Guanabenz Sensitizes Pancreatic β Cells to Lipotoxic Endoplasmic Reticulum Stress and Apoptosis

Deficient as well as excessive/prolonged endoplasmic reticulum (ER) stress signaling can lead to pancreatic beta cell failure and the development of diabetes. Saturated free fatty acids (FFAs) such as palmitate induce lipotoxic ER stress in pancreatic beta cells. One of the main ER stress response pathways is under the control of the protein kinase R-like endoplasmic reticulum kinase (PERK), leading to phosphorylation of the eukaryotic translation initiation factor 2 (eIF2 alpha). The antihypertensive drug guanabenz has been shown to inhibit eIF2 alpha dephosphorylation and protect cells from ER stress. Here we examined whether guanabenz protects pancreatic beta cells from lipotoxicity. Guanabenz induced beta cell dysfunction in vitro and in vivo in rodents and led to impaired glucose tolerance. The drug significantly potentiated FFA-induced cell death in clonal rat beta cells and in rat and human islets. Guanabenz enhanced FFA-induced eIF2 alpha phosphorylation and expression of the downstream proapoptotic gene C/EBP homologous protein (CHOP), which mediated the sensitization to lipotoxicity. Thus, guanabenz does not protect b cells from ER stress; instead, it potentiates lipotoxic ER stress through PERK/eIF2 alpha/CHOP signaling. These data demonstrate the crucial importance of the tight regulation of eIF2 alpha phosphorylation for the normal function and survival of pancreatic beta cells.