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Chromium

Nutrient Name: Chromium.
Synonyms: Chromium 3, chromium acetate, chromium aspartate, chromium chloride, chromium histidine, chromium nicotinate, chromium picolinate, chromium polynicotinate, chromium sulfate, trivalent chromium; Cr(III), Cr +3 .
Elemental Symbol: Cr.
Related Substances: Brewer's yeast, high-chromium yeast; hexavalent chromium (VI; Cr +6 ; toxic).

Summary Table

Drug/Class Interaction Type	Mechanism and Significance	Management
Beta-1-Adrenoceptor Antagonists	Patients on beta-blocker therapy may derive improvements in lipid status, particularly elevations in HDL cholesterol, with concomitant chromium administration. Preliminary evidence primarily involved middle-aged men with hypertension, but findings may reasonably be extrapolated to other patient populations.	Coadminister. Standard monitoring usually adequate.
Corticosteroids, oral /	Increased chromium excretion is associated with corticosteroid therapy and may play a role in steroid-induced diabetes. Coadministration can prevent drug-induced depletion and may reverse steroid-induced diabetes.	Coadminister. Standard monitoring usually adequate.
Insulin, glyburide, metformin Oral hypoglycemic agents / /	Compromised chromium status is quite common and may contribute to insulin resistance, dysglycemia, and onset of diabetes. Chromium potentiates insulin activity through multiple mechanisms, only some of which are well known, and is most active in those with chromium deficiency. Coadministration of chromium with exogenous insulin or oral hypoglycemic medications may provide therapeutic benefit by enhancing insulin activity and glucose control. However, inappropriate combining could induce hypoglycemic reaction.	Coadminister, especially with probable deficiency. Modify dosing of both agents gradually with titration. Monitor for hypoglycemia symptoms.
Sertraline Selective serotonin reuptake inhibitor (SSRI) antidepressants	Disparate and indirect evidence indicates that chromium may benefit individuals with depression through effects on glucose control and potentiation of insulin. In particular, chromium picolinate appears to increase peripheral availability of tryptophan for brain serotonin (5-HT) synthesis and alter sensitivity of central 5-HT(2A) receptors. Clinical trials have reported increased efficacy (including efficacy in therapy-refractory patients) of standard antidepressant treatment, specifically sertraline, with coadministration. No evidence of adverse effects has been presented.	Coadministration judicious and considered safe, especially with probable deficiency. Standard monitoring usually adequate.

nutrient description

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.

nutrient in clinical practice

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.”

safety profile

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

interactions review

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.

nutrient-drug interactions

Beta-1-Adrenoceptor Antagonists (Beta-1-Adrenergic Blocking Agents)

Oral forms (Systemic): Acebutolol (Sectral), atenolol (Tenormin); combination drugs: atenolol and chlorthalidone (Co-Tendione, Tenoretic); atenolol and nifedipine (Beta-Adalat, Tenif); betaxolol (Kerlone), bisoprolol (Zebeta), carteolol (Cartrol), esmolol (Brevibloc), labetalol (Normodyne, Trandate), metoprolol (Lopressor, Toprol XL); combination drug: metoprolol and hydrochlorothiazide (Lopressor HCT); nadolol (Corgard), nebivolol (Nebilet), oxprenolol (Trasicor), penbutolol (Levatol), pindolol (Visken), propranolol (Betachron, Inderal LA, Innopran XL, Inderal); combination drug: propranolol and bendrofluazide (Inderex); sotalol (Betapace, Betapace AF, Sorine), timolol (Blocadren).

Beneficial or Supportive Interaction, with Professional Management

Probability: 2. Probable
Evidence Base:

Preliminary to

Emerging

Effect and Mechanism of Action

Chromium supplementation may improve levels of HDL cholesterol through a mechanism that has not yet been fully elucidated.

Research

In a randomized, double-blind, placebo-controlled trial involving 63 men receiving beta-blocker therapy, primarily for hypertension, Roeback et al. ¹⁸ observed modest increases in HDL cholesterol levels after administration of 200 µg three times daily of “biologically active chromium” in the form of “glucose tolerance factor (GTF)–chromium” for 8 weeks.

Nutritional Therapeutics, Clinical Concerns, and Adaptations

Physicians prescribing beta blockers to individuals with hypertension can discuss with patients the potential benefits of adding chromium (e.g., 200 µg three times daily) to a comprehensive regimen for improving HDL cholesterol status as well as stabilizing glucose levels and generally reducing cardiovascular risk. Although not conclusive, these preliminary findings are promising in suggesting a potential role for chromium within an integrative strategy aimed at addressing the intertwining issues of dysglycemia, insulin resistance, hypertension, and cardiovascular risk. Furthermore, caution is appropriate in not summarily extrapolating from these findings based on men to presumed applicability to women. Further research through well-designed, long-term clinical trials is warranted to investigate the implications of this potential synergy and guide formulation of therapeutic options.

Corticosteroids, Oral

Betamethasone (Celestone), cortisone (Cortone), dexamethasone (Decadron), fludrocortisone (Florinef), hydrocortisone (Cortef), methylprednisolone (Medrol) prednisolone (Delta-Cortef, Orapred, Pediapred, Prelone), prednisone (Deltasone, Liquid Pred, Meticorten, Orasone), triamcinolone (Aristocort).

	Drug-Induced Nutrient Depletion, Supplementation Therapeutic, with Professional Management
	Prevention or Reduction of Drug Adverse Effect

Probability: 4. Plausible
Evidence Base:

Preliminary

Effect and Mechanism of Action

Corticosteroid therapy increases chromium excretion; this effect may play a role in the development of corticosteroid-induced glucose intolerance and diabetes. Chromium coadministration may reverse steroid-induced diabetes.

Research

Ravina et al. ¹⁹ measured the effects of corticosteroid treatment on chromium losses in 13 patients 2 days before steroid administration and 3 days after treatment. They observed that urinary chromium losses after corticosteroid treatment increased significantly in the first 3 days following treatment. These researchers also reported that administration of 600 µg/day of chromium (as chromium picolinate) to three patients with steroid-induced diabetes “resulted in decreases in fasting blood glucose values from greater than 13.9 mmol/L (250 mg/dL) to less than 8.3 mmol/L (150 mg/dL).” Notably, hypoglycemic drugs were also “reduced 50% in all patients when given supplemental chromium.” ¹⁹

Nutritional Therapeutics, Clinical Concerns, and Adaptations

Physicians prescribing oral corticosteroids, especially for extended periods and at high dosage levels, are advised to coadminister chromium, 200 µg three times daily, to counter drug-induced chromium excretion, support glucose control and insulin sensitivity, and prevent corticosteroid-induced diabetes. Patients being treated with hypoglycemic agents will require supervision and monitoring because gradual decreases in medication levels will often be appropriate in response to the effects of chromium administration. Further research through well-designed, long-term clinical trials is warranted to investigate the implications of this potential synergy and guide formulation of therapeutic options.

Insulin, Glyburide, Metformin, and Related Oral Hypoglycemic Agents

Insulin:Animal-source insulin (Iletin); human analog insulin (Humanlog); human insulin (Humulin, Novolin, NovoRapid, Oralin). Biguanides:Buformin (Andromaco Gliporal, Buformina), metformin (Dianben, Glucophage, Glucophage XR), phenformin (Debeone, Fenformin). Sulfonylureas:Acetohexamide (Dymelor), chlorpropamide (Diabinese), glimepiride (Amaryl), glyburide (Diabeta, Glibenclamide, Glynase Prestab, Glynase, Micronase, Pres Tab), glipizide (Glucotrol; Glucotrol XL), tolazamide (Tolinase), tobutamide (Orinase; Tol-Tab). Combination drugs: Glipizide and metformin (Metaglip); glyburide and metformin (Glucovance). Extrapolated, based on similar properties: Alpha-glucosidase inhibitors:Acarbose (Glucobay, Precose). Meglitinide Analog Oral Hypoglycemics:Nateglinide (Starlix), repaglinide (Prandin). Thiazolidinediones (glitazones):Pioglitazone (Actos), rosiglitazone (Avandia).

	Beneficial or Supportive Interaction, with Professional Management
	Bimodal or Variable Interaction, with Professional Management
	Potential or Theoretical Adverse Interaction of Uncertain Severity

Probability: 2. Probable
Evidence Base:

Emerging

Effect and Mechanism of Action

In vitro, in vivo, and human studies indicate that chromium participates in glucose and lipid metabolism, influences circulating insulin levels, and potentiates the peripheral activity of insulin. ^20-23 Chromium has been observed to improve insulin binding, insulin receptor number, insulin internalization, beta-cell sensitivity, and insulin receptor–related enzymes, with overall increases in insulin sensitivity. The proposed mechanism of action for chromium's effect is, at least in part, caused by enhanced intracellular tyrosine kinase activity that results from an interaction between chromium, chromodulin, and activated cell-surface insulin receptors. ²⁴ Other research suggests that the potential in vivo mechanism of chromium (picolinate) on insulin action in human skeletal muscle may occur by increasing the activation of Akt phosphorylation. ²⁵ This intracellular insulin-dependent protein facilitates the uptake of glucose into cells. Furthermore, by downregulating pancreatic islet beta-cell activity, chromium may increase glucagon secretion. ²⁶ Nevertheless, at this time, knowledge of the biochemical basis underlying these reported and hypothesized effects remains conflicting and evolving.

Exogenous insulin therapy is designed to augment or replace endogenous insulin in individuals lacking sufficient synthesis capacity in the islets of Langerhans of the pancreas. Oral sulfonylureas (e.g., glyburide) act by stimulating the production and release of insulin (not sensitivity, or at least not primarily), and as such, these agents can only be used in patients with an intact pancreas with functioning islet cells. There are probably other activities of the oral drugs, but at one level, both insulin and oral hypoglycemic agents simply increase the amount of available insulin, one exogenously and the other endogenously. In most type 1 diabetic patients the islet cells have undergone autoimmune destruction, so the sulfonylurea-based agents are not useful. To the degree that type 1 diabetic individuals have chromium insufficiency and decreased insulin receptor sensitivity, increased dietary chromium may have benefit, but virtually all will require some exogenous insulin therapy.

Research

Numerous clinical trials, some well-designed, others less so, have demonstrated the ability of chromium to potentiate insulin and improve glucose control, especially in diabetic patients and individuals with less-than-optimal chromium intake. The nutritional biochemistry, physiological function, and therapeutic applications of chromium are gradually becoming elucidated. Consequently, studies on the effectiveness of chromium administration in patients with glucose intolerance and type 2 diabetes have produced findings that are inconsistent and evolving. These conflicting results are caused by many factors, including characteristics of subject population, concomitant medications and dietary influences, dose and form of chromium used, and duration of therapy.

Numerous studies have shown an association between chromium deficiency and impaired glucose regulation, onset of type 2 diabetes in susceptible individuals, and increased risk for lipid disorders and cardiovascular diseases. ^27-34 The pathophysiology of diabetes itself may exacerbate chromium deficiency. For example, urinary loss of chromium is elevated in individuals with type 2 diabetes resulting, at least in part, from glycosuria. Thus, plasma chromium levels are about 40% lower in diabetic subjects compared with healthy individuals. In a symposium at the 59th annual scientific sessions of the American Diabetes Association (1999), Cefalu described an improvement in insulin sensitivity in obese people with prediabetic symptoms who received chromium picolinate. Conversely, excess chromium intake may result in tissue accumulation and subsequently could, at least theoretically, inhibit rather than enhance insulin activity. Findings from a rat study suggest that a chromium-induced increased in hepatic insulin clearance may offset the improvement in insulin sensitivity in some diabetic individuals, such that glycemic control might not improve appreciably. ³⁵ Adequate and balanced chromium nutriture is clearly essential for normal insulin activity and glucose control. However, given the lack of human studies suggesting such effects of excess supplemental chromium intake and the low oral absorption of chromium compounds, it may be quite difficult to induce chromium excess with oral supplementation, especially in diabetic patients, with their tendency toward increased chromium excretion. These considerations are further supported by the safe upper limit of 10 mg daily established by the U.K. regulatory authorities.

Administration of chromium picolinate may help prevent or delay the need for antidiabetic medication and can often be used synergistically with such medications once they have been prescribed. The most relevant data indicate that chromium picolinate improves clinical results when used in combination with standard treatments, including insulin, sulfonylureas, or metformin alone and in combinations. Improvements have been observed in glucose tolerance tests in adult diabetic patients ^36,37 and in glucose-intolerant men and women. ^38-40 Uusitupa et al. ⁴¹ reported that administration of chromium produced a beneficial effect on insulin response at 1 hour but no improvement in glucose tolerance tests in non-insulin-requiring diabetics. However, researchers in three trials found no significant benefit of chromium with glucose tolerance, insulin levels, or blood lipid concentrations. ^42-44

Notably, in two of these studies, one used chromium chloride, which is poorly absorbed, and the other a low dose (200 µg/day) of chromium picolinate.

In a clinical trial involving 243 individuals with type 1 (105) and type 2 (138) diabetes, Ravina and Slezack ⁴⁵ found that chromium supplementation (200 µg/day) decreased insulin, sulfonylurea drug, and metformin requirements in a significant number (115) of subjects. “The success rate was greater in those with NIDDM (57.2%) than in those with IDDM (33.6%). More women, of either type, reacted than men (62.5 vs. 50% in NIDDM and 37.6 vs. 28.6% in IDDM).” This trial exhibited major limitations; although frequently described as a controlled clinical trial, this study was largely open label in design with only 10 subjects enrolled in a double-blind protocol. In a subsequent placebo-controlled trial involving 48 patients with type 1 diabetes and 114 patients with type 2 diabetes, Ravina et al. ⁴⁶ compared diets supplemented with chromium picolinate (200 µg/day) with placebo. They reported a reduced need for insulin or oral hypoglycemic medications in approximately 70% of patients coadministered chromium. Again, it is notable that trials using 1000 µg (1 mg) of chromium picolinate per day in diabetic patients show a strong positive trend.

Anderson et al. ⁶ conducted a promising but controversial randomized, placebo-controlled trial involving 180 Chinese men and women with type 2 diabetes, comparing the effects of 1000 µg chromium, 200 µg chromium, and placebo. The therapeutic response appeared to be dose related. The group receiving 1000 µg demonstrated significant improvements in lipids and hemoglobin A ^1c (HbA ^1c ) values after 2 months; both groups receiving chromium showed such changes after 4 months. Fasting glucose was also lower in the higher dose (1000 µg) chromium group at 2 and 4 months, although no such change observed in the moderate (200 µg) chromium group. Serum insulin levels decreased significantly in both groups at 2 and 4 months. ⁶ The high dose used might be considered a strength of this trial because it is closer to the dosage levels found to be effective in clinical practice using monotherapy chromium in pharmacological doses. However, the characteristics of the Chinese patient population in this study may limit the applicability of its findings to patient populations in Europe and North America. Furthermore, the large number of subjects in this study has excluded it from some meta-analyses because it would overwhelm data from other, smaller trials. ⁴⁷

In a 4-month trial, Bahadori ⁴⁸ and a team of Austrian researchers studied the effects of chromium picolinate (500 µg twice daily) in 16 obese patients with type 2 diabetes who were pretreated with, and continued to receive stable doses of, a sulfonylurea and metformin. These researchers reported that chromium picolinate appeared to enhance the effects of metformin and oral sulfonylureas. Chromium coadministration was associated with significant reductions in fasting insulin levels, without a detrimental effect on glucose control. Insulin resistance assessed by the insulin suppression test was not affected. They concluded that the positive effects seen in this clinical study could be associated with an effect of chromium picolinate on insulin clearance.

In a double-blind crossover trial involving 78 type 2 diabetic patients, Bahajri et al. ³³ investigated the effects of brewer's yeast (23.3 µg Cr daily) and chromium chloride (200 µg Cr daily) sequentially with placebo in between, through four stages, each lasting 8 weeks. They found that both forms of chromium caused a significant decrease in the mean values of glucose (fasting and 2-hour post–glucose load), fructosamine, and triglycerides. The means of HDL cholesterol and serum and urinary chromium were all increased. Furthermore, the mean drug dosage decreased slightly (and significantly in an individual taking glibenclamide) after both supplements; some patients no longer required insulin. These researchers also noted that a higher percentage of subjects responded positively to brewer's yeast chromium.

In 2003, at the 18th International Diabetes Federation Congress, Cefalu et al. ²⁵ presented the findings from a subsequently published double-blind, placebo-controlled trial involving two cohorts of patients with type 2 diabetes who were treated with either sulfonylureas or a diet program and randomized to receive either chromium picolinate (1000 µg/day) or placebo. Hyperinsulinemic, euglycemic clamp studies were used to measure insulin sensitivity and assess the efficacy of glucose uptake on all subjects before randomization and at the end of the study. Of the 16 subjects, those administered chromium picolinate demonstrated a mean increase in insulin sensitivity of 8.9%, whereas those receiving placebo had a mean decrease of 3.6%. In addition, insulin-stimulated Akt activation was significantly increased at the end of the study compared with subjects on placebo. The authors stated that the enhanced activity of Akt phosphorylation associated with chromium administration in individuals with type 2 diabetes represents a possible mechanism to explain chromium picolinate's beneficial effect on insulin sensitivity. ²⁵

Rabinovitz et al. ⁴⁹ conducted a controlled clinical trial involving 39 diabetic subjects, average age 73 years (18 males and 21 females), undergoing rehabilitation after stroke or hip fracture, who received 200 µg chromium twice a day for a 3-week period. Both the treated group and a control group of 39 diabetic patients continued their standard treatment for diabetes and received a diet of approximately 1500 kcal/day. At the end of the study, these researchers measured significant differences in the fasting blood level of glucose compared to the baseline (190 vs. 150 mg/dL, p<0.001), improvements in HbA ^1c from 8.2% to 7.6% (p<0.01), and reductions in total cholesterol from 235 to 213 mg/dL (p<0.02). They also observed a trend toward lowered triglyceride levels. They concluded that, “in this population of elderly, diabetic patients undergoing rehabilitation, dietary supplementation with chromium is beneficial in moderating glucose intolerance.” ⁴⁹

An overview of the most relevant literature shows that nine single-blind and double-blind trials over 10 years, involving 1349 total subjects, produced findings that are consistent. These studies concentrated on the effects of chromium picolinate on markers of blood glucose or on insulin regulation in subjects with type 2 diabetes or in individuals with induced diabetes. Overall, they found that chromium picolinate exerts a beneficial effect on fasting insulin values and on HbA ^1c . ^{6,19,46,48,50-55} Cefalu et al. ⁵² and Morris et al. ⁵⁶ have suggested that chromium picolinate increases insulin sensitivity and glucose utilization and maintains normal blood glucose concentrations. Many human studies have also reported that administration of chromium is associated with improvements in lipids, particularly triglycerides, LDL and HDL cholesterol, ^57,58 and lipoprotein(a), as well as other benefits for coronary disease risk profiles that are important in both diabetic and nondiabetic populations. Nevertheless, in reviewing much of the same literature in a 2002 meta-analysis, Althuis et al. ⁴⁷ concluded that “data from randomized clinical trials are sparse and inconclusive.” Ultimately, everyone in the field agrees that further research emphasizing placebo-controlled, randomized clinical trials in well-characterized, at-risk populations is necessary to determine the effects of chromium, given in the more absorbable forms and in adequate amounts, on concentrations of glucose, insulin, and HbA ^1c .

The controversy surrounding the efficacy of chromium in diverse populations continues; research has yet to deliver a consistent pattern of findings that might provide an evidence-based foundation for consensus. For example, two papers published in 2006 presented seemingly conflicting results with divergent implications. Following on the research previously mentioned, Martin, Cefalu, et al. ^58a conducted a trial involving 37 subjects with type 2 diabetes in which they first placed subjects, after baseline, on a sulfonylurea (glipizide, 5 mg/day) with placebo for 3 months. They then randomized subjects, in a double-blind fashion, to receive either the glipizide plus continued placebo or the glipizide plus 1000 µg chromium picolinate (CrPic) for 6 months. At the end of the trial period, they found that subjects administered glipizide and placebo, as opposed to those randomized to glipizide and chromium, exhibited a “significant increase” in body weight (2.2 kg), percent body fat (1.17%), and total abdominal fat (32.5 cm ² ) from baseline. Conversely, those subjects receiving glipizide and chromium exhibited “significant improvements in insulin sensitivity corrected for fat-free mass” (28.8), HbA ^1c (glycosylated hemoglobin) (−1.16%), and free fatty acids (−0.2 mmol/L) “as opposed to sulfonylurea/placebo.” The authors concluded that “this study demonstrates that CrPic supplementation in subjects with type 2 diabetes who are taking sulfonylurea agents significantly improves insulin sensitivity and glucose control,” and that coadministration of chromium “significantly attenuated body weight gain and visceral fat accumulation compared with the placebo group.” In contrast, in a 6-month, double-blind trial involving 53 subjects (46 of whom completed the study), Kleefstra et al. ⁵⁹ found that, contrary to expectations, “high-dose chromium picolinate” (500 or 1000 µg) does not improve glycemic control or other parameters in “obese patients with poorly controlled, insulin-treated type 2 diabetes.” The study participants had an HbA ^1c greater than 8% and insulin requirements of greater than 50 units per day. The investigators reported that among the three groups, receiving placebo or 500 or 1000 g chromium picolinate daily, the decrease in HbA ^1c , the primary efficacy measure, was similar (−0.3%, −0.5%, and −0.3% for placebo, 500 µg, and 1000 µg, respectively). Secondary endpoints included changes in lipid profiles, body mass index (BMI), blood pressure, and insulin requirements. Likewise, no differences were observed in BMI, blood pressure, and insulin requirements; notably, however, a weak association was found between an increasing serum chromium concentration and improvement in the lipid profile. In light of the contrast between these results and earlier findings, the authors added: “Whether it is possible to select subgroups of patients with suitable certain phenotypes that may or may not benefit from chromium therapy also needs further attention.” ⁵⁹

Nutritional Therapeutics, Clinical Concerns, and Adaptations

The ongoing epidemic of dysglycemia, insulin resistance, and diabetes, severe problems contributing to lipid disorders and cardiovascular morbidity, forcefully establishes the need to develop an integrative understanding of the therapeutic role of chromium. General agreement exists that chromium intake is inadequate for much of the population, and that compromised chromium nutriture status is common, even (or even more so) in developed countries with processed food–based diets. The body of literature suggests that individuals with diabetes may benefit from chromium administration in many ways, including more stable insulin levels and enhanced glucose control. Although inclusion of chromium in a comprehensive therapeutic strategy may contribute to these and many other potential benefits, the appropriate dosage levels and character of effects may vary among individuals and even change over time for a given patient. Furthermore, because the current data imply that some individuals respond better to chromium picolinate than do others (nonresponders), further research is needed to establish accurate and sensitive laboratory methods to identify the most suitable candidates for treatment with chromium picolinate or other well-absorbed forms, such as GTF or the histidine chelate. To date, the picolinate has been the best studied of the apparently efficacious forms of chromium.

Chromium's ability to enhance endogenous regulation of blood glucose levels, together with its potentiation of insulin's activity, make it a valuable option in stabilizing diabetic physiology, potentially preventing diabetic complications, and eventually reducing dependence on medication. Health care professionals treating individuals with diabetes using conventional medications, natural therapies (e.g., acupuncture, herbs, other nutrients), and lifestyle changes (e.g., diet, exercise) will need to monitor such patients closely if chromium is introduced into the regimen. Thus, patients should be cautioned regarding the potential risks of inadvertent or unsupervised chromium administration in conjunction with conventional treatments, especially pharmaceutical treatments capable of inducing hypoglycemia. In particular, the prescribed dose of insulin or oral hypoglycemic medication may need to be reduced gradually to avoid a hypoglycemic reaction as the patient responds to the actions of chromium. Health care professionals trained and experienced in nutritional therapy typically prescribe chromium at a dosage of 200 µg, once or twice daily; higher dosage may be appropriate based on body surface area or failure to respond to lower doses. Chromium picolinate and chromium histidine are preferred forms.

Sertraline and Related Selective Serotonin Reuptake Inhibitor (SSRI) Antidepressants

Evidence: Sertraline (Zoloft). Extrapolated, based on similar properties: Citalopram (Celexa), escitalopram (S-citalopram; Lexapro), fluoxetine (Prozac, Sarafem), fluvoxamine (Faurin, Luvox), paroxetine (Aropax, Deroxat, Paxil, Seroxat).

Beneficial or Supportive Interaction, with Professional Management

Probability: 4. Plausible to 2. Probable
Evidence Base:

Preliminary to

Emerging

Effect and Mechanism of Action

Dysglycemia can play an important role in the susceptibility of many individuals to depressive disorders. Chromium may have antidepressant activities in some individuals, at least in part by potentiating the action of insulin. Insulin, in turn, inhibits the reuptake of norepinephrine and enhances the blood-brain transport of tryptophan, a precursor of serotonin. Furthermore, picolinic acid (a component of chromium picolinate) can alter serotonin, dopamine, and norepinephrine metabolism in the central nervous system (CNS). ¹⁷

Research

Following a patient's report of “dramatic response to the addition of chromium supplementation to sertraline pharmacotherapy” for dysthymic disorder, McLeod et al. ⁶⁰ conducted a set of single-blind and open-label trials in which they substituted other nutritional supplements in each of the patients to test the specificity of response to chromium supplementation. They described significant improvements in mood and “remission of dysthymic symptoms” in five patients being treated for antidepressant-refractory dysthymic disorder with sertraline who were coadministered chromium picolinate or chromium polynicotinate at dosage levels of 200 to 400 µg per day. The authors suggested further study through controlled trials; such research appears warranted.

In more recent research, Attenburrow et al. ¹⁷ examined the relationship of chromium to serotonin, particularly chromium picolinate's apparent effect of increasing the peripheral availability of tryptophan for brain serotonin (5-hydroxytryptamine, 5-HT) synthesis and altering the sensitivity of central 5-HT(2A) receptors. They compared the effects of short-term chromium administration on plasma concentrations of tryptophan and other large, neutral amino acids in human and animal models and assessed brain serotonin function by measuring the corticosterone/cortisol response to 5-hydroxytryptophan (5-HTP), the 5-HT precursor, which is hypothesized to be mediated via indirect activation of 5-HT(2A) receptors. These researchers observed that administration of chromium lowered the cortisol response to challenge with 5-HTP in both rats and humans. Changes in peripheral tryptophan availability were not seen in humans, but chromium increased peripheral and central tryptophan availability and elevated brain 5-HT content in rats.

Clinical Implications and Adaptations

Physicians prescribing SSRI medications for treatment of individuals diagnosed with depressive disorders are advised to evaluate potential therapeutic benefit on serotonin levels with concomitant administration of chromium, 200 µg once or twice daily. Integrative therapy combining chromium and antidepressants could prove efficacious, especially in patients with a history of hypoglycemia/dysglycemia, insulin resistance, or diabetes. Close monitoring and periodic reevaluation are necessary because gradual decreases in medication levels may be appropriate. Further research through well-designed, long-term clinical trials is warranted to investigate the implications of this potential synergy and guide formulation of therapeutic options.

theoretical, speculative, and preliminary interactions research, including overstated interactions claims

Antacids, Histamine (H ² ) Receptor Antagonists, and Proton Pump Inhibitors

Antacids:Aluminum carbonate gel (Basajel), aluminum hydroxide (Alternagel, Amphojel); combination drugs: aluminum hydroxide, magnesium carbonate, alginic acid, and sodium bicarbonate (Gaviscon Extra Strength Tablets, Gaviscon Regular Strength Liquid, Gaviscon Extra Strength Liquid); aluminum hydroxide and magnesium hydroxide (Advanced Formula Di-Gel Tablets, co-magaldrox, Di-Gel, Gelusil, Maalox, Maalox Plus, Mylanta, Wingel); aluminum hydroxide, magnesium trisilicate, alginic acid, and sodium bicarbonate (Alenic Alka, Gaviscon Regular Strength Tablets); calcium carbonate (Titralac, Tums), magnesium hydroxide (Phillips’ Milk of Magnesia MOM); combination drugs: magnesium hydroxide and calcium carbonate (Calcium Rich Rolaids); magnesium hydroxide, aluminum hydroxide, calcium carbonate, and simethicone (Tempo Tablets); magnesium trisilicate and aluminum hydroxide (Adcomag trisil, Foamicon); magnesium trisilicate, alginic acid, and sodium bicarbonate (Alenic Alka, Gaviscon Regular Strength Tablets); combination drug: sodium bicarbonate, aspirin, and citric acid (Alka-Seltzer).

Histamine (H ² ) receptor antagonists:Cimetidine (Tagamet; Tagamet HB), famotidine (Pepcid RPD, Pepcid, Pepcid AC), nizatidine (Axid, Axid AR), ranitidine (Zantac); combination drug: ranitidine, bismuth, and citrate (Tritec).

Proton pump inhibitors:

Evidence: Omeprazole (Losec, Prilosec).

Related: Esomeprazole (Nexium), lansoprazole (Prevacid, Zoton), pantoprazole (Protium, Protonix, Somac), rabeprazole (AcipHex, Pariet).

Antacids, H ² blockers, and proton pump inhibitors (PPIs) may inhibit chromium absorption and could contribute to chromium depletion, particularly in susceptible populations. The mechanism(s) underlying this apparent interaction include altered pH levels, formation of insoluble complexes, or some combination but remain unclear.

Concomitant intake of calcium carbonate can interfere with the absorption of chromium. Seaborn and Stocker ⁶¹ used an isotope of chromium in male rats to measure potential interaction between calcium and chromium. Their findings indicate that calcium carbonate may result in reduced absorption and tissue retention of chromium. Notably, this experiment employed chromium chloride, known for poor absorption compared to other forms. Subsequently, a related research team using female rats observed that administration of antacid (40 mg) by gastric intubation (0.5 mL), followed orally by 55 µg Cr 51 chromium chloride, resulted in decreased chromium absorption. ²⁰

Evidence is lacking to substantiate extension of these preliminary findings to humans. However, chromium status is marginal in a large segment of the population, increasing the probability of this possible interaction being clinically relevant in some individuals. Thus it is advisable to recommend that oral intake of chromium be separated from administration of any antacid (including calcium carbonate) by 2 to 3 hours to reduce the risk of interfering with absorption. Further research is warranted through well-designed clinical trials of sufficient size and power.

Antipsychotics

Aripiprazole (Abilify, Abilitat), chlorpromazine (Largactil, Thorazine), clozapine (Clozaril), fluphenazine (Permitil, Prolixin, Prolixin Decanoate, Prolixin Enanthate), haloperidol (Haldol), olanzapine (Zyprexa), prochlorperazine (Compazine, Stemetil), quetiapine (Seroquel), risperidone (Risperdal), ziprasidone (Geodon).

An interaction between chromium and antipsychotic medications is theoretically plausible, but no substantive evidence from case reports or clinical trials has emerged to confirm (or refute) this occurrence or articulate its clinical implications. Directly, and through its effects on insulin, chromium influences several neurotransmitters. Notably, insulin inhibits the reuptake of norepinephrine and enhances the blood-brain transport of tryptophan, a precursor of serotonin. Furthermore, picolinic acid, a component of chromium picolinate, is known to alter serotonin, dopamine, and norepinephrine metabolism in the CNS. Prudence suggests that, pending further research, the concomitant use of chromium preparations and antipsychotic medications should be avoided outside the context of supervision of health care professionals trained and experienced in both conventional psychopharmacology and nutritional therapeutics.

Lithium Carbonate

Lithium carbonate (Camcolit, Carbolith, Duralith, Eskalith, Li-Liquid, Liskonum, Litarex, Lithane, Lithobid, Lithonate, Lithotabs, PMS-Lithium, Priadel).

Lithium carbonate has been found to reduce blood glucose levels in diabetic individuals. Chromium potentiates the action of insulin. The combined effect of two substances with potential hypoglycemic action might present a significant risk for excessively low blood glucose levels. ⁶²

Chromium's ability to enhance endogenous regulation of blood glucose levels, together with its potentiation of insulin, make it a valuable tool in stabilizing diabetic physiology and eventually reducing dependence on insulin. Physicians prescribing lithium are advised to ask patients if they are taking or have been considering use of chromium supplementation. Such coadministration might be efficacious but requires close monitoring of blood glucose levels, especially in individuals with a history of hypoglycemia or in the presence of insulin/oral sulfonylurea therapy. Health care professionals experienced in nutritional therapeutics typically prescribe chromium at a dosage of 200 µg once or twice daily; chromium picolinate or histidine is the preferred form.

Meperidine

Meperidine (Demerol).

Tyramine intake may result in adverse effects in individuals taking meperidine (which has a lethal interaction with classic MAO inhibitor antidepressants). Brewer's yeast contains a significant amount of tyramine and thus should be considered a potentially harmful or serious adverse interaction.

It is highly improbable that the amount of tyramine contained in yeast-based chromium preparations is adequate to result in an adverse event, particularly at usual dosage levels. Nevertheless, physicians prescribing meperidine should advise patients to avoid significant intake of yeast, including chromium supplements containing yeast. Forms of chromium not derived from or containing yeast do not carry this potential risk.

Monoamine Oxidase (MAO) Inhibitors

MAO-A inhibitors: Isocarboxazid (Marplan), moclobemide (Aurorix, Manerix), phenelzine (Nardil), procarbazine (Matulane), tranylcypromine (Parnate).

MAO-B inhibitors: Selegiline (deprenyl, L-deprenil, L-deprenyl; Atapryl, Carbex, Eldepryl, Jumex, Movergan, Selpak), pargyline (Eutonyl), rasagiline (Azilect).

Tyramine intake will often result in adverse effects in individuals taking MAO inhibitors. Brewer's yeast contains a significant amount of tyramine and thus should be considered as potentially harmful or serious adverse interaction.

It is highly improbable that the amount of tyramine contained in yeast-based chromium preparations is adequate to result in an adverse event, particularly at usual dosage levels. In a 1984 survey and critical review of the literature on the subject of diet and MAO inhibitors, Sullivan and Shulman ⁶³ determined that “only four foods clearly warrant absolute prohibition: aged cheese, pickled fish (herring), concentrated yeast extracts and broad bean pods.” Nevertheless, physicians prescribing MAO inhibitors should advise patients to avoid significant intake of yeast, including chromium supplements containing yeast. Forms of chromium not derived from or containing yeast do not carry this potential risk.

Nicotinic Acid (Vitamin B ³ )

A potential interaction between chromium and nicotinic acid has been discussed, but only preliminary evidence is available as to its clinical implications. Nicotinic acid serves as substrate for synthesis of GTF, which is believed to facilitate insulin binding. Concomitant intake may improve glucose tolerance, particularly in individuals whose diet provides inadequate levels of dietary nicotinic acid. Consequently, inadvertent, excessive, or unsupervised coadministration might theoretically induce a hypoglycemic state. This largely unexplored territory is further confounded by the possibility that niacin may cause insulin resistance.

Urberg and Zemel ⁶⁴ conducted an experiment in which 16 healthy elderly volunteers were divided into three groups and given either 200 µg chromium chloride, 100 mg nicotinic acid, or 200 µg chromium plus 100 mg nicotinic acid daily for 28 days, with evaluations on days 0 and 28. They observed the combined chromium–nicotinic acid supplement caused a 15% decrease in a glucose area integrated total and a 7% decrease in fasting glucose, whereas chromium or nicotinic acid alone did not affect fasting glucose or glucose tolerance. None of the interventions exerted any significant effect on fasting or 1-hour insulin levels. These researchers interpreted their findings to suggest that the inability to respond to chromium administration may result from suboptimal levels of dietary nicotinic acid. These findings also raise the question as to whether, as analogs, picolinate and nicotinate may share the same transport system for intestinal absorption, and if so, picolinate could then block nicotinate absorption, and vice versa.

Individuals who do not respond to administration of chromium may have inadequate levels of vitamin B ³ . Coadministration may be beneficial. Patient caution, and possibly supervision by a health care professional trained and experienced in nutritional therapeutics, may be appropriate in the unlikely event (in the absence of prescription antidiabetic medication) that such intervention induces hypoglycemia.

Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)

COX-1 inhibitors:Diclofenac (Cataflam, Voltaren); combination drug: diclofenac and misoprostol (Arthrotec); diflunisal (Dolobid), etodolac (Lodine), fenoprofen (Dalfon), furbiprofen (Ansaid), ibuprofen (Advil, Excedrin IB, Motrin, Motrin IB, Nuprin, Pedia Care Fever Drops, Provel, Rufen); combination drug: hydrocodone and ibuprofen (Reprexain, Vicoprofen); indomethacin (indometacin; Indocin, Indocin-SR), ketoprofen (Orudis, Oruvail), ketorolac (Acular ophthalmic, Toradol), meclofenamate (Meclomen), mefenamic acid (Ponstel), meloxicam (Mobic), nabumetone (Relafen), naproxen (Aleve, Anaprox, Naprosyn), oxaprozin (Daypro), piroxicam (Feldene), salsalate (salicylic acid; Amigesic, Disalcid, Marthritic, Mono Gesic, Salflex, Salsitab), sulindac (Clinoril), tolmetin (Tolectin).

COX-2 inhibitor:Celecoxib (Celebrex).

The NSAIDs may increase chromium levels in the body by enhancing chromium absorption from oral intake while also delaying or inhibiting chromium elimination. In a rat model, indomethacin and aspirin have been shown to increase chromium absorption. ⁶¹ Evidence is lacking to substantiate these proposed actions, and no case reports or clinical trials have documented clinically significant adverse effects.

nutrient-nutrient interactions

Biotin

Chromium picolinate and biotin appear to work together to enhance glucose uptake in skeletal muscle cells and improve glucose disposal. Singer and Geohas ^64a conducted a placebo-controlled, double-blind, randomized trial investigating the effects on glycemic control of coadministering chromium and biotin in 43 type 2 diabetic subjects who were “poorly controlled” by oral antihyperglycemic agents. They coadminstered chromium picolinate (600 µg) and biotin (2 mg) daily, in addition to their prestudy oral antihyperglycemic agent therapy. After 4 weeks, they observed “a significantly greater reduction in the total area under the curve for glucose” during the 2-hour oral glucose tolerance test for the treatment group compared with the placebo group, along with “significantly greater reductions” in fructosamine, triglycerides, and triglycerides/HDL cholesterol ratio in the treatment group. The authors concluded that coadministration of chromium picolinate and biotin “may represent an effective adjunctive nutritional therapy to people with poorly controlled diabetes with the potential for improving lipid metabolism.” These findings indicate the need for continued research into the use of multiple nutritional interventions as complements to conventional pharmacological interventions within a broad and multifaceted, individualized and evolving strategic approach to dysglycemia and diabetes.

Calcium

The concomitant intake of calcium carbonate and chromium can interfere with the absorption of both agents and thus reduce the activity of chromium intake. ⁶⁵ Optimal absorption can be maintained by separating intake of the two substances by at least 2 hours.

Further research is warranted to determine whether, and to what degree, the observed effect is caused by the antacid effect of calcium carbonate, or could be specific to calcium per se.

Carbohydrates

Excessive intake of sugars and other simple carbohydrates may increase the amount of chromium excreted through the urine.

In a 12-week trial, Kozlovsky et al. ⁶⁶ compared chromium excretion in 37 subjects fed two diets containing equivalent chromium content, approximately 16 µg per 1000 calories. During the initial 6 weeks, the reference diet contained “optimal levels” of protein, fat, carbohydrate, and other nutrients, with 35% of total calories from complex carbohydrates and 15% from simple sugars. During the following 6 weeks, subjects consumed “high sugar diets” containing 15% complex carbohydrates and 35% simple sugars. During the high-sugar diets, subjects exhibited increased urinary chromium losses from 10% to 300% for 27 of 37 subjects, compared with the reference diets. The authors contextualized this significant stimulation of chromium loss associated with the high-sugar diet by further noting that “marginal intake of dietary Cr may lead to marginal Cr deficiency, which is associated with impaired glucose and lipid metabolism.”

Using a mouse model, Seaborn and Stoecker ⁶⁷ demonstrated that the source of carbohydrate can alter chromium absorption and retention. All animals were fed a diet in which 50% was composed of starch, sucrose, fructose, or glucose and compared with those fed a low-chromium diet and those administered 1 mg/kg chromium in the form of chromium chloride, a large dose. After 26 days they found that chromium concentrations were significantly higher in testes, spleen, kidney, and liver, as well as blood, epididymal fat pad, and femur, of animals given their carbohydrate load as starch than in animals fed sucrose, fructose, or glucose. Furthermore, elevated bone and kidney chromium concentrations and heart and muscle glycogen were associated with chromium administration.

In a small clinical trial, Anderson et al. ⁶⁸ administered five different carbohydrate-based drinks to 20 subjects in amounts corresponding to body weight. They found that glucose plus fructose was the most insulinogenic, followed by glucose alone, starch plus fructose, starch alone, and water plus fructose. Furthermore, they observed that subjects with the highest concentrations of circulating insulin displayed decreased ability to mobilize chromium on the basis of urinary chromium excretion. These researchers concluded that such urinary chromium losses parallel the insulinogenic properties of carbohydrates.

Urinary chromium excretion is greater in adults with diets high in simple sugars (e.g., sucrose) than in those with diets high in complex carbohydrates (e.g., whole grains). Increased insulin secretion in response to the consumption of simple sugars (vs. complex carbohydrates) appears to contribute significantly to this effect. ^68-71 Decreased chromium intake and potentially compromised chromium status are also strongly associated with diets higher in simple carbohydrates and refined foods.

Chromium, 200 µg once or twice daily, may be beneficial in individuals with dietary intake high in sugars and simple carbohydrates. A dietary approach emphasizing lean meats, healthy fats and oils, carbohydrate sources low on the glycemic index (especially nutrient-rich fruits, vegetables, and whole grains), and a minimum of processed foods and refined carbohydrates will enhance the action and retention of dietary and supplemental chromium support for healthy insulin function and reduce the risk of dysglycemia, obesity, diabetes, and cardiovascular disease. ⁷²

Hydroxycitric Acid

See Gymnema sylvestre.

Iron

Chromium and iron compete for binding on transferrin, the iron transport protein. Thus, excessive levels of either mineral can interfere with transport of the other.

In an 8-week placebo-controlled study of younger men doing resistance training, Lukaski et al. ⁷³ observed an insignificant decrease in transferrin saturation with iron after administration of 200 µg of chromium daily (3.3-3.5 µmol as chromium chloride or chromium picolinate). In a similar randomized, double-blind, placebo-controlled trial involving 18 older men (age 56-69) engaged in resistive training twice weekly, Campbell et al. ⁷⁴ found that 925 µg of chromium picolinate daily for 12 weeks did not significantly affect hematologic indices, measures of iron metabolism, or iron status. Based on these and related findings, it has also been hypothesized that decreased chromium transport might contribute to the diabetes associated with hereditary hemochromatosis.

Well-designed long-term studies have yet to be published investigating this interaction more thoroughly.

Vanadium

Evidence from in vitro and in vivo research has been accumulating for more than 20 years showing that vanadyl and vanadate (i.e., vanadium salts) mimic insulin action in isolated cell systems and lower glucose levels in diabetic animals. Diabetic patients administered vanadium salts, containing 25 to 100 mg of elemental vanadium, daily for up to 6 weeks have demonstrated partial normalization of glucose metabolic irregularities. ^75-78

Human trials investigating the potential synergy between chromium and vanadium are warranted. Pending such clarification, professional supervision is appropriate for individuals with diabetes who choose to undertake such therapies, especially within the context of conventional therapy using insulin or oral hypoglycemic medications.

Vitamin C

Concomitant intake of vitamin C may increase chromium absorption. Animal research has shown that simultaneous intake of chromium and vitamin C enhances chromium uptake. ⁷⁹ Seaborn et al. ⁸⁰ studied the effects of chromium and ascorbate depletion in a guinea pig model and observed a synergistic relationship between ascorbic acid and chromium. They noted that their “findings suggest that dietary Cr may affect ascorbic acid metabolism and the metabolic response to stress.”

A healthy intake of both chromium and vitamin C can play a role in the prevention and treatment of dysglycemia, lipid disorders, and cardiovascular disease.

Theoretically, an excess of chromium might result if a high intake was accompanied by high doses of vitamin C. The clinical significance of any potentially adverse effect is improbable, whereas the potential benefits of a synergistic interaction between these nutrients is plausible, even probable, at appropriate dosage levels in most individuals, particularly those with compromised dietary intake.

In vitro experiments have consistently found that the addition of ascorbic acid to plasma containing chromium(VI) leads to a dose-dependent reduction of chromium(VI) to chromium(III).

Zinc

Data from animal research indicate that coadministration of zinc and chromium may reduce intestinal content and absorption of zinc, particularly in the presence of zinc deficiency. ⁸¹ Pending further research, separating intake of these two minerals by at least several hours may be advisable to enhance absorption.

herb-nutrient interactions

Gymnema sylvestre

Gymnema sylvestre,a plant native to the tropical forests of India, has played a role in the Ayurvedic treatment of diabetes for centuries. It has been postulated that Gymnemaenhances the production of endogenous insulin. A typical dosage of G. sylvestreextract is 400 to 600 mg per day.

In a randomized, double-blind, placebo-controlled clinical trial, Preuss et al. ⁸² compared the effects of (-)-hydroxycitric acid alone and in combination with niacin-bound chromium and a standardized G. sylvestreextract in 60 moderately obese subjects over 8 weeks. Both groups receiving Gymnemademonstrated 5% to 6% reductions in body weight as well as significant reductions in food intake, total cholesterol, LDLs, triglycerides, and serum leptin levels, compared with those receiving placebo; HDL levels and excretion of urinary fat metabolites increased in both treated groups. The authors concluded that optimal doses of (−)-hydroxycitric acid and, to a greater degree, the combination of (−)-hydroxycitric acid, niacin-bound chromium, and G. sylvestreextract can serve as an effective and safe weight loss formula that can facilitate a reduction in excess body weight and BMI while promoting healthy blood lipid levels.

Citations and Reference Literature

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3.Panel on Dietary Antioxidants and Related Compounds, Food and Nutrition Board, Institute of Medicine. Dietary Reference Intakes for Vitamin A, Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon, Vanadium, and Zinc. Washington, DC: National Academy Press; 2001:65-126.
4.Bahijri SM, Mufti AM. Beneficial effects of chromium in people with type 2 diabetes, and urinary chromium response to glucose load as a possible indicator of status. Biol Trace Elem Res 2002;85:97-109.View Abstract
5.Hathcock JN. Vitamins and minerals: efficacy and safety. Am J Clin Nutr 1997;66:427-437.View Abstract
6.Anderson RA, Cheng N, Bryden NA et al. Elevated intakes of supplemental chromium improve glucose and insulin variables in individuals with type 2 diabetes. Diabetes 1997;46:1786-1791.View Abstract
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8.Wasser WG, Feldman NS, D’Agati VD. Chronic renal failure after ingestion of over-the-counter chromium picolinate. Ann Intern Med 1997;126:410.
9.Cerulli J, Grabe DW, Gauthier I et al. Chromium picolinate toxicity. Ann Pharmacother 1998;32:428-431.View Abstract
10.Martin WR, Fuller RE. Suspected chromium picolinate–induced rhabdomyolysis. Pharmacotherapy 1998;18:860-862.View Abstract
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