Antipsychotic olanzapine-induced misfolding of proinsulin in the endoplasmic reticulum accounts for atypical development of diabetes
Authors: Robert B Mackin
Takayuki Anazawa
Seiji Torii
Yasushi Ishihama
Koshi Imami
Shingo Kanemura
Misaki Kinoshita
Kazutoshi Mori
Tokiro Ishikawa
Takahiko Nagamine
Seiichiro Tada
Satoshi Ninagawa
Kenji Inaba
Hajime Umezawa
Masaki Okumura
Kenta Inoguchi
Journal: eLife (2020)
Discipline: BIOLOGY & BIOCHEMISTRY
Keywords: cell biology; degradation; diabetes; misfolding; mouse
Affiliations: Department of Biophysics, Graduate School of Science, Kyoto University, Kyoto, Japan., Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan., Frontier Research Institute for Interdisciplinary Sciences, Tohoku University, Sendai, Japan., School of Science and Technology, Kwansei Gakuin University, Sanda, Japan., Department of Molecular and Cellular BioAnalysis, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan., Department of Biomedical Sciences, Creighton University School of Medicine, Omaha, United States., Laboratory of Secretion Biology, Institute for Molecular and Cellular Regulation, Gunma University, Maebashi, Japan., Institute of Multidisciplinary Research for Advanced Materials, Tohoku University, Sendai, Japan., Sunlight Brain Research Center, Yamaguchi, Japan.

Abstract:  Second-generation antipsychotics are widely used to medicate patients with schizophrenia, but may cause metabolic side effects such as diabetes, which has been considered to result from obesity-associated insulin resistance. Olanzapine is particularly well known for this effect. However, clinical studies have suggested that olanzapine-induced hyperglycemia in certain patients cannot be explained by such a generalized mechanism. Here, we focused on the effects of olanzapine on insulin biosynthesis and secretion by mouse insulinoma MIN6 cells. Olanzapine reduced maturation of proinsulin, and thereby inhibited secretion of insulin; and specifically shifted the primary localization of proinsulin from insulin granules to the endoplasmic reticulum. This was due to olanzapine's impairment of proper disulfide bond formation in proinsulin, although direct targets of olanzapine remain undetermined. Olanzapine-induced proinsulin misfolding and subsequent decrease also occurred at the mouse level. This mechanism of olanzapine-induced Œ≤-cell dysfunction should be considered, together with weight gain, when patients are administered olanzapine. 

Retracted: No

PubPeer comments:
 The authors claim: Olanzapine reduced maturation of proinsulin, and thereby inhibited secretion of insulin; and specifically shifted the primary localization of proinsulin from insulin granules to the endoplasmic reticulum. This mechanism of olanzapine-induced b-cell dysfunction should be considered, together with weight gain, when patients are administered olanzapine. All the studies in this paper use 10-50 uM olanzapine. In patients the plasma concentration of olanzapine is approximately 200 nM. https: pubmed.ncbi.nlm.nih.gov 15048613 In humans patients olanzapine is 93% albumin bound meaning that the free concentration of olanzapine is around 10 nM. https: www.accessdata.fda.gov drugsatfda_docs label 2007 020592s042s043,021086s022s023,021253s026lbl.pdf#:~:text=the%20dose%20of%20olanzapine%20was%20recovered%20in%20the,for%20total%20radioactivity%2C%20indicating%20significant%20exposure%20to%20metabolites. This paper is conducted with olanzapine concentrations 1000-fold above physiologically relevant levels. , 
 #1 Thank you very much for your comment. Do you agree with the development of atypical diabetes in some patients taking olanzapine? We would like to draw your attention to the finding that daily oral administration of olanzapine produced HMP-1 and even higher molecular weight forms of proinsulin in mouse islets (Fig. 10EF), albeit we could not determine the concentration of olanzapine in serum. ,