Chromium is a transition metal that is the essential cofactor of the chromodulin protein (also called chromogranin or low-molecular-weight chromium-binding substance, LMWCr) — the protein that is the active form of chromium in the body and that is required for the normal function of the insulin receptor. Chromodulin is a chromium-binding protein that is synthesised in the cell and that binds four chromium ions per molecule in a biologically unusual coordinate covalent bonding arrangement, forming the chromodulin-Cr3+ complex that is the biologically active species. When insulin binds to the insulin receptor, the activated receptor tyrosine kinase phosphorylates its target proteins on tyrosine residues, and the chromodulin-Cr3+ complex amplifies this tyrosine phosphorylation by activating the insulin receptor kinase, thereby enhancing the insulin signal and improving insulin sensitivity. This chromium-chromodulin-insulin receptor connection is the primary mechanism by which chromium regulates insulin sensitivity, and its impairment (as occurs in chromium deficiency) produces the insulin resistance that is one of the primary mechanisms of the metabolic syndrome and type 2 diabetes.
Chromium and Insulin Sensitivity
The effect of chromium supplementation on insulin sensitivity is one of the most studied and most controversial topics in nutritional science. Multiple RCTs have demonstrated that chromium supplementation at 200-1,000mcg daily (as chromium picolinate, the most commonly used supplemental form) significantly improves insulin sensitivity in people with type 2 diabetes, with improvements in fasting blood glucose, fasting insulin, and HbA1c that are clinically meaningful. A meta-analysis of 15 RCTs in people with type 2 diabetes found that chromium supplementation significantly reduced fasting blood glucose (by approximately 0.9 mmol/L), fasting insulin (by approximately 3.5 mIU/L), and HbA1c (by approximately 0.9%) compared to placebo, with benefits that were apparent within 8-12 weeks of starting supplementation. The mechanism of these insulin-sensitising effects is the chromium-induced activation of the insulin receptor kinase through the chromodulin-Cr3+ complex, which amplifies the insulin signal and improves the responsiveness of the insulin target tissues (muscle, liver, adipose tissue) to insulin.
The clinical importance of chromium for insulin sensitivity is most clearly demonstrated by the effect of chromium deficiency on glucose metabolism. Chromium deficiency is associated with impaired glucose tolerance, hyperinsulinemia, and the insulin resistance that is the hallmark of the metabolic syndrome. The rare genetic deficiency of chromodulin (which has been described in a small number of patients) produces a clinical syndrome that includes severe insulin resistance, hyperglycaemia, and the progressive development of the complications of type 2 diabetes (including retinopathy, nephropathy, and neuropathy) in the absence of obvious dietary chromium deficiency. The treatment of chromodulin deficiency involves chromium supplementation at high doses (1,000-2,000mcg daily), which partially compensates for the impaired chromodulin function and improves insulin sensitivity.
Chromium and Body Composition
Chromium supplementation has also been studied for its potential effects on body composition — the hypothesis being that the improvement in insulin sensitivity that is produced by chromium would reduce the lipogenesis (fat storage) and increase the lipolysis (fat burning) that are regulated by insulin, leading to a reduction in body fat and an increase in lean body mass. However, the evidence for an effect of chromium on body composition is mixed — some studies show small reductions in body fat and small increases in lean body mass in people taking chromium supplements, while others show no significant effect. A meta-analysis of 11 RCTs found that chromium supplementation at 200-1,000mcg daily produced a small but statistically significant reduction in body weight (by approximately 0.5kg) and a small reduction in body fat (by approximately 0.5%), with no significant effect on lean body mass. These effects are modest and are unlikely to be clinically significant for most people, and chromium supplementation for body composition purposes is not supported by the evidence.
Practical Application
For general chromium supplementation (for the support of insulin sensitivity in people with type 2 diabetes or with the metabolic syndrome), the evidence-based dose is 200-1,000mcg of chromium daily (as chromium picolinate, which is the most bioavailable form). The RDA for chromium is 35mcg daily for adult men and 25mcg daily for adult women, and most people in the developed world achieve this from a varied diet that includes broccoli, whole grains, nuts, and the trace amounts of chromium that are present in most foods. Chromium is generally well-tolerated with no significant adverse effects at therapeutic doses, though very high doses can produce renal impairment and should be avoided in people with pre-existing renal disease. For comprehensive insulin sensitivity support, chromium pairs well with the alpha-lipoic acid (which also improves insulin sensitivity and which supports the mitochondrial function that is impaired in insulin resistance), with the omega-3 fatty acids (which have anti-inflammatory effects that reduce the insulin resistance that is driven by chronic inflammation), with the berberine (which activates the AMPK pathway and which has been shown in multiple RCTs to improve insulin sensitivity with an effect size that is comparable to that of metformin), and with the Mediterranean dietary pattern (which is associated with better insulin sensitivity and with reduced risk of type 2 diabetes).
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