We studied the effect of chromium picolinate on insulin-stimulated glucose uptake in a well-characterized population of non-obese non-diabetic subjects. We did not find evidence that serum chromium levels had a significant impact on insulin sensitivity in this population, nor did we find evidence that high chromium excretion was associated with insulin resistance. In investigating the use of daily chromium picolinate supplementation as a modulator of insulin action, we could find no evidence for a beneficial effect of this compound. Our principal finding was that those subjects with the highest levels of serum chromium following treatment had worsening of insulin sensitivity rather than an improvement. This negative effect of chromium supplementation was highlighted when we divided the chromium treated subjects into two groups using the medial serum chromium value of 3.1 μg/L – the subjects with the higher chromium levels had greater reduction in insulin sensitivity than the lower chromium levels. There were no obvious baseline characteristics that identified individuals who were likely to have greater serum levels of chromium. The increase in insulin resistance could not explained by weight gain or alterations in lipid levels.
While claims of benefits of chromium therapy on weight loss and increased muscle mass have been largely discredited
], this supplement is still being promoted for its beneficial effects on insulin action and glucose tolerance
]. In the 1970’s and 1980’s there were three clinical reports of
] of patients with small bowel loop syndromes on parental nutrition who developed glucose intolerance and who improved following chromium therapy. These case reports led to the routine addition of chromium to TPN solutions. They also provided impetus for other clinical studies (see reviews
]) of chromium therapy in normal subjects, people with glucose intolerance, and people with diabetes (both type 1 and type 2)
]. The results have been inconclusive, with some studies reporting a positive effect on glucose and/or insulin levels whereas others failing to show benefit. Design problems include open label studies
]; some studies including subjects with different disorders s e.g. type 1 and type 2 patients
]; type 2 subjects remaining on drugs that affect insulin secretion or insulin action
]; inadequate control of confounders such as hyperglycemia and obesity that affect insulin action
]; and failure to address the role of chromium levels on the measured parameters. A significant limitation of most of these studies is their use of surrogate measures such as fasting insulin and glucose tolerance tests which may not be sensitive enough to assess changes in insulin action with therapy. Very few studies employed the more accurate euglycemic hyperinsulinemic clamp technique to assess insulin action
]. The studies also used a wide range of chromium doses, formulations and durations of therapy. Supplementation with 200 to 1000 μg of chromium picolinate has been reported to improve glucose intolerance and lower circulating insulin levels
] with one study in type 2 diabetes patients showing a greater improvement with 1000 μg dose compared to 200 μg dose
]. The 1000 μg daily has been used in a number of other clinical studies
] and not associated with any toxic effects.
We have addressed many of these limitations in the present study. The subjects had normal glucose intolerance and were of normal weight. The absence of obesity and hyperglycemia removes two important confounders that can affect insulin action. We also measured serum and urine chromium levels to confirm compliance and also to assess effects of chromium levels on the measured parameters. We used the euglycemic hyperinsulinemic clamp rather than surrogate measures to assess insulin action before and after therapy. We also used chromium picolinate at a dose that previously had been reported to improve insulin resistance.
We did not observe an increase in insulin sensitivity in the treatment group, but observed a decrease in insulin sensitivity only in subjects who had high levels of serum or spot urinary chromium levels. Generally, the absorption of chromium picolinate has reported to be very low in the range of 2.8 ±1.14% (SD) but there is significant individual variation with peak urinary excretion varying 5 fold after acute dosing
]. Distribution studies with labeled chromium also suggest that trivalent chromium is stored in the body principally in the liver and also in kidneys, spleen and muscle
] and it is possible that the impact of chromium therapy may only become apparent in studies lasting several months.
In order to further explore the mechanism by which chromium picolinate induces insulin resistance, we used a human insulin signaling pathway PCR array to examine the expression of genes in skeletal muscle before and after chromium therapy. We were unable to demonstrate any changes in gene expression with therapy in 4 subjects who became insulin resistant with therapy. The expression array examines only the genes coding for proteins that have been directly implicated in, or affected by, insulin signaling. It is of course possible that chromium therapy affects the expression of other genes that were not studied; or that chromium affects muscle insulin signaling at the level of protein function, without an impact on expression of insulin-sensitive genes, through actions that may or may not originate in skeletal muscle. Proposed targets for chromium action include membrane phosphotyrosine phosphatase
], insulin receptor tyrosine kinase
], protein-tyrosine phosphatase 1B
Some additional limitations of our study need to be discussed. The original study was designed to evaluate group differences (placebo vs. chromium therapy) and not powered to examine subgroups (serum chromium levels). The results therefore should be viewed with some caution and need to be replicated. We restricted our recruitment to normoglycemic and non-obese subjects and it remains possible that people with glucose intolerance or frank diabetes may respond differently, due to effects of chromium on insulin secretion or glucose toxicity. Our subjects were healthy eating a normal diet and so were not chromium deficient. It is quite possible as noted in the case reports of short bowel syndrome patients on TPN in the 1970’s that extreme chromium deficiency causes defects in insulin secretion and/or action. The concept that extreme deficiency or excess of an agent can have the same clinical effect is not without precedence. Both magnesium deficiency and excess inhibits parathyroid hormone secretion resulting in hypocalcemia; and the hypocalcemia due to deficiency is corrected by magnesium supplements.