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Bis(hinokitiolato)zinc complex ([Zn(hkt)2]) activates Akt/protein kinase B independent of insulin signal transduction

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Abstract

Since many Zn complexes have been developed to enhance the insulin-like activity and increase the exposure and residence of Zn in the animal body, these complexes are recognized as one of the new candidates with action mechanism different from existing anti-diabetic drugs. However, the molecular mechanism by which Zn complexes exert an anti-DM effect is unknown. Therefore, we evaluated the activity of Zn complexes, especially related to the phosphorylation of insulin signaling pathway components. We focused on the insulin-like effects of the bis(hinokitiolato)zinc complex, [Zn(hkt)2], using 3T3-L1 adipocytes. [Zn(hkt)2] was taken up by cells and induced Akt phosphorylation in a time-dependent manner. Additionally, it showed inhibitory activity against PTP1B and PTEN, which are major negative regulators of insulin signaling. It did not promote the phosphorylation of IR (insulin receptor)-β or IRS (insulin receptor substrate)-1 by itself, but in combination with insulin, it enhanced the phosphorylation of IRβ. We conclude that [Zn(hkt)2] has effects on the proteins of insulin signaling pathway without insulin receptor mediation, and [Zn(hkt)2] promotes insulin function and shows the anti-DM effects. Thus, [Zn(hkt)2] may be the basis for improved DM treatments.

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Acknowledgments

The authors are deeply grateful to members of the Department of Analytical and Bioinorganic Chemistry, Division of Analytical and Physical Sciences of Kyoto Pharmaceutical University. Additionally, the authors would like to express their gratitude to Akihiro Hiraki, Ph.D. and Kentaro Nishida, Ph. D. of Kyoto Pharmaceutical University for their technical advice and kind cooperation.

This study was financially supported in part by a Grant from the Ministry of Education, Culture, Sports, Science, and Technology of Japan (MEXT) Supported Program for the Strategic Research Foundation at Private Universities, 2012–2016 (S1201008). This work was also supported by JSPS KAKENHI Grant Numbers 25460048 (to YY) and 26460636 (to HY).

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Authors and Affiliations

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

    Yuki Naito, Yutaka Yoshikawa & Hiroyuki Yasui

  2. Department of Health, Sports, and Nutrition, Faculty of Health and Welfare, Kobe Women’s University, 4-7-2 Minatojima-nakamachi, Chuo-ku, Kobe, 650-0046, Japan

    Yutaka Yoshikawa

  3. Department of Physical Chemistry, Graduate School of Clinical Pharmacy, Shujitsu University, 1-6-1 Nishigawara, Naka-ku, Okayama, 703-8516, Japan

    Kazufumi Masuda

Authors
  1. Yuki Naito
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  2. Yutaka Yoshikawa
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  3. Kazufumi Masuda
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  4. Hiroyuki Yasui
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Correspondence to Yutaka Yoshikawa or Hiroyuki Yasui.

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Naito, Y., Yoshikawa, Y., Masuda, K. et al. Bis(hinokitiolato)zinc complex ([Zn(hkt)2]) activates Akt/protein kinase B independent of insulin signal transduction. J Biol Inorg Chem 21, 537–548 (2016). https://doi.org/10.1007/s00775-016-1364-9

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  • DOI: https://doi.org/10.1007/s00775-016-1364-9

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