Deletion of apoptosis signal-regulating kinase 1 (ASK1) protects pancreatic beta-cells from stress-induced death but not from glucose homeostasis alterations under pro-inflammatory conditions.
BACKGROUND
Type 2 diabetes is characterized by pancreatic beta-cell dysfunction and is associated with low-grade inflammation. Recent observations suggest that apoptosis signal-regulating kinase 1 (ASK1) is involved in beta-cell death in response to different stressors. In this study, we tested whether ASK1 deficiency protects beta-cells from glucolipotoxic conditions and cytokines treatment or from glucose homeostasis alteration induced by endotoxemia.


RESULTS
Insulin secretion was neither affected upon shRNA-mediated downregulation of ASK1 in MIN6 cells nor in islets from ASK1-deficient mice. ASK1 silencing in MIN6 cells and deletion in islets did not prevent the deleterious effect of glucolipotoxic conditions or cytokines on insulin secretion. However, it protected MIN6 cells from death induced by ER stress or palmitate and islets from short term caspase activation in response to cytokines. Moreover, endotoxemia induced by LPS infusion increased insulin secretion during hyperglycemic clamps but the response was similar in wild-type and ASK1-deficient mice. Finally, insulin sensitivity in the presence of LPS was not affected by ASK1-deficiency.


CONCLUSIONS
Our study demonstrates that ASK1 is not involved in beta-cell function and dysfunction but controls stress-induced beta-cell death.
Betagenex Inc, Laval, QC, Canada, H7V5B7.
Emilie
E
Pepin
Inserm U1053, Team Endoplasmic Reticulum Stress and Cancer, Université de Bordeaux, Bordeaux, France, 33076.
Arisa
A
Higa
Groupe de Recherche Servier, Suresnes, France, 92284 Cedex.
Carole
C
Schuster-Klein
Groupe de Recherche Servier, Suresnes, France, 92284 Cedex.
Catherine
C
Bernard
Betagenex Inc, Laval, QC, Canada, H7V5B7; Physiogenex SAS, Labège, France, 31670.
Thierry
T
Sulpice
Groupe de Recherche Servier, Suresnes, France, 92284 Cedex.
Beatrice
B
Guardiola
Inserm U1053, Team Endoplasmic Reticulum Stress and Cancer, Université de Bordeaux, Bordeaux, France, 33076.
Eric
E
Chevet
Montreal Diabetes Research Center, Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), and Departments of Medicine, Biochemistry and Cell Biology and Pathology, Université de Montréal, Montréal, QC, Canada, H3T 1J4.
Thierry
T
Alquier
D000818:Animals; D002478:Cells, Cultured; D016207:Cytokines / Q000494:pharmacology; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism / Q000473:pathology*; D005947:Glucose / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D007249:Inflammation / Q000378:metabolism / Q000473:pathology*; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism* / Q000473:pathology; D008070:Lipopolysaccharides / Q000494:pharmacology; D048848:MAP Kinase Kinase Kinase 5 / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D019308:Palmitic Acid / Q000494:pharmacology; D013312:Stress, Physiological
D016207:Cytokines; D007328:Insulin; D008070:Lipopolysaccharides; D019308:Palmitic Acid; D048848:MAP Kinase Kinase Kinase 5; C482859:Map3k5 protein, mouse; D005947:Glucose