Section on Islet Cell and Regenerative Biology, Joslin Diabetes Center, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Harvard Stem Cell Institute, Boston, MA 02215, USA.
Chemical Biology and Therapeutics Science Program, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
Cell Metab. 2023 Jul 11;35(7):1242-1260.e9. doi: 10.1016/j.cmet.2023.05.007. Epub 2023 Jun 19.
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.
1 型（T1D）或 2 型糖尿病（T2D）是由功能性胰岛素分泌β细胞缺乏引起的。因此，鉴定β细胞营养因子可以开发出治疗策略来对抗糖尿病。丝氨酸蛋白酶抑制剂 B1（SerpinB1）的发现，它是一种促进人β细胞生长的弹性蛋白酶抑制剂，促使我们假设胰腺弹性蛋白酶（PE）调节β细胞活力。在这里，我们报告说，PE 在 T2D 患者的腺泡细胞和胰岛中上调，并对β细胞活力产生负面影响。使用高通量筛选测定法，我们鉴定出特拉普韦（telaprevir）是一种有效的 PE 抑制剂，它可以增加人和啮齿动物β细胞的活力在体外和体内，并改善胰岛素抵抗小鼠的葡萄糖耐量。磷酸化抗体微阵列和单细胞 RNA 测序分析鉴定出 PAR2 和机械信号通路是 PE 的潜在介质。总之，我们的工作强调了 PE 作为腺泡-β细胞串扰的潜在调节剂，其作用是限制β细胞活力，导致 T2D。
