Chromium in glucose metabolism

Chromium is an essential element involved in the regulation of blood glucose levels within the body.[1]

It is believed to interact with the low-molecular weight chromium (LMWCr) binding substance to amplify the action of insulin. Today, the use of chromium as a dietary supplement for the treatment of diabetes mellitus type 2 is still controversial. This is because most of the clinical studies that have been conducted around chromium have been administered only for short periods of time on small sample populations, and have in turn yielded variable findings. To better understand the potential role chromium may play in the treatment of type II diabetes, long-term trials need to be conducted for the future.[2]

History

The notion of chromium as a potential regulator of glucose metabolism began in the 1950s when Walter Mertz and his co-workers performed a series of experiments controlling the diet of rats. The experimenters subjected the rats to a chromium deficient diet, and witnessed an inability of the organisms to respond effectively to increased levels of glucose within the blood. They then included “acid-hydrolyzed porcine kidney and Brewer’s yeast” in the diet of these rats, and found that the rats were now able to effectively metabolize glucose. Both the porcine kidney and Brewer’s yeast were rich in chromium, and so it was from these findings that began the study of chromium as a regulator of blood glucose.[3]

The idea of chromium being used for the treatment of type II diabetes was first sparked in the 1970s. A patient receiving total parenteral nutrition (TPN) had developed “severe signs of diabetes,” and was administered chromium supplements based on previous studies that proved the effectiveness of this metal in modulating blood glucose levels. The patient was administered chromium for a total of two weeks, and by the end of this time-period, their ability to metabolize glucose had increased significantly; they also now required less insulin (“exogenous insulin requirements decreased from 45 units/day to none). It was these experiments that were performed in the 1950s and 1970s that paved the foundation for future studies on chromium and diabetes.[2]

Recent human and animal studies

Balk and colleagues conducted a literature search in two databases, for English language clinical trials spanning from the years, 1994 to 2006. About three-quarters of the 36 studies showed no statistical significance in the measured outcomes. The authors contended that the lack of statistical significance was not necessarily evidence of the lack of effect. Almost one-half of the studies were considered to be low quality, because there were large variations in the chromium (Cr) formulations, dosages (~5 to ~900µg, majority in the ~hundreds of µg) and test conditions. It was concluded that chromium treatment in type 2 diabetes patients may have an effect on glycemia and dyslipidemia (reducing glycated hemoglobin levels by 0.6% and fasting glucose by 1.0mM), but cautioned against this finding due to the aforementioned problems.[4]

Kleefstra and colleagues directly commented on the previous literature review and refuted the claims of the benefits of chromium. They cited their own randomized, placebo-controlled, double-blind study, which showed no difference in glycemic control within Western populations treated with chromium.[5] In the actual study, Kleefstra and other coworkers administered 400 µg of Cr daily as chromium yeast over 6 months, and monitored the subjects, primarily the HbA1c levels (glycated hemoglobin test), then of the associated, lipid profile, BMI, blood pressure, body fat and of the insulin resistance. It was concluded that there was no evidence to support chromium efficacy in glycemic control for Western patients.[6]

Literature review by Broadhurst and Domenico, made earlier than Balk's and Kleefstra's work, is much more optimistic for Cr efficacy, in the form of chromium picolinate, [Cr(Pic)3], for the treatment of type 2 diabetes. Thirteen of the 15 clinical trials (11 of which were randomized and controlled) with a total of 1 690 subjects (1 505 treated with [Cr(Pic3]), reported at least one positive outcome in glycemic control parameters. Various positive effects were combined with the reduced need to use other hypoglycemic (glucose reduction) medication, such as other Cr formulations and conventional medicine. The current review gives a reduction in the HbA1c levels of 0.95% from 10 trials. This represents a significant risk reduction because, a ~1% drop equates to a 37% reduced risk of microvascular complications, and a 21% reduced risk of diabetes-related death. The authors argue that the apparent lack of effect in other literature reviews, is due to the reviews combining disparate treatment formulations rather than discretely separating them.[7] This appears to be a problem encountered in the review by Balk and colleagues.[4]

In a study by Wang, Z. and colleagues, they used engineered rats (insulin-resistant cardiovascular disease models). They were treated with [Cr(pic)3], which increased the phosphorylation of IR, IRS1 (insulin receptor substrate 1) and Akt, and also increased PI3K activity after insulin was given. The increased insulin activity was hypothesized to be due to the presence of free intracellular Cr cations, rather than intact [Cr(pic)3] itself.[8]

Simply comparing chromium dosage between human clinical trials and rodent model studies, there appears to be a large disparity in the dosages. The maximum amount is 1 mg of Cr per day in humans, whereas rodent studies have used between 80 to 10 000 mg of Cr/kg of body weight per day. Translating the rodent dosage to that of humans, and accounting for their faster metabolism, results in about 2 to 260 mg of Cr per day for humans.[9]

Recent cell culture studies

Under the assumption that chromium (Cr) has pharmacological effects, Cr has typically been tested on cultured mammalian cells. The results are generally contradictory to human clinical studies, and in other mammalian models. Although discrepancies exist, an accepted outcome shared by all studies using, skeletal muscle, adipocyte or alike cultured cells, is that there is insulin-dependent enhancement of glucose uptake and its metabolism in the presence of Cr.[9]

There are two modes of action within the insulin signalling cascade under research. Firstly, the insulin receptors themselves and secondly, the chromium-peptide complexes that have been observed to improve glucose levels. These complexes also have upregulation effects on the associated mRNA levels: insulin receptor, GLUT4 (glucose 4 transporter), glycogen synthase and skeletal muscle cells’ UCP3 (uncoupling protein-3). A contentious point that has arisen is on whether there is an effect of Cr on the mRNA levels of the insulin receptor, Akt (protein kinase B), and other protein components within the insulin signalling cascade.[9]

One study by Wang, Y. and Yao using engineered insulin-resistant adipocytes, showed that chromium picolinate, [Cr(pic)3], increased glucose uptake, metabolism and increased GLUT4 translocation, but it had no effect on the studied mRNA levels (insulin receptor β or IR-β, Akt, c-Cbl, extracellular signal-regulated kinase or ERK, c-Jun phosphorylation and c-Cbl-associated protein or CAP). The mode of action was hypothesized to be through chromium interacting with p38 MAPK (p38 mitogen-activated protein kinases).[10] In a different study by Wang, H. and colleagues, engineered Chinese hamster ovary cells were incubated with either [Cr(pic)3], Cr-histidine complex, or CrCl3. It was found that the insulin receptor tyrosine kinase activity was activated at low insulin doses in the presence of Cr. Only the Cr-histidine activated receptors were tested for Cr concentration dependence, which was observed to exist. There were also no changes in the phosphorylation of the insulin receptors. It was concluded that cellular Cr somehow enhanced receptor kinase activity.[11] In a study by Hao and colleagues, engineered skeletal muscle cells were tested. Using oligosaccharide oligomannuonate, Cr(III) complexes derived from algae, it showed that Cr did enhance the phosphorylation of the insulin receptor and also, that of phosphatidylinositol 3-kinase (PI3K), and Akt.[12]

In a study by Dong and colleagues, treating engineered mouse adipocytes with [Cr(ᴅ-phenylalanine)3], increased insulin-stimulated glucose uptake. Increased insulin-stimulated phosphorylation of the insulin receptor did not occur, but it was seen in Akt phosphorylation.[13] In another study by Chen and colleagues, CrCl3 and [Cr(pic)3] were used on engineered adipocytes, which increased glucose transport and GLUT4 translocation. Phosphorylation levels of the insulin receptor, IRS-1 and Akt did not change. They hypothesized a different route of effect, unrelated to the insulin signalling cascade, in that Cr may have instigated change in cholesterol homeostasis by lowering its plasma membrane availability and by increasing the membrane permeability instead.[14]

In this small sample of recent experiments, the contended points are: the presence or absence and effect of phosphorylation, the nature of the Cr-protein complexes (deduced from its isolation or presence of corresponding mRNA) and, the mechanism of insulin-dependent enhancement of glucose uptake. Extrapolating from Cr(pic)3 studies, cultured cell studies are generally not representative of the whole, live organism and thus, the physiological conditions. This could be the significant reason for the numerous disagreements in the experimental results.[9][15]

Proposed mechanism of action

The mode of action through which chromium aided in the regulation of blood glucose levels is poorly understood. Recently, it has been suggested that chromium interacts with the low-molecular weight chromium (LMWCr) binding substance to potentiate the action of insulin.[2] LMWCr has a molecular weight of 1500, and is composed solely of the four amino acid residues of glycine, cysteine, aspartic acid and glutamate.[16] It is a naturally occurring oligopeptide that has been purified from many sources: rabbit liver, porcine kidney and kidney powder, bovine liver, colostrum, dog, rat and mouse liver.[17] Widely distributed in mammals, LMWCr is capable of tightly binding four chromic ions. The binding constant of this oligopeptide for chromium ions is very large, (K ≈ 1021 M−4), suggesting it is strong and tightly binding. LMWCr exists in its inactive or apo form within the cytosol and nucleus of insulin-sensitive cells.[16]

When insulin concentrations within the blood rise, insulin binds to the external subunit of the insulin-receptor proteins, and induces a conformational change. This change results in the autophosphorylation of the tyrosine residue located on the internal ß-subunit of the receptor, thereby activating the receptor’s kinase activity.[17] An increase in insulin levels also signals for the movement of transferrin receptors from the vesicles of insulin-sensitive cells to the plasma membrane. Transferrin, the protein responsible for the movement of chromium through the body, binds to these receptors, and becomes internalized via the process of endocytosis. The pH of these vesicles containing the transferrin molecules is then decreased (resulting in increased acidity) by the action of ATP-driven proton pumps, and as a consequence, chromium is released from the transferrin. The free chromium within the cell is then sequestered by LMWCr.[2] The binding of LMWCr to chromium converts it into its holo or active form, and once activated, LMWCr binds to the insulin receptors and aids in maintaining and amplifying the tyrosine kinase activity of the insulin receptors. In one experiment that was performed on bovine liver LMWCr, it was determined that LMWCr could amplify the activity of protein kinase receptors by up to seven-fold in the presence of insulin.[16] Furthermore, evidence suggests that the action of LMWCr is most effective when it is bound to four chromic ions.[17]

When the insulin signaling pathway is turned off, the insulin receptors on the plasma membrane relax and become inactivated. The holo-LMWCr is expelled from the cell and ultimately excreted from the body via urine.[16] LMWCr cannot be converted back into its inactive from due to the high binding affinity of this oligopeptide for its chromium ions. As of currently, the mechanism through which apo-LMWCr is replaced within the body is unknown.[17]

Side-effects and toxicity

There are some toxicity effects related to chromium picolinate. However, no conclusive results have been found and thus they tend to be self-contradictory. Chromium picolinate has been found in some cases to cause the following:

See also

References

  1. 1 2 3 Guerrero-Romero, F.; Rodríguez-Morán, M. (2005). "Complementary Therapies for Diabetes: The Case for Chromium, Magnesium, and Antioxidants". Archives of Medical Research 36 (3): 250–257. doi:10.1016/j.arcmed.2005.01.004. PMID 15925015.
  2. 1 2 3 4 Cefalu, W. T.; Hu, F. B. (2004). "Role of chromium in human health and in diabetes". Diabetes Care 27 (11): 2741–2751. doi:10.2337/diacare.27.11.2741. PMID 15505017.
  3. ↑ Schwarz, K.; Mertz, W. (1959). "Chromium(III) and the glucose tolerance factor". Archives of Biochemistry and Biophysics 85: 292–295. doi:10.1016/0003-9861(59)90479-5. PMID 14444068.
  4. 1 2 Balk, E. M.; Tatsioni, A.; Lichtenstein, A. H.; Lau, J.; Pittas, A. G. (2007). "Effect of Chromium Supplementation on Glucose Metabolism and Lipids: A systematic review of randomized controlled trials". Diabetes Care 30 (8): 2154–2163. doi:10.2337/dc06-0996. PMID 17519436.
  5. ↑ Kleefstra, N.; Houweling, S. T.; Bilo, H. J. G. (2007). "Effect of Chromium Supplementation on Glucose Metabolism and Lipids: A Systematic Review of Randomized Controlled Trials: Response to Balk et al". Diabetes Care 30 (9): e102. doi:10.2337/dc07-1015. PMID 17726181.
  6. ↑ Kleefstra, N.; Houweling, S. T.; Bakker, S. J. L.; Verhoeven, S.; Gans, R. O. B.; Meyboom-De Jong, B.; Bilo, H. J. G. (2007). "Chromium Treatment Has No Effect in Patients with Type 2 Diabetes in a Western Population: A randomized, double-blind, placebo-controlled trial". Diabetes Care 30 (5): 1092–1096. doi:10.2337/dc06-2192. PMID 17303791.
  7. ↑ Broadhurst, C. L.; Domenico, P. (2006). "Clinical Studies on Chromium Picolinate Supplementation in Diabetes Mellitus—A Review". Diabetes Technology & Therapeutics 8 (6): 677–687. doi:10.1089/dia.2006.8.677. PMID 17109600.
  8. ↑ Wang, Z. Q.; Zhang, X. H.; Russell, J. C.; Hulver, M.; Cefalu, W. T. (2006). "Chromium picolinate enhances skeletal muscle cellular insulin signaling in vivo in obese, insulin-resistant JCR:LA-cp rats". The Journal of Nutrition 136 (2): 415–420. PMID 16424121.
  9. 1 2 3 4 Vincent, J. B.; Love, S. T. (2012). "The Need for Combined Inorganic, Biochemical, and Nutritional Studies of Chromium(III)". Chemistry & Biodiversity 9 (9): 1923–1941. doi:10.1002/cbdv.201100440. PMID 22976981.
  10. ↑ Wang, Y. Q.; Yao, M. H. (2009). "Effects of chromium picolinate on glucose uptake in insulin-resistant 3T3-L1 adipocytes involve activation of p38 MAPK". The Journal of Nutritional Biochemistry 20 (12): 982–991. doi:10.1016/j.jnutbio.2008.09.002. PMID 19195868.
  11. ↑ Wang, H.; Kruszewski, A.; Brautigan, D. L. (2005). "Cellular Chromium Enhances Activation of Insulin Receptor Kinase†". Biochemistry 44 (22): 8167–8175. doi:10.1021/bi0473152. PMID 15924436.
  12. ↑ Hao, C.; Hao, J.; Wang, W.; Han, Z.; Li, G.; Zhang, L.; Zhao, X.; Yu, G. (2011). Stadler, Krisztian, ed. "Insulin Sensitizing Effects of Oligomannuronate-Chromium (III) Complexes in C2C12 Skeletal Muscle Cells". PLoS ONE 6 (9): e24598. doi:10.1371/journal.pone.0024598. PMC 3174176. PMID 21935427.
  13. ↑ Dong, F.; Kandadi, M. R.; Ren, J.; Sreejayan, N. (2008). "Chromium (D-phenylalanine)3 supplementation alters glucose disposal, insulin signaling, and glucose transporter-4 membrane translocation in insulin-resistant mice". The Journal of Nutrition 138 (10): 1846–1851. PMID 18806091.
  14. ↑ Chen, G.; Liu, P.; Pattar, G. R.; Tackett, L.; Bhonagiri, P.; Strawbridge, A. B.; Elmendorf, J. S. (2005). "Chromium Activates Glucose Transporter 4 Trafficking and Enhances Insulin-Stimulated Glucose Transport in 3T3-L1 Adipocytes via a Cholesterol-Dependent Mechanism". Molecular Endocrinology 20 (4): 857–870. doi:10.1210/me.2005-0255. PMID 16339278.
  15. ↑ Vincent, J. B. (2010). "Chromium: Celebrating 50 years as an essential element?". Dalton Transactions (Royal Society of Chemistry) 39 (16): 3787–3794. doi:10.1039/B920480F. PMID 20372701.
  16. 1 2 3 4 Vincent, J. B. (2000). "Elucidating a biological role for chromium at a molecular level". Accounts of Chemical Research 33 (7): 503–510. doi:10.1021/ar990073r. PMID 10913239.
  17. 1 2 3 4 Vincent, J. B. (2000). "The biochemistry of chromium". The Journal of Nutrition 130 (4): 715–718. PMID 10736319.
  18. 1 2 Cefalu, W. T. (2007). "Clinical effect of chromium supplements on human health". The Nutritional Biochemistry of Chromium (III). pp. 163–181. doi:10.1016/B978-044453071-4/50009-6. ISBN 9780444530714.
  19. 1 2 3 Massey, P. (2013). "Diabetes and the Role of Dietary Supplements". Bioactive Food as Dietary Interventions for Diabetes. pp. 17–94. doi:10.1016/B978-0-12-397153-1.00002-0. ISBN 9780123971531.
  20. 1 2 3 Bailey, M. M.; Boohaker, J. G.; Jernigan, P. L.; Townsend, M. B.; Sturdivant, J.; Rasco, J. F.; Vincent, J. B.; Hood, R. D. (2008). "Effects of Pre- and Postnatal Exposure to Chromium Picolinate or Picolinic Acid on Neurological Development in CD-1 Mice". Biological Trace Element Research 124 (1): 70–82. doi:10.1007/s12011-008-8124-9. PMID 18408898.
  21. 1 2 Vincent, J. B. (2012). "Beneficial Effects of Chromium(III) and Vanadium Supplements in Diabetes". Nutritional and Therapeutic Interventions for Diabetes and Metabolic Syndrome. pp. 381–391. doi:10.1016/B978-0-12-385083-6.00030-9. ISBN 9780123850836.
  22. ↑ Brown, M. (2003). "Harnessing chromium in the fight against diabetes". Drug Discovery Today 8 (21): 962–963. doi:10.1016/S1359-6446(03)02892-7. PMID 14643153.
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