Pervanadate stimulation of wortmannin-sensitive and -resistant 2-deoxyglucose transport in adipocytes

Pervanadate mimics several distinct insulin effects, including stimulation of hexose uptake in the in vitro system, and reduces the blood glucose level in streptozotocin-treated diabetic rats. It has been proposed that pervanadate induces insulin-like effects mediated through autophosphorylation and activation of insulin receptor (IR) even in the absence of insulin by inhibiting protein tyrosine phosphatases. This study focused on the mechanism of pervanadate action on hexose uptake. Both insulin (100 nM) and pervanadate (100 microM), a protein tyrosine phosphatase inhibitor, induced a marked increase in the phosphorylation at tyrosine residues of IR and insulin receptor substrate 1 (IRS-1) and in 2-deoxyglucose uptake in 3T3-L1 adipocytes. Wortmannin (1 microM), a specific phosphatidylinositol 3-kinase (PI 3-kinase) inhibitor, inhibited the increased 2-deoxyglucose uptake by insulin completely but that by pervanadate only partially. On the other hand, both insulin- and pervanadate-stimulated PI 3-kinase activities were inhibited completely by wortmannin (100 nM), suggesting that the pervanadate-induced wortmannin-resistant effect on hexose uptake may be mediated through a PI 3-kinase-independent pathway. This pervanadate-induced wortmannin-resistant effect was abolished by ST-638, a specific tyrosine kinase inhibitor. These data suggest that at least two distinct tyrosine phosphorylation pathways may be involved in the insulin-like effect of pervanadate.