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Action mechanism of bis(allixinato)oxovanadium(IV) as a novel potent insulin-mimetic complex: regulation of GLUT4 translocation and FoxO1 transcription factor

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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 KKAy 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 VOSO4; (2) VO(alx)2 stimulates the translocation of GLUT4 to the plasma membrane following activation of the tyrosine phosphorylation of the insulin receptor β-subunit (IRβ) 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 IRβ 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.

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Abbreviations

BSA:

Bovine serum albumin

ChIP:

Chromatin immunoprecipitation

DM:

Diabetes mellitus

DMEM:

Dulbecco’s modified Eagle’s medium

DTT:

Dithiothreitol

EGTA:

Ethylene glycol bis(2-aminoethyl ether)tetraacetic acid

FBS:

Fetal bovine serum

FITC:

Fluorescein isothiocyanate

FoxO1:

Forkhead box O1

G6Pase:

Glucose-6-phosphatase

GLUT4:

Glucose transporter 4

GSK3β:

Glycogen synthase kinase-3β

Hepes:

N-(2-Hydroxyethyl)piperazine-N′-ethanesulfonic acid

HNMPA-(AM)3 :

Hydroxy-2-naphthalenylmethylphosphonic acid tris(acetoxymethyl) ester

IRβ:

Insulin receptor β-subunit

IRE:

Insulin regulatory element

IRS:

Insulin receptor substrate

MAPK:

Mitogen-activated protein kinase

PBS:

Phosphate-buffered saline

PBST:

Phosphate-buffered saline containing 0.1% Tween 20

PEPCK:

Phosphoenolpyruvate carboxykinase

PI3K:

Phosphatidylinositol 3-kinase

PKA:

Protein kinase A

PMSF:

Polymethylsulfonyl fluoride

pNP:

p-Nitrophenol

pNPP:

p-Phosphonitrophenol

SDS:

Sodium dodecyl sulfate

STZ:

Streptozotocin

TBS:

Tris(hydroxymethyl)aminomethane (Tris)-buffered saline

Tris:

Tris(hydroxymethyl)aminomethane

VO(alx)2 :

Bis(allixinato)oxovanadium(IV)

VO(ma)2 :

Bis(maltolato)oxovanadium(IV)

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Acknowledgement

This study was supported in part by grants from the Ministry of Education, Culture, Sports, Science and Technology of the Japanese Government [Grants-in-Aid for Scientific Research (B), Scientific Research on Priority Areas, and Specially Promoted Research] to H.S.

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Author notes

  1. Makoto Hiromura

    Present address: Metallomics Research Unit, Riken, Wako, Saitama, 351-0198, Japan

Authors and Affiliations

  1. Department of Analytical and Bioinorganic Chemistry, Kyoto Pharmaceutical University, 5 Nakauchi-cho, Misasagi, Yamashina-ku, Kyoto, 607-8414, Japan

    Makoto Hiromura, Akihiro Nakayama, Yusuke Adachi, Miyuki Doi & Hiromu Sakurai

  2. Institute of Oriental Medicine, Suzuka University of Medical Science, 1001-1 Kishioka-cho, Suzuka, Mie, 510-0298, Japan

    Hiromu Sakurai

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  1. Makoto Hiromura
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Correspondence to Hiromu Sakurai.

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Hiromura, M., Nakayama, A., Adachi, Y. et al. Action mechanism of bis(allixinato)oxovanadium(IV) as a novel potent insulin-mimetic complex: regulation of GLUT4 translocation and FoxO1 transcription factor. J Biol Inorg Chem 12, 1275–1287 (2007). https://doi.org/10.1007/s00775-007-0295-x

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