Metformin suppresses MEN1-associated pancreatic and pituitary neuroendocrine tumors: evidence from mouse models and clinical data.

Pancreatic neuroendocrine tumors (PanNETs) represent a rare subset of pancreatic cancers, comprising approximately 1-2% of all cases. Non-functioning PanNETs (NF-PanNETs), which account for the majority of PanNETs, can be difficult to treat as they show no hormone-related symptoms and are often not diagnosed until more advanced stages. Current therapeutic agents have limited efficacy, highlighting the need for novel treatment strategies. Multiple endocrine neoplasia type 1 is a hereditary syndrome strongly associated with PanNETs and pituitary neuroendocrine tumors (PitNETs), caused by germline mutations in the MEN1 gene. Using Men1 f/f-RipCre+ mice, which develop both NF-PanNETs and PitNETs, we investigated whether long-term administration of metformin, a first-line anti-diabetic drug, could suppress tumor development and progression. Metformin significantly inhibited the elevation of blood glucose in Men1 f/f-RipCre+ mice, and longer-term treatment attenuated PanNETs and restored normal insulin secretion. Metformin suppressed the proliferative pathways, including the PI3K/Akt/mTOR signaling pathway. In addition to its effects on PanNETs, metformin also attenuated PitNET development, elevated antiproliferative pathways, and suppressed angiogenic pathways. Furthermore, clinical data revealed that NF-PanNET patients with prior metformin use exhibited improved prognosis. These findings demonstrate that blood glucose control through metformin represents a promising preventive and therapeutic strategy for NF-PanNETs and MEN1-associated neuroendocrine tumors.