 2013.[ Water does not coordinate to the Cr3+ center and is instead thought to ]hydrogen bond
In chemistry, a hydrogen bond (or H-bond) is a primarily electrostatic force of attraction between a hydrogen (H) atom which is covalently bound to a more electronegative "donor" atom or group (Dn), and another electronegative atom bearing a ...
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
A nutrient is a substance used by an organism to survive, grow, and reproduce. The requirement for dietary nutrient intake applies to animals, plants, fungi, and protists. Nutrients can be incorporated into cells for metabolic purposes or excret ...
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
The stomach is a muscular, hollow organ in the gastrointestinal tract of humans and many other animals, including several invertebrates. The stomach has a dilated structure and functions as a vital organ in the digestive system. The stomach i ...
, acidic hydrolysis
Hydrolysis (; ) is any chemical reaction in which a molecule of water breaks one or more chemical bonds. The term is used broadly for substitution reaction, substitution, elimination reaction, elimination, and solvation reactions in which water ...
of the complex occurs when in contact with the stomach mucosa
The gastric mucosa is the mucous membrane layer of the stomach, which contains the glands and the gastric pits. In humans, it is about 1 mm thick, and its surface is smooth, soft, and velvety. It consists of simple columnar epithelium, lamin ...
. The hydrolyzed Cr3+ is present in the hexaaqua form and polymerizes
In polymer chemistry, polymerization (American English), or polymerisation (British English), is a process of reacting monomer molecules together in a chemical reaction to form polymer chains or three-dimensional networks. There are many for ...
to form an insoluble Cr(III)-hydroxide-oxide (the process of olation In inorganic chemistry, olation is the process by which metal ions form polymeric oxides in aqueous solution. The phenomenon is important for understanding the relationship between metal aquo complexes and metal oxides, which are represented by m ...
) once it reaches the alkaline
In chemistry, an alkali (; from ar, القلوي, al-qaly, lit=ashes of the saltwort) is a base (chemistry), basic, ionic compound, ionic salt (chemistry), salt of an alkali metal or an alkaline earth metal. An alkali can also be defined as ...
pH of the small intestine
The small intestine or small bowel is an organ in the gastrointestinal tract where most of the absorption of nutrients from food takes place. It lies between the stomach and large intestine, and receives bile and pancreatic juice through the p ...
. Approximately 2% of Cr3+ is absorbed through the gut as chromium(III) picolinate via unsaturated passive transport
Passive transport is a type of membrane transport that does not require energy to move substances across cell membranes. Instead of using cellular energy, like active transport, passive transport relies on the second law of thermodynamics to d ...
. 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
Lipophilicity (from Greek λίπος "fat" and φίλος "friendly"), refers to the ability of a chemical compound to dissolve in fats, oils, lipids, and non-polar solvents such as hexane or toluene. Such non-polar solvents are themselves lipop ...
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
Starch or amylum is a polymeric carbohydrate consisting of numerous glucose units joined by glycosidic bonds. This polysaccharide is produced by most green plants for energy storage. Worldwide, it is the most common carbohydrate in human diets ...
, simple sugars
Monosaccharides (from Greek ''monos'': single, '' sacchar'': sugar), also called simple sugars, are the simplest forms of sugar and the most basic units (monomers) from which all carbohydrates are built.
They are usually colorless, water-solub ...
, oxalic acid
Oxalic acid is an organic acid with the systematic name ethanedioic acid and formula . It is the simplest dicarboxylic acid. It is a white crystalline solid that forms a colorless solution in water. Its name comes from the fact that early inve ...
, and some amino acid
Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha am ...
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. 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 to 100 μg/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
Transferrins are glycoproteins found in vertebrates which bind to and consequently mediate the transport of iron (Fe) through blood plasma. They are produced in the liver and contain binding sites for two Fe3+ ions. Human transferrin is encode ...
, 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
Aspartic acid (symbol Asp or D; the ionic form is known as aspartate), is an α-amino acid that is used in the biosynthesis of proteins. Like all other amino acids, it contains an amino group and a carboxylic acid. Its α-amino group is in the pro ...
, histidine
Histidine (symbol His or H) is an essential amino acid that is used in the biosynthesis of proteins. It contains an α-amino group (which is in the protonated –NH3+ form under biological conditions), a carboxylic acid group (which is in the de ...
, 2 tyrosine
-Tyrosine or tyrosine (symbol Tyr or Y) or 4-hydroxyphenylalanine is one of the 20 standard amino acids that are used by cells to synthesize proteins. It is a non-essential amino acid with a polar side group. The word "tyrosine" is from the Gr ...
residues and a bicarbonate
In inorganic chemistry, bicarbonate (IUPAC-recommended nomenclature: hydrogencarbonate) is an intermediate form in the deprotonation of carbonic acid. It is a polyatomic anion with the chemical formula .
Bicarbonate serves a crucial biochemic ...
ion that acts as a bidentate ligand to allow iron or other metals to bind to transferrin in a distorted octahedral geometry
In chemistry, octahedral molecular geometry, also called square bipyramidal, describes the shape of compounds with six atoms or groups of atoms or ligands symmetrically arranged around a central atom, defining the vertices of an octahedron. The oc ...
. Evidence supporting the binding of Cr3+ to transferrin comes from extensive clinical studies that showed a positive correlation between levels of ferritin
Ferritin is a universal intracellular protein that stores iron and releases it in a controlled fashion. The protein is produced by almost all living organisms, including archaea, bacteria, algae, higher plants, and animals. It is the primary ' ...
and of fasting glucose
Glucose is a simple sugar with the molecular formula . Glucose is overall the most abundant monosaccharide, a subcategory of carbohydrates. Glucose is mainly made by plants and most algae during photosynthesis from water and carbon dioxide, using ...
, insulin
Insulin (, from Latin ''insula'', 'island') is a peptide hormone produced by beta cells of the pancreatic islets encoded in humans by the ''INS'' gene. It is considered to be the main anabolic hormone of the body. It regulates the metabolism o ...
, and glycated hemoglobin
Glycated hemoglobin, also known as HbA1c, glycohemoglobin, hemoglobin A1c, A1C, is a form of hemoglobin (Hb) that is chemically linked to a sugar. Most monosaccharides, including glucose, galactose and fructose, spontaneously (i.e. non-enzymatic ...
(Hb1Ac) levels. Furthermore, an in vivo
Studies that are ''in vivo'' (Latin for "within the living"; often not italicized in English) are those in which the effects of various biological entities are tested on whole, living organisms or cells, usually animals, including humans, and ...
study in rats showed that 80% of isotopically labelled Cr3+ ended up on transferrin while the rest were bound to albumin
Albumin is a family of globular proteins, the most common of which are the serum albumins. All the proteins of the albumin family are water-soluble, moderately soluble in concentrated salt solutions, and experience heat denaturation. Albumins ...
. An in vitro
''In vitro'' (meaning in glass, or ''in the glass'') studies are performed with microorganisms, cells, or biological molecules outside their normal biological context. Colloquially called "test-tube experiments", these studies in biology an ...
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
In coordination chemistry, a stability constant (also called formation constant or binding constant) is an equilibrium constant for the formation of a complex in solution. It is a measure of the strength of the interaction between the reagents tha ...
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
Electron paramagnetic resonance (EPR) or electron spin resonance (ESR) spectroscopy is a method for studying materials that have unpaired electrons. The basic concepts of EPR are analogous to those of nuclear magnetic resonance (NMR), but the spin ...
(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 with hemochromatosis
Iron overload or hemochromatosis (also spelled ''haemochromatosis'' in British English) indicates increased total accumulation of iron in the body from any cause and resulting organ damage. The most important causes are hereditary haemochromatosi ...
, an iron-storage disease characterized by excessive iron saturation in transferrin.
Mechanism of action
Low-molecular-weight chromium-binding substance Low-molecular-weight chromium-binding substance (LMWCr; also known as chromodulin) is an oligopeptide that seems to transport chromium in the body. It consists of four amino acid residues; aspartate, cysteine, glutamate, and glycine, bonded with fou ...
(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
Aspartic acid (symbol Asp or D; the ionic form is known as aspartate), is an α-amino acid that is used in the biosynthesis of proteins. Like all other amino acids, it contains an amino group and a carboxylic acid. Its α-amino group is in the pro ...
, cysteine
Cysteine (symbol Cys or C; ) is a semiessential proteinogenic amino acid with the formula . The thiol side chain in cysteine often participates in enzymatic reactions as a nucleophile.
When present as a deprotonated catalytic residue, sometime ...
, glutamate
Glutamic acid (symbol Glu or E; the ionic form is known as glutamate) is an α-amino acid that is used by almost all living beings in the biosynthesis of proteins. It is a non-essential nutrient for humans, meaning that the human body can syn ...
, and glycine
Glycine (symbol Gly or G; ) is an amino acid that has a single hydrogen atom as its side chain. It is the simplest stable amino acid (carbamic acid is unstable), with the chemical formula NH2‐ CH2‐ COOH. Glycine is one of the proteinogeni ...
, 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
Chromium deficiency is described as the consequence of an insufficient dietary intake of the mineral chromium. Chromium was first proposed as an essential element for normal glucose metabolism in 1959, and was widely accepted as being such by the ...
. Despite recent efforts to characterize chromodulin, the exact structure is still relatively unknown.
Although chromodulin's exact mechanism of action on the insulin receptor
The insulin receptor (IR) is a transmembrane receptor that is activated by insulin, IGF-I, IGF-II and belongs to the large class of receptor tyrosine kinase. Metabolically, the insulin receptor plays a key role in the regulation of glucose homeo ...
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
Insulin (, from Latin ''insula'', 'island') is a peptide hormone produced by beta cells of the pancreatic islets encoded in humans by the ''INS'' gene. It is considered to be the main anabolic hormone of the body. It regulates the metabolism o ...
is released into the bloodstream and binds to an external α-subunit of the insulin receptor, a transmembrane protein
A transmembrane protein (TP) is a type of integral membrane protein that spans the entirety of the cell membrane. Many transmembrane proteins function as gateways to permit the transport of specific substances across the membrane. They frequentl ...
. The insulin receptor consists of 2 extracellular α-subunits and 2 transmembrane β-subunits. As soon as insulin binds to the insulin receptor, a conformational change in the receptor occurs, causing all 3 tyrosine
-Tyrosine or tyrosine (symbol Tyr or Y) or 4-hydroxyphenylalanine is one of the 20 standard amino acids that are used by cells to synthesize proteins. It is a non-essential amino acid with a polar side group. The word "tyrosine" is from the Gr ...
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.
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
Adipocytes, also known as lipocytes and fat cells, are the cells that primarily compose adipose tissue, specialized in storing energy as fat. Adipocytes are derived from mesenchymal stem cells which give rise to adipocytes through adipogenesis. I ...
) 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
In biochemistry, a kinase () is an enzyme that catalysis, catalyzes the transfer of phosphate groups from High-energy phosphate, high-energy, phosphate-donating molecules to specific Substrate (biochemistry), substrates. This process is known as ...
or up-regulating the amount of insulin receptor mRNA
In molecular biology, messenger ribonucleic acid (mRNA) is a single-stranded molecule of RNA that corresponds to the genetic sequence of a gene, and is read by a ribosome in the process of Protein biosynthesis, synthesizing a protein.
mRNA is ...
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
Insulin receptor substrate 1 (IRS-1) is a signaling adapter protein that in humans is encoded by the ''IRS-1'' gene. It is a 131 kDa protein with amino acid sequence of 1242 residues. It contains a single pleckstrin homology (PH) domain at the N-te ...
, elevated Thr308 and Ser473 phosphorylation
In chemistry, phosphorylation is the attachment of a phosphate group to a molecule or an ion. This process and its inverse, dephosphorylation, are common in biology and could be driven by natural selection. Text was copied from this source, wh ...
of Akt
Protein kinase B (PKB), also known as Akt, is the collective name of a set of three serine/threonine-specific protein kinases that play key roles in multiple cellular processes such as glucose metabolism, apoptosis, cell proliferation, transc ...
, and increased PI3-K
Phosphoinositide 3-kinases (PI3Ks), also called phosphatidylinositol 3-kinases, are a family of enzymes involved in cellular functions such as cell growth, proliferation, differentiation, motility, survival and intracellular trafficking, which i ...
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
Glucose transporter type 4 (GLUT4), also known as solute carrier family 2, facilitated glucose transporter member 4, is a protein encoded, in humans, by the ''SLC2A4'' gene. GLUT4 is the insulin-regulated glucose transporter found primarily in adi ...
translocation to the cell surface, thus causing greater uptake of glucose.
It has also been shown that chromium(III) can alleviate insulin resistance
Insulin resistance (IR) is a pathological condition in which cell (biology), cells fail to respond normally to the hormone insulin.
Insulin is a hormone that facilitates the transport of glucose from blood into cells, thereby reducing blood gluco ...
by reducing endoplasmic reticulum
The endoplasmic reticulum (ER) is, in essence, the transportation system of the eukaryotic cell, and has many other important functions such as protein folding. It is a type of organelle made up of two subunits – rough 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
c-Jun N-terminal kinases (JNKs), were originally identified as kinases that bind and phosphorylate c-Jun on Ser-63 and Ser-73 within its transcriptional activation domain. They belong to the mitogen-activated protein kinase family, and are ...
), 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
In biology and biochemistry, the active site is the region of an enzyme where substrate molecules bind and undergo a chemical reaction. The active site consists of amino acid residues that form temporary bonds with the substrate (binding site) a ...
cysteine residue on protein-tyrosine phosphatase 1B (PTP1B
Tyrosine-protein phosphatase non-receptor type 1 also known as protein-tyrosine phosphatase 1B (PTP1B) is an enzyme that is the founding member of the protein tyrosine phosphatase (PTP) family. In humans it is encoded by the ''PTPN1'' gene. PTP1B i ...
). 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
In biochemistry, an oxidoreductase is an enzyme that catalyzes the transfer of electrons from one molecule, the reductant, also called the electron donor, to another, the oxidant, also called the electron acceptor. This group of enzymes usually uti ...
) which then oxidize the thiol
In organic chemistry, a thiol (; ), or thiol derivative, is any organosulfur compound of the form , where R represents an alkyl or other organic substituent. The functional group itself is referred to as either a thiol group or a sulfhydryl gro ...
of the cysteine residue on PTP1B to sulfenic acid
In chemistry, a sulfenic acid is an organosulfur compound and oxoacid with the general formula . It is the first member of the family of organosulfur oxoacids, which also include sulfinic acids () and sulfonic acids (), respectively. The base ...
, 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
In coordination chemistry, a stability constant (also called formation constant or binding constant) is an equilibrium constant for the formation of a complex in solution. It is a measure of the strength of the interaction between the reagents tha ...
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
Body weight
Chromium(III) picolinate has been marketed in the United States as an aid to body development for athlete
An athlete (also sportsman or sportswoman) is a person who competes in one or more sports that involve physical strength, speed, or endurance.
Athletes may be professionals or amateurs. Most professional athletes have particularly well-devel ...
s and as a means of losing weight. Reviews have reported either no effect on either muscle growth or fat loss, or else a modest but statistically significant -1.1 kg (2.4 lb) weight loss in trials longer than 12 weeks. The European Food Safety Authority
The European Food Safety Authority (EFSA) is the agency of the European Union (EU) that provides independent scientific advice and communicates on existing and emerging risks associated with the food chain. EFSA was established in February 2002, ...
reviewed the literature and concluded that there was insufficient evidence to support a claim.
Diabetes
There are claims that the picolinate form of chromium supplementation aids in reducing insulin resistance
Insulin resistance (IR) is a pathological condition in which cell (biology), cells fail to respond normally to the hormone insulin.
Insulin is a hormone that facilitates the transport of glucose from blood into cells, thereby reducing blood gluco ...
and improving glucose metabolism
Carbohydrate metabolism is the whole of the biochemical processes responsible for the metabolic formation, breakdown, and interconversion of carbohydrates in living organisms.
Carbohydrates are central to many essential metabolic pathways. Plants ...
, particularly in type 2 diabetics
Diabetes, also known as diabetes mellitus, is a group of metabolic disorders characterized by a high blood sugar level (hyperglycemia) over a prolonged period of time. Symptoms often include frequent urination, increased thirst and increased app ...
, but reviews showed no association between chromium and glucose or insulin concentrations for non-diabetics, and inconclusive results for diabetics. The authors of the second review mentioned that chromium picolinate decreased HbA1c
Glycated hemoglobin, also known as HbA1c, glycohemoglobin, hemoglobin A1c, A1C, is a form of hemoglobin (Hb) that is chemically linked to a sugar. Most monosaccharides, including glucose, galactose and fructose, spontaneously (i.e. non-enzymatic ...
levels by 0.7% in type 2 diabetes patients, they observed that poor quality studies produced larger positive outcomes than higher quality studies. Two reviews concluded that chromium(III) picolinate may be more effective at lowering blood glucose
Glycaemia, also known as blood sugar level, blood sugar concentration, or blood glucose level is the measure of glucose concentrated in the blood of humans or other animals. Approximately 4 grams of glucose, a simple sugar, is present in the blo ...
levels compared to other chromium-containing dietary supplements.
In 2005, the U.S. Food and Drug Administration
The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respon ...
(FDA) approved a qualified health claim for chromium picolinate
Chromium(III) picolinate is a chemical compound with the formula Cr(C5H4N(CO2H))3, commonly abbreviated as CrPic3. It is sold as a nutritional supplement to treat type 2 diabetes and promote weight loss. This bright-red coordination compound is de ...
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. In 2006 the FDA added that the "relationship between chromium(III) picolinate intake and insulin resistance is highly uncertain".
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.
Safety and toxicity
Initial concerns were raised that chromium(III) picolinate is more likely to cause DNA damage
DNA repair is a collection of processes by which a cell identifies and corrects damage to the DNA molecules that encode its genome. In human cells, both normal metabolic activities and environmental factors such as radiation can cause DNA da ...
and mutation
In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, mi ...
than other forms of trivalent
In chemistry, the valence (US spelling) or valency (British spelling) of an element is the measure of its combining capacity with other atoms when it forms chemical compounds or molecules.
Description
The combining capacity, or affinity of an ...
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.
A study was published to assess the toxicity of Cr(III) picolinate 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
Nicotinamide adenine dinucleotide (NAD) is a coenzyme central to metabolism. Found in all living cells, NAD is called a dinucleotide because it consists of two nucleotides joined through their phosphate groups. One nucleotide contains an aden ...
or cysteine
Cysteine (symbol Cys or C; ) is a semiessential proteinogenic amino acid with the formula . The thiol side chain in cysteine often participates in enzymatic reactions as a nucleophile.
When present as a deprotonated catalytic residue, sometime ...
. This reduced form of Cr(II) is shown to react with H2O2 to generate radical species which in turn oxidize
Redox (reduction–oxidation, , ) is a type of chemical reaction in which the oxidation states of substrate change. Oxidation is the loss of electrons or an increase in the oxidation state, while reduction is the gain of electrons or a d ...
DNA base pairs. With this knowledge in mind, the researchers administered ten women with 400 μg 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 titer
Titer (American English) or titre (British English) is a way of expressing concentration. Titer testing employs serial dilution to obtain approximate quantitative information from an analytical procedure that inherently only evaluates as positiv ...
s, 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
Studies that are ''in vivo'' (Latin for "within the living"; often not italicized in English) are those in which the effects of various biological entities are tested on whole, living organisms or cells, usually animals, including humans, and ...
.
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 μg per day. This low toxicity has generally been associated with low absorbance of Cr(III) in the body through the lungs
The lungs are the primary organs of the respiratory system in humans and most other animals, including some snails and a small number of fish. In mammals and most other vertebrates, two lungs are located near the backbone on either side of th ...
, skin
Skin is the layer of usually soft, flexible outer tissue covering the body of a vertebrate animal, with three main functions: protection, regulation, and sensation.
Other cuticle, animal coverings, such as the arthropod exoskeleton, have diffe ...
and gastrointestinal tract
The gastrointestinal tract (GI tract, digestive tract, alimentary canal) is the tract or passageway of the digestive system that leads from the mouth to the anus. The GI tract contains all the major organ (biology), organs of the digestive syste ...
, coupled with high excretion. Normally, 99% of chromium(III) taken can be recovered in the feces of the user. There have been isolated incidences of chromium(III) supplementation leading to kidney failure, however this relationship is unclear and has yet to be 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 be genotoxic Genotoxicity is the property of chemical agents that damage the genetic information within a cell causing mutations, which may lead to cancer. While genotoxicity is often confused with Mutagen, mutagenicity, all mutagens are genotoxic, but some geno ...
(cause cancer). The committee also noted two case reports of kidney failure
Kidney failure, also known as end-stage kidney disease, is a medical condition in which the kidneys can no longer adequately filter waste products from the blood, functioning at less than 15% of normal levels. Kidney failure is classified as eit ...
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. 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.
References
External links
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Merck Manual
{{DEFAULTSORT:Chromium(Iii) Picolinate
Coordination complexes
Dietary supplements
Picolinates
Chromium(III) compounds