Par-4-dependent apoptosis of pancreatic islet B cells in type 2 diabetes

Pancreatic islet b-cell dysfunction is an underlying cause of type 2 diabetes. Long-term metabolic disorders lead to pancreatic islet b-cell apoptosis, which is one of the main reasons for islet ß-cell dysfunction. However, the mechanisms underlying this process are not well understood. The tumor suppressor Par-4, the protein product of the PAWR gene, sensitizes a variety of normal tissue cells to apoptosis induced by diverse insults. Our own research demonstrated that Par-4 plays an important role in the apoptosis pathway activated by high glucose/high fat leading to dysfunction of the islet ß-cells and type 2 diabetes. Recent investigations also suggest that Par-4 may induce cell death through autophagy dysfunction, which contributes to islet b-cell elimination. We review the role of secreted and intracellular Par-4 in sensitizing islet b-cells to apoptosis via the caspase-8 and caspase-9 pathways. The significance of Par-4 interactions particularly with the NF-κB pathway and telomerase reverse transcriptase (TERT) in regulating autophagy dysfunction and apoptosis of islet b-cells is highlighted.