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

• Published in: Endocrinology (Philadelphia) Vol. 158; no. 6; pp. 1659 - 1670
• Main Authors: Abdulkarim, Baroj, Hernangomez, Miriam, Igoillo-Esteve, Mariana, Cunha, Daniel A, Marselli, Lorella, Marchetti, Piero, Ladriere, Laurence, Cnop, Miriam
• Format: Journal Article
• Language: English
• Published: United States Oxford University Press 01-06-2017
• Subjects: Animals; Antihypertensive Agents - pharmacology; Antihypertensives; Apoptosis; Apoptosis - drug effects; Beta cells; CCAAT/enhancer-binding protein; Cell death; Cell survival; Cells, Cultured; Cellular stress response; Dephosphorylation; Diabetes mellitus; Drug Resistance - drug effects; Endoplasmic reticulum; Endoplasmic Reticulum Stress - drug effects; Glucose tolerance; Guanabenz - pharmacology; Humans; Initiation factor eIF-2; Insulin-Secreting Cells - drug effects; Insulin-Secreting Cells - metabolism; Kinases; Lipids - toxicity; Male; Palmitic acid; Pancreas; Phosphorylation; Protein kinase R; Proteins; Rats; Rats, Wistar
• ISSN: 0013-7227; 1945-7170
• DOI: 10.1210/en.2016-1773

Deficient as well as excessive/prolonged endoplasmic reticulum (ER) stress signaling can lead to pancreatic β cell failure and the development of diabetes. Saturated free fatty acids (FFAs) such as palmitate induce lipotoxic ER stress in pancreatic β 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 (eIF2α). The antihypertensive drug guanabenz has been shown to inhibit eIF2α dephosphorylation and protect cells from ER stress. Here we examined whether guanabenz protects pancreatic β cells from lipotoxicity. Guanabenz induced β 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 β cells and in rat and human islets. Guanabenz enhanced FFA-induced eIF2α phosphorylation and expression of the downstream proapoptotic gene C/EBP homologous protein (CHOP), which mediated the sensitization to lipotoxicity. Thus, guanabenz does not protect β cells from ER stress; instead, it potentiates lipotoxic ER stress through PERK/eIF2α/CHOP signaling. These data demonstrate the crucial importance of the tight regulation of eIF2α phosphorylation for the normal function and survival of pancreatic β cells.