title: Action mechanism of bis(allixinato)oxovanadium(IV) as a novel potent insulin-mimetic complex: regulation of GLUT4 translocation and FoxO1 transcription factor.
abstract: 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.
authors.affiliation: Department of Analytical and Bioinorganic Chemistry, Kyoto Pharmaceutical University, 5 Nakauchi-cho, Misasagi, Yamashina-ku, Kyoto, Japan. mhiromura@riken.jp
authors.forename: Makoto
authors.initials: M
authors.lastname: Hiromura
authors.forename: Akihiro
authors.initials: A
authors.lastname: Nakayama
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Adachi
authors.forename: Miyuki
authors.initials: M
authors.lastname: Doi
authors.forename: Hiromu
authors.initials: H
authors.lastname: Sakurai
mesh_terms: D000818:Animals; D040761:Biomimetic Materials / Q000378:metabolism / Q000494:pharmacology*; D002460:Cell Line; D004247:DNA / Q000378:metabolism; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D051275:Glucose Transporter Type 4 / Q000378:metabolism*; D005952:Glucose-6-Phosphatase / Q000037:antagonists & inhibitors; D006801:Humans; D007004:Hypoglycemic Agents / Q000378:metabolism / Q000494:pharmacology*; D007328:Insulin / Q000378:metabolism* / Q000494:pharmacology; D051379:Mice; D009942:Organometallic Compounds / Q000378:metabolism / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D014639:Vanadium / Q000032:analysis