A Passe-par2 for [Beta]-Cell Regeneration and Protection

Cell and tissue damage, particularly to pancreatic β-cells, is an essential characteristic of diabetes mellitus, triggered by autoimmune destruction of β-cells in type-1 (T1D) and by obesity associated factors or insulin resistance in type 2. Thus, stimulating β-cell regeneration has long been a most important goal of diabetes research. Recently, we have shown that pancreatic injury consisting of acinar cell inflammation and β-cell destruction led to islet cell transdifferentiation. In this work, we report that the molecular mechanism for this process requires the activation of the protease-activated receptor-2 (PAR2), a G-protein-coupled receptor. PAR2 modulation was sufficient to induce islet cell transdifferentiation in the β-cells ablated animals as PAR2 Knock out mice and mice injected with PAR2 pharmacological activator showed that it was necessary and sufficient for the induction of islet cell transdifferentiation in the settings of β-cell ablation. PAR2 expression was modified in an islet cell type-specific manner in murine and human T1D. In addition to transdifferentiation, PAR2 regulated β-cell apoptosis in caerulein-mediated pancreatitis, demonstrating that PAR2 was required for β-cell survival and protection during inflammation.