Chromium potentiates the biological actions of insulin, a hormone that is critical for the normal regulation of carbohydrate, lipid and protein metabolism. Evidence of chromium's role was first suggested in 1957 when a "glucose tolerance factor" (GTF), found in brewer's yeast, prevented an age-related decline of glucose tolerance in rats. Chromium III was identified shortly after as the active ingredient of GTF.
Chromium was declared an essential nutrient in 1977 after significant elevations in blood sugar levels were first observed in a hospitalized patient receiving total parenteral nutrition devoid of chromium (Food & Nutrition Board, 2001; Jeejeebhoy et al, 1977). Blood sugar levels returned to normal after the addition of chromium to her diet.
More recently, studies have begun to reveal the mechanism of chromium's actions. Research has suggested that after chromium is absorbed into the body, the chromium ions bind to an oligopeptide in order to become biologically active. The chromium-bound peptide complex then binds to the insulin-receptor and increases the activity of the insulin receptor tyrosine kinase, thereby amplifying insulin action; chromium also has been shown to stimulate intracellular activity leading to enhanced glucose uptake in muscle cells.
Recent reports suggest that chromium increases insulin receptor number, enhances GLUT 4 translocation, insulin receptor substrate levels, PI3 kinase expression and Akt phosphorylative activity.
2005
Chromium Picolinate Enhances Tyrosine Kinase Gene Expression in Human Skeletal Muscle Cells from Subjects with Type 2 Diabetes
Chromium Picolinate (CrPic) has been suggested as a cofactor for insulin action, but the specific cellular mechanism has not been elucidated. Data has been obtained that has suggested that CrPic may enhance cellular signalling through the insulin receptor and increase GLUT-4 translocation.
In order to assess potential cellular mechanisms of action, we examined the gene expression profile of skeletal muscle as regulated by CrPic using microarray and real time PCR. Skeletal muscle biopsies were taken during hyperinsulinemic euglycemic clamp studies from 5 individuals with Type 2 diabetes {Mean age = 60.4 years, Mean total body glucose disposal (M Value)= 310 mg/min}. Primary cell culture was initiated from the skeletal muscle biopsies and grown to approx. 80% confluence. Cultures were then incubated in the presence of CrPic (10 ng/ml) or control media only.
Total RNA was isolated after 16 hours of treatment. Microarray data demonstrated that one hundred forty-nine genes were significantly upregulated (p <0.05) and two hundred eleven genes were significantly down regulated (P<0.05) with CrPic treatment. Major pathways that were significantly regulated included twenty-nine genes involved in protein modification, glucose uptake, lipid metabolism and energy metabolism pathways. Based on the microarray analysis and additional observations, real time PCR was evaluated for 5 specific genes. Specifically, Tyrosine kinase 2 expression assessed with Real Time PCR was up-regulated about 1.5 fold in the presence of CrPic (Arbitrary Unit: control=2.42, CrPic treatment=3.65, p < 0.05).
There was no significant change in gene expression using Real Time PCR for Citrate synthase, AMPKΑ2, PGCΑ1 and Β1.
These results suggest that the mechanism of action by which CrPic may improve cellular insulin signalling is through regulation of protein tyrosine kinase-2 gene expression.
2003
Changes in Plasma Membrane Architecture as a Basis for
Chromium-Activated GLUT4 Translocation
Studies suggest that the essential micronutrient chromium can be beneficial in individuals with insulin resistance, as evidenced by decreased blood glucose values and decreased insulin requirements. While available evidence implicates a role for chromium in glucose metabolism, the molecular mechanism by which chromium enhances insulin function is not known. Since it has been shown that chromium increases membrane fluidity and that the physical state of the plasma membrane influences insulin action, the present work tested the hypothesis that changes in cell surface membrane properties are the basis for the permissive effects of chromium on glucose metabolism. Exposure of 3T3L1 adipocytes to chromium chloride or chromium picolinate for 16 h increased the basal-state plasma membrane level of the insulin-responsive glucose transporter, GLUT4.
Interestingly, the enhancing effects of chromium chloride and chromium picolinate were higher in cultured cells incubated in 25 mM glucose rather than in 5.5 mM glucose, consistent with its selective action in hyperglycaemic conditions in vivo. Insulin-stimulated GLUT4 translocation was augmented by both forms of chromium concomitant with the potentiation of insulin receptor and insulin receptor substrate-1 tyrosine phosphorylation. Consistent with the documented effect of chromium on membrane fluidity, the amount of plasma membrane cholesterol was moderately diminished in cells exposed to chromium chloride and chromium picolinate. Restoration of the cholesterol level by cholesterol-loaded methyl-β-cyclodextrin blocked the chromium-stimulated recruitment of GLUT4 to the plasma membrane.
Although chromium treatment led to a moderate reduction in plasma membrane cholesterol content, propidium iodide and caveolin-1 staining revealed that there was no apparent effect on membrane integrity. In addition, indicative of normal endocytic rates, the basal-state plasma membrane levels of both GLUT1 and TnFR were not elevated following chromium exposure.
In conclusion, these data are consistent with the idea that chromium-induced cell surface membrane changes enhance GLUT4 translocation during the hyperglycaemic state.
Chromium picolinate enhances skeletal muscle cellular insulin
signalling in vivo in obese, insulin-resistant JCR:LA-cp rats.
Chromium is one of the few trace minerals for which a specific cellular mechanism of action has not been identified. Recent in vitro studies suggest that chromium supplementation may improve insulin sensitivity by enhancing insulin receptor signalling, but this has not been demonstrated in vivo. We investigated the effect of chromium supplementation on insulin receptor signalling in an insulin-resistant rat model, the JCR:LA-corpulent rat. Male JCR:LA-cp rats (4 mo of age) were randomly assigned to receive chromium picolinate (CrPic) (obese n=6, lean n=5) or vehicle (obese n=5, lean n=5) for 3 mo. The CrPic was provided in the water, and based on calculated water intake, rats randomized to CrPic received 80 microg/(kg.d). At the end of the study, skeletal muscle (vastus lateralis) biopsies were obtained at baseline and at 5, 15, and 30 min post-insulin stimulation to assess insulin signalling. Obese rats treated with CrPic had significantly improved glucose disposal rates and demonstrated a significant increase in insulin-stimulated phosphorylation of insulin receptor substrate (IRS)-1 and phosphatidylinositol (PI)-3 kinase activity in skeletal muscle compared with obese controls. The increase in cellular signalling was not associated with increased protein levels of the IRS proteins, PI-3 kinase or Akt.
However, protein tyrosine phosphatase 1B (PTP1B) levels were significantly lower in obese rats administered CrPic than obese controls. When corrected for protein content, PTP1B activity was also significantly lower in obese rats administered CrPic than obese controls. Our data suggest that chromium supplementation of obese, insulin-resistant rats may improve insulin action by enhancing intracellular signalling.
Wang ZQ, Zhang XH, Russell JC, Hulver M, Cefalu WT.
Pennington Biomedical Research Center, Division of Nutrition and Chronic Diseases, Louisiana state University System, Baton Rouge, LA, USA.
2005
A Novel Cholesterol-Dependent Mechanism for Chromium's Role
in Enhancing Insulin Action and Glucose Transport
Accumulating evidence suggests that chromium supplementation may alleviate symptoms associated with diabetes, such as high blood glucose and lipid abnormalities, yet a molecular mechanism remains unclear. Here, we report that chromium mobilizes the glucose transporter, GLUT4, to the cell surface membrane in 3T3-L1 adipocytes. Concomitant with this redistribution of GLUT4, insulin-stimulated glucose transport was enhanced.
In contrast, the chromium-mobilized pool of transporters was not active in the absence of insulin. Highly purified plasma membrane fragments showed less chromium-mobilized GLUT4 than biochemically prepared membrane fractions that would likely contain some tethered and/or docked GLUT4-containing vesicles. Microscopic analysis of an exofacially Myc-tagged EGFP-GLUT4 construct revealed that the chromium-induced accumulation of GLUT4-containing vesicles occurred adjacent to the inner cell surface membrane. However, with insulin these transporters physically incorporated into the plasma membrane as determined by anti-Myc labelling of unpermeabilized cells.
The chromium-enhanced positioning of GLUT4 beneath the inner plasma membrane did not result from known effectors of insulin action. Interestingly, chromium action was coupled with a reduction in plasma membrane cholesterol. Concomitantly, sterol regulatory element binding protein (SREBP) processing and ATP-binding cassette transporter A1 (ABCA1) expression increased and decreased, respectively, in response to the chromium-induced loss of plasma membrane cholesterol. Remarkably, exogenous cholesterol add-back that restored plasma membrane cholesterol diminished by chromium treatment prevented the beneficial effect of chromium on the cellular redistribution of GLUT4 and amplified insulin-stimulated glucose transport. Together, these data reveal that GLUT4 movement to the cell surface and insulin-stimulated glucose transport are augmented by a chromium-induced loss of plasma membrane cholesterol.
