The
following is a summary of the presentations given at the “Chromium
in Health and Disease” summit, held on April 1-2, 2003
sponsored by the non-profit organization The Council for the
Advancement of Diabetes Research and Education (CADRE). The
Summit was co-chaired by William T. Cefalu, MD, University
of Vermont and Frank Hu, MD, PhD, Harvard School of Public
Health. Attending the conference were leading experts in chromium
research, including academic and government scientists who
have ongoing or recently completed studies on this topic.
Background
Evidence of chromium’s
impact on health and disease was first researched by Walter
Mertz in the late 1950’s. Additional studies
evaluating
chromium’s relationship with impaired glucose tolerance
were conducted in the 1960’s and 1970’s. However,
significant interest in chromium research was initiated in
1997 when Dr. Richard Anderson (USDA) published the landmark
study demonstrating the efficacy and safety of chromium picolinate
supplementation in people with type 2 diabetes. Since then,
the number of studies conducted on chromium and chromium picolinate
has almost reached the total number of studies published in
the previous 30 years. The recent Summit was designed to review
and to engage in a scientific exchange about chromium research
conducted or initiated over the past few years.
Chromium and Glucose Metabolism
The effect of chromium on
glucose metabolism has been studied in retrospective epidemiological
studies and in prospective clinical studies. Dr. Hu presented
on epidemiological research. Dr. Cefalu, and Dr. Richard Anderson
of the Beltsville Human Nutrition Research Center in Maryland
presented data from clinical studies.
Dr. Hu pointed out that several lines of evidence, from in
vitro to epidemiological studies, suggest that inadequate
intakes of trace minerals, such as chromium, could be risk
factors for type 2 diabetes. Prior human studies have suggested
that chromium picolinate improves glucose metabolism in obese
people and people with type 2 diabetes. During the past two
decades, there have been several studies of chromium picolinate
involving human subjects with glucose intolerance or diabetes.
One of the most notable was done in China, where researchers
found 500 micrograms to 1,000 micrograms of chromium as chromium
picolinate per day to be effective in improving glucose, insulin
and lipid levels in people with type 2 diabetes.
Dr. Cefalu reported on an animal study, in which he found
that chromium picolinate supplements given to obese rats resulted
in a 50% improvement in insulin sensitivity and glucose tolerance,
compared to controls. Chromium picolinate did not have a significant
effect, however, in lean animals. He also discussed a new
6-month study of people with type 2 diabetes that is currently
underway in which he is seeing 100% response in obese subjects
taking 1,000 micrograms of chromium as chromium picolinate
per day.
Dr. Anderson pointed out that in his studies he has found
that 200 micrograms of chromium as chromium picolinate per
day, may not be enough to see an effect on insulin sensitivity.
But he has observed a “nice effect” at 1,000 micrograms
a day. Dr. Anderson also emphasized that chromium picolinate
benefits people with hyperglycemia and hypoglycemia. If you
give chromium to people with high blood glucose, then blood
glucose will go down. If you give it to people with low blood
sugar, both insulin and blood glucose improve. Moreover, he
said that even people with type 1 diabetes show improvement
with chromium supplementation. For people with type 2 diabetes,
the improvement with chromium occurs even for those who are
taking medication to control blood sugar levels i.e., the
effects of chromium supplementation are in addition to medications.
Chromium and Coronary Heart Disease
Two recent studies have
been done to measure tissue levels of chromium and associate
them with the risk of myocardial infarctions (MIs). Chromium
levels in toenails are thought to be a possible indicator
of chromium status in the body. Eliseo Guallar, M.D., Dr.Ph.,
of Johns Hopkins University, found an inverse relationship
between toenail chromium concentration and risk of first,
nonfatal MIs in men. The study collected data from men in
eight European countries and Israel. He found that the lower
the levels of toenail chromium, the greater the risk of MIs.
Dr. Guallar concluded that the results add to a growing body
of evidence pointing to the importance of chromium for cardiovascular
health.
Eric Rimm, Sc.D., of Harvard School of Public Health, presented
an abstract from his presentation at the 2002 American Heart
Association Annual Convention that revealed the collection
of chromium data from men in the Health Professionals’
Follow-Up Study. He also found a similar inverse relationship
between chromium levels in toenails and risk of MI, including
fatal MIs. The relationship was especially strong in subjects
who were overweight.
Gary Evans, Ph.D., formerly USDA and long-time chromium researcher,
who consults for Nutrition 21, Inc., reviewed studies that
showed 200 micrograms of chromium as chromium picolinate per
day given to people with high cholesterol, decreased total
cholesterol, LDL cholesterol and apolipoprotein B levels.
Chromium and Women’s Health
A session of this Summit
was focused on the benefits of chromium supplementation seen
in women’s health. Lois Jovanovic, M.D., of the Sansum
Medical Research Center in Santa Barbara, CA, and Patty Trail,
R.N.C., C.D.E., of Eastern Virginia Medical School in Norfolk,
presented research on gestational diabetes. Michael L. Lydic,
M.D., of the State University of New York at Stony Brook,
presented research on polycystic ovarian syndrome (PCOS).
According to Dr. Jovanovic, gestational diabetes is the most
common problem complicating pregnancy today. An estimated
135,000 women have gestational diabetes, posing a risk to
both the mother and the infant. High levels of blood sugar
in the pregnant woman cross the placenta, triggering the beginnings
of insulin resistance in utero. The child is then predisposed
to overweight. If the child is female, she is more likely
to develop gestational diabetes during her own pregnancy as
an adult and pass it on to her child. A significant percentage
of women with gestational diabetes require insulin to manage
blood glucose levels. Pregnancy is a normal state of chromium
wasting, so it seems logical that intake should be increased.
Most prenatal vitamins, however, contain no chromium. A clinical
study was conducted in which 20 gestational diabetic women
were given either chromium picolinate supplements or placebo.
After eight weeks, those who were given chromium supplements
had significantly lower glucose and insulin levels compared
with their own baseline levels and with the placebo group.
Dr. Jovanovic concluded her presentation by saying that reduction
of the severity of glucose intolerance in pregnancy by chromium
supplementation might provide an easy and inexpensive means
to reduce the problems related to maternal hyperglycemia and
the devastating health effects on both mother and infant.
Patty Trail reported on six case studies in which women were
at high risk for developing gestational diabetes and were
given chromium picolinate supplementation throughout their
pregnancy. The good pregnancy outcome that involved delivery
of healthy full term babies observed in these test cases,
she said, suggested the possible benefit of chromium supplementation
in high-risk patients. Ms. Trail is currently initiating a
randomized, placebo-controlled study to assess if dietary
supplementation with chromium picolinate during pregnancy
can decrease the incidence and severity of glucose intolerance
in pregnancies at risk for gestational diabetes.
Both researchers concluded that chromium picolinate supplementation
during pregnancy could provide an easy and inexpensive means
to reduce the fetal and maternal problems related to hyperglycemia.
PCOS is associated with infertility, anovulation, obesity,
hyperandrogenism, and insulin resistance. Affected women have
increased risk for glucose intolerance, gestational diabetes
and type 2 diabetes. Dr. Lydic presented information about
a study, for which he is currently recruiting subjects, to
investigate the effects of 1,000 micrograms of chromium as
chromium picolinate on insulin sensitivity and levels of circulating
androgens in women with PCOS. He has studied three patients
so far and has found a trend of improvement in insulin sensitivity
with chromium picolinate supplementation. Three more patients
are currently being studied. Dr. Lydic plans to conduct an
additional study in a larger group of women with PCOS, to
confirm the positive results.
Chromium and Depression
Dr. Jonathan Davidson of
the Duke University Medical Center in Durham, North Carolina,
presented his findings of a pilot study he completed, suggesting
that chromium picolinate may be a promising new treatment
for atypical depression. Atypical depression is a form of
depression, characterized by symptoms of carbohydrate cravings,
weight gain, and lethargy.
Dr. Davidson’s study
was conducted in 15 patients with atypical depression. Over
the 8-week trial, patients received either a placebo or 400
micrograms of chromium as chromium picolinate a day; after
two weeks, the dose was increased to 600 micrograms of chromium
as chromium picolinate per day. Dr. Davidson’s results
suggest that chromium picolinate provides relief from symptoms,
in some cases rapid relief, with relatively no side effects.
Seventy percent of patients taking chromium picolinate in
the study experienced relief from symptoms. None of the patients
on placebo responded. The usual response to antidepressant
medications is 40% to 50% remission rates.
Monoamine oxidase inhibitors (MAOIs), which are the drugs
of choice for treating depression, frequently have side effects.
Selective Serotonin Reuptake Inhibitors (SSRIs), which are
also commonly prescribed to treat depression cause side effects
as well. In fact, 44% of patients taking SSRI drugs stop within
4 to 6 weeks, due to side effects. A larger chromium trial
for the treatment of depression is now in the planning stages.
Dr. Davidson commented that if the findings can be replicated
in this larger trial, chromium picolinate could be revolutionary
for the treatment of depression.
Absorption of Chromium
Chromium from foods and
supplements is poorly absorbed. Certain exogenous factors
have been found to effect absorption. And, various chelating
agents have been used to enhance chromium absorption. Dr.
Anderson, presented on this topic.
Dr. Anderson stated that
the body’s response to chromium is dependent on several
factors, including the chromium status of an individual, the
stage of glucose intolerance or diabetes, and absorption and
stability of the chromium compound used. Stresses to chromium
status include high sugar intake, acute exercise, pregnancy,
lactation, infection and physical trauma. Chromium losses
also increase with age, as does the risk for type 2 diabetes.
Despite that fact, the most recent recommended intakes from
the Food and Nutrition Board for people over age 50 were set
at lower levels than for younger people.
Vitamin C and oxalate increase chromium absorption. Prostaglandins
decrease chromium absorption, and aspirin and indomethacin,
which inhibit prostaglandins, increase absorption. Components
involved in formulating chromium capsules can also affect
absorption. Carbohydrates used as fillers in supplement capsules
have been shown to bind to several forms of chromium, including
chromium polynicotinate and chromium chloride, making them
essentially inert regarding absorption. Picolinic acid and
histidine forms are stable complexes of chromium and allow
them to be readily absorbed and are not affected by starch
fillers. Even though one study shows chromium nicotinic acid
to be better absorbed than chromium picolinate, this study
used very low levels of radiolabeled chromium, which acts
differently than the higher doses normally taken in supplement
form. Because chromium absorption is increased at lower levels
of intake, a greater absorption is seen. Chromium glutathione
is also not absorbed and has no effects on glucose metabolism.
Mechanism of Action
Dr. Cefalu, John Vincent,
Ph.D. from the University of Alabama, David Brautigan, Ph.D.
of the University of Virginia School of Medicine and Dennis
Mynarcik, Ph.D. of the State University of New York at Stony
Brook, presented theories and findings regarding the mechanism
of action of chromium on insulin in cells.
The biochemistry of chromium has been poorly understood, until
recently. Dr. Brautigan reported the results of a study on
the effects of chromium on insulin receptors in cell culture.
He concluded that chromium specifically interacts with insulin
receptor tyrosine kinase, an important component in insulin
signaling, and enhances insulin’s activity.
Dr. Mynarcik studied individuals
with and without HIV lipodystrophy, which is associated with
loss of adipose tissue, insulin resistance and elevated tryglycerides,
and supplemented them with 1,000 micrograms of chromium as
chromium picolinate per day for 8 weeks. He found that insulin
sensitivity improved in patients with and without lipodystrophy.
He suggested that the direct action of chromium at the site
of insulin signaling initiation improves insulin sensitivity,
rather than increasing activity of the activated insulin receptor.
Dr. Cefalu evaluated a potential cellular mechanism by assessing
skeletal muscle PI-3 kinase activity (an enzyme involved in
glucose metabolism) after insulin stimulation in obese and
lean rats given chromium picolinate, and compared those findings
to controls. Obese rats treated with chromium picolinate showed
a significant increase in PI3KA after insulin stimulation,
versus obese control. An increase in membrane-associated Glut-4,
a glucose transporter protein, was also observed, compared
with controls. These results suggested that reduced activity
of PI3KA in obese states may be partially restored with chromium
picolinate and that glucose transport across cells may be
enhanced.
Dr. Vincent states that chromium is required for proper carbohydrate
and lipid metabolism. Conditions that increase circulating
glucose and insulin concentrations increase urinary chromium,
in the form of the small peptide, chromodulin. Dr. Vincent
believes that the mechanism of action for chromodulin may
be the framework for future studies testing the role of chromium
in metabolism.
Safety
John Hathcock, Ph.D., from
the Council for Responsible Nutrition and Merlin Lindemann,
Ph.D., from the University of Kentucky, presented data on
the safety of chromium and chromium picolinate.
Dr. Hathcock presented information regarding the safety of
chromium picolinate. He emphasized that the Food and Nutrition
Board did not find any toxicological basis for setting a tolerable
upper level for chromium in their most recent report on Dietary
Reference Intakes for the essential mineral. In addition,
the United Kingdom’s Expert Group on Vitamins and Minerals
has found no credible evidence of adverse effects, but has
identified a “guidance level” of 10,000 micrograms
per day, based on extrapolation from animal research on chromium
picolinate. The safety of chromium is also reflected in the
high reference dose set by the Environmental Protection Agency.
In addition, the Food and Nutrition Board recently released
a draft prototype monograph on the safety of chromium picolinate.
Though the preliminary draft did not reach risk assessment
conclusions (the full report is due out summer ’03),
the animal data show safety of very high intakes. Dr. Anderson
also emphasized that findings of DNA damage from in vitro
studies and studies with insects, can be over-interpreted
and over-extrapolated to give false positive results i.e,
they suggest DNA damage from chromium picolinate, where none
exists.
Dr. Hathcock concluded that there is no recognizable pattern
of adverse effects of chromium picolinate supplements in humans
and that well-conducted clinical trials show no evidence of
adverse effects at 1,000 micrograms of chromium as chromium
picolinate per day.
Looking in more detail at animal studies, Dr. Lindemann presented
several findings regarding the lack of negative effects and
the observed beneficial effects of chromium picolinate supplementation
in swine, poultry, dogs and cattle. Though the extent of positive
results varied among species, he has found that chromium supplementation
can benefit immunocompetence, cortisol levels and glucose
metabolism, as well as milk production in lactating animals.
In pigs, whose metabolic system most closely mirrors that
of humans, he found improvements in several measurements of
breeding, such as litter size, growth rate, increased ovulation
rate and improved embryo survival. Dr. Lindeman reported the
beneficial effects were seen in one of the largest animal
studies done to date, involving over 100,000 litters and 1,000,000
piglets.
The conclusion from both experts was that the potential for
toxicity of chromium and chromium picolinate is very low,
and there have not been any confirmed studies documenting
negative effects of nutritional levels of chromium in humans
or farm animals.
Summary
In summary, chromium research
has grown considerably over the last few years. No longer
are the only studies in weight loss and body composition.
There is a clear link between chromium and insulin sensitivity.
Chromium supplementation appears to be safe and beneficial
in a number of conditions caused by insulin resistance. Epidemiological
research is also beginning to further clarify the impact of
chromium deficiency. It was encouraging to see the number
of studies currently ongoing or planned that should continue
to add to a large body of science demonstrating the benefits
of chromium supplementation.
