Metabolic intervention that reduces glucose-insulin signaling suppresses the onset and progression of neuroendocrine tumors

Ohki, R.; Chen, Y.; Sada, A.; Tabata, Y.; Moro, T.; Sakaguchi, Y.; Tajima, T.; Takahashi, Y.; Yokoyama, A.; Hijioka, S.

doi:10.1101/2022.10.21.507065

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bioRxiv · 10.1101/2022.10.21.507065

Metabolic intervention that reduces glucose-insulin signaling suppresses the onset and progression of neuroendocrine tumors

Ohki, R.·Chen, Y.·Sada, A.·Tabata, Y.·Moro, T.·Sakaguchi, Y.·Tajima, T.·Takahashi, Y.·Yokoyama, A.·Hijioka, S.

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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 signal within the neuroendocrine cells and has a striking suppressive effect on the development and progression of both pancreatic and pituitary NETs.

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Ohki, R., Chen, Y., Sada, A., Tabata, Y., Moro, T., Sakaguchi, Y., Tajima, T., Takahashi, Y., Yokoyama, A., Hijioka, S.. 2022-10-22. Metabolic intervention that reduces glucose-insulin signaling suppresses the onset and progression of neuroendocrine tumors. https://doi.org/10.1101/2022.10.21.507065

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