Enhanced signaling downstream of ribonucleic Acid-activated protein kinase-like endoplasmic reticulum kinase potentiates lipotoxic endoplasmic reticulum stress in human islets.
BACKGROUND
Free fatty acids cause pancreatic beta-cell apoptosis and may contribute to beta-cell loss in type 2 diabetes via the induction of endoplasmic reticulum (ER) stress. Eukaryotic translation initiation factor 2alpha (eIF2alpha) phosphorylation is an adaptive response to ER stress, and reductions in eIF2alpha phosphorylation trigger beta-cell failure. Salubrinal inhibits eIF2alpha dephosphorylation and has been proposed as a novel therapy for diabetes.


OBJECTIVE
The objective of the study was to examine whether salubrinal modulates human islet susceptibility to lipotoxicity.


METHODS
Human islets were treated with oleate or palmitate, alone or in combination with salubrinal, and examined for apoptosis, ultrastructure, and gene expression.


RESULTS
Salubrinal enhanced signaling downstream of eIF2alpha and markedly induced the proapoptotic transcription factor CCAAT/enhancer-binding protein homologous protein, but it did not induce the inositol requiring-1alpha or activating transcription factor 6 ER stress pathways. Salubrinal potentiated the deleterious effects of oleate and palmitate in human islets. This proapoptotic effect involved ER dilation and mitochondrial rounding and fragmentation.


CONCLUSIONS
Excessive eIF2alpha phosphorylation is poorly tolerated by human islets and exacerbates fatty acid-induced apoptosis through ER and mitochondrial mechanisms. This should be taken into consideration when designing approaches to pharmacologically modulate the beta-cell ER stress response in type 2 diabetes.
Ladrière
Laurence
L
Laboratory of Experimental Medicine, Université Libre de Bruxelles CP-618, Route de Lennik 808, 1070 Brussels, Belgium.
Igoillo-Esteve
Mariana
M
Cunha
Daniel A
DA
Brion
Jean-Pierre
JP
Bugliani
Marco
M
Marchetti
Piero
P
Eizirik
Décio L
DL
Cnop
Miriam
M
D000704:Analysis of Variance; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D022762:CCAAT-Enhancer-Binding Proteins / Q000378:metabolism; D002460:Cell Line; D002478:Cells, Cultured; D002934:Cinnamates / Q000494:pharmacology*; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism*; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D006801:Humans; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism*; D008854:Microscopy, Electron; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D019301:Oleic Acid / Q000494:pharmacology; D019308:Palmitic Acid / Q000494:pharmacology; D010766:Phosphorylation; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013890:Thiourea / Q000031:analogs & derivatives* / Q000494:pharmacology
D022762:CCAAT-Enhancer-Binding Proteins; D002934:Cinnamates; D015852:Eukaryotic Initiation Factor-2; C496827:salubrinal; D019301:Oleic Acid; D019308:Palmitic Acid; D013890:Thiourea