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

  • Nat Commun. 2023 Oct 18;14(1):6584. doi: 10.1038/s41467-023-42334-y.
Kotaro Soeda  1  2 ,  Takayoshi Sasako  1  2 ,  Kenichiro Enooku  3 ,  Naoto Kubota  2 ,  Naoki Kobayashi  1 ,  Yoshiko Matsumoto Ikushima  1 ,  Motoharu Awazawa  1 ,  Ryotaro Bouchi  4 ,  Gotaro Toda  1  2 ,  Tomoharu Yamada  3 ,  Takuma Nakatsuka  3 ,  Ryosuke Tateishi  3 ,  Miwako Kakiuchi  5 ,  Shogo Yamamoto  5 ,  Kenji Tatsuno  5 ,  Koji Atarashi  6  7 ,  Wataru Suda  7 ,  Kenya Honda  6  7 ,  Hiroyuki Aburatani  5 ,  Toshimasa Yamauchi  2 ,  Mitsuhiro Fujishiro  3 ,  Tetsuo Noda  8 ,  Kazuhiko Koike  3 ,  Takashi Kadowaki  2  9  10 ,  Kohjiro Ueki  11  12
Affiliations
  • 1. Department of Molecular Diabetic Medicine, Diabetes Research Center, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan.
  • 2. Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
  • 3. Department of Gastroenterology, The University of Tokyo, Tokyo, Japan.
  • 4. Diabetes and Metabolism Information Center, Diabetes Research Center, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan.
  • 5. Genome Science Division, The University of Tokyo, Tokyo, Japan.
  • 6. Department of Microbiology and Immunology, Keio University School of Medicine, Tokyo, Japan.
  • 7. RIKEN Center for Integrative Medical Sciences, Yokohama City, Kanagawa, Japan.
  • 8. Department of Cell Biology, Cancer Institute, Japanese Foundation of Cancer Research, Tokyo, Japan.
  • 9. Department of Prevention of Diabetes and Lifestyle-Related Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
  • 10. Toranomon Hospital, Tokyo, Japan.
  • 11. Department of Molecular Diabetic Medicine, Diabetes Research Center, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan. [email protected].
  • 12. Department of Molecular Diabetology, Graduate School of Medicine, the University of Tokyo, Tokyo, Japan. [email protected].
PMID: 37852976 DOI: 10.1038/s41467-023-42334-y
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.

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