Excess pancreatic elastase alters acinar-β cell communication by impairing the mechano-signaling and the PAR2 pathways

Type 1 (T1D) or type 2 diabetes (T2D) are caused by a deficit of functional insulin-producing β cells. Thus, the identification of β cell trophic agents could allow the development of therapeutic strategies to counteract diabetes. The discovery of SerpinB1, an elastase inhibitor that promotes human β cell growth, prompted us to hypothesize that pancreatic elastase (PE) regulates β cell viability. Here, we report that PE is up-regulated in acinar cells and in islets from T2D patients, and negatively impacts β cell viability. Using high-throughput screening assays, we identified telaprevir as a potent PE inhibitor that can increase human and rodent β cell viability in vitro and in vivo and improve glucose tolerance in insulin-resistant mice. Phospho-antibody microarrays and single-cell RNA sequencing analysis identified PAR2 and mechano-signaling pathways as potential mediators of PE. Taken together, our work highlights PE as a potential regulator of acinar-β cell crosstalk that acts to limit β cell viability, leading to T2D. Video abstract eyJraWQiOiI4ZjUxYWNhY2IzYjhiNjNlNzFlYmIzYWFmYTU5NmZmYyIsImFsZyI6IlJTMjU2In0.eyJzdWIiOiJhYzE3NWNkNGIyYzFkYWU3ZjgwMjMyNTI3YjNlNzNkYyIsImtpZCI6IjhmNTFhY2FjYjNiOGI2M2U3MWViYjNhYWZhNTk2ZmZjIiwiZXhwIjoxNzA5NzY5NTk4fQ.E9MAMjQprQbZMJdHXIMi4X9yyYVk1UKQvRSA0o9KLb388P4GG-p81EKGDR4lV05RXuKs04584Y8T1o7ulOZWhFGBtby2WFN7CbZW6O9STgwaMRwphR8fnJ_6Cy2Xw-BRv1W9ozCUIHtRnY-D53WWb0Cqo9rEAo1WRHwRzp4zZmv6Fk4DG66N4BHEaPn_WXWZGLkCptXrdvRx8UeX52DVnqOrbS0IyPwuVwBRzVGB5X46uOa1yqxALmHQG2sGjlbF3_UFj2A9Q7A8I9m4kTDe2BWTIcDAf4lXaGQIqRd3lZwp515FLBgUciYl_7sXdEu9PetPJJtE79EQzVtv5D6twQ (mp4, (13.32 MB) Download video