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
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
150 Anderson and Cefalu
Table 1 Signs and Symptoms of Chromium Deficiency
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
Elevated serum cholesterol and
Human, rat, mouse, cattle, pig
Increased incidence of aortic
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
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
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
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
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
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.
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
has been suggested that Cr enhances insulin binding, insulin
receptor number, insulin internalization, and -cell
sensitivity (8). All of these effects contribute to improved
Chromium, like insulin, also stimulates mRNA and
protein levels for Ca2+-ATPase, a protein involved in calcium
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
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.
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
Source: From Ref. 65.
154 Anderson and Cefalu
60-min GLUCOSE (mmol/L)
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).
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.
glucose intolerance, and neuropathy reversed by
chromium supplementation, in a patient receiving longterm
total parenteral nutrition. Am J Clin Nutr 1977; 30(4):
deficiency after long-term total parenteral nutrition. Dig Dis
Sci 1986; 31(6):661–664.
total parenteral nutrition. JAMA 1979; 241(5):496–498.
1995; 11(suppl 1):83–86.
due to possible chromium deficiency in long-term
parenteral nutrition that closely mimic metronidazoleinduced
syndromes. JPEN J Parenter Enteral Nutr 1996;
reverses extreme insulin resistance in a cardiothoracic ICU
patient. Nutr Clin Pract 2008; 23(3):325–328.
J Am Coll Nutr 1998; 17(6):548–555.
8. Anderson RA. Chromium and insulin sensitivity. Nutr Res
Rev 2003; 16:267–275.
9. Mertz W, Schwarz K. Relationship of glucose tolerance to
impaired intravenous glucose tolerance of rats on stock diets.
Am J Physiol 1959; 196:614–618.
10. Anderson RA. Chromium: Physiology, dietary sources and
requirements. In: Sadler MJ, Strain JJ, Caballero B, eds. Encyclopedia
of Human Nutrition. London: Academic Press,
11. Anderson RA, Kozlovsky AS. Chromium intake, absorption
and excretion of subjects consuming self-selected diets. Am
J Clin Nutr 1985; 41(6):1177–1183.
12. Anderson RA, Bryden NA, Polansky MM, et al. Dietary
chromium effects on tissue chromium concentrations and
chromium absorption in rats. J Trace Elem Exp Med 1996;
13. Anderson RA, Polansky MM, Bryden NA. Stability and
absorption of chromium and absorption of chromium histidinate
complexes by humans. Biol Trace Elem Res 2004;
14. Seaborn CD, Stoecker BJ. Effect of antacid or ascorbic acid on
tissue accumulation and urinary excretion of 51 chromium.
Nutr Res 1992; 12:1229–1234.
15. Seaborn CD, Stoecker BJ. Effects of starch, sucrose, fructose
and glucose on chromium absorption and tissue concentrations
in obese and lean mice. J Nutr 1989; 119(10):1444–
16. Cefalu WT, Hu FB. Role of chromium in human health and
in diabetes. Diabetes Care 2004; 27(11):2741–2751.
17. Cefalu WT, Bell-Farrow AD, Stigner J, et al. Effect of
chromium picolinate on insulin sensitivity in vivo. J Trace
Elem Exp Med 1999; 12:71–84.
18. Althuis MD, Jordan NE, Ludington EA, et al. Glucose and
insulin responses to dietary chromiumsupplements:Ametaanalysis.
Am J Clin Nutr 2002; 76(1):148–155.
19. 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
20. Ghosh D, Bhattacharya B, Mukherjee B, et al. Role of
chromium supplementation in Indians with type 2 diabetes
mellitus. J Nutr Biochem 2002; 13(11):690–697.
21. Jovanovic L, Gutierrez M, Peterson CM. Chromium supplementation
for women with gestational diabetes mellitus. J
Trace Elem Exp Med 1999; 12:91–98.
22. Ravina A, Slezak L, Mirsky N, et al. Control of steroidinduced
diabetes with supplemental chromium. J Trace Elem
Exp Med 1999; 12:375–378.
23. Ravina A, Slezak L, Mirsky N, et al. Reversal of
corticosteroid-induced diabetes mellitus with supplemental
chromium. Diabet Med 1999; 16(2):164–167.
24. Albarracin C, Fuqua B, Geohas J, et al. Combination of
chromium and biotin improves coronary risk factors in
hypercholesterolemic type 2 diabetes mellitus: A placebocontrolled,
double-blind randomized clinical trial. J Cardiometab
Syndr 2007; 2(2):91–97.
25. Singer GM, Geohas J. The effect of chromium picolinate and
biotin supplementation on glycemic control in poorly controlled
patients with type 2 diabetes mellitus: A placebocontrolled,
double-blinded, randomized trial. Diabetes Technol
Ther 2006; 8(6):636–643.
26. Bartlett HE, Eperjesi F. Nutritional supplementation for type
2 diabetes: A systematic review. Ophthalmic Physiol Opt
27. Cheng N, Xixing Z, Shi H, et al. Follow-up survey of people
in China with type 2 diabetes mellitus consuming supplemental
chromium. J Trace Elem Exp Med 1999; 12:55–60.
28. Wang ZQ, Qin J, Martin J, et al. Phenotype of subjects with
type 2 diabetes mellitus may determine clinical response to
chromium supplementation. Metabolism 2007; 56(12):1652–
29. Cefalu WT, Rood J, Pinsonat P, et al. Characterization of the
metabolic and physiologic response from chromium supplementation
in subjects with type 2 diabetes. Metabolism
30. Altomare E, Vendemiale G, Chicco D, et al. Increased lipid
peroxidation in type 2 poorly controlled diabetic patients.
Diabetes Metab 1992; 18(4):264–271.
31. Armstrong AM, Chestnutt JE, Gormley MJ, et al. The effect
of dietary treatment on lipid peroxidation and antioxidant
status in newly diagnosed noninsulin dependent diabetes.
Free Radic Biol Med 1996; 21(5):719–726.
32. Preuss HG, Grojec PL, Lieberman S, et al. Effects of different
chromiumcompounds on blood pressure and lipid peroxidation
in spontaneously hypertensive rats. Clin Nephrol 1997;
33. Anderson RA, Roussel AM, Zouari N, et al. Potential antioxidant
effects of zinc and chromium supplementation in
people with type 2 diabetes mellitus. J Am Coll Nutr 2001;
34. Cheng HH, Lai MH, Hou WC, et al. Antioxidant effects
of chromium supplementation with type 2 diabetes mellitus
and euglycemic subjects. J Agric Food Chem 2004;
35. Lai MH. Antioxidant effects and insulin resistance improvement
of chromium combined with vitamin C and e supplementation
for type 2 diabetes mellitus. J Clin Biochem Nutr
36. Anderson RA. Effects of chromium on body composition and
weight loss. Nutr Rev 1998; 56(9):266–270.
37. Pittler MH, Stevinson C, Ernst E. Chromium picolinate for
reducing body weight: Meta-analysis of randomized trials.
Int J Obes Relat Metab Disord 2003; 27(4):522–529.
38. Lindemann MD, Wood CM, Harper AF, et al. Dietary
chromium picolinate additions improve gain: Feed and carcass
characteristics in growing-finishing pigs and increase
litter size in reproducing sows. J Anim Sci 1995; 73(2):457–
39. Vincent JB. The potential value and toxicity of chromium
picolinate as a nutritional supplement, weight loss agent and
muscle development agent. Sports Med 2003; 33(3):213–230.
40. Frank A, Danielsson R, Jones B. Experimental copper and
chromium deficiency and additional molybdenum supplementation
in goats. II. Concentrations of trace and minor
elements in liver, kidneys and ribs: Haematology and clinical
chemistry. Sci Total Environ 2000; 249(1–3):143–170.
41. Frank A, Anke M, Danielsson R. Experimental copper and
chromium deficiency and additional molybdenum supplementation
in goats. I. Feed consumption and weight development.
Sci Total Environ 2000; 249(1–3):133–142.
42. Anton SD, Morrison CD, Cefalu WT, et al. Effects of
chromium picolinate on food intake and satiety. Diabetes
Technol Ther 2008; 10(5):405–412.
43. Martin J, Wang ZQ, Zhang XH, et al. Chromium picolinate
supplementation attenuates body weight gain and increases
insulin sensitivity in subjects with type 2 diabetes. Diabetes
Care 2006; 29(8):1826–1832.
44. Davidson JR, Abraham K, Connor KM, et al. Effectiveness of
chromium in atypical depression: A placebo-controlled trial.
Biol Psychiatry 2003; 53(3):261–264.
45. Paykel ES, Mueller PS, de la Vergne PM. Amitriptyline,
weight gain and carbohydrate craving: A side effect. Br J
Psychiatry 1973; 123(576):501–507.
46. Attenburrow MJ, Odontiadis J, Murray BJ, et al. Chromium
treatment decreases the sensitivity of 5-HT2Areceptors. Psychopharmacology
(Berl) 2002; 159(4):432–436.
156 Anderson and Cefalu
47. Docherty JP, Sack DA, Roffman M, et al. A double-blind,
placebo-controlled, exploratory trial of chromium picolinate
in atypical depression: Effect on carbohydrate craving. J Psychiatr
Pract 2005; 11(5):302–314.
48. Piotrowska A, Mlyniec K, Siwek A, et al. Antidepressantlike
effect of chromium chloride in the mouse forced swim
test: Involvement of glutamatergic and serotonergic receptors.
Pharmacol Rep 2008; 60(6):991–995.
49. Vincent JB. The biochemistry of chromium. J Nutr 2000;
50. Clodfelder BJ, Emamaullee J, Hepburn DD, et al. The trail
of chromium(III) in vivo from the blood to the urine: The
roles of transferrin and chromodulin. J Biol Inorg Chem 2001;
51. Davis CM, Vincent JB. Chromium oligopeptide activates insulin
receptor kinase activity. Biochemistry 1997; 36:4382–
52. Davis CM, Sumrall KH, Vincent JB. A biologically active
form of chromium may activate a membrane phosphotyrosine
phosphatase (PTP). Biochemistry 1996; 35(39):12963–
53. Moore JW, Maher MA, Banz WJ, et al. Chromium picolinate
modulates rat vascular smooth muscle cell intracellular calcium
metabolism. J Nutr 1998; 128(2):180–184.
54. Miranda ER, Dey CS. Effect of chromium and zinc on insulin
signaling in skeletal muscle cells. Biol Trace Elem Res 2004;
55. Wang H, Kruszewski A, Brautigan DL. Cellular chromium
enhances activation of insulin receptor kinase. Biochemistry
56. Horvath EM, Tackett L, Elmendorf JS. A novel membranebased
anti-diabetic action of atorvastatin. Biochem Biophys
Res Commun 2008; 372(4):639–643.
57. Horvath EM, Tackett L, McCarthy AM, et al. Antidiabetogenic
effects of chromium mitigate hyperinsulinemiainduced
cellular insulin resistance via correction of plasma
membrane cholesterol imbalance. Mol Endocrinol 2008;
58. Pattar GR, Tackett L, Liu P, et al. Chromium picolinate positively
influences the glucose transporter system via affecting
cholesterol homeostasis in adipocytes cultured under hyperglycemic
diabetic conditions. Mutat Res 2006; 610(1–2):93–
59. Chen G, Liu P, Pattar GR, et al. Chromium activates glucose
transporter 4 trafficking and enhances insulin-stimulated
glucose transport in 3T3-L1 adipocytes via a cholesteroldependent
mechanism. Mol Endocrinol 2006; 20(4):857–
in simple sugars on urinary chromium losses. Metabolism
61. Anderson RA. Stress effects on chromium nutrition of humans
and farm animals. In: Lyons TP, Jacques KA, eds. Proceedings
of Alltech’s Tenth Symposium, Biotechnology in
the Feed Industry. Nottingham, England: University Press,
62. Anderson RA, BrydenNA,PolanskyMM.Dietary chromium
intake—freely chosen diets, institutional diets and individual
foods. Biol Trace Elem Res 1992; 32:117–121.
63. National Research Council. Recommended Dietary Allowance.
10th ed.Washington, DC: National Academy Press,
in chromium levels in 51,665 hair, sweat, and serum
samples from 40,872 patients—implications for the prevention
of cardiovascular disease and type II diabetes mellitus.
Metabolism 1997; 46(5):469–473.
65. Anonymous. 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, 2001:197–
66. Anderson RA, Polansky MM, Bryden NA, et al.
Supplemental-chromium effects on glucose, insulin,
glucagon, and urinary chromium losses in subjects consuming
controlled low-chromium diets. Am J Clin Nutr 1991;
67. Anderson RA, Bryden NA, Polansky MM. Lack of toxicity
of chromium chloride and chromium picolinate in rats. J Am
Coll Nutr 1997; 16(3):273–279.
http://ntp.niehs.nih.gov (Search: chromium picolinate).
2003. Accessed on April 19, 2010.
regarding nutritional roles and safety. Nutr Today 2005;