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

Kotaro Soeda, Takayoshi Sasako, Kenichiro Enooku, Naoto Kubota, Naoki Kobayashi, Yoshiko Matsumoto Ikushima, Motoharu Awazawa, Ryotaro Bouchi, Gotaro Toda, Tomoharu Yamada, Takuma Nakatsuka, Ryosuke Tateishi, Miwako Kakiuchi, Shogo Yamamoto, Kenji Tatsuno, Koji Atarashi, Wataru Suda, Kenya Honda, Hiroyuki Aburatani, Toshimasa Yamauchi, Mitsuhiro Fujishiro, Tetsuo Noda, Kazuhiko Koike, Takashi Kadowaki and Kohjiro Ueki ()
Additional contact information
Kotaro Soeda: National Center for Global Health and Medicine
Takayoshi Sasako: National Center for Global Health and Medicine
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
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
Wataru Suda: RIKEN Center for Integrative Medical Sciences
Kenya Honda: Keio University School of Medicine
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
Kohjiro Ueki: National Center for Global Health and Medicine

Nature Communications, 2023, vol. 14, issue 1, 1-18

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-42334-y

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