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 b cell failure and the development of diabetes. Saturated free fatty acids (FFAs) such as palmitate induce lipotoxic ER stress in pancreatic b 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 (eIF2a). The antihypertensive drug guanabenz has been shown to inhibit eIF2a dephosphorylation and protect cells from ER stress. Here we examined whether guanabenz protects pancreatic b cells from lipotoxicity. Guanabenz induced b 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 b cells and in rat and human islets. Guanabenz enhanced FFA-induced eIF2a 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/eIF2a/CHOP signaling. These data demonstrate the crucial importance of the tight regulation of eIF2a phosphorylation for the normal function and survival of pancreatic b cells.