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Molecular mechanism of antidiabetic zinc–allixin complexes: regulations of glucose utilization and lipid metabolism

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Abstract

We previously reported new zinc complexes of allixin [bis(allixinato)zinc] and its derivative bis(thioallixin-N-methyl)zinc that demonstrated excellent antidiabetic activity in type 2 diabetic mellitus KKAy mice. However, the molecular mechanism of these complexes is not fully understood. Thus, we attempted to reveal the intracellular mechanism of these complexes in 3T3-L1 adipocytes. Both zinc complexes induced Akt/protein kinase B (Akt/PKB) phosphorylation. The phosphorylation of Akt/PKB enhanced glucose transporter 4 translocation to the plasma membrane; this in turn enhanced the glucose utilization in a dose- and time-dependent manner. Glucose utilization by the complexes depended on the intracellular zinc concentration. Moreover, zinc complexes suppressed the cyclic AMP dependent protein kinase mediated phosphorylation of hormone-sensitive lipase (HSL), leading to the inhibition of free fatty acid release from the 3T3-L1 adipocytes. Such responses were inhibited by wortmannin, suggesting that the suppression of HSL by zinc complexes was dependent in the phosphoinositide 3-kinase–Akt/PKB signaling cascade. On the basis of these results, we proposed that both zinc complexes activated the Akt/PKB-mediated insulin-signaling pathway and improved both glucose utilization and lipid metabolism.

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Abbreviations

ANOVA:

Analysis of variance

BSA:

Bovine serum albumin

cAMP:

Cyclic AMP

DM:

Diabetes mellitus

DMEM:

Dulbecco’s modified Eagle’s medium

FBS:

Fetal bovine serum

FFA:

Free fatty acid

GLUT4:

Glucose transporter 4

HSL:

Hormone-sensitive lipase

IBMX:

3-Isobutyl-1-methylxanthine

IRβ:

Insulin receptor β-subunit

2-NBDG:

2-[N-(7-Nitrobenz-2-oxa-1,3-diazol-4-yl) amino]-deoxy-d-glucose

PBS:

Phosphate-buffered saline

PDE:

Phosphodiesterase

PDE3B:

Phosphodiesterase 3B

PI3K:

Phosphoinositide 3-kinase

PKA:

Cyclic AMP dependent protein kinase

PKB:

Protein kinase B

PTEN:

Phosphatases and tensin homologue deleted chromosome 10

Zn(alx)2 :

Bis(allixinato)zinc

Zn(tanm)2 :

Bis(thioallixin-N-methyl)zinc

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Acknowledgments

This study was supported in part by grants from the Ministry of Education, Culture, Sports, Science, and Technology of the Japanese Government [Grant-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

    Akihiro Nakayama, Makoto Hiromura, Yusuke Adachi & Hiromu Sakurai

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

    Hiromu Sakurai

Authors
  1. Akihiro Nakayama
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  2. Makoto Hiromura
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Corresponding author

Correspondence to Hiromu Sakurai.

Additional information

A. Nakayama and M. Hiromura contributed equally to this work.

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Nakayama, A., Hiromura, M., Adachi, Y. et al. Molecular mechanism of antidiabetic zinc–allixin complexes: regulations of glucose utilization and lipid metabolism. J Biol Inorg Chem 13, 675–684 (2008). https://doi.org/10.1007/s00775-008-0352-0

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  • DOI: https://doi.org/10.1007/s00775-008-0352-0

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