Safranal, a novel protein tyrosine phosphatase 1B inhibitor, activates insulin signaling in C2C12 myotubes and improves glucose tolerance in diabetic KK-Ay mice

Authors

  • Ayumi Maeda,

    1. Department of Biological Chemistry, Division of Applied Life Science, Graduate School of Life and Environmental Sciences, Osaka Prefecture University, Sakai, Japan
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  • Kenji Kai,

    1. Department of Biological Chemistry, Division of Applied Life Science, Graduate School of Life and Environmental Sciences, Osaka Prefecture University, Sakai, Japan
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  • Megumi Ishii,

    1. Department of Biological Chemistry, Division of Applied Life Science, Graduate School of Life and Environmental Sciences, Osaka Prefecture University, Sakai, Japan
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  • Takeshi Ishii,

    1. Department of Food and Nutritional Sciences, and Global COE Program, University of Shizuoka, Shizuoka, Japan
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  • Mitsugu Akagawa

    Corresponding author
    1. Department of Biological Chemistry, Division of Applied Life Science, Graduate School of Life and Environmental Sciences, Osaka Prefecture University, Sakai, Japan
    • Correspondence: Dr. Mitsugu Akagawa, Department of Biological Chemistry, Division of Applied Life Science, Graduate School of Life and Environmental Sciences, Osaka Prefecture University, 1-1 Gakuen-cho, Naka-ku, Sakai 599-8531, Japan

      E-mail: akagawa@biochem.osakafu-u.ac.jp

      Fax: +81-72-254-9460

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Abstract

Scope

Protein tyrosine phosphatase 1B (PTP1B) negatively regulates insulin signaling by tyrosine dephosphorylation of insulin receptor, and its increased activity and expression is implicated in the pathogenesis of insulin resistance. Hence, PTP1B inhibition is anticipated to improve insulin resistance in type 2 diabetic subjects. The aim of this study was to find a novel PTP1B inhibitor from medicinal food and to evaluate its antidiabetic effects.

Methods and results

We found that saffron (Crocus sativus L.), which is used both as a spice and as a traditional medicine, potently inhibits PTP1B activity. Analyses of saffron extracts demonstrated that safranal, the saffron's aroma compound, is a principal PTP1B inhibitor, and induces a ligand-independent activation of insulin signaling in cultured myotubes. Our data implied that the molecular mechanism underlying the inactivation of PTP1B could be attributed to the covalent modification of the catalytic cysteinyl thiol by safranal through a Michael addition. Furthermore, safranal significantly enhanced glucose uptake through the translocation of glucose transporter 4. We also demonstrated that 2-wk oral administration of 20 mg/kg/day safranal improved impaired glucose tolerance in type 2 diabetic KK-Ay mice.

Conclusion

Our results strongly suggest the usefulness of safranal in antidiabetic treatment for type 2 diabetic subjects.

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