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

Cell Metab. 2023 Oct 26:S1550-4131(23)00372-8. doi: 10.1016/j.cmet.2023.10.003. Online ahead of print.ABSTRACTThe 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.PMID:37913768 | DOI:10.1016/j.cmet.2023.10.003

Source: Cell Metabolism - November 1, 2023 Category: Cytology Authors: 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 Source Type: research