Cell Death and Disease (Sep 2023)

Metabolic intervention by low carbohydrate diet suppresses the onset and progression of neuroendocrine tumors

  • Yu Chen,
  • Tatsuki Yamamoto,
  • Yura Takahashi,
  • Tomoka Moro,
  • Tomoko Tajima,
  • Yukiko Sakaguchi,
  • Naoaki Sakata,
  • Akihiko Yokoyama,
  • Susumu Hijioka,
  • Akane Sada,
  • Yuko Tabata,
  • Rieko Ohki

DOI
https://doi.org/10.1038/s41419-023-06123-1
Journal volume & issue
Vol. 14, no. 9
pp. 1 – 13

Abstract

Read online

Abstract Insulin signaling often plays a role in the regulation of cancer, including tumor initiation, progression, and response to treatment. In addition, the insulin-regulated PI3K-Akt-mTOR pathway plays an important role in the regulation of islet cell proliferation, and this pathway is hyperactivated in human non-functional pancreatic neuroendocrine tumors (PanNETs). We, therefore, investigated the effect of a very low carbohydrate diet (ketogenic diet) on a mouse model that develops non-functional PanNETs to ask how reduced PI3K-Akt-mTOR signaling might affect the development and progression of non-functional PanNET. We found that this dietary intervention resulted in lower PI3K-Akt-mTOR signaling in islet cells and a significant reduction in PanNET formation and progression. We also found that this treatment had a significant effect on the suppression of pituitary NET development. Furthermore, we found that non-functional PanNET patients with lower blood glucose levels tend to have a better prognosis than patients with higher blood glucose levels. This preclinical study shows that a dietary intervention that results in lower serum insulin levels leads to lower insulin signals within the neuroendocrine cells and has a striking suppressive effect on the development and progression of both pancreatic and pituitary NETs.