Activation of a Yap1-mesenchymal-like program in β-cells during diabetes.

A critical driver of type 2 diabetes is the failure of insulin-secreting β cells due to dysfunction and loss of cell number or identity. The signaling pathways that trigger these events remain unclear. Here, we identify an epithelial-to-mesenchymal (EMT)-like program that is activated in β cells to promote their loss with type 2 diabetes. This program is initiated in human and mouse β cells by the EMT transcription factor Yap1. While this protein is normally not present in β cells, Yap1 becomes upregulated in response to oxidative stress and impaired mitochondrial function. Chemical inhibition of Yap1 in islets reverses EMT-like activation while its overexpression in cells triggered the appearance of mesenchymal-like vimentin+ cells. Functionally, blocking Yap1 in isolated islets and in mice improves insulin secretion and alleviates diabetes. Taken together, we have identified a novel pathway of β-cell failure during type 2 diabetes, revealing a potential target for future diabetes treatment.