How chromium serves as a cofactor for insulin action is not fully understood. From several in vivo and in vitro studies (15), it was initially thought that chromium potentiated the actions of insulin as part of an organic complex, GTF. More recent studies (15) have suggested that chromium may function as part of the oligopeptide low–molecular weight (MW) chromium (LMWCr)-binding substance (MW ~1,500 Da), which is composed of glycine, cysteine, glutamic acid, and aspartic acid. The interaction of chromium with LMWCr and the manner in which this complex influences insulin metabolism is considered in greater detail below.
Very little chromium (<2%) in the form of inorganic compounds is absorbed but may be higher with certain organic formulations (14). Once absorbed, chromium is distributed to various tissues of the body, but appears to be most concentrated in the kidney, muscle, and liver (16). The principal carrier protein for chromium is transferrin, which also plays a critical role in the movement of chromium from blood to LMWCr. It has been suggested that migration of transferrin receptors to the plasma membranes of insulin-insensitive cells after insulin stimulation is the initial step in this process. Transferrin containing the plasma-bound chromium is postulated to bind to the transferrin receptors and is internalized by endocytosis (Figs. 1 and 2). The pH of the internalized vesicle is reduced by ATP-driven proton pumps, chromium is released from transferrin, and the resulting free chromium is postulated to be sequestered by LMWCr (15,17). With this step, chromium is transferred from transferrin to LMWCr, which normally exists in insulin-dependent cells in the apo, or inactive, form. Binding with chromium ions converts inactive LMWCr to its holo, or active, form. It is proposed that LMWCr then participates as part of an insulin signal amplification system as it binds to insulin-activated insulin receptors and results in stimulating its tyrosine kinase activity. The result of this process is the activation of insulin receptor kinase and potentiation of the actions of insulin (15,18,19). Importantly, LMWCr without bound chromium or in the presence of other metal ions is ineffective in activating insulin-dependent kinase activity and thus enhancing the actions of insulin (19).
Chromium has also been demonstrated to inhibit phosphotyrosine phosphatase, the enzyme that cleaves phosphate from the insulin receptor, leading to decreases in insulin sensitivity. Activation of insulin receptor kinase and inhibition of insulin receptor phosphatase would lead to increased phosphorylation of the insulin receptor and increased insulin sensitivity (20). The balance between kinase and phosphatase activity may facilitate the role of insulin in rapidly moving glucose into cells. In addition, it has been suggested (7) that chromium enhances insulin binding, insulin receptor number, insulin internalization, and ß-cell sensitivity.
The controversy surrounding chromium supplementation is due in part to substantial variability in the results of studies that have evaluated the effects of chromium in patients with or without diabetes. Results from some trials (21–26) have indicated that chromium supplementation increases muscle gain and fat loss associated with exercise and improves glucose metabolism and the serum lipid profile in patients with or without diabetes. In contrast, those from other studies (27–32) have indicated little or no benefit of chromium on any of these variables.
Recent meta-analyses (33,34) of results from studies that evaluated the effects of chromium supplementation have suggested limited benefit in individuals with or without diabetes. The major conclusions from these analyses were that chromium has a very small effect versus placebo in reducing body weight and that the clinical relevance of this small decrease is debatable and should be interpreted with caution. It was also concluded that chromium has no effect on glucose metabolism or insulin concentrations in individuals without diabetes and that data for patients with diabetes are currently inconclusive. It is important to note that these conclusions are based largely on data from patients without diabetes and failed to include key positive results for chromium supplementation in diabetic patients and subjects with gestational diabetes or the metabolic syndrome.
There is no clinically defined state of chromium deficiency, but diabetes has been shown (32) to develop because of low chromium levels in experimental animals and in humans sustained by prolonged TPN. These results suggest that there may be a more general relationship between chromium levels and glucose and/or lipid metabolism. It has also been suggested (35–37) that low chromium concentrations and the associated impairments in insulin, glucose, and lipid metabolism may also result in increased cardiovascular risk. In a cross-sectional analysis (38), lower toenail chromium levels have also been associated with increased risk of type 2 diabetes. Adequate dietary chromium intake may be especially problematic in the elderly (39,40). Consumption of refined foods, including simple sugars, exacerbates the problem of insufficient dietary chromium because these foods are not only low in dietary chromium but also increase its loss from the body (41). Chromium losses are also increased during pregnancy and as a result of strenuous exercise, infection, physical trauma, and other forms of stress (40). Reduced chromium levels are reported in the elderly and in patients with diabetes (42,43). However, one of the major problems with assessing chromium status in biological tissues and fluids is extremely low levels of chromium in these tissues. Regardless, recent studies have demonstrated the successful determination of chromium. One study reported that in >40,800 patients from ages 1 to >75 years, chromium levels in hair, sweat, and blood diminished significantly with age, with values decreasing from 25 to 40% depending on the tissue of interest (43). Additionally, it appears that diabetic subjects may have altered chromium metabolism compared with nondiabetic subjects, as both absorption and excretion may be higher (44,45). Hair and blood levels are reported (46) to be lower in diabetic subjects, with mean levels of plasma chromium of ~33% lower in 93 type 2 diabetic subjects compared with control subjects. Another study reported that chromium levels were reduced >50% in both diabetic men and women compared with control subjects (42), which was supported by Elmekcioglu et al. (47), who reported significantly lower chromium levels in the plasma of type 2 diabetic individuals compared with nondiabetic healthy control subjects. Yet, another study (48) suggested no alteration of chromium levels in type 2 diabetes; however, only 11 subjects were reported.