The mode of action through which chromium aided in the regulation of blood glucose levels is poorly understood. Recently, it has been suggested that chromium interacts with the low-molecular weight chromium (LMWCr) binding substance to potentiate the action of insulin. LMWCr has a molecular weight of 1500, and is composed solely of the four amino acid residues of glycine, cysteine, aspartic acid and glutamate. It is a naturally occurring oligopeptide that has been purified from many sources: rabbit liver, porcine kidney and kidney powder, bovine liver, colostrum, dog, rat and mouse liver. Widely distributed in mammals, LMWCr is capable of tightly binding four chromic ions. The binding constant of this oligopeptide for chromium ions is very large, (K ≈ 10 M), suggesting it is strong and tightly binding. LMWCr exists in its inactive or apo form within the cytosol and nucleus of insulin-sensitive cells.
When insulin concentrations within the blood rise, insulin binds to the external subunit of the insulin-receptor proteins, and induces a conformational change. This change results in the autophosphorylation of the tyrosine residue located on the internal ß-subunit of the receptor, thereby activating the receptor's kinase activity. An increase in insulin levels also signals for the movement of transferrin receptors from the vesicles of insulin-sensitive cells to the plasma membrane. Transferrin, the protein responsible for the movement of chromium through the body, binds to these receptors, and becomes internalized via the process of endocytosis. The pH of these vesicles containing the transferrin molecules is then decreased (resulting in increased acidity) by the action of ATP-driven proton pumps, and as a consequence, chromium is released from the transferrin. The free chromium within the cell is then sequestered by LMWCr. The binding of LMWCr to chromium converts it into its holo or active form, and once activated, LMWCr binds to the insulin receptors and aids in maintaining and amplifying the tyrosine kinase activity of the insulin receptors. In one experiment that was performed on bovine liver LMWCr, it was determined that LMWCr could amplify the activity of protein kinase receptors by up to seven-fold in the presence of insulin. Furthermore, evidence suggests that the action of LMWCr is most effective when it is bound to four chromic ions.
When the insulin signaling pathway is turned off, the insulin receptors on the plasma membrane relax and become inactivated. The holo-LMWCr is expelled from the cell and ultimately excreted from the body via urine. LMWCr cannot be converted back into its inactive from due to the high binding affinity of this oligopeptide for its chromium ions. As of currently, the mechanism through which apo-LMWCr is replaced within the body is unknown.