Evidence that the etiology of the syndrome containing type 2 diabetes mellitus results from abnormal magnesium metabolism.

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 ATP4-, produced by the cell, to form MgATP2-, the currency of metabolic energy. Consequently, in both prediabetes and overt diabetes, the intracellular concentration of the interdependent Mg2+ and MgATP2- 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 [MgATP2-] are responsible for (i) insulin resistance and (ii) decreased insulin secretion and (or) production, the 2 pathophysiological 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 MgATP2- 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 [MgATP2-] 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.

Abnormal magnesium metabolism in etiology of salt-sensitive hypertension and type 2 diabetes mellitus.

A previously unknown genetic defect in magnesium metabolism (i.e., the magnesium-binding defect [MgBD]) was found to be associated with the cause of "salt-sensitive" essential hypertension in humans and rats. It inhibits the entrance of Mg2+ into the cell so that the intracellular concentrations of Mg2+ and MgATP2- are decreased. Consequently, the 300 enzyme reactions in the cell, especially the 100 that either use or produce MgATP2-, are inhibited. Thus, because the extrusion of intracellular Na+ requires MgATP2-, hypertension results when the involved MgATP2- requiring enzyme is inhibited. The MgBD is corrected by the tachykinin substance P, which occurs in normal blood plasma, and by the pentapeptide and its contained tetrapeptide, which are released from the C-terminal region of substance P by plasma aminopeptidases. In vivo, the intravenous administration of the tetrapeptide corrects the hypertension and the MgBD as well. The MgBD also occurs in type 2 diabetes mellitus and, thus, the decreased intracellular concentrations of Mg2+ and MgATP2- ions appear to be involved also in the cause of this disease, which is reputed to be the fifth most deadly disease in the world.

A test for adequacy of chromium nutrition in humans--relation to type 2 diabetes mellitus.

When Na(2)51CrO(4) is added to blood the 51CrO(4)(2-) ions enter the erythrocytes readily, and nearly exclusively, and are reduced to 51Cr(III) ions. We have observed that a fraction of these ions becomes bound to the cell membrane in a concentration which seemingly depends on that of the dietary derived intracellular Cr(III) ions. Thus, when constant amounts of 51CrO(4)(2-) ions enter constant amounts of erythrocytes, the resulting 51Cr(III) ions become bound to the cell membrane in a concentration that varies inversely as the initial, intracellular concentration of Cr(III) ions which, in turn, depends directly on the adequacy of chromium nutrition. Therefore, we have determined an arbitrary set of conditions under which the concentration of 51Cr(III) ions bound to the erythrocyte membrane becomes an indicator of the adequacy of chromium nutrition. The application of this test to 25 Type 2 diabetes mellitus subjects and 35 normal controls, both randomly selected, indicates that the concentrations of membrane bound 51Cr(III) ions in the two groups were not significantly different. Consequently, it is concluded that the level of chromium nutrition which is normally adequate in humans has only a minor role, if any, in the genesis of Type 2 diabetes mellitus.

Adipokinin, a proopiomelanocortin-derived lipid-mobilizing anterior pituitary hormone.

Hormonal control of lipid metabolism during prolonged fasting is unclear. The involvement of the classical, lipid-mobilizing hormone from the anterior pituitary, i.e., beta-lipotropin (beta-LPH), is suspect. It and adrenocorticotropin (ACTH) are formed concurrently in the pituitary during the processing of the prohormone, proopiomelanocortin (POMC), and are secreted together. During prolonged fasting the control of metabolism requires minimal participation by ACTH and maximal lipid-mobilizing activity which is inconsistent with the present concept of ACTH and beta-LPH secretion. Hypothetically, the needed control can be satisfied by the alteration of the accepted processing of POMC so as to form beta-LPH and a new lipid-mobilizing hormone which also has modest ACTH-like activity. It is proposed that this hormone be named 'adipokinin'. An analog of this proposed hormone appears to have been isolated previously from porcine pituitaries.