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espite widespread use by patients contained a glucose tolerance factor
with diabetes and anecdotal reports (GTF) that prevented diabetes in experi- broccoli, meat, brewers yeast, and some
in the past regarding its efficacy, mental animals (1). This factor was even- brands of wine and beer (8,9). Chromium
until recently, data in humans concerning tually suggested to be a biologically active is also present in many multivitamin/
chromiums effects on insulin action in form of trivalent chromium that could mineral supplements, and there are also
vivo or on cellular aspects of insulin ac- substantially lower plasma glucose levels specific chromium picolinate (CrP) sup-
tion were scarce. Consequently, signifi- in diabetic mice (2). Interest regarding plements that contain 200 600 g chro-
cant controversy still exists regarding the chromium administration in patients mium per tablet (10). The U.S. National
effect of chromium supplementation on with diabetes was kindled by the observa- Academy of Sciences has established the
parameters assessing human health. Fur- tion in the 1970s that it truly was an es- Recommended Daily Allowances for
thermore, elucidating the cellular and sential nutrient required for normal chromium as 50 200 g/day for adult
molecular mechanisms by which chro- carbohydrate metabolism. A patient re- men and women (11), which is also the
mium supplements affect carbohydrate ceiving total parenteral nutrition (TPN) Estimated Safe and Adequate Daily Di-
metabolism in vivo is necessary before developed severe signs of diabetes, in- etary Intake (ESADDI) for chromium for
specific recommendations can be made cluding weight loss and hyperglycemia children aged 7 years to adulthood (7,12).
regarding its routine use in the manage- that was refractory to increasing insulin However, it appears that Americans nor-
ment of diabetes. This review focuses on dosing (3). Based on previous animal mally ingest 50 60% of the minimum
providing current information about this studies and preliminary human studies, suggested daily intake of 50 g (7). Re-
trace minerals specific mechanisms of ac- the patient was given supplemental chro- sults from one study (10) indicated that
tion and clinical trials in patients with mium. In the following 2 weeks, signs and daily chromium intakes for men and
diabetes. symptoms of diabetes were ameliorated, women in the U.S. were 33 and 25 g,
Chromium, one of the most common with markedly improved glycemic status respectively. Therefore, normal dietary
elements in the earths crust and seawater, and greatly reduced insulin requirements intake of chromium for adults may be
exists in our environment in several oxi- (exogenous insulin requirements de- suboptimal.
dation states, principally as metallic (Cr0), creased from 45 units/day to none). Other At dietary intakes 50 g/day, chro-
trivalent (3), and hexavalent (6) chro- studies (4,5) of the beneficial effects of mium absorption is 0.4%, but the triva-
mium. The latter is largely synthesized by chromium in patients receiving TPN have lent formulation also significantly
the oxidation of the more common and also been documented in the scientific lit- influences bioavailability. At a dose of
naturally occurring trivalent chromium erature. Chromium is now routinely 1,000 g/day, absorption of chromium
and is highly toxic. Trivalent chromium, added to TPN solutions (5). from chromium chloride (CrCl 3 ) is
found in most foods and nutrient supple- The results of these studies strongly 0.4%, whereas that from CrP may be as
ments, is an essential nutrient with very implicated chromium as a critical cofactor high as 2.8% (7,13,14). Once absorbed,
low toxicity. in the action of insulin (6,7). Whereas chromium is distributed widely in the
The interest in chromium as a nutri- chromium replacement in deficiency body, with the highest levels being found
tional enhancement to glucose metabo- states is well established, the role of chro- in the kidney, liver, spleen, and bone
lism can be traced back to the 1950s, mium supplementation to enhance glu- (14).
when it was suggested that brewers yeast cose metabolism in subjects is
BIOLOGIC ACTIONS OF
From the 1Pennington Biomedical Research Center, Louisiana State University, Baton Rouge, Louisiana; and CHROMIUM H o w c h r o m i u m
2
Harvard University School of Public Health, Boston, Massachusetts. serves as a cofactor for insulin action is
Address correspondence and reprint requests to William T. Cefalu, MD, Division of Nutrition and not fully understood. From several in vivo
Chronic Disease, The Pennington Biomedical Research Center, Louisiana State University, 6400 Perkins Rd., and in vitro studies (15), it was initially
Baton Rouge, LA 70808. E-mail: cefaluwt@pbrc.edu.
Received for publication 15 July 2004 and accepted in revised form 21 July 2004. thought that chromium potentiated the
F.B.H. has received grant support from Nutrition 21. actions of insulin as part of an organic
Abbreviations: CrP, chromium picolinate; CVD, cardiovascular disease; FPG, fasting plasma glucose; complex, GTF. More recent studies (15)
GTF, glucose tolerance factor; HPFS, Health Professionals Follow-up Study; LMWCr, lowmolecular weight have suggested that chromium may func-
chromium; MI, myocardial infarction; MW, molecular weight; TPN, total parenteral nutrition.
A table elsewhere in this issue shows conventional and Systeme International (SI) units and conversion tion as part of the oligopeptide low
factors for many substances. molecular weight (MW) chromium
2004 by the American Diabetes Association. (LMWCr)-binding substance (MW
CLINICAL INTERVENTION
WITH CHROMIUM T h e m o s t
recent recommendations of the American
Diabetes Association state that at the
present, benefit from chromium supple-
mentation in persons with diabetes has
not been conclusively demonstrated
(49).
Results
Study Chromium supplement Technique
Reference type Study length (dose) Subjects n assessed Glucose Insulin HbA1c IS
Studies using CrCl, brewers yeast,
and CrN formulation
Trow et al. (50) OL 2 months Brewers yeast (100 g/day Type 2 12 OGTT NA NA
Cr3)
Sherman et al. (51) DB 4 months CrCl3 (150 g/day) Type 1/2/Nondiabetic 14 OGTT NA NA NA
Rabinowitz et al. (32) DB 4 months CrCl3 (150 g/day), brewers Type 2 43 Meal challenge NA NA
yeast (13 g/day Cr3)
Uusitupa et al. (30) DB 6 months Brewers yeast (160 g/day IGT, elderly 26 OGTT NA
Chromium in diabetes and cardiovascular risk
Cr3)
Uusitupa et al. (52) DB 6 weeks CrCl3 (200 g/day) Type 2 10 OGTT, HbA1c 2 NA
Potter et al. (21) OL 3 months CrCl3 (200 g/day) IGT 5 Hyperglycemic 1
clamp
Mossop (53) DB 3 months CrCl3 (600 g/day) Type 1/2 26 FBG 2 NA NA NA
Nath et al. (54) OL 2 months CrCl3 (500 g/day) Type 2 12 OGTT 2 2 NA NA
Glinsmann and Mertz (55) OL 18133 days CrCl3 (1803,000 g/day) Type 1/2 6 IVGTT, OGTT 2 NA NA NA
Wilson and Gondy (31) DB 3 months CrN (220 g/day) Nondiabetic, young 26 FBG/insulin 2* NA NA
Studies using CrP formulation
Anderson et al. (45) R 4 months CrP (200 or 1000 g/day) Type 2 180 OGTT, HbA1c 2 2 2 NA
Amato, Morales, and Yes (56) DB 2 months CrP (1,000 g/day) Nondiabetic, elderly 19 Minimal model NA
Jovanovic, Gutierrez, and DB 2 months CrP (320 or 640 g/day)* Gestational diabetes 20 OGTT, HbA1c 2 2 NA
Peterson (57)
Ravina et al. (58) OL 17 days CrP (600 g/day) Diabetes 3 FBG 2 NA NA NA
Morris et al. (59) OL 3 months CrP (400 g/day) Type 2 5 Insulin tolerance, 2 NA 1
HOMA
Cheng et al. (60) OL 110 CrP (500 g/day) Type 2 833 Fasting, postmeal 2 NA NA NA
months
Ghosh et al. (22) DB 3 months Cr3 (200 g/day) Type 2 50 FBG, HbA1c 2 NA 2 NA
Cefalu et al. (64) R 8 months CrP (1,000 g/day) Pre-diabetes 29 Minimal model 2 NA 1
Ravina et al. (68) OL 10 days CrP (200 g/day) Type 1/2 48/114 Insulin tolerance, NA NA 2 1
HbA1c
Lee and Reasner (70) DB, 2 months CrP (200 g/day) Type 2 30 FBG, HbA1c NA NA
Evans (78) DB 42 days CrP (200 g/day) Type 2 11 FBG, HbA1c 2 NA 2 NA
1, increased; 2, decreased; , no change; CrCl, chromium chloride; CrN, chromium nicotinate; DB, double blind; FBG, fasting blood glucose; IGT, impaired glucose tolerant; IS, insulin sensitivity; IVGTT,
intravenous glucose tolerance test; NA, not assessed; OGTT, oral glucose tolerance test; OL, open label; R, randomized. *In hyperinsulinemic patients only; -cell sensitivity to glucose.
mendously as several studies grouped Assessment of chromium status. Many significant decreases in mean FPG, 2-h
type 1 and type 2 diabetic subjects to- of the earlier reported studies did not ad- glucose, and fructosamine. Chromium
gether in the evaluation of chromiums ef- dress the role of chromium blood levels at treatment also slightly reduced required
fect (Table 1). Indeed, even in studies in baseline or recorded changes, if any, with doses of antidiabetic drugs, and this de-
which only subjects with type 2 diabetes supplementation. In addition, objective cline achieved statistical significance for
were reported, subjects were assessed markers to measure compliance with the glibenclamide. Another group assessed
while on various therapies (e.g., diet, sul- regimen were not evaluated. the effects of jiangtangkang (8 g t.i.d.), a
fonylureas, metformin, insulin) and at Techniques to assess response. The chrysanthemum product high in chro-
different levels of glycemic control major limitation of the earlier studies, mium, on glucose and insulin metabolism
(32,50,55,58,60). It is well established however, may be the lack of sophisticated in 188 patients with type 2 diabetes (67).
that hyperglycemia secondary to glucose metabolic techniques used to assess car- After 2 months, jiangtangkang treatment
toxicity may contribute to attenuation in bohydrate metabolism. Many of the stud- reduced fasting and postprandial blood
insulin action (61), and the effect of med- ies evaluated response by fasting blood glucose and HbA1c without any corre-
ications to alter insulin action is well stud- levels only or used glucose tolerance or sponding change in plasma insulin. A 16-
ied (62,63). mixed-meal tests (Table 1). Although month, double-blind, randomized,
Dosage, formulation, duration of these tests are frequently used in clinical crossover trial (32) of chromium chlo-
study. The duration of supplementation studies, they do not provide the sensitiv- ride, brewers yeast that contained chro-
evaluated (ranging from 1 day to 8 ity required to precisely assess insulin ac- mium as GTF, brewers yeast extract
months) and the dose used (ranging from tion. Our literature search did not find without GTF, and a placebo in 43 patients
100 to 3,000 g daily) varied tremen- any study that evaluated the effect of with diabetes also demonstrated positive
dously in earlier studies. Studies that spe- chromium supplementation on insulin effects of chromium on glucose and insu-
cifically evaluated 200 g of chromium sensitivity by using the gold standard for lin metabolism. FPG and the glucose re-
chloride failed to elicit a clinical response assessing insulin action, i.e., the hyperin- sponse to either a standard meal or
in those with type 2 diabetes (Table 1). sulinemic-euglycemic clamp. One study tolbutamide were not significantly altered
Uusitupa et al. (52) demonstrated a posi- (65) used the euglycemic clamp, but only by any of the treatments, but ketosis-
tive effect at 200 g of the CrCl salt; how- to assess the relationship of blood chro- resistant patients experienced a signifi-
mium and insulin and did not supple- cant increase in postprandial insulin after
ever, the remaining variables in that study
ment the subjects. Another study (21) treatment with the brewers yeast that
did not appear to be altered by supple-
evaluated subjects with a hyperglycemic contained GTF. Results from an addi-
mental chromium. A more consistent
clamp and demonstrated that significant tional study indicated that chromium
clinical response is observed with daily
increases in glucose utilization were ob- supplementation has significant positive
supplementation of chromium 200 g/
served and associated with increases in effects on glucose and insulin metabolism
day for a duration of 2 months (Table
-cell sensitivity to glucose following in patients with diabetes. One study (68)
1). In addition, other forms of chromium, chromium supplementation. Of the other reported that 10 days of treatment with
especially CrP, appear to be more bio- three studies that evaluated a more so- CrP (200 g/day) significantly increased
available and clinically more effective phisticated technique to assess insulin ac- insulin sensitivity in patients with type 1
than chromium chloride in both human tion, one did not show an improvement in or 2 diabetes and also permitted reduc-
and animal studies. Evidence for a dose insulin sensitivity (56) using the minimal tions in dosages of insulin and/or oral an-
effect of CrP was provided by a study of model technique, in contrast to Cefalu et tidiabetic drugs in these patients.
Chinese type 2 diabetic subjects (45). al. (64). A separate study (59) demon- A large long-term study showed that
Short-term (2 months) and long-term (4 strated beneficial effects in type 2 diabet- 10 months of treatment with CrP (500
months) efficacy were observed, as evi- ics using the insulin tolerance test and g/day) in 833 patients with type 2 dia-
denced by reductions in fasting and 2-h homeostasis model assessment method. betes significantly improved both FPG
glucose and insulin values and long-term and postprandial plasma glucose versus
reductions in HbA1c concentrations uti- Individuals with diabetes baseline (Fig. 3) and reduced the inci-
lizing varying doses of CrP (200 or 1,000 Type 1 and 2 diabetes. Chinese patients dence of diabetes symptoms, including
g). The effectiveness of the 1,000-g with type 2 diabetes receiving CrP expe- fatigue, thirst, and frequent urination
dose in the Chinese study was reproduced rienced significant improvements in (60).
in a study of individuals with the meta- HbA1c, fasting plasma glucose (FPG), 2-h Not all studies have demonstrated
bolic syndrome (64). In a study (57) of 30 glucose (i.e., glucose levels 2 h after chal- significant positive effects of chromium
women with gestational diabetes receiv- lenge), and fasting and 2-h insulin (45). supplementation in patients with diabe-
ing placebo or 4 or 8 g kg1 day1 of Other investigators studied the effects of tes. One group (69) reported no signifi-
CrP, after 8 weeks the two groups taking brewers yeast (23.3 g chromium/day) cant effect of chromium supplementation
chromium had significantly lower glu- and chromium chloride (200 g chromi- (716 months of 250 g/day) versus pla-
cose and insulin levels. Finally, another um/day) on glucose tolerance, serum lip- cebo on serum glucose levels in 76 pa-
(58) observed that corticosteroid-treated ids, and antidiabetic drug dosage in a 16- tients aged 42 83 years (25 of whom had
subjects have accelerated chromium week, randomized, double-blind, type 2 diabetes) with atherosclerotic dis-
losses and that steroid-induced diabetes crossover trial that included 78 patients ease. These results are consistent with
was reversed with CrP supplementation with type 2 diabetes (23,66). Both forms those of another small-scale trial (70) that
at 600 g/day. of chromium supplementation resulted in indicated no significant effects of chro-
1, increased; 2, decreased; apo, apolipoprotein; CO, crossover, Cr3, trivalent chromium, CrN, chromium nicotinate, DB, double blind; JKT, jiangtangkang; PC, placebo controlled; R, randomized; TG,
in men. This relationship remained signif-
cholesterol1, apoA-I1
TG2, HDL cholesterol1
TG2, HDL cholesterol1
Key results
apoB2, apoA-I1
Total cholesterol2
Total cholesterol2
Total cholesterol2
HDL cholesterol1
HDL cholesterol1
LDL cholesterol2
safety of chromium supplementation
arise from results of several cell culture
studies using supraphysiological doses
No change
No change
No change
No change
No change
No change
No change
that suggested that chromium, particu-
larly in the form of CrP, may increase
TG2
TG2
Brewers yeast
78 (type 2 diabetes)
30 (type 2 diabetes)
180 (type 2 diabetes)
50 (type 2 diabetes)
188 (type 2 diabetes)
10 (type 2 diabetes)
11 (type 2 diabetes)
72
23
28
40
44
26
19
29
R, DB, PC, CO
DB, PC, CO
DB, PC, CO
DB, PC, CO
R, DB, PC
R, DB, PC
R, DB, PC
R, DB, PC
R, DB, PC
R, DB, PC
R, PC
R, PC
R, PC
relationship.
Offenbacher and Pi-Sunyer (74)
Chen S, Sun, and Chen X (67)
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12. Anderson RA: Chromium, glucose intol- overweight African-American women.
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