Chromium in glucose metabolism

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

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.

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.

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.

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 ~100's 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.

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. 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.

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. This appears to be a problem encountered in the review by Balk and colleagues.

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.

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.

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.

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.

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). 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. 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.

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. 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.

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.

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. LMWCr has a molecular weight of 1500, and is composed solely of the four amino acid residues of glycine, cysteine, aspartic acid and glutamate. 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. 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.

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. 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. 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. Furthermore, evidence suggests that the action of LMWCr is most effective when it is bound to four chromic ions.

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. 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.

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:


 * Generally there have been no negative side effects on 70% of the population taking the supplement.


 * The supplement has also been linked to carbohydrate cravings and appetite regulation in depressed patients.


 * The use of other medications while using this supplement will affect the serum chromium levels. For example, steroids will cause increased chromium loss in urine.


 * Pregnant or nursing women and people with renal and liver disease must take caution when taking these supplements.


 * With high doses (about 600-2400 μg), rare side effects may occur such as damage to the liver, kidney, and bone marrow, as well as rhabdomyolysis and psychiatric disturbances in some cases. They have also been related to chromosomal damage and increased incidence of cervical arch defects as they are capable of cleaving DNA.


 * The use of the supplements over a prolonged period of time may result in a risk of chromium poisoning. This is due to chromium’s nuclear affinity, tending to result in its accumulation within cells.


 * Studies have suggested that the supplement has carcinogenic properties, as it is deemed to be a potent genotoxin. This effect has been proved for cultured cells and fruit flies. It has also been proven to have one type of carcinogenicity on male rats, with no harmful effects on females. Clastogenic and mutagenic effects have also been found in Chinese hamster ovary cells. However, recent studies have shown that the commercial supplement causes no such damage. This only occurs when dimethyl sulfoxide is used as a solvent as it is a free radical trap that quenches reactive oxygen species. As such, the UK’s Food Standard Agency has advised against it, however in the United States it is still identified as being safe.


 * The European Food Safety Authority deemed the supplement can be taken at 250μg of Cr/day without any concerns, while the Expert Group on Vitamins and Minerals in the UK deemed 10μg of Cr/day.