The insulin-like properties of vanadium : new perspectives for the treatment of insulin resistance and diabetes ?

Vanadium is an ubiquitous trace element in nature. It is found at very low concentrations in most living organisms, but conclusive demonstration of its essentiality for mammals is still lacking.
In vitro, vanadium salts mimic most, thought not all, effects of insulin on various cell types. One hypothesis ascribes these effects to enhanced phosphorylation of the insulin receptor, but it is still unresolved whether this results from a stimulation of the tyrosine kinase present in the receptor itself, from a direct esterification (vanadylation) of tyrosine residues or from a inhibition of a tyrosine phosphatase. The alternative hypothesis suggests that vanadium salts act at steps distal to the insulin receptor.
In vivo, pharmacological doses of oral vanadate are practically without effect on glucose homeostasis in normal rats, but cause a spectacular fall of blood glucose levels in animals made insulin-deficient and diabetic by streptozotocin injection (model of Type I diabetes). We first confirmed this glucose-lowering effect of vanadate. Next, we demonstrated that this beneficial action could be maintained for more than two months, was observed during glucose tolerance tests as well as under basal conditions, and did not result from a rise in circulating insulin levels. Euglycemic-hyperinsulinemic clamp studies further showed that chronic treatment with vanadium salts restored the ability of insulin to stimulate peripheral glucose disposal and to inhibit hepatic glucose production in diabetic rats. These results are in agreement with those of in vitro studies performed on tissues obtained from similar animals. A shift of the predominating gluconeogenic flux into a glycolytic flux was particularly striking in liver of treated-diabetic rats. We demonstrated that this effect of vanadate was due to correction of altered expression of genes involved in hepatic glucose metabolism. In vivo studies have, however, not solved the controversy about the cellular mechanisms implicated in the glucose-lowering action of vanadium compounds. The tyrosine kinase activity of insulin receptors from tissues of treated-diabetic rats has been found to be enhanced or unchanged. If the latter finding is correct, this suggests that vanadate acts at a postreceptor level.
Beside insulin deficiency, resistance of target tissues to the action of insulin is the other major cause of glucose intolerance. All means susceptible to increase the sensitivity to the hormone or to bypass its action may thus prove extremely useful for controlling perturbations of glucose metabolism. We therefore investigated whether oral vanadate can improve glucose homeostasis in hyperinsulinemic, insulin-resistant rats and mice (models of Type II diabetes). In genetically obese and mildly glucose-intolerant fa/fa rats, 3 months of vanadate treatment markedly decreased plasma insulin levels and improved the tolerance to glucose loads. This improvement could not simply be explained by the lower body weight gain resulting from the anoresigenic action of the element, not by a decrease in insulin counter-regulatory hormones. Changes in FFA levels with subsequent attenuation of the “glucose-fatty acid” cycle were also excluded. The beneficial effects of vanadate can rather be ascribed to a direct correction of impaired tissue sensitive to insulin. Englycemic-hyperinsulinemic clamps have shown that the increment of whole-body glucose disposal brought about by insulin is larger in fa/fa rats treated with vanadate, and that the increase in glucose uptake occurs essentially in muscles. This is particular interest because muscle is the major site of insulin-mediated glucose disposal. Since we found no change in insulin receptor number or affinity, and others did not observe any alteration of receptor tyrosine kinase activity, vanadate action is likely to involve step(s) distal to the receptor. As glucose transport is the rate-limiting step for glucose metabolism, we investigated whether vanadate treatment affects the expression of the insulin-responsive glucose transporter, GLUT4. Both GLUT4 mRNA and protein were unmodified in muscle of treated fa/fa rats. This suggests that a functional improvement of glucose transporters, due to more efficient translocation to plasma membrane and/or increased intrinsic activity, probably plays a major role in the beneficial effect of vanadate. Vanadate was also effective in ob/ob mice, in which insulin resistance leads to overt diabetes. Marked and sustained decreases in plasma glucose and insulin concentrations were observed. The cellular mechanisms involved are likely to be similar to those in fa/fa rats. In addition, the glucose-lowering effect of vanadate indirectly prevents the exhaustion of pancreatic insulin stores.
In conclusion, the insulin-like properties of vanadium salts are not a mere curiosity. They will certainly help elucidating the cellular and molecular mechanisms of insulin action and the causes of its perturbations. In particular, vanadium salts may be instrumental in finding a solution to the difficult problem of insulin resistance. It is significant that the NIH has just launched a clinical research programme “Vanadium salts in the clinical treatment of Diabetes Mellitus”. We believe that our studies in insulin-resistant animals have paved the way of such clinical studies