加拿大英属哥伦比亚大学Janel L. Kopp等研究人员合作发现，高胰岛素血症通过增加消化酶的分泌和炎症来引发胰腺癌。2023年10月31日，《细胞—代谢》杂志在线发表了这项成果。

研究人员表示，肥胖和2型糖尿病导致的胰腺癌发病率上升与高胰岛素血症这一独立的癌症风险因素密切相关。先前的研究表明，减少胰岛素分泌可抑制Kras突变小鼠的胰腺上皮内瘤变（PanIN）癌前病变。然而，其病理生理和分子机制仍不清楚，尤其是不清楚高胰岛素血症是直接还是间接影响PanIN癌前病变细胞。

研究人员证明了在饮食诱导的高胰岛素血症和肥胖的情况下，Kras^G12D表达的胰腺泡细胞中的胰岛素受体（Insr）对于葡萄糖稳态是可有可无的，但对于高胰岛素血症驱动的PanIN形成却是必要的。从机理上讲，这归因于消化酶蛋白翻译的扩大、局部炎症的触发以及体内PanIN的新生。在体外，胰蛋白酶和胰岛素依赖性的胰岛素剂量依赖性地增加了腺泡细胞向导管细胞化生形成。总之，这些数据揭示了肥胖驱动的高胰岛素血症与胰腺癌发展之间的关联机制。

附：英文原文

Title: Hyperinsulinemia acts via acinar insulin receptors to initiate pancreatic cancer by increasing digestive enzyme production and inflammation

Author: Anni M.Y. Zhang, Yi Han Xia, Jeffrey S.H. Lin, Ken H. Chu, Wei Chuan K. Wang, Titine J.J. Ruiter, Jenny C.C. Yang, Nan Chen, Justin Chhuor, Shilpa Patil, Haoning Howard Cen, Elizabeth J. Rideout, Vincent R. Richard, David F. Schaeffer, Rene P. Zahedi, Christoph H. Borchers, James D. Johnson, Janel L. Kopp

Issue&Volume: 2023-10-31

Abstract: The rising pancreatic cancer incidence due to obesity and type 2 diabetes is closelytied to hyperinsulinemia, an independent cancer risk factor. Previous studies demonstratedreducing insulin production suppressed pancreatic intraepithelial neoplasia (PanIN)pre-cancerous lesions in Kras-mutant mice. However, the pathophysiological and molecular mechanisms remained unknown,and in particular it was unclear whether hyperinsulinemia affected PanIN precursorcells directly or indirectly. Here, we demonstrate that insulin receptors (Insr) in KrasG12D-expressing pancreatic acinar cells are dispensable for glucose homeostasis but necessaryfor hyperinsulinemia-driven PanIN formation in the context of diet-induced hyperinsulinemiaand obesity. Mechanistically, this was attributed to amplified digestive enzyme proteintranslation, triggering of local inflammation, and PanIN metaplasia in vivo. In vitro, insulin dose-dependently increased acinar-to-ductal metaplasia formation in a trypsin-and Insr-dependent manner. Collectively, our data shed light on the mechanisms connectingobesity-driven hyperinsulinemia and pancreatic cancer development.

DOI: 10.1016/j.cmet.2023.10.003

Source: https://www.cell.com/cell-metabolism/fulltext/S1550-4131(23)00372-8