Excess pancreatic elastase alters acinar-ß cell communication by impairing the mechano-signaling and the PAR2 pathways.
Cell Metab
; 35(7): 1242-1260.e9, 2023 07 11.
Article
em En
| MEDLINE
| ID: mdl-37339634
ABSTRACT
Type 1 (T1D) or type 2 diabetes (T2D) are caused by a deficit of functional insulin-producing ß cells. Thus, the identification of ß cell trophic agents could allow the development of therapeutic strategies to counteract diabetes. The discovery of SerpinB1, an elastase inhibitor that promotes human ß cell growth, prompted us to hypothesize that pancreatic elastase (PE) regulates ß cell viability. Here, we report that PE is up-regulated in acinar cells and in islets from T2D patients, and negatively impacts ß cell viability. Using high-throughput screening assays, we identified telaprevir as a potent PE inhibitor that can increase human and rodent ß 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-ß cell crosstalk that acts to limit ß cell viability, leading to T2D.
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Base de dados:
MEDLINE
Assunto principal:
Diabetes Mellitus Tipo 2
/
Células Secretoras de Insulina
Idioma:
En
Ano de publicação:
2023
Tipo de documento:
Article