Evidence is reviewed supporting the presence of an inherited structural defect in the plasma membranes of somatic cells of humans who have type 2 diabetes mellitus and sodium-sensitive essential hypertension. This magnesium-binding defect (MgBD) consists of a decreased content of tightly bound Mg2+ ion in the cell membrane and limits the amount of Mg2+ that enters the cell, some of which combines with ATP(4-), produced by the cell, to form MgATP(2-), the currency of metabolic energy. Consequently, in both prediabetes and overt diabetes, the intracellular concentration of the interdependent Mg2+ and MgATP(2-) ions is significantly less than normal. These 2 ions are required as cofactors and (or) substrates for some 300 enzyme systems in human metabolism, many of which are involved with insulin. Thus the decreased activities of particular ones of these enzyme systems due to the decreased intracellular [Mg2+] and its dependent [MgATP(2-)] are responsible for (i) insulin resistance and (ii) decreased insulin secretion and (or) production, the 2 patho-physiological processes required for the occurrence of type 2 diabetes mellitus. These 2 processes can account for all of the morbid symptoms associated with this disease. Thus, the decreased intracellular concentration of the interdependent Mg2+ and MgATp(2-) ions constitutes the etiology of genetic predisposition to type 2 diabetes mellitus and can be corrected by 2 identified peptide Mg2+-binding promoters that are derived from the carboxyl terminal of the tachykinin substance P and occur in normal blood plasma. Decreased intracellular [Mg2+] and [MgATp(2-)] can also result from a dietary deficiency of magnesium or from an abnormal accumulation of saturated fatty acids in cell membranes, which inhibits the entrance of Mg2+ into the cell; thus it is also the etiology not only of diabetes caused by magnesium deficiency, but also of the "lipotoxic" type 2 diabetes mellitus. Although these pathologies cannot be corrected by the Mg2+-binding promoters, they can be corrected, respectively, by dietary magnesium supplementation or by exercise plus dietary caloric and lipid restriction. Theoretically, the disease syndrome containing type 2 diabetes mellitus may involve approximately 30% of the population.