The Antipsychotic Olanzapine Induces Apoptosis in Insulin-secreting Pancreatic β Cells by Blocking PERK-mediated Translational Attenuation

Abstract

ABSTRACT. 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 β 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 α 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 β cells may contribute to the undesirable metabolic consequences of olanzapine treatment in some cases.

Role of endoplasmic reticulum stress in drug‐induced toxicity

“…Another study showed that olanzapine induced ER stress and reduced insulin secretion in hamster pancreatic β cells (Ozasa et al. 2013). However, the pathophysiological significance of this effect remains unclear since this drug classically induces hyperinsulinemia, even in the absence of weight gain (Melkersson and Dahl 2003; Teff et al.…”

Olanzapine-induced severe hyperglycemia was completely reversed by the restoration of insulin secretion after switching to aripiprazole and initiating insulin therapy

“…Olanzapine has the highest binding affinity with the M3 receptor of all the SGAs [10] and also alters M3 receptor density in discrete 32 nuclei of the hypothalamus and caudal brainstem regions that regulate glucose homeostasis and insulin secretion through vagal innervation of the pancreas [11]. Recently, Ozasa et al [12] showed that olanzapine but not risperidone evoked mild endoplasmic reticulum (ER) stress, as evidenced by mild activation of the ER stress sensor molecule PKR-like ER kinase (PERK) on a hamster pancreatic β cell line. However, phosphorylation of the α subunit of eukaryotic initiation factor 2 (elF2α), an event immediately downstream of PERK activation [13], was not observed in cells treated with olanzapine.…”

Does olanzapine impair pancreatic beta-cell function directly?

“…Antipsychotic structural differences may be key to the effect on eIF2α [13]. It is speculated that the chemical structure of olanzapine interferes with recruitment of eIF2α by interacting with PERK's large kinase insert loop, which is particularly important when PERK is only mildly activated [12]. In conclusion, olanzapine seems to directly impair pancreatic beta cell function.…”

“…However, phosphorylation of eIF2α was not observed in cells treated with olanzapine. Thus, protein synthesis continued despite PERK activation, and ER stress was sustained, which resulted in marked apoptosis of beta cells by olanzapine [12]. Antipsychotic structural differences may be key to the effect on eIF2α [13].…”