Glucagon-like peptide-1 agonists protect pancreatic beta-cells from lipotoxic endoplasmic reticulum stress through upregulation of BiP and JunB.
OBJECTIVE
Chronic exposure of pancreatic beta-cells to saturated free fatty acids (FFAs) causes endoplasmic reticulum (ER) stress and apoptosis and may contribute to beta-cell loss in type 2 diabetes. Here, we evaluated the molecular mechanisms involved in the protection of beta-cells from lipotoxic ER stress by glucagon-like peptide (GLP)-1 agonists utilized in the treatment of type 2 diabetes.


METHODS
INS-1E or fluorescence-activated cell sorter-purified primary rat beta-cells were exposed to oleate or palmitate with or without the GLP-1 agonist exendin-4 or forskolin. Cyclopiazonic acid was used as a synthetic ER stressor, while the activating transcription factor 4-C/EBP homologous protein branch was selectively activated with salubrinal. The ER stress signaling pathways modulated by GLP-1 agonists were studied by real-time PCR and Western blot. Knockdown by RNA interference was used to identify mediators of the antiapoptotic GLP-1 effects in the ER stress response and downstream mitochondrial cell death mechanisms.


RESULTS
Exendin-4 and forskolin protected beta-cells against FFAs via the induction of the ER chaperone BiP and the antiapoptotic protein JunB that mediate beta-cell survival under lipotoxic conditions. On the other hand, exendin-4 and forskolin protected against synthetic ER stressors by inactivating caspase 12 and upregulating Bcl-2 and X-chromosome-linked inhibitor of apoptosis protein that inhibit mitochondrial apoptosis.


CONCLUSIONS
These observations suggest that GLP-1 agonists increase in a context-dependent way the beta-cell defense mechanisms against different pathways involved in ER stress-induced apoptosis. The identification of the pathways modulated by GLP-1 agonists allows for targeted approaches to alleviate beta-cell ER stress in diabetes.
Cunha
Daniel A
DA
Laboratory of Experimental Medicine, Université Libre de Bruxelles, Brussels, Belgium.
Ladrière
Laurence
L
Ortis
Fernanda
F
Igoillo-Esteve
Mariana
M
Gurzov
Esteban N
EN
Lupi
Roberto
R
Marchetti
Piero
P
Eizirik
Décio L
DL
Cnop
Miriam
M
D000818:Animals; D000943:Antigens, Differentiation / Q000378:metabolism; D017209:Apoptosis; D015153:Blotting, Western; D002470:Cell Survival; D005576:Colforsin / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism* / Q000517:prevention & control; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D000077270:Exenatide; D052216:Glucagon-Like Peptide 1 / Q000819:agonists* / Q000378:metabolism*; D000067757:Glucagon-Like Peptide-1 Receptor; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D007004:Hypoglycemic Agents / Q000494:pharmacology; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D050356:Lipid Metabolism / Q000187:drug effects; D008297:Male; D010455:Peptides / Q000494:pharmacology; D016133:Polymerase Chain Reaction; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D051381:Rats; D017208:Rats, Wistar; D018027:Receptors, Glucagon / Q000378:metabolism; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors / Q000378:metabolism; D015854:Up-Regulation; D014688:Venoms / Q000494:pharmacology; D000091342:Endoplasmic Reticulum Chaperone BiP
D000943:Antigens, Differentiation; D005576:Colforsin; D004268:DNA-Binding Proteins; D000077270:Exenatide; D052216:Glucagon-Like Peptide 1; D000067757:Glucagon-Like Peptide-1 Receptor; D006360:Heat-Shock Proteins; D007004:Hypoglycemic Agents; D010455:Peptides; D011518:Proto-Oncogene Proteins; D016755:Proto-Oncogene Proteins c-jun; D018027:Receptors, Glucagon; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors; D014688:Venoms; C051684:GRP78 protein, rat; D000091342:Endoplasmic Reticulum Chaperone BiP; C000593835:Glp1r protein, rat; C489287:Ppp1r15a protein, rat