题名：The Antipsychotic Olanzapine Induces Apoptosis in Insulin-secreting Pancreatic beta Cells by Blocking PERK-mediated Translational Attenuation.
作者：OZASA R; OKADA T; NADANAKA S; NAGAMINE T; ZYRYANOVA A; HARDING H; RON D; MORI K;
来源：Cell Struct Funct. 2013 Aug 8;38(2):183-94. Epub 2013 Jun 28. [ IF= 0.00 ] ]
URL ：N U L L
摘要：Patients with schizophrenia receive medication to alleviate various symptoms, but
some efficacious second generation antipsychotics, particularly olanzapine, can
cause obesity, dyslipidemia, and diabetes mellitus. It has been generally
considered that olanzapine contributes to the development of diabetes by inducing
obesity and subsequent insulin resistance. In this study, we examined the effect
of olanzapine and risperidone, another second generation antipsychotic, on a
hamster pancreatic beta cell line, and found that both evoked mild endoplasmic
reticulum (ER) stress, as evidenced by mild activation of the ER stress sensor
molecule PERK. Surprisingly, only olanzapine induced marked apoptosis.
Phosphorylation of the alpha subunit of eukaryotic initiation factor 2, an event
immediately downstream of PERK activation, was not observed in cells treated with
olanzapine, protein synthesis continued despite PERK activation, and ER stress
was thereby sustained. Secretion of insulin was markedly inhibited, and both
proinsulin and insulin accumulated inside olanzapine-treated cells. Inhibition of
protein synthesis and knockdown of insulin mRNA, which result in less unfolded
protein burden, both attenuated subsequent olanzapine-induced apoptosis. Given
clinical observations that some patients taking olanzapine exhibit hyperlipidemia
and hyperglycemia without gaining weight, our observations suggest that damage to
pancreatic beta cells may contribute to the undesirable metabolic consequences of
olanzapine treatment in some cases.