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

Cell metabolism Pub Date : 2023-12-05 Epub Date: 2023-10-31 DOI:10.1016/j.cmet.2023.10.003
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
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Abstract

The rising pancreatic cancer incidence due to obesity and type 2 diabetes is closely tied to hyperinsulinemia, an independent cancer risk factor. Previous studies demonstrated reducing 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 precursor cells directly or indirectly. Here, we demonstrate that insulin receptors (Insr) in KrasG12D-expressing pancreatic acinar cells are dispensable for glucose homeostasis but necessary for hyperinsulinemia-driven PanIN formation in the context of diet-induced hyperinsulinemia and obesity. Mechanistically, this was attributed to amplified digestive enzyme protein translation, 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 connecting obesity-driven hyperinsulinemia and pancreatic cancer development.

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高胰岛素血症通过腺泡胰岛素受体通过增加消化酶的产生和炎症来引发胰腺癌症。
由于肥胖和2型糖尿病导致的癌症发病率上升与高胰岛素血症密切相关,高胰岛素血症是癌症的一个独立危险因素。先前的研究表明,减少胰岛素产生可以抑制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然未知,特别是高胰岛素血症是否直接或间接影响PanIN前体细胞尚不清楚。在这里,我们证明了表达KrasG12D的胰腺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,但对于饮食诱导的高胰岛素血症和肥胖背景下高胰岛素血症驱动的PanIN形成是必要的。从机制上讲,这归因于消化酶蛋白翻译的扩增、局部炎症的触发以及体内PanIN化生。在体外,胰岛素以胰蛋白酶和Insr依赖的方式剂量依赖性地增加腺泡到导管化生的形成。总之,我们的数据揭示了肥胖驱动的高胰岛素血症与胰腺癌症发展之间的机制。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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