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Antidiabetic effect of enterolactone in cultured muscle cells and in type 2 diabetic model db/db mice

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Abstract

Enterolactone (ENL) is formed by the conversion of dietary precursors like strawberry lignans via the gut microbiota. Urinary concentrations of lignan metabolites are reported to be significantly associated with a lower risk of Type 2 diabetes (T2D). In the present study, antidiabetic effect of ENL and its modes of action were studied in vitro and in vivo employing a rat skeletal muscle-derived cell line, L6 myocytes in culture, and T2D model db/db mice. ENL dose-dependently increased glucose uptake in L6 myotubes under insulin absent condition. This increase by ENL was canceled by compound C, an inhibitor of 5′-adenosine monophosphate-activated protein kinase (APMK). Activation (=phosphorylation) of AMPK and translocation of glucose transporter 4 (GLUT4) to plasma membrane in L6 myotubes were demonstrated by Western blotting analyses. Promotion by ENL of GLUT4 translocation to plasma membrane was also visually demonstrated by immunocytochemistry in L6 myoblasts that were transfected with glut4 cDNA-coding vector. T2D model db/db mice were fed the basal 20 % casein diet (20C) or 20C supplemented with ENL (0.001 or 0.01 %) for 6 weeks. Fasting blood glucose (FBG) levels were measured every week and intraperitoneal glucose tolerance test (IPGTT) was conducted. ENL at a higher dose (0.01 % in 20C) suppressed the increases in FBG levels. ENL was also demonstrated to improve the index of insulin resistance (HOMA-IR) and glucose intolerance by IPGTT in db/db mice. From these results, ENL is suggested to be an antidiabetic chemical entity converted from dietary lignans by gut microbiota.

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Abbreviations

AMPK:

5′-Adenosine monophosphate-activated protein kinase

ENL:

Enterolactone

FBG:

Fasting blood glucose

GLUT4:

Glucose transporter 4

HOMA-IR:

Homeostasis model assessment of insulin resistance

IPGTT:

Intraperitoneal glucose tolerance test

KHH buffer:

Krebs–Henseleit–Hepes buffer

TBARS:

Thiobarbituric acid-reactive substances

TG:

Triglyceride

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Acknowledgments

This work was supported in part by the Regional Innovation Strategy Support Program, MEXT, Japan, in part by the Japan Society for the Promotion of Science, Japan, and in part by the Tojuro Iijima Foundation for Food Science and Technology, Japan.

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Authors and Affiliations

  1. Department of Applied Biological Chemistry, Tokyo University of Agriculture and Technology, Fuchu, Tokyo, 183-8509, Japan

    Fang Zhou, Keisuke Furuhashi, Myoung Jin Son, Yutaka Miura & Kazumi Yagasaki

  2. Center for Bioscience Research and Education, Utsunomiya University, Utsunomiya, Tochigi, 321-8505, Japan

    Miku Toyozaki, Fumiaki Yoshizawa & Kazumi Yagasaki

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  1. Fang Zhou
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  2. Keisuke Furuhashi
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  3. Myoung Jin Son
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  4. Miku Toyozaki
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  5. Fumiaki Yoshizawa
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  6. Yutaka Miura
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  7. Kazumi Yagasaki
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Correspondence to Kazumi Yagasaki.

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Zhou, F., Furuhashi, K., Son, M.J. et al. Antidiabetic effect of enterolactone in cultured muscle cells and in type 2 diabetic model db/db mice. Cytotechnology 69, 493–502 (2017). https://doi.org/10.1007/s10616-016-9965-2

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  • DOI: https://doi.org/10.1007/s10616-016-9965-2

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