Article ; Online: Excess pancreatic elastase alters acinar-β cell communication by impairing the mechano-signaling and the PAR2 pathways.
2023 Volume 35, Issue 7, Page(s) 1242–1260.e9
Abstract: 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 ... ...
| Abstract | 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. |
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| MeSH term(s) | Humans ; Mice ; Animals ; Acinar Cells/metabolism ; Diabetes Mellitus, Type 2/metabolism ; Pancreatic Elastase/metabolism ; Insulin-Secreting Cells/metabolism ; Insulin/metabolism ; Cell Communication |
| Chemical Substances | Pancreatic Elastase (EC 3.4.21.36) ; Insulin |
| Language | English |
| Publishing date | 2023-06-19 |
| Publishing country | United States |
| Document type | Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't |
| ZDB-ID | 2176834-1 |
| ISSN | 1932-7420 ; 1550-4131 |
| ISSN (online) | 1932-7420 |
| ISSN | 1550-4131 |
| DOI | 10.1016/j.cmet.2023.05.007 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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