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 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.
ULB Center for Diabetes Research, Université Libre de Bruxelles, 1070 Brussels, Belgium.
Baroj
B
Abdulkarim
ULB Center for Diabetes Research, Université Libre de Bruxelles, 1070 Brussels, Belgium.
Miriam
M
Hernangomez
ULB Center for Diabetes Research, Université Libre de Bruxelles, 1070 Brussels, Belgium.
Mariana
M
Igoillo-Esteve
ULB Center for Diabetes Research, Université Libre de Bruxelles, 1070 Brussels, Belgium.
Daniel A
DA
Cunha
Department of Endocrinology and Metabolism, University of Pisa, 56126 Pisa, Italy.
Lorella
L
Marselli
Department of Endocrinology and Metabolism, University of Pisa, 56126 Pisa, Italy.
Piero
P
Marchetti
ULB Center for Diabetes Research, Université Libre de Bruxelles, 1070 Brussels, Belgium.
Laurence
L
Ladriere
ULB Center for Diabetes Research, Université Libre de Bruxelles, 1070 Brussels, Belgium.|Division of Endocrinology, Erasmus Hospital, 1070 Brussels, Belgium.
Miriam
M
Cnop
D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002478:Cells, Cultured; D004351:Drug Resistance / Q000187:drug effects; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D006143:Guanabenz / Q000494:pharmacology*; D006801:Humans; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000378:metabolism; D008055:Lipids / Q000633:toxicity*; D008297:Male; D051381:Rats; D017208:Rats, Wistar
D000959:Antihypertensive Agents; D008055:Lipids; D006143:Guanabenz