12 Jan Study Finds No Evidence of Benefit from Chromium Supplements
MedicalResearch.com Interview with:
Prof. Peter Lay PhD
Professor of Inorganic Chemistry
School of Chemistry | Faculty of Science
Director, Vibrational Spectroscopy Core Facility
The University of Sydney
Medical Research: What is the background for this study? What are the main findings?
Response: My group has been studying the molecular mechanisms of chromium(VI)-induced cancers and the biochemistry of vanadium over the last three decades. Vanadium drugs have been in clinical trials for their anti-diabetic effects that occur via species with very similar chemistry to chromium(VI). The more we understood the biochemistry of each, the more we questioned whether the efficacies of anti-diabetic chromium(III) supplements were associated with the generation of carcinogenic chromium(VI) and chromium(V). To test this, we conducted experiments to either provide evidence for our hypothesis or disprove it. This work commenced some 15 years ago with studies on the changes in the nature of chromium(III) supplements exposed to simulated gastrointestinal juices, as well as in human and animal blood serum over times that mimicked the residence time of the supplements in the human body.
We discovered that all supplements were changed to a range of different Cr(III) species in both the GI tract and the blood.1,2 Common species were observed, but the rates at which they formed were dependent on the nature of the chromium(III) supplement. Both the supplements themselves and the chromium(III) species that formed in blood serum were partially oxidised to Cr(VI) at concentrations of the oxidant, hydrogen peroxide (a type of bleach), found in the blood of people with type II diabetes.1,2 One of the clinical features of patients with type II diabetes is increased levels of oxidants, such as hydrogen peroxide, in their blood and cells. These oxidants are associated with many of the side-effects of type II diabetes that are associated with reduced life expectancy.
These transformed chromium(III) species bound to blood proteins were more easily oxidised to chromium(VI) than the administered Cr(III) supplements. The faster a particular chromium(III) supplement reacted with blood proteins to form these easily oxidised chromium(III)-protein species, the more active was the Cr(III) supplement in its anti-diabetic activity in animal and human studies reported by other groups.1-5 According to many health and regulatory bodies, chromium(III) has minimal or no efficacy in glucose metabolism and no other beneficial effects, such as weight loss or muscle building, in well conducted human and animal trials with non-diabetic subjects. This is consistent with our proposed mechanism of action. It is only under oxidising physiological conditions associated with type II diabetes that chromium(III) can be partially transformed to sufficient concentrations of carcinogenic chromium(VI) to enable significant biological activity. In a large clinical trial where diabetic patients were treated with high doses of chromium(III) picolinate (one of the least efficacious supplements in animal studies), there was no efficacy in patients with controlled type II diabetes. Only those patients with uncontrolled type II diabetes exhibited improved glucose metabolism. These patients, who have the highest concentrations of oxidants with the ability to transform chromium(III) to chromium(VI) in blood, are therefore at the greatest risk of developing Cr-induced cancers. Even where efficacy was observed, glucose metabolism was only reduced to the levels in patients with controlled type II diabetes; i.e., no patients exhibited a return to normal glucose metabolism.4,5
Coupled with all of this information our separate studies showed that chromium(VI) and chromium(V), but not chromium(III), are strong inhibitors of protein tyrosine phosphatase (PTP) enzymes. The relevance of this is that drugs that inhibit PTPs activate circulating insulin in people with type II diabetes. That is, it causes insulin to bind more strongly to cells involved in glucose metabolism (such as fat cells) to bring about the cascade of biochemical reactions that import glucose into cells and metabolise it.1-5
Thus we were able to link all of the animal, human and in vitro studies to show that physiological conditions under which chromium(III) had the highest probability of being transformed to chromium(VI) were also those in which chromium(III) supplements were most active.1-5 Moreover, we were able to provide a mechanism of activity that required chromium(VI) and chromium(V) to be generated for insulin enhancing activity.1-5 What remained was to establish whether we could observe Cr(VI) and Cr(V) in cells treated with chromium(III) supplements. This has now been established in our most recent study6 that have just been published. Contrary to the press releases of the dietary supplement industry, the published paper was carefully planned to mimic those conditions found in vivo. The chromium(III) supplement chosen was that which had a chemical structure most closely resembling those generated in blood plasma. Thus we were able to complete the circle in linking our extensive studies on the biochemistry of chromium(III) species generated from chromium(III) supplements in the blood and show that such species were absorbed by the relevant cells and partially oxidised to chromium(VI) and chromium(V).
This research is the culmination of many years of work by many students, postdoctoral fellows and colleagues who all made important contributions. I would like to make special mention of Dr Aviva Levina, who is an Australian Research Council funded senior research associate in my group and co-supervised much of the research. She also co-authored the reviews and book chapters listed below that summarise the above data. Of particular relevance to the current study, were Dr. Lindsay Wu’s contributions. He commenced the research with fat cells in my group as an Honours student and much of the research published in the most recent paper was based on his Honours research. The research was also supported by the Australian Synchrotron and the Australian Synchrotron Research Program. They provided travel funds to conduct research at the Advanced Photon Source at the Argonne National Laboratory in the USA to obtain the maps or Cr and other elements in fat cells, and the Australian National Beamline Facility at the Photon Factory in Japan. At the Photon Factory extensive research was conducted over many years to obtain X-ray spectra of reactive chromium(VI) and chromium(V) species to unambiguously establish the nature of the Cr species in the cells. The Advanced Photon Source is a US Department of Energy Office of Science User Facility that generates ultra-bright, high-energy X-rays required for the elemental mapping.
Medical Research: What should clinicians and patients take away from your report?
Response: On the websites of many regulatory and government health research websites and many websites dealing with dietary supplements, you will find an incorrect statement that Cr is established as an essential trace element. However, the current state of knowledge is that there is no definitive evidence for Cr being an essential trace element, which has been extensively discussed in reviews and book chapters published by our group and a range of other groups that are most knowledgeable in Cr biochemistry. These seem to be largely ignored in many of these websites, which simply restate folklore without reference to the most recent solid scientific evidence.1-7
The early work on which the Cr dietary industry was based was the “glucose tolerance factor”, which was said to have Cr as the pharmacologically active component and was required for glucose metabolism. When purified, the active form was found not to have chromium. Subsequently, the term chromodulin was used by Vincent to describe a protein that bound chromium(III) and many of the above websites quote this as the essential form of chromium, required for glucose metabolism.1-6 We provided strong evidence in 2007 that this was an artefact and even the original proposer of chromodulin, Vincent, in his most recent reviews, has stated that currently there is no evidence for an essential role of chromium.7
Taken together with the evidence that is stated on the regulatory body websites that there is no significant beneficial effects of Cr supplementation to healthy people, and our research that the only conditions under which Cr supplements have an effect is under physiological conditions that are most likely to generate the highest concentrations of chromium(VI), why would you risk taking the supplements?
In summary; there is no longer any definitive evidence for chromium being an essential trace element; there is no benefit for healthy individuals; and there is a potential risk of contracting Cr-induced cancers by taking Cr supplements over long times and/or at high concentrations, especially for those people with diabetes.
Medical Research: What recommendations do you have for future research as a
result of this study?
Response: The dietary industry states that many human studies have shown that Cr dietary supplements are safe, but these have no relevance to the cancer risk. There have been no long-term human studies covering 10 or more years that is required to determine cancer risk given the latency time for chromium-induced cancers is typically 10-40 years.
While not clinical trials, one study of more than 50 women found that there was 2.5 times more chromium in the hair of patients with breast cancer compared to matched patients without cancer.8 Other smaller studies have shown that there is highly significant increases in chromium (along with a range of other toxic metals) in breast cancers compared to normal breast tissue.9
It is also worth noting that a series of long-term clinical trial studies on high levels of vitamin E, folic acid or beta-carotene supplementation all showed that these increased the risk of certain forms of cancers. Prior to these studies, the supplement industry made similar claims about the safety and efficacy of these supplements for a range of conditions; including general applications in the prevention of cancers!
- Does the Antidiabetic Activity of Chromium(III) Involve Carcinogenic Chromium(VI)? Mulyani, I.; Levina, A.; Lay, P. A. Angew. Chem., Int. Ed. 2004, 43(34), 4504-4507. 10.1002/anie.200460113
- Reactivity of Chromium(III) Nutritional Supplements in Biological Media: an X-Ray Absorption Spectroscopic Study Nguyen, A.; Mulyani, I.; Levina, A.; Lay, P. A. Inorg. Chem. 2008, 47, 4299-4309
- Chemical Properties and Toxicity of Chromium(III) Nutritional Supplements. Levina, A.; Lay, P. A. Chem. Res. Toxicol. 2008, 21(3), 563-571, 10.1021/tx700385t.
- Metal-Based Anti-diabetic Drugs: Advances and Challenges. Levina, A.; Lay, P. A. Dalton Trans. 2011, 40(44), 11675-11686, DOI:10.1039/C1DT10380F.
- Chromium. Lay, P. A.; Levina, A. In Binding, Transport and Storage of Metal Ions in Biological Cells, RSC, Maret, W.; Wedd, A. Eds., Ch 7; 2014, pp 188-222. DOI:10.1039/9781849739979-00188
- Carcinogenic Chromium(VI) Compounds Formed by Intracellular Oxidation of Chromium(III) Dietary Supplements by Adipocytes, Wu, L. E.; Levina, A.; Harris, H. H.; Cai, Z.; Lai, B.; Vogt, S.; James D. E.; Lay, P. A. Angew. Chem., Int. Ed, 2016, DOI: 10.1002/ange.201509065
- Is chromium pharmacologically relevant? Vincent, J. B.; J. Trace Elements Med. Biol. 2014, 28, 397-405.
- Chromium and Manganese Levels in the Scalp Hair of Normals and Patients with Breast Cancer, Eser K., Recep, S., Asuman D., Engin O. Biological Trace Element Research Vol. 102, 2004, 19-25,
Wu, L. E., Levina, A., Harris, H. H., Cai, Z., Lai, B., Vogt, S., James, D. E. and Lay, P. A. (2015), Carcinogenic Chromium(VI) Compounds Formed by Intracellular Oxidation of Chromium(III) Dietary Supplements by Adipocytes. Angew. Chem. Int. Ed.. doi:10.1002/anie.201509065
Dr. Peter Lay (2016). Study Finds No Evidence of Benefit from Chromium Supplements