The paradox of the contrasting roles of chronic magnesium deficiency in metabolic disorders and field cancerization.

Magnesium (Mg(2+)) deficiency is common in metabolic disorders such as obesity, type 2 diabetes, and insulin resistance. These disorders are also associated with a high incidence of cancer. Mg(2+) is the regulator par excellence of metabolism, largely through its role as a cofactor for all phosphoryl transfers in the cell. Because Mg(2+) deficiency inhibits energy production it might be expected to inhibit tumor production. However, the high incidence of cancer in metabolic disorders makes that seem unlikely. In order to understand this seeming paradox, it is important to understand the regulatory role of Mg(2+) in normal and neoplastic cells. Free Mg(2+) is the primary regulator of glycolysis and the Krebs cycle. It also acts as a second messenger for growth factors in regulating protein synthesis. Varying Mg(2+) concentrations result in the same set of coordinated responses as varying serum concentrations. Selection by serial rounds of high cell density or reduced serum concentration at low cell density results in progressive stages of field cancerization. Highly transformed cells proliferate in much lower concentrations of Mg(2+) and grow to much higher saturation densities than normal cells. It remains to be seen whether reduction in Mg(2+) in sparse, exponentially proliferating cultures selects for increases in saturation density and transformed foci.