Studies on the mechanism of the insulin-mimetic effects of vanadium in streptozotocin-diabetic rats

A series of studies was conducted to examine the possible mechanism(s) involved in the insulin-mimetic effects of vanadium in streptozotocin (STZ)-diabetic rats. It was hypothesized that vanadium treatment may induce a glucose-lowering effect and an overall amelioration of the diabetic state by 3 general mechanisms: i) by preventing the STZ-induced cytotoxic effects on (i-cells, resulting in the chronic reversal of the diabetic state, ii) by reducing food intake, or iii) by enhancing the peripheral effects of insulin. The goal was to examine the significance of the apparent multiple roles for vanadium both at the level of the R-cell and in peripheral tissues. Since delayed vanadium treatment up to 17 days after STZ did not reduce the incidence of normoglycemia or correction of adipose tissue function, it is unlikely that vanadium treatment shortly (3 days) after the induction of STZ-diabetes resulted from a direct inhibition of the acute STZ-induced R-cytotoxicity. However, the residual insulin secretory function in these animals may have contributed to an effective response to vanadium. Indeed, the more severely diabetic animals which were previously unresponsive to vanadium treatment developed normoglycemia with higher amounts of either naglivan (a more orally potent organic vanadyl compound) or vanadyl sulfate, suggesting that vanadium and insulin work in a complementary manner in vivo. Vanadium-treated diabetic animals were found to maintain long-term (20-30 weeks) normoglycemia after withdrawal from treatment, a phenomenon which was linked to an improved R-cell secretory function. The post-withdrawal normoglycemia could not be demonstrated in rats treated with vanadium prior to the administration of STZ alone, suggesting the lack of a direct inhibitory effect of vanadium on STZ-induced fi-cytotoxicity in vivo. However, continued treatment for 2 weeks after STZ induced a partial preservation of fi-cells which was sufficient for a chronic reversal of the diabetic state. It appeared that the small changes in pancreatic insulin content had profound consequences on glucose homeostasis in animals with a reduced ft-cell mass. Although the modest effects of a reduced food intake on improving glycemia and residual pancreatic insulin content suggest that it may contribute to the overall effects of vanadium treatment, the partial lowering of glycemia in pair-fed diabetic rats was linked to residual insulin levels in the plasma and pancreas, unlike vanadium-treated animals which maintained normoglycemia at relatively low levels of both circulating and pancreatic insulin. Thus, the mechanism(s) of glucose-lowering by food reduction is distinct from that of vanadium. However, the protection of residual insulin stores by vanadium or food restriction may be secondary to a higher threshold for insulin release. A possible mechanism for vanadium in improving glucose tolerance in diabetic animals is an enhanced glucose transport in insulin-sensitive tissues. The effect of vanadium treatment on the adipose tissue insulin-regulatable glucose transporter (GLUT4) translocation in vivo in response to an i.v. glucose load was examined. Vanadium treatment did not enhance the effects of insulin on GLUT4 translocation at least in adipose tissue in control and diabetic animals. Alternately, the improved glucose tolerance and maintenance of adipose tissue intracellular GLUT4 pool in diabetic rats treated with vanadium appear to be secondary to the preservation of pancreatic insulin stores.Pharmaceutical Sciences, Faculty ofGraduat