Bis(allixinato)oxovanadium(IV), VO(alx)(2) (alx is 3-hydroxy-5-methoxy-6-methyl-2-pentyl-4-pyrone), has been reported to act as an
antidiabetic agent in
streptozotocin-induced type-1-like and
obesity-linked KKA(y) type 2 diabetic model mice. VO(alx)(2) is also proposed as a candidate agent for treating
metabolic syndromes in animals. However, its functional mechanism is yet to be clarified. In this study, we examined whether VO(alx)(2) contributes to both the activation of the
insulin signaling cascade that activates
glucose transporter 4 (GLUT4) translocation and the regulation of the forkhead box O1 (FoxO1)
transcription factor that controls the gene transcription of gluconeogenesis genes. The following three important results were obtained: (1) intracellular
vanadium concentration in 3T3-L1 adipocytes is higher
after treatment with VO(alx)(2) than with VOSO(4); (2) VO(alx)(2) stimulates the translocation of GLUT4 to the plasma membrane following activation of the
tyrosine phosphorylation of the
insulin receptor beta-subunit (IRbeta) and
insulin receptor substrate (IRS) as well as Akt
kinase in 3T3-L1 adipocytes; and (3) the mechanism of inhibition of
glucose-6-phosphatase (G6Pase) catalytic subunit gene expression by
vanadium is due to disruption of FoxO1 binding with the G6Pase promoter, which indicates that FoxO1 is phosphorylated by VO(alx)(2)-stimulated Akt in HepG2 cells. On the basis of these results, we propose that the critical functions of VO(alx)(2) involve the activation of
phosphatidylinositol 3-kinase-Akt signaling through the enhancement of
tyrosine phosphorylation of IRbeta and IRS, which in turn transmits the signal to activate GLUT4 translocation, and the regulation of the
DNA binding activity of the FoxO1
transcription factor.