Chromium

Chromium is an essential mineral in the human diet and a common dietary supplement used to enhance insulin sensitivity and improve diabetes. ^[2]

Chromium can be found in:

• Bovine colostrum (in the form of a zinc-rich chromodulin oligopeptide, with one chromium atom per four amino acids ^{[3] [4]} ) yielding 220µg chromium per 1,035g of protein (193ng/g protein) ^[3]

• Skimmed milk, at a concentration of 252µg chromium per 1,172g of protein (215ng/g protein) ^[3]

Chromium itself is a dietary mineral and an element (Cr) with multiple valences. The fully-oxidized form of chromium (Cr(VI)), which is hexavalent (+6 oxidation state), is highly toxic and employed in a variety of industrial applications^[5]. Given the high degree of toxicity, hexavalent chromium is never used as a supplement. Supplemental forms of chromium include divalent (Cr(II)) or trivalent (Cr(III)), the latter being the most stable form. ^[2]

At least 0.005–0.2mg (5-20µg) of dietary chromium is needed daily to prevent deficiency, and the recommended intake is 21-25µg for women and 25-35µg for men daily with the 18-45 age bracket requiring amounts at the higher end of this range. ^[6] Woman of all ages who are breast-feeding require 45µg of chromium per day. ^[6] Children have a recommended intake of 11µg (1-3 years old) or 15µg (4-8 years old). ^[6]

Standard circulating chromium concentrations in a non-deficient state have been measured in the range of 2.8–45 µg/L in whole blood and 0.12-2.1 µg/L in serum. ^[7]

A deficiency of chromium can be induced with long-term total parenteral nutrition (TPN) lacking chromium, and has been reversed with supplementation of 150µg daily added to the TPN in one case study ^[8] and 250µg daily for 2 weeks followed by a maintenance dose of 20µg daily for 18 months in another. ^[9] The main symptoms of deficiency in these cases appeared to be significantly impaired glucose tolerance and insulin sensitivity associated with weight loss, as well as neuropathy and encephalopathy which were reversible upon replenishment of chromium. ^{[9] [8]}

Severe chromium deficiency is associated with type-I diabetic-like symptoms (impaired glucose tolerance and weight loss) as well as neuropathy, and can be reversed by administering chromium.

Subclinical deficiencies in chromium are associated with insulin resistance, since chromium concentrations have been found to be lower in diabetics relative to controls ^[10] (the evidence is mixed for gestational diabetes, however ^{[11] [12]} ). Chronic high-sugar diets (35% of daily calories) have been noted to accelerate urinary chromium losses, ^[13] although diets composed of high glycemic index foods failed to acutely influence urinary chromium elimination in healthy subjects despite showing a trend over six days. ^[14]  

This acclerated urinary chromium loss is thought to occur via release of chromodulin from insulin-sensitive cells into the bloodstream followed by its elimination in the urine. ^[15] Chromodulin is a peptide which exists inside of cells. When combined with chromium taken into cells from the bloodstream, it amplifies insulin signaling by binding to insulin-stimulated insulin receptors. ^[15] Chromodulin binds chromium ion with very high affinity, forming a complex that can only be separated under non-physiological conditions. Once insulin levels drop, however, the insulin receptors no longer need to be sensitized, so the entire complex must be eliminated as a whole. ^{[15]   [16]} This hypothesis is supported by detection of chromodulin in the urine ^[17] and its tight correlation with insulin secretion rates and exposure under nonsupplemental conditions. ^{[17] [18][19]}

Insulin resistant states may be associated with lower chromium levels, although not low enough to be considered a legitimate deficiency. This may be related to an increase in urinary chromium losses which seems to be caused by a diet high in sugars.

Urinary chromium concentrations are elevated with endurance exercise (a five-fold increase following two hours of running, but only two-fold over the course of the day) in a manner that is not related to an increase in serum insulin and not related to an increase in any other urinary ion.^[19] This situation, despite no increase in insulin levels, is known to require higher glucose uptake in muscle tissue sustained by higher release of glucose from the liver. ^[20]

Trivalent chromium (the type found in supplements), appears to have toxic effects at concentrations above 20µg/mL in the serum or cells; this toxicity is associated with oxidative damage to DNA. ^[21] This is the same mechanism by which hexavalent chromium is toxic, except the latter is toxic at much lower concentrations, ^[22] particularly after inhalation during occupations involving the handling of hexavalent chromium. ^{[23] [5]}

Chromium picolinate is a term referring to chromium in the trivalent state (Cr(III)) which is bound to three molecules of picolinic acid, a structural analogue of niacin. This form of chromium is highly stable^[24] aside from possible acid induced degradation, which would remove a picolinate molecule and lead to two chromium ions binding together.^[25] The picolinate ligands are in such a position that the Cr(III) can be reduced into Cr(II) in cell culture without losing the picolinate,^[26] a property that seems to be unique to picolinate relative to other supplemental forms (chloride and nicotinate) and is thought to underlie possible carcinogenic properties at high concentrations. ^[27]

Chromium picolinate is thought to be physiologically inactive until it releases free chromium, ^[27] suggesting that it serves as a chromium prodrug.

Chromium picolinate is a readily absorbed prodrug for chromium that is also highly stable when outside of the body (in processing and in storage).

Chromium is known to be present in yeast, where it plays a major physiological role. ^{[28] [29]} Within yeast cells is 'glucose tolerance factor' (GTF) ^[30] , which was first derived from brewer's yeast. ^[31] GTF can be purified from yeast after methanolic extraction and subsequent filtration, yielding a set of molecules 1,000 and 3,500 Da in size. ^{[32] [33]} The major active components in this set of molecules are thought to be trivalent chromium nicotinic acid along with some amino acids (glycine, L-cysteine, and glutamic acid). ^[34] Dietary intake of yeast seems to confer some of the benefits of chromium supplementation, probably due to GTF and chromium intake. ^[30]

Chromium from yeast is thought to be chromium nicotinic acid, although there may be other forms of chromium in yeast that have not yet been found.

Chromium nicotinic acid (also known as chromium polynicotinate) is chromium complexed with nicotinic acid (Niacin or Vitamin B3), and is reported to have cholesterol reducing effects. ^{[35] [36]} The studies in which cholesterol is reduced do not necessarily find glucose metabolism benefits, ^{[35] [36]} suggesting that it is the niacin that is causing these effects.

Chromium nicotinic acid is a form of chromium bound to niacin (vitamin B3), which has cholesterol-lowering effects. Because studies noting reduced cholesterol failed to show effects on glucose metabolism, the cholesterol-lowering effects of this chromium compound may be due to niacin.

Chromium dinicocysteinate (CDNC) is a complex of the chromium ion with the amino acid L-cysteine. One study comparing 400µg of chromium as CDNC against 400µg of chromium as picolinate found improvements in insulin levels and sensitivity only with CDNC. ^[37]

Chromium dinicocysteinate (CDNC) is a form of chromium bound to L-cysteine. While preliminary evidence suggests that it is effective, the body of evidence is not large enough to conclude its efficacy relative to chromium picolinate or brewer's yeast.

One of the major mechanisms thought to be related to chromium supplementation involves modulation of the insulin signalling pathway. ^[38] This was first discovered when a low molecular weight chromium-binding oligopeptide was identified that augmented the effects of insulin on glucose oxidation. ^[39] Also called LMCr or Chromodulin ^[40] , this oligopeptide is produced in the liver of rats following chromium injections ^[41] and has a mass of approximately 1500 kDa. ^{[40] [42]}

It was found that chromodulin increased insulin signalling in the presence of insulin 5-8 times higher than baseline activity, without affecting signalling in the absence of insulin. ^[43] Depleting chromodulin of chromium ablates the activity, ^[43] which positively correlates with the chromium content of the peptide. Also, other minerals failed to replicates its effects. ^[44]  

Ultimately, chromodulin increases autophosphorylation of the insulin receptor. Insulin receptor signalling requires that insulin or a mimetic (something that behaves like insulin) binds to the extracellular α-subunit of the receptor ^[45] which allows the intracellular β-subunit to be autophosphorylated. ^[45] Chromodulin appears to act intracellularly at the β-subunit of the insulin receptor. ^[15]

The chromium-dependent functions of chromodulin are likely the biological reason chromium is an essential mineral ^[46] , although chromium's essential nature has recently come into dispute. ^[47]

An oligopeptide known as chromodulin binds to chromium, and requires chromium to augment insulin receptor signaling. This may be one of the biological reasons chromium is arguably an essential nutrient, and deficiencies in chromium are thought to impair chromodulin's ability to enhance insulin signalling.

Adenosine Monophosphate Kinase (AMPK) is a key sensor of cellular energy status, constantly monitoring ATP levels to maintain metabolic homeostasis. AMPK is activated during low energy states (signified by increased AMP to ATP ratios) where it coordinates fatty acid and glucose metabolism in an anti-obesity and anti-diabetic manner. ^[48] When activated, AMPK suppresses anabolic pathways such as protein, triglyceride and fatty acid synthesis while activating catabolic pathways such as glycolysis and fatty acid oxidation to augment ATP production. ^[49]  

Chromium (trivalent with D-phenylalanine) has been noted to activate AMPK at its catalytic site (Thr172) in cardiomyocytes and skeletal muscle cells at 25μM, suggesting that organic chromium complexes may be novel activators of the AMPK pathway. ^[50]

Chromium in complex with D-phenylalanine has been implicated as an AMPK activator. It is not clear whether this effect is common to all types of chromium complexes, or may be unique to this particular form. Thus, it is also not clear whether this effect is relevant to oral chromium supplementation.

Absorption of dietary chromium is inversely correlated with intake, varying from 0.4% to 2.0%, with the more efficient absorption (2%) at lower dietary intake of around 10µg in adult humans. ^[51] This declines to around 0.5% when dietary intake reaches 40 µg where it seems to bottom-out, as chormium intake in the range of 40-240 µg has an absorption of around 0.4%. ^{[51] [52]}

Chromium absorption is influenced by a number of dietary factors. In rats, chromium absorption appears to be hindered by phytate coingestion, which prevents transport and absorption across the intestines. ^[53] Zinc deficiency has been shown to increase chromium absorption, which is increased in zinc-deficient rats and reduced by supplemental zinc, ^[54] suggesting that these two minerals may compete for absorption. Chromium absorption in rats is also enhanced by oxalate, an organic acid found in many vegetables and grains. ^[53] Although informative, care must be taken when extrapolating results from rat studies to humans, as recent studies have noted that absorption of dietary chromium in humans is significantly greater than rats for a number of chromium complexes tested. ^[55]  

Amino acids appear to enhance absorption of chromium from the diet as they form complexes that enhance absorption by reducing the tendency of chromium to precipitate in the alkaline intestinal fluid. ^[2] Chromium absorption in humans is also significantly increased in the presence of ascorbic acid and nicotinic acid. ^[2]

Percentage-wise, chromium is not well absorbed, and dietary intake is inversely correlated with absorption. The most efficient absorption (around 2%) occurs with less (around 10 μg), rather than more (40+ μg) chromium, which is absorbed in the 0.4-0.5% range. Chromium absorption is also affected by the presence of dietary factors such as amino acids, minerals such as zinc, and certain organic acids.

In type II diabetics, 1,000µg daily chromium supplementation (as chromium picolinate) was sufficient to bring fasting chromium levels in serum from 2.40 ± 0.19 vs. 0.16 ± 0.05 ng/dL at baseline after 12 weeks and 2.62 +/- 0.09 ng/dL vs. 0.17 +/- 0.04 ng/dL at baseline after 24 weeks supplementation. ^[56]

Transferrin is a transport protein in serum known to bind to minerals (notably iron). It has been noted to have affinity for trivalent chromium, ^[57] binding two ions of chromium per transferrin molecule. ^{[58] [59]} Transferrin is thought to donate chromium to the chromium-binding oligopeptide chromodulin. ^[60] Altough earlier studies suggested that chromodulin donates chromium to transferrin, this work was conducted at higher temperatures, which may have caused chromodulin degradation. ^[61] More recent studies have shown that chromodulin does not release chromium to transferrin, however. ^[60] Since transferrin releases ions within a cell after endocytosis, ^[62] it seems that chromodulin accepts and retains these ions from transferrin.

Transferrin is a protein known to transport many divalent and trivalent ions, including chromium. Following uptake by a cell, it can release free chromium ions which are then taken up by the chromium-binding oligopeptide chromodulin.

Supplementation of chromium results in increased urinary elimination of chromium. ^[56]

One rat study has noted that toxic levels of chromium (100µg/kg food intake) seem to bioaccumulate more with chromium chloride relative to chromium picolinate, due in part to a higher excretion rate seen with picolinate. ^[63] This was hypothesized to be due to the picolinate (picolinic acid), which has been noted to increase elimination of minerals such as zinc. ^[64]

Low doses of chromium picolinate in the food (providing 1ppm of chromium) of Long-Evans rats extended both median and maximal lifespan, which was associated with reduced age-related increases in glucose and insulin concentrations. ^[65] This was also supported by toxicity studies; chromium supplementation in rats at either 0.5ppm ^[66] or 7.7ppm (cited indirectly via review ^[67] ) in drinking water was associated with longer lifespan relative to controls.

Chromium supplementation has been reported to improve glucose tolerance in the elderly. ^[68] When investigating only well-nourished elderly people, however, it seems that chromium is without effect, ^[69] suggesting that chromium supplementation may be associated with anti-aging effects in humans only in the context of dietary deficiency.

Chromium has been shown to have robust anti-aging effects in rats that were attributed to reduced age-associated increases in glucose and insulin levels. Limited studies in humans suggest that chromium may only confer anti-aging effects in the context of a dietary deficiency, however.

Oral ingestion of chromium picolinate by rats for two weeks (100mg/kg in the diet, estimated 10mg/kg bodyweight) is able to increase brain concentrations of noradrenaline by 59.1% relative to a control diet. ^[70] The mechanism by which chromium is acting here is uncertain, although it has been hypothesized to be insulin-mediated; ^[71] insulin can cross the blood-brain barrier and increase synaptic noradrenaline concentrations by preventing its reuptake. ^[72]

It is thought that chromium can desensitize signalling through the 5-HT2A serotonin receptor since it impairs the increase in cortisol normally seen with 5-HTP (a serotonin precursor) administration in rats (100mg/kg chromium picolinate in the diet) and humans (400µg as picolinate). ^[73]

It is thought that chromium can reduce serotonin signalling via the 5-HT_2A receptors.

It is hypothesized that chromium sensitizes the hypothalamus in particular to the effects of insulin, thus affecting glucose metabolism. This can result in increased glycolysis (usage of glucose) and production of serotonin. ^[65] Higher serotonin activity correlates with increased insulin sensitivity in the periphery (at least in healthy subjects), which may in part account for chromium's effect on glucose utilization. ^[74]

It is thought that chromium is able to increase production of serotonin in the brain, which may lead to changes in how sugar is used by the body.

Chromium injections acutely and dose-dependently increase plasma tryptophan and brain serotonin concentrations (20-50mg/kg of chromium picolinate) in rats, ^[70] and 100mg/kg chromium picolinate in the rat diet (estimated 10mg/kg intake based on bodyweight) for two weeks increased free (but not total) tryptophan by 61.9% while also increasing serotonin by 38.5%. ^[70] This has been replicated elsewhere in rats fed chromium picolinate at the same dose, ^[73] however oral ingestion of 400µg chromium (as picolinate) in humans has failed to modify free or total plasma tryptophan concentrations. ^[73]

Rat studies demonstrate an increase in brain serotonin with oral chromium supplementation. Evidence for this effect in humans is weaker.

Oral supplementation of chromium picolinate (estimated 10mg/kg based on rat bodyweight, and an estimated human equivalent of 2,000-3,000µg elemental chromium) significantly increases melatonin concentrations in the pineal gland, noted alongside a general increase in brain serotonin levels. ^[70] and an increase in synaptic noradrenaline (noradrenaline reuptake inhibitors tend to increase melatonin in the pineal gland ^[75] ).

Several studies have suggested that chromium supplementation may promote reduced food intake and appetite in both human and animal subjects. A recent meta-analysis of 10 randomized, double-blind, placebo-controlled studies concluded that chromium picolinate had a relatively modest, but significant weight-loss inducing effect when compared to placebo ^[76] , possibly suggesting an appetite-suppressing effect. The mechanism(s) associated with putative food intake suppressing effects of chromium are currently unknown, although it has been proposed to occur via neurotransmitters in the brain that control appetite and cravings. ^{[73] [77]}  

This was confirmed in a recent study in overweight adult women who reported intense carbohydrate cravings (at least twice a week). Daily supplementation with 1,000μg chromium (as picolinate) over the course of eight weeks resulted in a greater reduction in food intake (25%) compared to placebo (8%). ^[78] Reduction in food intake was associated with decreased hunger and cravings, however macronutrient composition was unaffected and these changes were independent of any effects on insulin sensitivity. ^[78] In a parallel trial by the same research group, it was found that peripheral administration of chromium in rats (via IP injection) resulted in only a modest decrease in food intake, compared to a significant, dose-dependent decrease in food intake when administered centrally (directly into the brain). ^[78] Taken together, this work suggests that chromium supplementation may promote reduced food intake by affecting neurotransmitters in the brain that control appetite and cravings.

Chromium has been shown to promote reduced food intake in rats. This effect has also been demonstrated in human subjects, although it is not clear whether it may be specific to certain populations. Studies in rats suggest the food-intake reducing effects of chromium may occur via direct effects in the brain, via regulation of neurotransmitters that control appetite and feeding behavior.

In atypical depression patients (which is a particular subset of depression associated with higher food intake, sleep, and mood reactivity ^[79] ), 600μg chromium as picolinate for eight weeks failed to significantly influence the majority of depressive symptoms. However, there were significant improvements in carbohydrate cravings and food intake with a greater effect in those reporting larger carbohydrate cravings at baseline. ^[77] In persons with binge eating disorder, the rate of decline in binging frequency was greater with 1,000μg chromium than placebo and 600μg, although the overall reduction failed to reach statistical significance. ^[80]

Chromium may promote reduced food intake in those afflicted with abnormally high appetite or carbohydrate cravings that often co-occur with depression or binge-eating disorders. It may also promote reduced food intake in those with atypically strong cravings in the absence of any pathological diagnosis.

Supplementation of 1,000µg chromium (as picolinate) for 12 weeks to elderly adults with organic memory decline failed to exert antidepressive effects as assessed by the Geriatric Depression Scale. ^[81]

In a pilot study (no placebo control) for persons with rapid-cycling bipolar disorder, only a minority of subjects that received 600-800µg chromium daily alongside their standard medication exhibited less depressive symptoms (30% responders on the HAMD, 39% on MADRS) after three weeks. ^[82] In contrast, a series of case studies in dysthymic disorder have noted that chromium may significantly reduce depressive symptoms. ^[83] Moreover, a pilot study in atypical depression noted that 600µg chromium (picolinate) was better than placebo at reducing symptoms of depression in 70% (7/10) of subjects ^[84] . Although promising, it should also be noted that whole-group benefits of chromium supplementation in this study failed to reach statistical significance, as assessed by SCL-90 and HAM-D). ^[84]

Although Chromium has shown promise in reducing depressive symptoms, its efficacy may be limited to particular disorders, such as dysthymia or atypical depression.

Supplementation of chromium (picolinate) providing 1,000µg elemental chromium over 12 weeks in older adults with evidence of memory decline failed to improve memory (short, long, and recognition memory) but reduced inclusion errors during testing. ^[81] This reduction in inclusion errors was associated with increased activity (assessed by fMRI) in the right thalamic, temporal, and posterior parietal regions as well as the bilateral frontal regions during a working memory task. ^[81]

Suboptimal chromium levels have recently been identified as a possible risk factor for cardiovascular disease. Low chromium concentrations in the toenail (which builds up minerals from the body similar to hair) is associated with an increased risk of nonfatal myocardial infarction. ^[85] In a double-blind, placebo-controlled crossover study, type II diabetics who supplemented with 1,000µg chromium (as picolinate) daily for three months exhibited a shortened QTc interval. ^[86] QTc interval prolongation, which has been linked to impaired glucose homeostasis in type II diabetics, is a powerful predictor of caridiac death ^{[87] [88]} , suggesting that chromium supplementation may exhibit a moderate cardioprotective effect by promoting improved glucose homeostasis. Consistent with this, benefits of three months of supplementation were carried over for an additional three months without supplementation and occurred concurrently with reductions in serum insulin levels. This effect occurred independently of any changes in glucose or HbA1c levels and heart rate was unaffected. ^[86]

Low chromium levels have been linked to increased risk for cardiovascular disease in men. Chromium supplementation has been shown to shorten the QTc interval in type II diabetics, which is suggestive of a cardioprotective effect.

The concentration of chromium in red blood cells (RBCs) tends to be higher (3.84–69.2nM) than that in serum (2.3–40.3nM). ^[89]

RBC membrane abnormalities are prevalent in diabetes and associated with oxidative damage. ^[90] When RBCs were treated with high glucose in vitro to simulate a diabetic state, they were structurally protected by chromium chloride, ^[91] suggesting that chromium may confer a layer of protection against erythrocyte oxidative damage during impaired glucose homeostasis.

Chromium does not appear to effect triglycerides. In a recent meta-analysis of five trials that evaluated the effects of 250μg or greater chromium supplementation for a period of over three months, the authors failed to find any effect on triglycerides relative to placebo. ^[92]

A meta-analysis of chromium supplementation (250µg or more) in type II diabetics for a period of greater than three months ^[92] failed to find any evidence of significant improvements in total cholesterol, HDL cholesterol, LDL cholesterol, or vLDL cholesterol relative to placebo.

Supplementation of 1,000µg chromium (as picolinate) in two divided doses for 24 weeks in type II diabetics failed to significantly influence hepatic glucose production relative to placebo. ^[56] (Hepatic glucose production is often pathologically elevated in diabetics ^[93] )

Chromium does not affect gluconeogenesis, a process where glucose is produced in the liver from non-carbohydrate carbon substrates that is pathologically increased in diabetics.

When medicated diabetics consumed 200µg chromium (as chloride) added to a milk powder product daily for 16 weeks, blood glucose and insulin levels were significantly reduced while insulin sensitivity improved. ^[94] The results of this study were somewhat gender-specific however, as significant improvements in the aforementioned markers of glucose homeostasis occurred in male subjects only. ^[94]

Chromodulin is an endogenous oligopeptide ^[42] containing chromium which positively mediates signalling of the insulin receptor when in the presence of insulin. ^[39] Injecting of chromium (as potassium chromate) into rats increases urinary and fecal concentrations of this oligopeptide. ^[95] However, urinary chromodulin does not appear to be saturated under basal conditions, implying that more chromium could be bound to the oligopeptide. ^[95] Since the potency of chromodulin in enhancing insulin signaling correlates with the amount of chromium bound to it, ^[44] and injections of potassium chromate in rats result in rapid association with chromodulin, ^{[61] [96]} it is possible that increased dietary chromium could increase the activity of this oligopeptide.

Operating under the assumption that typical dietary chromium intakes are insufficient to saturate chromodulin, chromium supplementation could theoretically enhance insulin signaling by increasing chromium-chromodulin association.

In studies using trivalent chromium, there appears to be an increase in insulin receptor kinase activity (in the presence of insulin) when 1-10μM chromium is added to mammalian cell culture. ^[97] This increase is independent of any direct influence on either phosphorylation or autophosphorylation ^[97] and distinct from that of chromodulin, which influences autophosphorylation. ^[43]

Some complexes with trivalent chromium have minor interactions with the insulin receptor, with complexes bound to small endogenous molecules such as histidinate, lactate, acetate or propionate showing minor inhibitory effects at concentrations around 100μM. Of these complexes, chromium-propionate appears to be more potent, showing inhibitory effects at concentrations as low as 1μM. ^[98]

Chromium itself has been implicated in enhancing insulin signalling, although the mechanism with chromium ions seems to differ from that seen with chromodulin and requires a significantly higher concentration. Chromium itself does not appear to directly influence the insulin receptor like chromodulin can.

Protein-tyrosine phosphatase 1B (PTP1B) is a negative regulator of insulin receptor signaling ^[99] that may be suppressed by endogenous chromium. Although chromodulin was found to activate membrane PTP activity in one earlier study, ^[100] there are many endogenous PTP enzymes, and PTP1B was not specifically examined in this study. Trivalent chromium has been shown to inhibit PTP1B by 21-33% in both rat and human hepatoma cells,^[101] suggesting that chromium may potentiate insulin signaling by suppressing PTB1B-mediated dephosphorylation of the insulin receptor. In contrast, a more recent study noted that chromium failed to inhibit recombinant human PTP1B phosphatase activity in a pure in vitro system, suggesting that chromium may potentiate insulin signaling by mechanisms distinct from any effects on PTP1B. ^[97]

In an in vivo study, obese diabetic rats fed 80μg/kg chromium (as picolinate) experienced an overall decrease in PTP1B activity as well as protein expression which correlated with increased insulin signaling in skeletal muscle. ^[102] This decrease was not observed in lean rats given chromium at the same dose, however. ^[102]

Phosphorylation of IRS-1, an important transducer of insulin signaling that is inhibited by phosphorylation at Serine307, ^[103] is not affected by 10µM chromium in various trivalent forms. ^[98] Moreover, IRS protein expression remained unaffected with up to 80μg/kg chromium supplementation in rats. ^[102] In the absence of insulin however, basal IRS-1 signaling is slightly increased at 10µM chromium, which is thought to be due to decreased phosphorylation of Serine307 ^[98] by Jun NH(2)-terminal kinase (JNK). ^[38] JNK negatively regulates IRS signaling via phosphorylation at Serine307, ^{[103] [104]} which is increased in obese mice, ^{[105] [106]} causing insulin resistance. Notably, JNK-mediated attenuation of insulin signaling in obese rats is suppressed by chromium. ^{[105] [106]}

The above JNK activation could be traced back to endoplasmic reticulum (ER) stress in theory, ^[107] and agents that reduce ER stress also attenuate diabetic symptoms. ^{[108] [109]} ER stress is known to be increased in cells from obese and diabetic animals and is treatable with chromium. ^[105]

Chromium interactions with PTP1B, a negative regulator of insulin receptor activity are not well-understood. Some studies suggest that chromium may not have appreciable effects on PTP1B signaling. It is possible, however, that chromium suppresses JNK-mediated attenuation of insulin signaling in the context of a pre-existing insulin resistant state.

Chromium does not appear to augment insulin receptor expression in the presence or absence of insulin, suggesting that its affects on insulin signaling occur independent of any changes in insulin receptor levels. ^{[110] [98]} Moreover, when incubated with insulin, chromium does not affect the interaction of insulin with the insulin receptor. ^[97] This suggests that chromium does not affect insulin sensitivity via augmenting insulin receptor affinity.

Chromium does not affect insulin receptor expression levels or influence binding of insulin to the insulin receptor.

An early study conducted in 1992 revealed that chromium increases insulin internalization at 1µM (418ng/mL), which was associated with increased membrane fluidity and not replicated with other chelations of chromium or zinc picolinate. ^[111] The novel discovery that insulin is internalized into the cell was later revealed to be an important negative feedback mechanism for insulin receptor signaling. After insulin binds its receptor, the insulin-receptor complex is internalized by endocytosis, ^[112] triggering insulin degradation ^[113] and effectively reducing the number of insulin receptors displayed on the cell surface as a mechanism to attenuate the insulin response. ^[114]

After binding to its receptor outside the cell, insulin triggers movement of the insulin-receptor complex to inside the cell. This reduces the number of insulin receptors displayed on the cell surface and functions as a negative feedback mechanism to limit the insulin signaling response.

In response to an oral glucose tolerance test, supplementation of 200µg for eight weeks failed to increase the insulin response when measured after 10 minutes in type II diabetics ^[94] while 1,000µg (as picolinate) in non-diabetic persons with metabolic syndrome over 16 weeks has increased the insulin response despite no other change in diabetic biomarkers. ^[115]

One study noted that in spite of failure to find statistically significant improvements in insulin sensitivity for the whole group of subjects, 46% of subjects who also had higher baseline levels of insulin resistance improved by 10%. ^[56] Notably, there was no difference in the absorption or kinetics of chromium between responders and nonresponders, ^[56] suggesting that chromium supplementation may increase insulin sensitivity in the context of insulin resistance.

Moreover, supplementation of 1,000µg chromium (as picolinate) for 24 weeks in type II diabetics has been noted to slightly reduce intramuscular lipid concentrations relative to placebo. ^[56] Because buildup of lipids within muscle tissue is one of several pathological causes of insulin resistance, ^[116] this work further suggests that chromium supplementation may increase insulin sensitivity in those who are already insulin-resistant.

Chromium supplementation may promote improved insulin sensitivity in those who are already insulin-resistant.

A meta-analysis of trials in type II diabetics with over 250µg chromium supplementation lasting over three months failed to find any influence on HbA1c relative to placebo treatment. ^[92] This is in opposition to previous reviews assessing only trials in diabetics with a baseline HbA1c over 7%, where chromium supplementation resulted in a reduction in HbA1c by 0.34% relative to placebo. ^[117] Other reviews have noted reductions of 0.6%, ^[118] and as much as 0.9% when all forms of diabetes and insulin resistance were included. ^[119] It should be noted, however, that some of these analyses included trials lasting less than three months, ^[118] which may not be sufficient to measure authentic changes in HbA1c. ^[92]

Depending on the population studied and the type and quality of studies looked at, evidence that chromium affects hemoglobin A1C levels is mixed.

Supplementation with 400 or 800µg chromium (as picolinate) alongside a test meal in otherwise healthy adults reduced glucose area under the curve (AUC) by 30-36% in responders, with the low-dose being more effective. ^[120] Notably, responders were classified by having a relatively lower meat and milk intake, ^[120] suggesting that chromium may affect postprandial glucose-metabolism in those with lower baseline levels of chromium. The reduction in glucose was not associated with any changes in insulin, excluding an insulinogenic effect, and occurred in persons without impaired glucose metabolism. ^[120]

Chromium supplementation may promote blood glucose-disposal, particularly in those with low dietary chromium intake.

In a meta-analysis of trials assessing chromium supplementation over 250µg in type II diabetics over a three month period (or longer), ^[92] the seven trials which were included in meta-analysis ^{[56] [89] [121] [122] [123] [124] [125]} failed to show a reduction in HbA1c levels in serum despite a mild reduction in blood glucose (RR of -0.95 and a 95% CI of -1.4 to -0.5). ^[92]

An analysis of observational data from the National Health and Nutrition Examination Survey (NHANES) found that people who consumed a dietary supplement containing chromium had a lower odds of having diabetes (OR = 0.73), defined by having an HbA1c level greater than 6.5. The use of supplements in general did not have a statistically significant effect on the odds of diabetes in this study. ^[126]

In studies pairing chromium with resistance training, chromium has failed to influence lean mass accrual in older persons (with a mean age around 60) after 13 weeks training while supplementing 1,000µg chromium picolinate. ^[127] In women around the same age and given the same protocol, chromium failed to affect body composition, strength or muscle fiber composition. ^[128] Another study investigating only older men reached similar conclusions in regards to the lack of effect of chromium supplementation on skeletal muscle. ^[129]

In youth wrestlers, 200µg chromium daily for 14 weeks failed to modify body composition or muscular performance. ^[130] Moreover, chromium supplementation at the same dose failed to have an effect on skeletal muscle in untrained people given a weight-training routine. ^[131]

Chromium does not seem to promote the growth of muscle mass in any population at any dose.

Chromium supplementation failed to increase power output in elderly women given 1,000µg chromium (as picolinate) over the course of 13 weeks. ^[128] Half this dose (500µg) in young female athletes similarly failed to increase power output. ^[132]

In young male wrestlers, 200µg chromium (as picolinate) over 14 weeks also failed to modify power output or muscular endurance. ^[130]

Chromium does not seem to affect power outoput in any population at any dose.

The addition of 400µg chromium (as picolinate) to a carbohydrate containing beverage prior to a shuttle run test in otherwise healthy and active men failed to modify the benefits of the carbohydrate containing beverage relative to water control, suggesting no additional benefits. ^[133]

One study using chromium (600µg as picolinate) daily for a month prior to a glycogen depletion exercise noted that immediately after exercise and for the next hour, the chromium group had significantly higher lactate levels relative to placebo. ^[134] In another study utilizing a shuttle-run exercise model, this increase in lactate failed to occur over 75 minutes of testing following consumption of 400µg chromium picolinate alongside carbohydrate or water control. ^[133] Moreover, lactate concentration at fatigue was similar in this study between both groups and water control. ^[133]

Results of studies examining the effect of chromium supplementation on lactate production are mixed, likely varying with the exercise model and sampling protocol. Taking the evidence into account, chromium does not appear to have a robust, meaningful effect on lactate production.

Glycogen synthase is the enzyme responsible for converting glucose to glycogen, the primary storage form of carbohydrate in the body. Likewise, glycogen phosphorylase is involved in breaking down these carbohydrate stores into glucose for energy. Because of its effects on glucose metabolism, chromium has been investigated for its impact on glycogen stores. Preliminary evidence revealed that rats fed chromium preserved liver glycogen better than a control group during fasting.^[135] Later, it was noted that chromium increased the activity of the glycogen synthase enzyme in trained rat muscle and liver relative to nonsupplemental control, but glycogen phosphorylase was unaffected. ^[136]

Limited evidence in rats suggests that chromium supplementation can increase the storage and production of glycogen in skeletal muscle. Chromium does not seem to affect the breakdown of glycogen to free up glucose for energy, however.

In overweight and lightly trained or sedentary adults given supplementation of chromium (600µg as picolinate) daily for a month alongside a standardized diet with the last two days designed to deplete glycogen, supplementation failed to modify glycogen levels or the rate of resynthesis (from a carbohydrate containing beverage) relative to placebo. ^[134]

Chromium supplementation in overweight, untrained humans failed to affect glycogen resynthesis following exercise.

According to a meta-analysis on weight in type II diabetics supplementing chromium (over 250µg) for over three months, there is no significant alteration in weight relative to placebo despite a modest reduction in blood glucose. ^[92] In contrast, another meta-analysis found that overweight and obese adults who supplemented with chromium picolinate reduced body weight in the dosage range of 200-1,000µg, regardless of diabetic status. Weight loss was very modest however, totaling only 1.1kg (95% CI in the range of 0.4-1.7kg). ^[137] Of note, this latter meta-analysis deemed the quality of evidence less than optimal, calling into question any chromium-mediated effects on weight loss. ^[137]

Chromium supplementation has little to no influence on weight. Although results from some studies are suggestive of very modest effect, robust, reliable evidence for weight loss is currently lacking.

One trial noted that weight gain associated with sulfonylurea therapy (0.9kg over 10 months) in diabetics was mitigated by coingestion of 1,000µg chromium. ^[124] Importantly, these results may be limited to those who are undergoing sulfonylurea therapy. When diabetic subjects who were not currently medicated were instructed to follow a weight-maintenance diet, 1,000µg chromium picolinate failed to modify food intake, appetite, or body weight. ^[56]

Chromium has also been used in an attempt to mitigate weight gain associated smoking cessation, as people who quit smoking often tend to gain a considerable amount of weight. ^[138] This trial used Hypericum perforatum (900mg) as the initial anti-smoking aid and then divided study subjects into chromium or placebo groups. Unfortunately, the trend for chromium to attenuate weight gain was unable to be tested with sufficient power, due to low success rates with the aforementioned herb. The effects of chromium were promising, however, possibly attenuating a 5.76 kg weight gain to 2.7 kg after six months). ^[1]

Certain trace minerals, as well as balance between different trace minerals, has been hypothesized to influence immune response. In postmenopausal women with high cholesterol, chromium supplementation (200μg daily for 12 weeks) failed to influence the counts of different immune cell types (lymphocytes, monocytes, neutrophils and eosinophils). However, proliferation of lymphocytes in response to mitogens (used as an indicator of immune function) was enhanced with chromium supplementation, which was ablated with copper at a dose of 3mg daily administered daily alongside chromium. ^[139]

Lipid peroxidation, a form of oxidation that causes oxidative damage to cellular membrane lipids, is identified by increased biomarkers such as TBARS and MDA. Increased lipid peroxidation is often associated with diabetes alongside increased HbA1c, a marker of dysfunctional glucose metabolism. ^[90] Thus, chromium has been investigated for its affect on lipid peroxidation alongside its role in glucose metabolism.

Chromium supplementation at 1,000µg daily for 6 months reduced lipid peroxidation as measured by a reduction in TBARS by 12-21% in people whose HbA1c exceeded 6.8%, independent of any changes in antioxidant enzyme levels (superoxide dismutase, catalase, glutathione peroxidase). ^[140] In people with normal HbA1c levels (below 6%), however, TBARS actually increased by 28.6%, suggesting that chromium acted as a pro-oxidant in this group. ^[140] In contrast, a reduction in TBARS of 13.6% without changes in antioxidant enzyme levels was noted in a study of diabetics after six months with 400µg of chromium. ^[141] Similar results were achieved with 30mg Zinc (as gluconate), which was mildly additive in patients given both chromium and zinc (reaching 18.6% with combination therapy). ^[141]

Chromium may reduce lipid peroxidation in certain populations. More studies are needed, however, to determine the appropriate dose as well as who may benefit.

Chromium (as trivalent picolinate) has been shown to induce chromosomal damage in chinese hamster ovary (CHO) cells at concentrations of 50µM or greater, although this damage is thought to be caused by the picolinate ligands and not the chromium itself, since other forms of chromium failed to induce damage. ^[142] Other trivalent chromium complexes have been noted to cause DNA strand breaks, however, ^{[21] [143]} albeit at a much higher concentration than the toxic hexavalent form. ^[144] It is thought that the DNA strand breaks are caused by CrIII being reduced to CrII, which can then be oxidized back to CrIII in a process which creates pro-oxidants that damage DNA. ^{[27] [145]}

Chromodulin, the peptide which contains chromium, does not appear to damage DNA nor does it appear to release free chromium under physiologically relevant conditions.^[146]

Daily supplementation with 400µg chromium (as picolinate) for eight weeks in obese women failed to alter levels of the anti-HMdU (5-hydroxymethyl-2'-deoxyuridine) antibody in titers, ^[147] an oxidized DNA base and indicator of DNA damage. ^[148] This lack of increase was reported to demonstrate absence of genotoxicity. ^[147]

Chromium picolinate, more than other trivalent forms of chromium, has the ability to form prooxidants that can potentially cause DNA damage. The relevance to standard oral supplementation is not known, since the concentration required to damage DNA (in upwards of 50µM) is significantly higher than what is seen in the blood following oral ingestion of supplements. Moreover, studies in human subjects have failed to note DNA damage with standard supplemental doses.

The concentration of chromium in the testes of diabetic rats (0.36µg/g dry weight) is less than that of control rats (0.63µg/g). ^[149] Injections of trivalent chromium at a dose of 500µg/kg bodyweight for three days can be detected in the testicular tissue of both normal and diabetic rats, with most of the accumulation occurring in the cytosol (with minimal accumulation in the nucleus, mitochondria, lysosome, or microsomes). This asymmetrical accumulation occurs despite the fact that chromium losses asscoated with diabetes occur in all subfractions of the cell. ^[149]

Hexavalent chromium, the form used in industries but not supplementation, is known to be toxic to testicular tissue. ^{[150] [151]} In contrast, high concentrations of trivalent chromium (up to 1mM) have failed to suppress cellular proliferation of sertoli-like cells, ^[152] suggesting a lack of apparent toxicity.

Chromium accumulates in the testes of rats when injected, although the possible benefits or harm in the testicles with oral supplementation of chromium have not been studied. Hexavalent chromium, the toxic form not found in supplements, is known to be toxic to the testes.

Chromium was found to be present in breast milk at concentrations of 1.73–8.85nM in one study ^[153] with other studies finding similar results. ^{[154] [155][156] [157]} Acute supplementation of chromium (400µg as trichloride once daily for three days) does not appear to significantly influence breast milk chromium concentrations despite appearing in serum. ^[153] This lack of correlation with serum chromium has been reported previously,^[155] suggesting that breast milk chromium is more reflective of chronic chromium status and, unlike the blood, tightly regulated against acute fluctuations.

Chromium intake of lactating women, without prompting to consume chromium, tends to be greater than that of age-matched female controls. ^{[157] [155]}

Supplementation of 400µg chromium as picolinate (a dose suggested to hinder 5-HT_2A signalling ^[73] thereby acting as an antipsychotic ^[158] ) to persons with schizophrenia on stable medication failed to provide any benefits over three months as assessed by PANSS or the HAM-D rating scales. ^[159]

Polycystic ovarian syndrome (PCOS) is a syndrome associated with insulin resistance due to high androgen levels in women, A preliminary study in five women given 470µg chromium (as picolinate) twice daily for two months noted a significant increase in glucose disposal rates of 38% and a trend to reduce insulin levels, suggesting improved insulin sensitivity. ^[160]

A double-blind, placebo-controlled study using 200 µg chromium picolinate supplementation for 8 weeks found significant decreases in plasma insulin levels and improved insulin sensitivity in women with PCOS. There was also a trend toward improved lipid profiles, although none of the differences were statistically significant. ^[161] Another such study also using 200 µg chromium picolinate for 8 weeks found reduced acne, hirsutism, and C-reactive protein and improved plasma total antioxidant capacity but no change in reproductive hormones (FSH, LH, prolactin, and free testosterone). ^[162]

Chromium supplementation may improve some symptoms and the metabolic profile of women with polycystic ovarian syndrome, although no impact on reproductive hormone levels has been found.

Chromium ingestion at 400µg (as picolinate) failed to influence baseline cortisol levels, but does reduce the increase caused by 5-HTP administration. ^[73] The authors of the study discovering this suggested that this effect due to desensitization by chromium of the 5-HT_2A receptor, which mediates cortisol levels. ^[73]

Chromium is known to be transported in the blood with the same transporter that carries iron and some other dietary minerals, known as transferrin. ^[59] Minerals in general may be competitive at this level, ^[163] and high levels of chromium given to rats (1,000µg/kg for 45 days) have been noted to reduce total iron binding capacity (11%) and serum iron (28%) via competitive inhibition. ^[164] This has led to the investiagtion of the potential for chromium to reduce iron status in humans.

One study noted that supplementation of a low dose of chromium (187µg as picolinate) over a 12 week period does not influence total iron binding capacity of the blood or iron status of otherwise healthy women. ^[165] Another study found that eight weeks of supplementation of 500µg chromium via Brewer's yeast failed to alter serum or hair concentrations of iron (and other minerals, such as copper and zinc) despite an increase of chromium in serum (116%) and in hair (20.6%). ^[166] These results are suggestive that chromium supplementation at low levels does not affect iron status in humans.

Although studies in rats taking very high doses of chromium have suggested that chromium may interfere with iron transport, human studies of chromium supplementation at normal doses have not borne this out. It seems that chromium supplementation at normal dosing has no effect on iron state in humans.

Grape seed extract (GSE) is a source of procyanidins (similar to pycnogenol) that is claimed to have cardioprotective effects, and it has been investigated in conjunction with chromium supplementation. It has been hypothesized ^[167] that the cardiovascular benefits of this combination are secondary to interactions between insulin sensitizers (in this case, chromium) and antioxidants (GSE), since diseases characterized by insulin resistance also have high free radical production. ^[168]  

One pilot study assessing the combination found a decrease in total cholesterol with the combination of 200µg chromium (as polynicotinate) paired with 100mg GSE that was not present in either group alone ^[35] while a reduction in LDL oxidation seemed to be mostly due to GSE with no contribution from chromium. ^[35]

GSE and chromium are speculated to be additive or synergistic in alleviating the signs of metabolic syndrome, but at this moment the evidence to support synergism is limited.

Inositol is an insulin-sensitizing sugar is used as a dietary supplement, and could in principle be complementary with chromium due to their similar uses.

In older sedentary adults, 924µg chromium (as picolinate) daily for 13 weeks alongside resistance training and a controlled diet (given to both chromium and placebo groups) has failed to influence either total urinary inositols or the ratio of myo-inositol:D-chiro-inositol. ^[169]

Two months ingestion of chromium (nanoparticles of picolinate) at 600-1,000µg/kg food intake in rats failed to demonstrate any organ damage or modification of H₂O₂-induced DNA damage in mouse hepatocytes in vitro. ^[170] Higher doses of chromium (as either chloride or picolinate) up to 100mg/kg failed to show organ damage to the kidneys or liver and induced no abnormalities in blood parameters. ^[171] Elsewhere, chromium (1-100µg/g food intake or 1-100mg/kg) has been noted to elevate liver enzymes associated with a low liver weight in rats despite no histopathological changes, and these changes were more significant with picolinate (relative to chloride). ^[63]  

It was suggested that a dietary intake of chromium of 100mg/kg of food was approximately an equal to an intake of 10mg/kg body weight, ^[63] and since minor increases in liver enzymes were noted at 1mg/kg in the rat diet (or 100µg/kg in relation to bodyweight) it suggests that adverse effects could occur in humans above this dose. ^[63]

In rats, liver damage appears to be able to be induced with an intake of chromium which is above recommended supplemental levels.

There is a case study of a woman ingesting 1200-2400µg chromium (as picolinate) for 4-5 months who exhibited symptoms of renal damage ^[172] and one case of a bodybuilder who developed rhabdomyolysis associated with 1,200 over the course of two days. ^[173]