The trace element chromium, and particularly chromium picolinate, will likely find a greater role in the management of insulin resistance and Type 2 diabetes (T2D) in the coming years, as clinical evidence accumulates to support its antiglycemic, insulin-sensitizing effects. Chromium researchers from across the globe recently gathered to share their findings at a summit sponsored by the Council for the Advancement of Diabetes Research and Education (CADRE).
Clinical interest in chromium began in the 1950s, when Walter Mertz and colleagues at the US Department of Agriculture published findings that chromium bound to picolinic acid in brewer’s yeast could attenuate diabetes. The relationship between low chromium levels and impaired glucose tolerance was further documented throughout the 1960s and 70s, and early experiments suggested that chromium could reduce blood glucose levels and accelerate loss of body fat while preserving lean muscle mass. Chromium was originally promoted as a weight loss aid, a “safe” alternative to anabolic steroids.
But the glucose-lowering effect of chromium was largely ignored by mainstream endocrinologists and diabetologists who were more focused on improving insulin regimens and managing end-stage complications. Still, today, most prominent diabetologists view chromium as necessary only in patients with frank deficiencies, something they consider rare.
But this may not be as rare as conventional wisdom would lead you to believe. There is some evidence that diabetes itself can create a chromium deficient state. Diabetics tend to lose far more chromium in their urine than non-diabetics and they have lower average blood levels. Further, blood chromium levels tend to decline with age—elderly people have 20% to 40% lower levels than young people. Age associated changes in chromium tend to track inversely with risk of diabetes and cardiovascular disease.
According to Richard Anderson, PhD, a biochemist who heads the Nutrient Requirements and Functions Lab at the USDA’s Beltsville Human Nutrition Research Center, chromium plays a role in regulating insulin-dependent reactions including glucose uptake, glucose oxidation, and storage of glucose as fat.
The USDA sponsored a number of seminal human studies including a major trial led by Dr. Anderson that involved 180 patients in China with T2D. In subjects taking 200 μg chromium picolinate daily for 4 months, HbA1c declined from a baseline mean of 8.5% to 7.5%. In those taking 1,000 μg, the post-treatment HbA1c mean was 6.6%. Chromium also appeared to have positive effects on insulin levels and lipid variables, particularly at the higher dose (Anderson RA, et al. Diabetes 1997; 46:1786–1791).
Dr. Anderson noted that one particularly interesting facet of chromium’s glycemic effect is that it is bivalent. In hyperglycemic individuals, it reduces blood glucose levels, whereas in hypoglycemic people it seems to raise glucose levels. He added that while the bulk of the human research has been in T2D, there is also some evidence that patients with Type 1 disease also show improvements in glucose levels with chromium supplementation.
William Cefalu, MD, of the University of Vermont College of Medicine, Burlington, reported on a double-blind trial comparing 1,000 μg chromium picolinate versus placebo in obese, non-diabetic but insulin resistant individuals. He found significant improvements in insulin sensitivity after both 4 and 8 months of chromium supplementation. There were no changes in the placebo-treated subjects.
Dr. Cefalu, formerly head of the Diabetes Comprehensive Care and Research Program at Bowman Gray School of Medicine, is currently leading a 6-month study of 1,000 μg chromium picolinate in obese individuals with T2D. Though the trial has not yet been completed, he reported that so far he’s seeing a 100% response to the chromium in terms of improved insulin sensitivity (Cefalu WT, et al. J Trace Elem Exp Med 1999; 12:71–83).
He and others contend that chromium exerts stronger effects in obese versus lean individuals, and recently completed an experiment to assess the impact of chromium on JCR:LA corpulent rats—an animal model of human insulin resistance—and normal lean rats. The animals were randomly assigned to chromium or placebo control. After 3 months, he observed significant improvements in fasting insulin levels and glucose tolerance in the chromium-treated corpulent rats. Interestingly, there was no significant effect in the lean animals (Cefalu WT, et al. J Nutr 2002; 132:1107–1114).
Dr. Cefalu believes there is a similar preferential effect in obese versus lean humans, and that people with obese phenotypes are more likely to benefit from supplemental chromium than their lean counterparts.
Chromium has strong potential in the management of gestational diabetes, and therefore in the prevention of neonatal macrosomia and other anomalies, reported Lois Jovanovic, MD, chief scientific officer, Sansum Medical Research Institute, Santa Barbara, CA. “Chromium has been shown to improve insulin secretion and decrease post-prandial glucose excursions, thereby decreasing hyperinsulinemia in non-pregnant diabetic patients. We therefore designed a study to observe the safety and efficacy of chromium therapy for gestational diabetic women,” explained Dr. Jovanovic, who is also clinical professor of endocrinology, UCLA Medical Center.
Twenty gestational diabetic women were randomized, at 20–24 weeks gestation, to placebo or chromium picolinate, 4 μg per day per kg body weight. Ten additional women, matched for glucose intolerance and BMI, were given chromium at 8 μg per day per kg. Blood chemistry and response to a 100 g glucose load were assessed at baseline and after 8 weeks.
At 8 weeks, the women taking chromium had significantly lower glucose and insulin levels compared with their baselines and with the women in the placebo group. Those on the higher dose had lower postprandial glucose than those on the lower dose. Interestingly, though, the women taking 4 μg/kg/day showed a statistically significant mean reduction in HbA1c from 5.6% to 5.2% at 8 weeks, whereas those on 8 μg/kg/day did not (Jovanovic L, et al. J Trace Elem Exp Med 1999; 12:91–97).
“Reduction of the severity of glucose intolerance by chromium supplementation might provide an easy and inexpensive means to reduce the problems related to maternal hyperglycemia,” she said.
Polycystic Ovarian Syndrome (PCOS) is strongly associated with insulin resistance, and it may also be responsive to chromium, predicted Michael Lydic, MD, a reproductive endocrinologist at the State University of New York, Stonybrook. He recently initiated a trial of 1,000 μg/d chromium picolinate in nonpregnant reproductive-age women with PCOS, insulin resistance and BMI over 26. He and his colleagues will assess insulin and glucose levels, insulin responsiveness, as well as complete reproductive hormone profiles, BMI, and ovarian anatomy after 2 months of treatment.
“Improvement of PCOS by chromium picolinate may suggest a safe alternative for prevention of T2D in these high-risk women,” said Dr. Lydic. Such an alternative is sorely needed because while some women with PCOS will respond to oral insulin sensitizing drugs, the cost and the side-effect burden are often prohibitive.
Speaking of side-effects and safety, chromium picolinate appears to be one of the safest and best-tolerated natural products ever studied. There were no chromium-associated adverse effects in any of the studies reported at the CADRE summit or in any of the earlier literature, even at doses of 1,000 μg/d. Further, chromium does not appear to have any problematic interactions with injected insulin or other diabetes drugs. A number of the clinical trials reported at the conference included patients on conventional medications. If anything, chromium will enhance the therapeutic efficacy of conventional treatment.
The human body cannot produce chromium endogenously; it must be obtained either from food or dietary supplements. It is found naturally, but in very small amounts, in common foods including: apples, bananas, beef, brewer’s yeast, broccoli, coffee, green beans, orange juice, red wine, tea, whole grain wheat bread, and certain cheeses. However, it is virually impossible to obtain therapeutic dose levels from food sources alone.
As a supplement, chromium is commonly available in three different forms: chromium polynicotinate, chromium chloride, and chromium picolinate. Of the three, the picolinate form has the highest bioavailability and is not rendered inert in the presence of starches, as is the case with other forms. Chromax® is a patented formulation of chromium picolinate produced by Nutrition 21, a branded ingredient manufacturer with a strong commitment to clinical research (www.Nutrition21.com).
The exact mechanisms by which chromium exerts its insulin sensitizing and glucose lowering effects are slowly coming to light. At the target cell level, the mineral appears to influence phosphorylation of tyrosine kinase, a necessary step in the activation of insulin receptors, explained David Brautigan, PhD, of the Center for Cell Signaling, University of Virginia, Charlottesville. The question is whether chromium enhances tyrosine phosphorylation or inhibits protein tyrosine phosphatase, an enzyme that down-regulates insulin receptor activity. The answer may well be “both.”
Dr. Cefalu added that in his studies of obese rats, he found that chromium could markedly increase activity of PI-3 kinase, another enzyme involved in glucose metabolism, in skeletal muscle. The animals treated with chromium showed an increased stimulation of this enzyme, as well as cell membrane associated Glut-4, a critical protein for transport of glucose into cells. Dr. Brautigan stressed that research into the molecular activity of chromium is just beginning.
Biotin, a water-soluble B vitamin, is an important co-factor in carboxylase enzyme reactions. It also enhances glucose uptake in muscle cells, and appears to work synergistically with chromium picolinate. Two years ago, Nutrition 21 launched a product called Diachrome™, which combines 600 μg chromium picolinate with 2 mg biotin. It is specifically intended for the management of diabetes and severe insulin resistance.
In 2001, the National Institutes of Health issued a program announcement calling for research on chromium as an adjuvant therapy for management of diabetes. Hopefully, data obtained from NIH sponsored studies will confirm the role of this humble but essential mineral in the prevention and treatment of insulin resistance, Syndrome X, and T2D.
