Chemistry and Forms

Chromium exists in several forms, with chrome-iron ore the predominant form in the planetary crust. The trivalent and hexavalent states constitute the most common valence states, with trivalent chromium being the stable and biologically active form found in most food sources and hexavalent chromium primarily associated with industrial exposure and toxicity.

Physiology and Function

Chromium is an essential trace mineral well known for its role in carbohydrate, lipid, and protein metabolism in general and insulin activity and glucose homeostasis in particular. Emerging knowledge indicates that chromium also plays an important role in nucleic acid synthesis and gene expression. Nevertheless, chromium, as an ultratrace element, is found in very low concentrations in the human body.

Dietary chromium is poorly absorbed (0.5% to 2.8% of intake), and almost all of an ingested dose is excreted in the feces. Absorption occurs in the small intestine by processes other than simple diffusion, the mechanisms of which are not yet fully understood. Chromium is subsequently transported in the serum or plasma bound to transferrin (named for its role in binding and transporting iron) primarily and albumin secondarily. Chromium is widely distributed throughout the human body, with highest concentrations in the bone, spleen, liver, and kidney into four different compartments that have rapid, medium, slow, and very slow turnover. Chromium that has been absorbed is excreted mainly in the urine. Small amounts are also lost in hair and sweat. Little excretion occurs via the biliary route.

Organic chromium increases insulin sensitivity, promotes glucose uptake, and potentiates the action of insulin by increasing insulin binding to cells, increasing the number of insulin receptors, and activating insulin receptor kinase. Trivalent chromium serves as the active component of a substance called glucose tolerance factor (GTF), along with nicotinic acid (a form of vitamin B3) and amino acids in the form of a small oligopeptide known as chromodulin, or low-molecular-weight chromium-binding substance (LMWCr). Once activated by binding to chromium, chromodulin binds to insulin-activated insulin receptors in insulin-dependent cells and participates in auto-amplification of insulin signaling, thereby stimulating its tyrosine kinase activity and potentiating the activity of insulin. Chromium may also inhibit tyrosine phosphatase, which inactivates the insulin receptor. Such combined effects on insulin receptor kinase activity and tyrosine phosphatase would lead to increased phosphorylation of the insulin receptor and an associated increase in insulin sensitivity. Thus, through GTF, chromium acts as a cofactor to mediate the activity of insulin and facilitate glucose transport across cell membranes.

Chromium appears to possess hypocholesterolemic and antiatherogenic activities. Chromium can decrease levels of total cholesterol, low-density lipoprotein (LDL) cholesterol, and apolipoprotein B and may increase levels of high-density lipoprotein (HDL) cholesterol. The possible antiatherogenic activity of chromium is most likely derived from its glucose-regulatory activity. Chromium, like insulin, also increases uptake of amino acids into muscle, heart, and liver and enhances protein synthesis.

At this time, chromium remains the only essential transition metal whose mechanism of action has not been fully elucidated.

Known or Potential Therapeutic Uses

In 1957, researchers observed impaired glucose tolerance in chromium-deficient rats and discovered that administration of a chromium-containing compound extracted from pork kidney to diabetic rats maintained normal glucose tolerance and enabled more efficient use of insulin. They called this substance “glucose tolerance factor” (GTF). Later, other researchers reported an increased occurrence of glucose intolerance, weight loss, and peripheral neuropathy in patients receiving long-term total parenteral nutrition (TPN) without chromium. Intravenous administration of chromium chloride reversed these symptoms. Over the subsequent decades, chromium research has grown, with an emerging consensus confirming its therapeutic value in supporting insulin activity and glucose homeostasis. Wide-ranging and unresolved controversy surrounds its purported efficacy in weight loss, athletic training, dyslipidemia, depression, hyperactivity, and related conditions. Rigorous, blinded, and well-controlled studies of sufficient size and power are needed to assess fully the efficacy and mechanism of action of chromium administration and to establish clinical guidelines for its role within an integrative strategy for type 2 diabetes and impaired glucose tolerance.

Historical/Ethnomedicine Precedent

Based on familiarity with folk medicine traditions and empirical practice, naturopathic physicians and other practitioners of nutritional therapeutics have advocated the administration of brewer's yeast and foods rich in chromium for the prevention and treatment of hypoglycemia and diabetes for more than a century.

Possible Uses

Acne, atherosclerosis, athletic performance, atypical depression, depression, diabetes mellitus type 1, diabetes mellitus type 2, dysthymic disorder, gestational diabetes, glaucoma, hypercholesterolemia, hypertriglyceridemia, hypoglycemia, insulin resistance syndrome (metabolic syndrome/syndrome X), low HDL cholesterol, migraine, obesity, polycystic ovarian syndrome (PCOS), premenstrual syndrome (PMS), psoriasis, Turner's syndrome, weight loss.

Deficiency Symptoms

Suboptimal chromium intake is widespread, with as much as 90% of American diets low in chromium. Nevertheless, gross chromium deficiency is rare. Clinically, chromium deficiency was first characterized in three patients receiving long-term TPN lacking chromium. Compromised chromium status is most common in the elderly, individuals with diets high in simple carbohydrates and refined foods, pregnant women, and individuals experiencing extended periods of physiological stress, including those with chronic infections or those who regularly engage in strenuous exercise. Well-controlled studies have demonstrated chromium depletion in subjects with chromium intake level of 5 µg/1000 kcal. The primary sign of marginal chromium deficiency is impaired glucose tolerance, characterized by elevated levels of blood glucose and elevated circulating insulin concentration. Long-term deficiency results in elevated circulating cholesterol and triglyceride concentrations. Other observed effects include glycosuria, fasting hyperglycemia, hypoglycemia, decreased insulin binding, decreased insulin receptor number, impaired growth, central and peripheral neuropathy, and impaired humoral immune response. In many respects, chromium deficiency symptoms parallel those of diabetes. Low levels of chromium are also associated with increased risk of cardiovascular disease.

Dietary Sources

The amount of chromium in foods is variable because the actual chromium content in many foods can vary significantly in different batches of the same food. Brewer's yeast (particularly yeast grown in chromium-rich soil), lean meats (especially processed meats), oysters, liver and other organ meats, beer, and potatoes are relatively high in chromium. Seafood, whole grains, cheeses, chicken, bran, mushroom, oatmeal, prunes, nuts, broccoli, green beans, and asparagus are intermediate in chromium content. Most vegetables, fruit, refined grains, and processed foods (except for processed meats) contain low amounts of chromium. Notably, foods high in simple sugars, such as sucrose and fructose, not only are low in chromium content, but also are known to promote chromium loss. ¹

• Note:   Nutritional yeast and torula yeast do not contain significant amounts of chromium.

Nutrient Preparations Available

Several forms of trivalent chromium are available as stand-alone supplements or within combination nutrient formulations. Organic forms are preferable, including chromium aspartate, chromium histidine, chromium nicotinate, chromium picolinate, chromium polynicotinate; high-chromium yeast, and chromium-GTF. Chromium picolinate was considered the superior form for many years until chromium histidine was introduced by researchers from the U.S. Agricultural Research Service. Anderson et al. ² found that men and women absorbed an average 3.1 µg of chromium from the chromium-histidine complex, compared with 1.8 µg from chromium picolinate, 0.4 µg from chromium chloride, and 0.2 µg from chromium polynicotinate. Typical maintenance doses of supplemental chromium range from 50 to 200 µg daily, expressed as elemental chromium. Chromium is best administered between meals, preferably in divided doses.

Dosage Forms Available

Capsule, tablet.

Source Materials for Nutrient Preparations

Trivalent chromium: Salt formed with picolinic acid, chloride, sulfate, nicotinic acid (niacin), or amino acid chelates, such as with histidine. Some forms of supplemental chromium are combined with GTF extracted from brewer’s yeast.

Dosage Range

In recognition of the inadequacy of available data on chromium requirements the Food and Nutrition Board (FNB) of the U.S. Institute of Medicine proposed an adequate intake level (AI) based on the chromium content in normal diets rather than establish a recommended dietary allowance (RDA).

Adult

Dietary: Estimated average chromium intakes in the U.S. range from 23 to 29 µg per day for adult women and 39 to 54 µg per day for adult men. ³ The estimated safe and adequate daily dietary intake (ESADDI) for adults is 50 to 200 µg.

Supplemental/Maintenance: 50 to 200 µg/day.

The AI for chromium in adult males is 30 to 35 µg per day and for females 20 to 25 µg per day (except while pregnant or lactating).

Pharmacological/Therapeutic: 200 to 3000 µg/day.

An individual's requirement for chromium parallels their degree of glucose intolerance.

Toxic: Some initial research indicated that doses as low as 300 µg per day were potentially toxic over extended periods. In the United States (U.S.), no tolerable upper level of intake (UL) has been set for chromium by the FNB. However, in the United Kingdom (U.K.) in 2004 the Food Standards Agency (FSA) established a maximum upper level of 10 mg (10,000 µg) elemental chromium from chromium picolinate per day.

Pediatric (<18 Years)

Dietary: Breast-fed infants consume less than 1 µg/day.

• Infants, 7 to 12 months: 5.5 µg/day (AI, adequate intake)
• Children, 1 to 3 years: 11 µg/day (AI)
• Children, 4 to 8 years: 15 µg/day (AI)

Supplemental/Maintenance: None established.

Pharmacologic/Therapeutic: 1 to 50 µg/day.

Toxic: None established.

Laboratory Values

No biomarker has established itself as the standard for assessing chromium status and distinguishing adequate or deficient chromium levels.

• Serum chromium: Less than 2.0 nmol/L may indicate chromium deficiency, but this is a relatively insensitive indicator of tissue stores.
• Whole-blood chromium: Normal range: 14 to 185 nmol/L.
• Urinary chromium: Normal range: approximately 3 to 4 nmol/L; greater than 38 nmol/L indicates toxicity.

These tests have generally been considered to be of limited value in assessing status because of the extremely low concentrations of chromium present in biological tissues and fluids, and because these tests have only limited sensitivity in measuring response to chromium intake. Thus, they have primarily been used to measure overexposure to environmental chromium. Neutron activation analysis, mass spectrometry, and graphite furnace atomic absorption spectrometry represent the only analytical techniques with the required sensitivity to adequately provide clinically relevant measurements. However, these analytical methods are not widely available, are susceptible to interference from the sample matrix, and are too expensive to be clinically applicable. Additional investigation of urinary chromium in response to very low levels of intake has been suggested.

In a randomized, double-blind, crossover design involving 78 non-insulin-dependent diabetes mellitus patients, Bahijri and Mufti ⁴ (2002) found that both brewer's yeast and chromium chloride caused a significant increase in the mean values of urinary chromium (Cr) and a significant decrease in the means of glucose and fructosamine, concluding that “urinary Cr response to glucose load could be used as an indicator of Cr status.”

Overview

The limited safety data available suggest that chromium supplements are generally well tolerated at usual dosage levels. Both solubility and oxidation state affect the potential for toxicity. Furthermore, the type of complex may impact toxicity. There have been reports of toxic reactions to chromium picolinate at doses significantly higher than those typically used. No cause-effect relationship has been confirmed in human research. After several years of controversy regarding the potential toxicity of chromium, especially chromium picolinate, a consensus emerged in 2004 supporting the safety of chromium as a nutritional supplement.

Long-term daily intake of trivalent chromium (Cr⁺³) and chromium in brewer's yeast in the range of 50 to 300 µg is generally considered safe. Supplementation with chromium picolinate at daily dosage levels of up to 1000 µg for as long as 64 months in adults has produced no adverse effects. ^5-7Even so, doses greater than 400 µg daily should generally not be taken for extended periods outside the context of care by a health care professional trained in nutritional therapies.

In contrast, chronic exposure to airborne or waterborne hexavalent chromium (Cr⁺⁶), such as chromium dust in metalworking, printing, paint, textile, and other industrial settings, is associated with dermatitis and increased risk of lung and other cancers.

Nutrient Adverse Effects

General Adverse Effects

Self-administered chromium picolinate, at relatively high dosage levels, has been associated with adverse effects in a handful of case reports. Two case reports of renal failure, involving women consuming 600 and 1200 to 2400 µg chromium picolinate daily for 6 weeks and 5 months, respectively, have not been qualified to establish a causal link. ^8,9Toxic reactions to chromium picolinate have also been suspected in individual cases of interstitial nephritis, liver and kidney damage, thrombocytopenia, acute generalized exanthematous pustulosis, and rhabdomyolysis. ^9-12However, the dosage levels described in these unqualified reports are generally not recommended, especially outside the context of professional supervision.

Isolated in vitro evidence, mixed and still inconclusive, has suggested that chromium picolinate in high concentrations may be clastogenic. However, if proven, the picolinate component, rather than the chromium, might be the mutagenic factor because no reports have involved chromium chloride or chromium nicotinate. In vivo animal studies arrived at mixed conclusions. The significance of these results on humans taking the supplement for prolonged periods is unknown. In the U.K. the Committee on Mutagenicity commissioned by the FSA conducted a thorough genotoxicity review and, based on their recommendation, concluded that available evidence supported the safety of chromium at doses up to 10 mg per day. Nevertheless, judicious practice suggests that long-term intake of chromium picolinate, particularly at doses higher than 400 µg daily, are best undertaken under supervision of a health care professional trained and experienced in nutritional therapeutics. Continued study and postmarket surveillance is warranted.

Adverse Effects Among Specific Populations

The risk of chromium toxicity could theoretically be greater in individuals with preexisting liver or kidney disease. ³

Pregnancy and Nursing

The maximum safe dosage levels of chromium for women who are pregnant or nursing have not been established. However, in a study involving 10 women administered 400 µg chromium picolinate daily, Kato et al. ¹³ found no evidence of increased oxidative damage to DNA, as measured by antibody titers to an oxidized DNA base of 5-hydroxymethyl uracil.

Chromium appears to be safe when used to improve glycemic control in gestational diabetes. ¹⁴ Furthermore, chromium appears safe in lactation when used orally; supplements do not appear to increase normal chromium concentration in human breast milk. ¹⁵

Infants and Children

The maximum safe dosage levels of chromium for infants and children have not been established.

Contraindications

Chromium is contraindicated in those hypersensitive to any component of a chromium-containing formulation. Sensitivity to yeast warrants avoidance of yeast-derived or yeast-containing forms of chromium.

Precautions and Warnings

Pregnant women and nursing mothers should avoid doses of chromium greater than 50 µg per day.

Caution and professional supervision may be appropriate when introducing chromium to individuals with a history of hypoglycemia. Conversely, those with a history of hyperglycemia or type 2 diabetes mellitus who are taking prescription medications for blood sugar control should only initiate, use, or significantly change dosage levels of chromium supplements within the context of professional supervision and close monitoring.

Concern has been expressed that chromium picolinate might be contraindicated for individuals with depression, bipolar disease, or schizophrenia because picolinate can alter levels of neurotransmitters and chromium picolinate may decrease the sensitivity of 5-HT(2A) receptors by increasing the peripheral availability of tryptophan for brain serotonin (5-HT) synthesis. ^16,17

Strategic Considerations

For decades, chromium has played a central role in the prevention and treatment of hypoglycemia, insulin resistance, glucose intolerance, and diabetes mellitus within the clinical practice of nutritional therapeutics and natural medicine. Chromium is rarely, if ever, relied on as a monotherapy, or even a dominant intervention, within such a context. Exercise and lifestyle modification, balanced diet emphasizing low glycemic index/load foods, moderately high protein intake, and healthy fats and oils, along with individualized programs of nutrients and herbs, constitute the components of a more typical strategy.

Although often used in the treatment of dysglycemia in general, and hypoglycemic tendencies and insulin resistance in particular, chromium can also help prevent diabetes in susceptible individuals and play an adjunctive role in the treatment of diabetes. The dietary chromium intake of most individuals in the U.S. does not meet the level of 50 to 200 µg per day recommended by the U.S. National Academy of Science. Many clinicians and researchers have noted the parallels between suboptimal chromium levels, high intake of simple carbohydrates and sugars, and the escalating rates of insulin resistance and obesity, diabetes, and heart disease. An emerging pattern of evidence, but as yet not consistent, comprehensive, or conclusive, indicates that chromium may also improve lipid status by increasing HDL cholesterol and lowering total cholesterol. Furthermore, individuals with diabetes often have additional chromium depletion as a result of the disease process itself. Collectively, these findings suggest strongly that chromium may play a significant role in the prevention of heart disease through a variety of interconnected influences. Notably, chromium supplementation may also be of benefit in the treatment of individuals with Turner's syndrome through its effect on glucose tolerance. Preliminary research suggesting that chromium can reduce body fat, induce weight loss, and enhance lean muscle gain is intriguing and consistent with known activity, but has yet to be supported by a consistent and substantive body of evidence based on clinical trials of adequate size, strength, and design. At this point, the consistent theme in chromium research is that its therapeutic effect is greatest in individuals with diets low in chromium.

Chromium administration at typical dosage levels is generally unlikely to result in adverse effects or interactions with conventional medications. The available evidence regarding chromium interactions indicates that the use of supplemental chromium within the context of an integrative care model is likely to be safe and may provide added therapeutic benefits with reasonable administration and standard monitoring. In particular, concomitant use of chromium by diabetic patients introduces a high probability of enhanced insulin activity in response to the influence of the nutrient, especially in the context of suboptimal chromium intake and a diet high in refined carbohydrate foods, which contributes to both inadequate intake and increased urinary excretion. Thus, extra monitoring through stabilization may be required with chromium coadministration in patients being treated with conventional antidiabetic medications, such as insulin or oral hypoglycemic agents, because dosage requirements may be reduced as sensitivity of the insulin receptors to insulin increase.

Further research in all these areas is warranted. The findings likely to emerge over the coming decade will undoubtedly assist in clarifying knowledge, understanding, and effective clinical application of chromium in supporting healthy glucose regulation, preventing dysfunction of insulin and lipid metabolism, and treating resultant pathology.

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