TY - JOUR TI - Antipsychotic olanzapine-induced misfolding of proinsulin in the endoplasmic reticulum accounts for atypical development of diabetes AU - Ninagawa, Satoshi AU - Tada, Seiichiro AU - Okumura, Masaki AU - Inoguchi, Kenta AU - Kinoshita, Misaki AU - Kanemura, Shingo AU - Imami, Koshi AU - Umezawa, Hajime AU - Ishikawa, Tokiro AU - Mackin, Robert B AU - Torii, Seiji AU - Ishihama, Yasushi AU - Inaba, Kenji AU - Anazawa, Takayuki AU - Nagamine, Takahiko AU - Mori, Kazutoshi A2 - Miller, Elizabeth A A2 - Malhotra, Vivek A2 - Miller, Elizabeth A VL - 9 PY - 2020 DA - 2020/11/17 SP - e60970 C1 - eLife 2020;9:e60970 DO - 10.7554/eLife.60970 UR - https://doi.org/10.7554/eLife.60970 AB - 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 β-cell dysfunction should be considered, together with weight gain, when patients are administered olanzapine. KW - proinsulin KW - misfolding KW - degradation KW - diabetes JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -