详细记录  
题名:Selective serotonin reuptake inhibitors (SSRIs) inhibit insulin secretion and action in pancreatic beta cells.
作者:ISAAC R; BOURA-HALFON S; GUREVITCH D; SHAINSKAYA A; LEVKOVITZ Y; ZICK Y;
来源:J Biol Chem. 2013 Feb 22;288(8):5682-93. doi: 10.1074/jbc.M112.408641. Epub 2012 [ IF= 0.00 ] ]
URL :10.1074/jbc.M112.408641
日期:20130228
摘要:Selective serotonin reuptake inhibitors (SSRIs) are antidepressants used for the
treatment of mood and anxiety disorders. Here, we demonstrate that incubation (2
h) of murine islets or Min6 beta cell line with the SSRIs paroxetine, fluoxetine,
or sertraline inhibited insulin-induced Tyr phosphorylation of insulin receptor
substrate (IRS)-2 protein and the activation of its downstream targets Akt and
the ribosomal protein S6 kinase-1 (S6K1). Inhibition was dose-dependent with
half-maximal effects at approximately 15-20 muM. It correlated with a rapid
dephosphorylation and activation of the IRS kinase GSK3beta. Introduction of
GSK3beta siRNAs eliminated the inhibitory effects of the SSRIs. Inhibition of
IRS-2 action by 30 muM SSRI was associated with a marked inhibition of
glucose-stimulated insulin secretion from murine and human pancreatic islets.
Secretion induced by basic secretagogues (KCl and Arg) was not affected by these
drugs. Prolonged treatment (16 h) of Min6 cells with sertraline resulted in the
induction of inducible nitric oxide synthase; activation of endoplasmic reticulum
stress, and the initiation of the unfolded protein response, manifested by
enhanced transcription of ATF4 and C/EBP homologous protein. This triggered an
apoptotic process, manifested by enhanced caspase 3/7 activity, which resulted in
beta cell death. These findings implicate SSRIs as inhibitors of IRS protein
function and insulin action through the activation of GSK3beta. They further
suggest that SSRIs inhibit insulin secretion; induce the unfolded protein
response; activate an apoptotic process, and trigger beta cell death. Given that
SSRIs promote insulin resistance while inhibiting insulin secretion, these drugs
might accelerate the transition from an insulin-resistant state to overt
diabetes.

================  评  论  部  分=================

重要性:
分类:(参照 Faculty of 1000 的分类体系)


评语:

评论密码:   返回前页  [全部]