# The Double Face of Metals: The Intriguing Case of Chromium
## 4 The Role of Chromium and Its Mechanism of Action in the Body  
The first literature study about a physiological role of chromium in the body appeared in 1959 by [PERSON] and [PERSON] [67]. The authors isolated from pig kidney and Brewer's yeast the GTF, a component capable of rebalancing impaired glucose tolerance in rats; the active component of this factor was discovered to be chromium. About forty years later chromium was considered an element necessary in small quantities for proper functioning of human beings [68]; anyway nowadays, chromium is classified as a nutritional supplementation factor.  
In recent years, several studies on the influence of chromium on cholesterol level and lipid profile have been published. Dietary supplementation with high amounts of chromium has been demonstrated that, while decreasing the serum level of total cholesterol, LDL-cholesterol (LDL-c), nonesterified fatty acids and triglycerides, led to an enhanced concentration of high density lipoprotein (HDL)-cholesterol and \(\beta\)-oxidation process [69]. The oral administration in mice of chromium nitrate cancels and counteracts the anti-carcinogenic mechanism of selenium effects in the development and growth of mouse mammary tumors caused by mouse mammary tumor virus (MMTV) [70]. Despite the numerous studies published so far, it is still unclear how chromium ions can operate in the metabolism of lipids and carbohydrates. Probably, the active form of Cr(III) is transported through the body via chromodulin, a low-molecular-weight chromium-binding substance (LMWCr), that is thought to influence lipid and carbohydrate metabolism. LMWCr is a small 1500 Da oligopeptide consisting of ten amino acids (2 Gly, 2 Cys, 2 Asp, 4 Glu) [71]. LMWCr has been demonstrated to be within the cytoplasm and nucleus of the cell in an inactive form (i.e., apochromodulin). After insulin binding and activation of the transferrin receptor, there is an internalization in the cell of transferrin-chromium complex. Chromodulin binds four Cr(III) ions, and then is converted into holochromodulin, the biologically active form. This holopeptide may bind the insulin receptor at the level of \(\beta\)-subunit, activating the tyrosine kinase receptor and thus enhancing the insulin signal. All these mechanisms mediate glucose transport into the cell through the cell membrane thanks to the protein glucose transporter 4 (GLUT4) [72]. Other theories are known to justify the importance of chromium in glucose metabolism. For example, according to [PERSON] and collaborators (2006), the Cr ions act on the membrane fluidity regulating the glucose uptake by the cells [73]. The fluidity of the membrane, also considering the presence of Cr ions, is associated with the reduced content of cholesterol in the cellular membranes. The lower presence of cholesterol, which affects membrane fluidity, is considered to be another factor that diminishes insulin-controlled glucose intake. Furthermore, [PERSON] et al. (2011) demonstrated that Cr(II) ions modify the structure of the lipid bilayer [74]. [PERSON] et al. (2017) studied the mechanism responsible for contact dermatitis by chromium [75]. It seems that Cr(VI) penetrates through the skin and is then reduced to Cr(III), which may react with proteins to form a hapten, thus creating the complex recognized by T cells. Chromium activates T cells leading to inflammation and, lastly, symptoms [76].