Historic perspective and recent developments on the insulin-like actions of vanadium; toward developing vanadium-based drugs for diabetes

Intensive studies have been carried out during the last two decades, on the insulinomimetic effects of vanadium. Vanadium compounds mimic most of the metabolic effects of insulin on the main tissues of the hormone in vitro. Vanadium therapy induces normoglycemia and improves glucose homeostasis in insulin deficient and insulin resistant diabetic rodents. Improved sensitivity to insulin in liver and muscle tissues of Type II diabetic patients following vanadium therapy was observed as well. The key mechanisms involved are inhibition of protein-phosphotyrosine phosphatases and activation of nonreceptor protein-tyrosine kinases, in an insulin-receptor tyrosine kinase independent fashion. Vanadate activates glucose-metabolism in vitro at a site preceding activation of phosphatidylinositol-3-kinase (PI3-kinase). Regarding inhibition of lipolysis, vanadate (but not insulin) acts at a site downstream to the activation of PI3 kinase. Additional vanadium-dependent mechanism, operating in vivo, is the restoration of glucose-6-phosphate levels in liver, muscle and adipose tissue of hyperglycemic diabetic rats. This is attributed to vanadate-dependent inhibition of liver glucose-6-phosphatase, and of nonspecific hexose-6-phosphatases of the diabetic muscle and adipose tissues. Initial clinical studies were already performed. Several beneficial effects were documented. The potential usage of vanadium in the future care of diabetes in human, however, depends on manipulations that would elevate the insulinomimetic efficacy of vanadium without increasing its toxicity. Organically chelated vanadium compounds, in particular, the L-isomer of Glu(gamma) monohydroxamate (L-Glu(gamma)HXM) are active in potentiating the capacity of free vanadium to activate glucose metabolism, in vitro and in diabetic rats in vivo. L-Glu(gamma)HXM differs from other vanadium ligands in being an amino acid derivative that permeates into peripheral tissues through the amino acid transport system. In rat adipocytes, L-Glu(gamma)HXM itself activates partially glucose metabolism, by permeating into cell interior, associating with the minute quantity of intracellular vanadium, and turning it into an insulinomimetic active species. L-Glu(gamma)HXM, associates with the vanadyl (+4) cation, and the vanadate (+5) anion, at neutral pH with nearly the same binding affinity. Both these oxidation states of vanadium are insulinomimetic. The therapeutical potency of L-Glu(gamma)HXM vanadium complexes is actively studied. Preliminary results on this issue are to be presented. (C) 2002 Elsevier Science B.V. All rights reserved.