The imidazoline RX871024 induces death of proliferating insulin-secreting cells by activation of c-jun N-terminal kinase.
An insufficient number of insulin-producing beta-cells is a major cause of defective control of blood glucose in both type 1 and type 2 diabetes. The aim of this study was to clarify whether the insulinotropic imidazolines can affect the survival of highly proliferating insulin-secreting cells, here exemplified by the MIN6 cell line. Our data demonstrate that RX871024, but not efaroxan, triggered MIN6 cell death and potentiated death induced by a combination of the pro-inflammatory cytokines interleukin-1beta, interferon- gamma and tumor necrosis factor-alpha. These effects did not involve changes in nitric oxide production but correlated with stimulation of c-jun N-terminal kinase (JNK) activity and activation of caspases-1, -3, -8 and -9. Our results suggest that the imidazoline RX871024 causes death of highly proliferating insulin-secreting cells, putatively via augmentation of JNK activity, a finding that may impact on the possibility of using compounds of similar activity in the treatment of diabetes.
Zaitseva
I I
II
The Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
Størling
J
J
Mandrup-Poulsen
T
T
Berggren
P-O
PO
Zaitsev
S V
SV
D000818:Animals; D001572:Benzofurans / Q000494:pharmacology; D020169:Caspases / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D016207:Cytokines / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D007211:Indoles / Q000494:pharmacology*; D050417:Insulin-Secreting Cells / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D051379:Mice; D009569:Nitric Oxide / Q000096:biosynthesis
C101943:2-(2-imidazolin-2-yl)-1-phenyl-1H-indole; D001572:Benzofurans; D016207:Cytokines; D007093:Imidazoles; D007211:Indoles; D009569:Nitric Oxide; D048031:JNK Mitogen-Activated Protein Kinases; D020169:Caspases; C062597:efaroxan