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Gut insulin action protects from hepatocarcinogenesis in diabetic mice comorbid with nonalcoholic steatohepatitis

Author

Listed:
  • Kotaro Soeda

    (National Center for Global Health and Medicine
    The University of Tokyo)

  • Takayoshi Sasako

    (National Center for Global Health and Medicine
    The University of Tokyo)

  • Kenichiro Enooku

    (The University of Tokyo)

  • Naoto Kubota

    (The University of Tokyo)

  • Naoki Kobayashi

    (National Center for Global Health and Medicine)

  • Yoshiko Matsumoto Ikushima

    (National Center for Global Health and Medicine)

  • Motoharu Awazawa

    (National Center for Global Health and Medicine)

  • Ryotaro Bouchi

    (National Center for Global Health and Medicine)

  • Gotaro Toda

    (National Center for Global Health and Medicine
    The University of Tokyo)

  • Tomoharu Yamada

    (The University of Tokyo)

  • Takuma Nakatsuka

    (The University of Tokyo)

  • Ryosuke Tateishi

    (The University of Tokyo)

  • Miwako Kakiuchi

    (The University of Tokyo)

  • Shogo Yamamoto

    (The University of Tokyo)

  • Kenji Tatsuno

    (The University of Tokyo)

  • Koji Atarashi

    (Keio University School of Medicine
    RIKEN Center for Integrative Medical Sciences)

  • Wataru Suda

    (RIKEN Center for Integrative Medical Sciences)

  • Kenya Honda

    (Keio University School of Medicine
    RIKEN Center for Integrative Medical Sciences)

  • Hiroyuki Aburatani

    (The University of Tokyo)

  • Toshimasa Yamauchi

    (The University of Tokyo)

  • Mitsuhiro Fujishiro

    (The University of Tokyo)

  • Tetsuo Noda

    (Cancer Institute, Japanese Foundation of Cancer Research)

  • Kazuhiko Koike

    (The University of Tokyo)

  • Takashi Kadowaki

    (The University of Tokyo
    The University of Tokyo
    Toranomon Hospital)

  • Kohjiro Ueki

    (National Center for Global Health and Medicine
    the University of Tokyo)

Abstract

Diabetes is known to increase the risk of nonalcoholic steatohepatitis (NASH) and hepatocellular carcinoma (HCC). Here we treat male STAM (STelic Animal Model) mice, which develop diabetes, NASH and HCC associated with dysbiosis upon low-dose streptozotocin and high-fat diet (HFD), with insulin or phlorizin. Although both treatments ameliorate hyperglycemia and NASH, insulin treatment alone lead to suppression of HCC accompanied by improvement of dysbiosis and restoration of antimicrobial peptide production. There are some similarities in changes of microflora from insulin-treated patients comorbid with diabetes and NASH. Insulin treatment, however, fails to suppress HCC in the male STAM mice lacking insulin receptor specifically in intestinal epithelial cells (ieIRKO), which show dysbiosis and impaired gut barrier function. Furthermore, male ieIRKO mice are prone to develop HCC merely on HFD. These data suggest that impaired gut insulin signaling increases the risk of HCC, which can be countered by restoration of insulin action in diabetes.

Suggested Citation

  • Kotaro Soeda & Takayoshi Sasako & Kenichiro Enooku & Naoto Kubota & Naoki Kobayashi & Yoshiko Matsumoto Ikushima & Motoharu Awazawa & Ryotaro Bouchi & Gotaro Toda & Tomoharu Yamada & Takuma Nakatsuka , 2023. "Gut insulin action protects from hepatocarcinogenesis in diabetic mice comorbid with nonalcoholic steatohepatitis," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-42334-y
    DOI: 10.1038/s41467-023-42334-y
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