Chromium health benefits

Chromium

In by Raphikammer

Chromium is the 13th most common element in the

earth’s crust and 26th most common element in seawater

 

It is present in the environment in oxidation states ranging from −2 to +6 but principally as metallic (Cr0), trivalent (+3), and hexavalent (+6) Cr. The valence state in which the Cr is present in the environment is of critical importance. Trivalent Cr, the most common and naturally occurring form of Cr, is an essential nutrient with very low toxicity and is the subject of this entry.

This review will also focus on the role of Cr in humans. Hexavalent, the form of Cr used for industrial purposes, is largely a man-made product formed by the oxidation of the naturally occurring trivalent Cr. It is highly toxic and does not occur normally in biological tissues. Low amounts of hexavalent Cr can be reduced in biological systems to trivalent Cr.

 

BIOCHEMISTRY AND PHYSIOLOGIC FUNCTIONS

Essentiality

Chromium was shown to be an essential element in humans

during the 1970s when a patient on total parenteral

nutrition (TPN) developed severe signs of diabetes including

weight loss, glucose intolerance, and peripheral

neuropathy that were refractory to insulin (1). Since conventional

treatments for diabetes, including 45 units of

insulin per day, were unsuccessful, the patient was given

supplemental Cr based on previous animal studies and

preliminary human studies. Following two weeks of supplemental

Cr, signs and symptoms of diabetes were reversed

and exogenous insulin requirements dropped from

45 units per day to 0. Beneficial effects of Cr on patients on

TPN have been confirmed on numerous occasions and

documented in the scientific literature from three separate

laboratories (2–4). Chromium presently added to

TPN solutions may not be adequate for some patients. Peripheral

neuropathy and glucose intolerance of a patient

receiving recommended levels of Cr in these TPN solutions

(total parenteral intake approximately 15 g daily)

were alleviated by an additional 250 g daily dose of Cr

as Cr chloride. Peripheral neuropathy was improved significantly

within four days of additional Cr and normalization

of nerve conduction within three weeks. Glucose

intolerance was also normalized within three weeks of

supplemental Cr (5). Recently, a patient developed severe

insulin resistance following surgical repair of a thoracic

aorta aneurysm. Postoperatively, the patient required

2110 units of insulin for more than 40 hours while receiving

pressors and glucocorticoids. After the administration

of intravenous Cr at 3 g/hr, the blood sugar normalized

and insulin therapy was discontinued (6). This

case represents a unique approach using intravenous Cr

to achieve glycemic control in a patient with extreme insulin

resistance and acute critical illness. Chromium is

routinely added to TPN solutions as a daily administration

for adults of 10 to 15 g and 0.14 to 0.20 g/kg for

pediatric TPN patients (4).

Signs of Chromium Deficiency

Signs and symptoms of marginal Cr deficiency are not

limited to patients on TPN and may be widespread in

the general population. Insufficient dietary intake of Cr

leads to increases in risk factors associated with diabetes

and cardiovascular diseases including elevated circulating

insulin, glucose, triglycerides, total cholesterol, reduced

high-density lipoprotein cholesterol (HDL-C), and

impaired immune function (7,8).

Chromium was shown to be an essential nutrient

for animals almost five decades ago when it was shown

that rats that fed on a Torula yeast-based diet developed

impaired glucose tolerance that was reversed by an insulin

potentiating factor whose active component was shown

to be trivalent Cr (9). Chromium has subsequently been

shown to be an essential element for fish, mice, squirrel

monkeys, guinea pigs, pigs, cattle, and humans (Table 1).

Chromium Absorption and Excretion

Absorbed Cr is excreted primarily in the urine and only

small amounts are lost in the hair, perspiration, or bile.

Therefore, urinary Cr excretion can be used as an indicator

of Cr absorption. Chromium absorption is inversely

related to dietary intake. At daily dietary intakes of 10 g,

Cr absorption is approximately 2% and at intakes of

40 g is 0.5% (11). This leads to absorption of approximately

0.2 g/day, which appears to be a minimal basal

level. At dietary intakes above 50 g Cr/day, Cr absorption

is approximately 0.4%. The form of Cr also influences

the absorption, that is, absorption of Cr from Cr chloride

is usually in the region of 0.4% and Cr from Cr picolinate

(the most common Cr supplement) is approximately

1.2%. Chromium incorporation into rat tissues was shown

to vary widely depending upon its form. The highest concentrations

of Cr were found in the kidney followed by

liver, spleen, heart, lungs, and gastrocnemius muscle (12).

The absorption of nutritional forms of Cr by human subjects

was shown to be the greatest for Cr as Cr histidinate

followed by Cr picolinate, Cr methionate, and Cr pidolate

(13). In addition to its form, oxidation state and route of

149

150 Anderson and Cefalu

Table 1 Signs and Symptoms of Chromium Deficiency

Function Species

Impaired glucose tolerance Human, rat, mouse, squirrel

monkey, guinea pig, cattle

Elevated circulating insulin Human, rat, pig, cattle

Glycosuria Human, rat

Fasting hyperglycemia Human, rat, mouse

Impaired growth Human, rat, mouse, turkey

Hypoglycemia Human

Elevated serum cholesterol and

triglycerides

Human, rat, mouse, cattle, pig

Increased incidence of aortic

plaques

Rabbit, rat, mouse

Increased aortic intimal plaque area Rabbit

Nerve disorders Humana

Brain disorders Humana

Corneal lesions Rat, squirrel monkey

Increased ocular eye pressure Human

Decreased fertility and sperm count Rat

Decreased longevity Rat, mouse

Decreased insulin binding Human

Decreased insulin receptor number Human

Decreased lean body mass Human, pig, rat

Elevated percentage of body fat Human, pig

Impaired humoral immune response Cattle

Increased morbidity Cattle

aThese effects have been observed only in patients on TPN.

Source: From Ref. 10.

administration, ascorbic acid, carbohydrates, phytate, oxalate,

aspirin, antacids, and indomethacin also alter Cr

absorption. Ascorbic acid was shown to significantly increase

Cr absorption in humans with similar results in rats

(14). Using radioactively labeled Cr chloride, animals that

were fed starch were shown to have higher Cr absorption

than those fed on sucrose, fructose, or glucose (15).

Phytate has been reported to have either no effect on Cr

absorption or an inhibitory effect. Oxalate also inhibits Cr

absorption. Prostaglandin inhibitors such as aspirin and

indomethacin enhance Cr absorption, and antacids such

as Maalox R (trade name of Vovartis, Fremont, MI) and

Tums R (Glaxo Smith Kline, Research Triangle Park, NC)

inhibit Cr absorption.

Glucose Intolerance and Diabetes

Chromium supplementation to the general public, and

in participants with diabetes in particular, is widespread

but the efficacy of supplemental Cr is controversial. The

controversy surrounding Cr supplementation stems from

many factors, but the lack of definitive randomized trials

is a major contributor. Specifically, many of the earlier

studies evaluating Cr were open label and therefore generated

substantial bias. Additional concerns from these

earlier studies were the lack of “gold standard” techniques

to assess glucose metabolism (e.g., euglycemichyperinsulinemic

clamps), the use of differing doses and

formulations, and the study of heterogeneous study populations.

Based on these concerns, conflicting data have

been reported that have contributed greatly to the confusion

among health care providers regarding the routine

use of Cr as a dietary supplement. More recent evidence,

however, supports the concept that Cr supplementation

yields more consistent clinical effects on carbohydrate

metabolism particularly when consumed at higher doses,

for example, 200 g or greater daily consumption (7,8,16–

18). Subjects with varying levels of blood lipids have also

been shown to improve following Cr supplementation,

with the greatest improvements in total cholesterol, HDL

cholesterol, and triglycerides in subjects with the highest

initial levels. In the past decade, Cr has been shown to

improve the signs and/or symptoms of diabetes in people

with glucose intolerance and type 1, type 2, gestational

and steroid-induced diabetes. The amounts of supplemental

Cr shown to have beneficial effects in these

studies ranged from 200 to 1000 g/day. In a double-blind

placebo-controlled study involving 180 subjects with type

2 diabetes mellitus, Cr effects were greater at 1000 g/day

than at 200g/day (19). The most dramatic improvements

were shown in hemoglobin A1C (HbA1C), which is a reliable

indicator of long-term glucose control. HbA1C in the

placebo group was 8.5 °æ 0.2%, 7.5 °æ 0.2% in the 200 g

group, and 6.6 °æ 0.1% in the group of subjects receiving

1000 g of Cr as Cr picolinate per day for four months

(the upper level of reference range is approximately 6.5%).

Similar results were observed in a double-blind placebocontrolled

crossover study involving 50 subjects with type

2 diabetes supplemented with 200 g of Cr twice daily as

Cr picolinate (20). Improvements in fasting insulin levels

and one-hour glucose and insulin levels following a 100

g glucose tolerance test in women with gestational diabetes

were greater in the group receiving 8 g/kg body

weight per day compared with those receiving 4 g/kg

body weight (21). Steroid-induced diabetes that could not

be controlled by oral hypoglycemic medications and/or

insulin was also improved to acceptable levels in 47 of 50

people given 600 g of Cr as Cr picolinate per day for two

weeks followed by a daily Cr maintenance dose of 200 g

(22,23). Insulin sensitivity of obese subjects with a family

history of diabetes also improved following 1000 g of

supplemental Cr daily as Cr picolinate (17).

A combination of Cr and biotin (600 g as Cr

picolinate and 2 mg of biotin) led to significant decreases

in HbA1C and glucose compared with the placebo

group in a double-blind study involving 348 subjects

with type 2 diabetes mellitus (DM). In subjects with

high cholesterol and type 2 DM, there were also significant

improvements in total cholesterol and low-density

lipoprotein cholesterol (LDL-C) levels and atherogenic

index in the group consuming the Cr biotin combination.

Significant decreases in LDL-C, total cholesterol,

HbA1C, and very low-density cholesterol levels were

also observed in the Cr biotin group taking statins (24).

In a related study involving poorly controlled subjects

with type 2 DM, there was a significantly greater reduction

in the total area under the curve for glucose

during a two-hour glucose tolerance test in the group

receiving the Cr biotin combination. There were also reductions

in fructosamine, triglycerides, and triglycerides/

HDL-C ratio (25).

Chromium was found to be the most often studied

nutritional supplement in type 2 diabetes (26). MEDLINE

and EMBASE databases were searched using a systematic

approach. Only double-masked randomized controlled

trials were selected. A majority of the trials found a positive

effect of Cr on fasting plasma glucose. Studies have

involved individual case studies to studies with more than 800 subjects for more than one year (27). However, a metaanalysis

of published studies on the effects of Cr on glucose

and insulin (18) concluded, based upon the studies

analyzed, that there were no significant effects of Cr. However,

several positive studies were not included in this

analysis owing to lack of specific data and inability to have

an access to the original data. Several studies not reporting

beneficial effects of supplemental Cr involved healthy

normal subjects, with good glucose tolerance, who would

not be expected to respond to additional Cr (8). Response

to Cr is also dependent upon the amount and form of Cr

consumed, and studies involving 200 g of Cr or less or

a form of Cr that is poorly absorbed would also not be

expected to demonstrate effects of supplemental Cr (8).

In an attempt to determine who responds to supplemental

Cr, 73 subjects with type 2 diabetes mellitus

were assessed in a double-blinded, randomized, placebo controlled

study (28). Subjects were assessed at baseline

for glycemic control with glycated hemoglobin measures,

oral glucose tolerance tests, and body weight and body fat

measures (dual-energy X-ray absorptiometry). The only

subject variable significantly associated with the clinical

response to Cr was the baseline insulin sensitivity,

as assessed with the hyperinsulinemic-euglycemic clamp

[partial R(2) = 0.4038] (P = 0.0004). Subject phenotype

appears to be very important when assessing the clinical

response to Cr because baseline insulin sensitivity was

found to account for nearly 40% of the variance in the

clinical response to Cr (28).

A follow-up study with use of “state-of-the-art”

metabolic techniques and in a well-characterized cohort

of individuals with type 2 diabetes representing a wide

range of both phenotype and parameters assessing whole

body insulin action, suggested that a consistent effect of Cr

to improve insulin action and glycemia was not observed.

However, this study is the first to show that Cr levels after

supplementation do not differ between “responders”

and “nonresponders,” and provides the first comprehensive

assessment of physiological and biochemical characteristics

of individuals who responded to Cr. Specifically,

“response” to Cr is more likely in insulin-resistant individuals

who have more elevated fasting glucose and A1C

levels. Another novel finding was that tissue lipids are

decreased in subjects randomized to Cr. Thus, it may be

postulated that Cr alters insulin sensitivity through modulation

of lipid metabolism in peripheral tissues and may

represent a unique mechanism of action for trace minerals.

The mechanism for this effect is the focus of ongoing

studies (29).

Chromium Antioxidant Effects

Increased oxidative stress in relation to abnormal glucose

metabolism is well documented in people with diabetes

(30,31), and the antioxidative effects of Cr have also been

demonstrated in animal studies (32). Chromium has also

been shown to function as an antioxidant in people with

type 2 diabetes (33) and confirmed in subjects with type

2 diabetes with HbA1C values greater than 8.5% (34). Following

six months of supplementation with Cr and Cr

in combination with the antioxidant vitamins, C and E,

there were significant reductions in both groups in thiobarbituric

reactive substances in a double-blind study involving

adult subjects with type 2 diabetes and HbA1C >

8.5%. Total antioxidative status and glutathione peroxidase

levels were also higher in the Cr group and the Cr

plus antioxidative vitamins group (35). In addition, fasting

glucose, HbA1C, and insulin resistance also improved

in groups consuming Chromium.

Weight and Lean Body Mass

While there are a number of animal and human studies

that suggest an effect of supplemental Cr on increasing

lean body mass and decreasing body weight, there are

also a number of studies showing no detectable effects of

supplemental Cr (36,37). It may take more than six months

to detect changes in lean body mass in humans and there

may not be an effect on total body weight, as increases in

lean body mass and decreases in fat may lead to small or

minimal changes in total weight. Future studies involving

body weight and lean body mass should be for 24 weeks or

longer and involve 400 g of Cr or more daily. Additional

studies shorter than 24 weeks will be of minimal benefit

and will likely serve to cloud the issue of whether supplemental

Cr has an effect on body composition and weight

loss in humans (36). Beneficial effects of Cr on lean body

mass in humans have been substantiated in studies with

pigs (38). The lack of the effect of Cr on lean body mass

has been presented (39). A meta-analysis reported a body

weight reduction of 1.1 to 1.2 kg during an intervention

period of 10 to 13 weeks of Cr supplementation, considered

too small to be clinically significant (37). However,

long-term administration studies should be performed to

determine whether the reduction in body weight could be

maintained.

The controversial area of Cr, weight, and lean body

mass was clarified when it was shown that goats eating

a diet high in refined carbohydrates ate more than those

eating the diet supplemented with Cr (40,41). Increases in

weight were attributed to the antilipolytic effects of insulin

leading to accumulation of triglycerides in the adipose tissue.

Elevated insulin levels in the low Cr animals would

also lead to decreased glucagon. As glucagon stimulates

lipolysis, decreased glucagon may lead to decreased lipolysis

and subsequent accumulation of body fat and weight

gain and may explain the effects on lean body mass in

humans.

In the above-mentioned study involving goats, it

also took more than 28 weeks to detect significant changes

in body weight in rapidly growing goats. This is consistent

with human studies, usually 12 weeks or less in duration,

which are unable to detect significant changes in weight

of people eating conventional diets with supplemental Cr.

Supplemental Cr, 1000 g of Cr as Cr picolinate, was

also shown to decrease food intake (P < 0.0001), hunger

levels (P < 0.05), and fat cravings (P < 0.0001), and tended

to decrease body weight (P = 0.08) in 42 overweight

women who reported craving carbohydrates. Study

design was double-blind placebo controlled (42). In a related

study involving rats, intraperitoneal administration

of Cr resulted in a subtle decrease in food intake but when

administered centrally, Cr picolinate dose dependently

decreased food intake. The authors concluded that Cr has

a role in food intake regulation, which may be mediated

by a direct effect on the brain (42).

152 Anderson and Cefalu

• BODY WEIGHTdecrease

• GLUCOSE-decrease

• INSULIN-decrease

• FFA-decrease

A well-controlled study demonstrated

that weight gain in people with type 2 diabetes

was clearly regulated by supplemental Cr (43). Thirtyseven

subjects with type 2 diabetes were placed on sulfonylurea

drugs to control blood sugar for three months

and then randomized to receive either Cr or placebo. Subjects

receiving the supplemental Cr had smaller increases

in body weight, percent body fat, and total abdominal

fat compared with those in the placebo group. Subjects

receiving Cr also had increased insulin sensitivity, corrected

for fat-free-mass, and decreased free fatty acids

Chromium & Depression

A small pilot study suggested that Cr might be effective in

the treatment of atypical depression. The study involved

15 patients with major depression, was double-blind, randomized,

and placebo controlled (44). Seventy percent

of the subjects responded to Cr with no negative side

effects. Traditionally, depression has been treated with

monoamine oxidase inhibitors; the toxicity and side effects

of this class of drugs represent major limitations and

the response is usually 50% or less. Depression has been

associated with insulin resistance (45) and it is conceivable

that increased insulin sensitivity leads to an enhanced

central noradrenergic and serotonergic activity. Postsynaptic

brain serotonin receptor downregulation by Cr in

humans has also been reported, which could relate to insulin

sensitivity and depression (46). However, larger and

more comprehensive studies are required to address this

problem.

In a double-blind, multicenter, eight-week replication

study, 113 adult outpatients with atypical depression

were randomized 2:1 to receive 600 g/day of elemental

Cr, as provided by Cr picolinate, or placebo (47). Primary

efficacy measures were the 29-item Hamilton Depression

Rating Scale (HAM-D-29) and the Clinical Global Impressions

Improvement Scale (CGI-I). The main effect of Cr

was on carbohydrate craving and appetite regulation in

depressed patients demonstrating that 600 g of elemental

Cr may be beneficial for patients with atypical depression

who also have severe carbohydrate craving. Further

studies are needed to evaluate Cr in depressed patients

specifically selected for symptoms of increased appetite

and carbohydrate craving as well as to determine whether

a higher dose of Cr would have an effect on mood.

The involvement of glutamatergic and serotonergic

receptors in the antidepressant-like activity of Cr has

been demonstrated in mice (48). The study confirmed

the antidepressant-like activity of Cr in the mouse forced

swim test and indicates the major role of the -amino-

3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)

receptor and participation of N-methyl-D-aspartate

(NMDA) glutamatergic and 5-HT (1) and 5-HT (2 A/C)

serotonin receptors in this activity.

Mechanism

How Cr serves as a cofactor for insulin action is not fully

understood, and Cr remains as one of the only traceable

minerals where a specific mechanism of action has

not been identified. Several in vivo and in vitro studies

have postulated a potential mechanism, but it must

be stated that this mechanism has not been studied as

to whether this is applicable to in vivo states. However,

a low-molecular-weight chromium-binding substance

(LMWCr) termed chromodulin (MW ≈ 1500 Da)

has been described, which appears to be involved in mediating

the intracellular effects of Cr. It is composed of

glycine, cysteine, glutamic acid, and aspartic acid (49).

The principal carrier protein for Cr in the blood is suggested

to be transferrin, which also is suggested to play a

critical role in movement of Cr from blood to LMWCr. It

has been postulated that an initial step in this process is the

migration of transferrin receptors (Tf-R) to plasma membranes

of insulin-insensitive cells after insulin stimulation.

Transferrin containing the bound Cr binds to the Tf-R and

is internalized by endocytosis. The pH of the internalized

vesicle is reduced by adenosine triphosphate-driven

proton pumps, Cr is released from transferrin, and the resulting

free Cr is postulated to be sequestered by LMWCr

(49,50). With this step, Cr is transferred from transferrin

to LMWCr, which normally exists in insulin-dependent

cells in the apo, or inactive, form. Binding with Cr ions

converts inactive LMWCr to its holo, or active, form. It

is proposed that LMWCr then participates as part of an

insulin signal amplification system as it binds to insulin activated

insulin receptors and results in stimulating its

tyrosine kinase activity. The end result of this process is

postulated to be the activation of insulin receptor kinase

and potentiation of the actions of insulin. Importantly,

LMWCr without bound Cr or in the presence of other

metal ions has been shown to be ineffective in activating

insulin-dependent kinase activity and thus enhancing the

actions of insulin (51). Thus, although this is an attractive

hypothesis, definitive data for this mechanism as to

whether it is operative in humans is lacking.

Chromiumhas also been reported to modulate phosphotyrosine

phosphatase (52), the enzyme that cleaves

phosphate from the insulin receptor leading to decreases

in insulin sensitivity. The balance between kinase and

phosphatase activity is suggested to facilitate insulin’s

role in rapidly moving glucose into cells. In addition, it

Chromium 153

has been suggested that Cr enhances insulin binding, insulin

receptor number, insulin internalization, and -cell

sensitivity (8). All of these effects contribute to improved

insulin sensitivity.

Chromium, like insulin, also stimulates mRNA and
protein levels for Ca2+-ATPase, a protein involved in calcium
transport.

A combination of insulin and Cr as Cr picolinate

caused a greater stimulation of the Ca2+-ATPase

mRNA than either insulin or Cr alone (53). Fluorometric

analysis of the rate of ionized calcium recovery following

stimulation with arginine also showed an effect of Cr;

Cr picolinate alone increased recovery rate of 35% and Cr

plus insulin 133%, compared to the increased recovery rate

of 83% caused by insulin alone. In skeletal muscle cells,

Cr was shown to stimulate tyrosine phosphorylation of

the insulin receptor and insulin receptor substrate 1 (54).

Wang et al. (55) also reported increased phosphorylation

of the insulin receptor and concluded that cellular Cr potentiates

insulin signaling by increasing insulin receptor

kinase activity, separate from inhibition of phosphotyrosine

phosphatase. Elmendorf and colleagues conducted a

series of studies demonstrating that the cholesterol content

of the plasma membrane regulates the response to

Cr (56–59). They reported that a loss of plasma membrane

phosphatidylinositol 4,5-bisphosphate-regulated filamentous

actin structure contributes to insulin-induced insulin

resistance. They also reported that Cr picolinate augments

insulin-regulated glucose transport in insulin-sensitive

3T3-L1 adipocytes by lowering plasma membrane cholesterol.

Insulin-induced insulin-resistant adipocytes display

elevated plasma membrane cholesterol with a reciprocal

decrease in plasma membrane phosphatidylinositol 4,5-

bisphosphate. This lipid imbalance and insulin resistance

was corrected by the cholesterol-lowering action of Cr picolinate

(57). The plasma membrane lipid imbalance did

not impair insulin signaling, nor did Cr picolinate amplify

insulin signal transduction demonstrating that plasma

membrane cholesterol is involved in the response to Cr

and may be important in subjects who respond to supplemental

Cr. In summary, although the precise mechanism

of action of Cr is not known, the data that are available

suggest effects on the insulin signaling processes that may

be regulated by plasma membrane cholesterol content.

Chromium Food Sources

Not only is the total dietary intake of Cr important but also

the total diet consumed. For example, increased intakes of

simple sugars lead to increased losses of supplemental Cr

(60). This becomes a double-edged sword, as high sugar

foods are often also low in Cr. Diets high in simple sugars

lead to elevated levels of circulating insulin and once

insulin increases, Cr is mobilized. Chromium does not

appear to be reabsorbed by the kidney and is lost in the

urine. Other stresses such as acute exercise, pregnancy and

lactation, infection, and physical trauma also increase Cr

losses (61).

Foods high in Cr that are also low in simple sugars

include broccoli, green beans, apples, and high fiber

breakfast cereals (62). When unprocessed fruits, vegetables,

and high fiber foods are consumed, the requirement

for Cr is postulated to be lower because the Cr losses are

lower. Chromium content of foods cannot be calculated

from food composition tables, as there are large variations

in individual foods owing likely to the contamination that

occurs during growing and processing.

REFERENCE INTAKES

The estimated safe and adequate daily dietary intake

(ESADDI) for Cr for children aged seven years to adult

of 50 to 200 g/day was established by committees of the

US National Academy of Sciences in 1980 and affirmed

in 1989 (63). The Food and Drug Administration proposed

a Reference Dietary Intake for Cr effective in 1997 of

120 g/day. The new committee of the National Academy

of Sciences has established that the normal intake of Cr

should serve as the adequate intake of 20 g for women

and 30 g for men older than 50 years and 25 g for

women and 35 g for men aged 19 to 50 years (Table 2).

It is unclear why the adequate intake for Cr is lower for

people older than 50 years, other than total caloric intake.

It is recognized that Cr is a cofactor for insulin action, and

insulin action is known to be diminished with aging, but

unsure whether this is a major reason. Indices of Cr status

such as the Cr content of hair, sweat, and urine were

shown to decrease with age in a study involving more

than 40,000 people (64).

The proposed adequate intake appears to be the average

intake as reported in 1985, which appears to be suboptimal.

Average daily intake (mean °æ SEM) of subjects

consuming normal diets was 25 °æ 1 g for women and

33°æ3 g for men (11). There have been more than 30 studies

reporting beneficial effects of supplemental Cr on people

with blood glucose values ranging from marginally

elevated to glucose intolerance and diabetes when consuming

diets of similar Cr content.

Consumption of controlled normal diets in the lowest

quartile of normal Cr intake, but near the new adequate

intakes, led to detrimental effects on glucose

(Fig. 2) in subjects with marginally impaired glucose

Table 2 Proposed Adequate Intakes for Chromium

Group Proposed adequate daily intake (g)

0–6 mo 0.2

7–12 mo 5.5

1–3 yr 11

4–8 yr 15

Boys, 9–13 25

Boys, 14–18 35

Girls, 9–13 21

Girls, 14–18 24

Men, 19–30 35

Men, 31–50 35

Women, 19–30 25

Women, 31–50 25

Men, 51–70 30

Men, >70 30

Women, 51–70 20

Women, >70 20

Pregnancy 30

Lactation 45

Source: From Ref. 65.

154 Anderson and Cefalu

10

b

a

WEEK 1

WEEK 4

PLACEBO

+CHROMIUM

a

8 a

6

60-min GLUCOSE (mmol/L)

4

2

CONTROLS HYPERGLY

Figure 2 Effects of dietary Cr on people with good glucose tolerance and

those with marginally impaired glucose tolerance consuming 20 g or less

of Cr daily. Subjects with good glucose tolerance, controls, are subjects with

blood glucose levels less than 5.5 mmol/L (100 mg/dL), 90 minutes after

consuming an oral glucose load of 1 g/kg body weight. Subjects defined as

marginally hyperglycemic have 90-minute glucose levels between 5.5 and

11.1 mmol/L following an oral glucose load of 1 g/kg. Bars with different

superscripts are significantly different at P < 0.05. Subjects with good

glucose tolerance are able to maintain normal glucose levels at these low

intakes, but not subjects with varying degrees of glucose intolerance. Source:

From Ref. 66.

tolerance [90-minute glucose between 5.5 and 11.1

mmol/L (100–200 mg/dL) following an oral glucose load

of 1 g/kg body weight]. The average person older than

25 years has blood glucose in this range. Consumption of

these same diets by people with good glucose tolerance

(90-minute glucose less than 5.5 mmol/L) did not lead to

changes in glucose and insulin variables. This is consistent

with previous studies demonstrating that the requirement

for Cr is related to the degree of glucose intolerance and

demonstrates that an intake of 20 g/day of Cr is not adequate

for people with marginally impaired glucose tolerance

and certainly not for those with impaired glucose

tolerance or diabetes.

Safety of Chromium

Trivalent Cr, the form of Cr found in foods and nutrient

supplements, is considered as one of the least toxic

nutrients. The reference dose established by the US Environmental

Protection Agency for Cr is 350 times the upper

limit of the ESADDI as established in 1980 and affirmed

in 1989, 3500 times the new adequate intake for women

and 2333 times for men. The ratio of the reference dose

to the required levels for most mineral and trace minerals

is less than 10. The reference dose is defined as an

estimate (with uncertainty spanning perhaps an order of

magnitude) of a daily exposure to the human population,

including sensitive subgroups, that is likely to be without

an appreciable risk of deleterious effects during a lifetime.

With these large safety factors, it is highly unlikely that

there would be any reproducible signs of Cr toxicity at

daily supplementation ranges of 1000 g or less. There has

been no evidence of toxicity in any of the nutritional studies

involving Cr supplementation, but there have been

individual case studies reporting detrimental effects that

have not been confirmed (67). Since the absorption of Cr

is very low, it is likely that there would be indigestion and

vomiting before enough Cr was absorbed to cause toxicity.

However, Cr does bind to many biological substances

including DNA and, at high enough levels, could (like almost

all nutrients) lead to signs of toxicity in sensitive individuals.

The toxic effects of Cr under non physiological

conditions have been reviewed (39). The National Toxicology

Program (NTP) (68) has completed independent in

vitro and in vivo genotoxicity assays and evaluation of Cr

picolinate, the most popular form of Cr in nutrient supplements,

demonstrating that Cr picolinate did not produce

chromosome damage in in vivo mouse assays and had no

effect in two bacterial mutation assays (69). The absence of

negative effects of Cr picolinate as reviewed by the NTP

has led to the addition of Cr picolinate to generally recognized

as safe list (68,69). Owing to the low toxicity of

trivalent Cr, there is no upper limit established for Cr in

the new National Academy of Sciences Guidelines (65).

CONCLUSION

The effects of Cr on glucose and insulin metabolism are

well documented. Normal dietary intake of Cr appears

to be suboptimal because several studies have reported

beneficial effects of Cr on people with elevated blood glucose

or type 2 diabetes eating conventional diets. Stresses

that alter blood glucose often lead to increased mobilization

of Cr that is subsequently lost from the body via the

urine. The mechanism of action of Cr is largely through

improvements in insulin sensitivity. Chromium makes insulin

more effective and in the presence of Cr in a useable

form, lower levels of insulin are required. There is no established

upper limit for the supplemental Cr as it has

very low toxicity and there have been no documented

negative side effects in any of the more than 35 clinical

studies. Number of subjects per study ranged from less

than 10 to more than 800.

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