Antipsychotic olanzapine-induced misfolding of proinsulin in the endoplasmic reticulum accounts for atypical development of diabetes.

Autor:	Ninagawa S; Department of Biophysics, Graduate School of Science, Kyoto University, Kyoto, Japan., Tada S; Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan., Okumura M; Frontier Research Institute for Interdisciplinary Sciences, Tohoku University, Sendai, Japan., Inoguchi K; Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan., Kinoshita M; Frontier Research Institute for Interdisciplinary Sciences, Tohoku University, Sendai, Japan., Kanemura S; Frontier Research Institute for Interdisciplinary Sciences, Tohoku University, Sendai, Japan.; School of Science and Technology, Kwansei Gakuin University, Sanda, Japan., Imami K; Department of Molecular and Cellular BioAnalysis, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan., Umezawa H; Department of Biophysics, Graduate School of Science, Kyoto University, Kyoto, Japan., Ishikawa T; Department of Biophysics, Graduate School of Science, Kyoto University, Kyoto, Japan., Mackin RB; Department of Biomedical Sciences, Creighton University School of Medicine, Omaha, United States., Torii S; Laboratory of Secretion Biology, Institute for Molecular and Cellular Regulation, Gunma University, Maebashi, Japan., Ishihama Y; Department of Molecular and Cellular BioAnalysis, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan., Inaba K; Institute of Multidisciplinary Research for Advanced Materials, Tohoku University, Sendai, Japan., Anazawa T; Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan., Nagamine T; Sunlight Brain Research Center, Yamaguchi, Japan., Mori K; Department of Biophysics, Graduate School of Science, Kyoto University, Kyoto, Japan.
Jazyk:	angličtina
Zdroj:	ELife [Elife] 2020 Nov 17; Vol. 9. Date of Electronic Publication: 2020 Nov 17.
DOI:	10.7554/eLife.60970
Abstrakt:	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. Competing Interests: SN, ST, MO, KI, MK, SK, KI, HU, TI, RM, ST, YI, KI, TA, TN, KM No competing interests declared (© 2020, Ninagawa et al.)
Databáze:	MEDLINE
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