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

ELife
Satoshi NinagawaKazutoshi Mori

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 β-cell dysfunction should be considered, together with weight gain, when patients are administered olanzapine.

References

Jul 1, 1992·The Journal of Cell Biology·M S SegalM J Gething
Feb 2, 2000·European Archives of Psychiatry and Clinical Neuroscience·S KasperS Quiner
Jun 28, 2000·Biopharmaceutics & Drug Disposition·M AravagiriS R Marder
Sep 23, 2000·American Journal of Physiology. Endocrinology and Metabolism·K MinamiS Seino
May 31, 2002·Clinical Pharmacokinetics·Bernd MeibohmHartmut Derendorf
Jul 20, 2002·Pharmacotherapy·Elizabeth A Koller, P Murali Doraiswamy
Aug 15, 2002·Biochemical and Biophysical Research Communications·Helen Roderigo-MilnePeter M Jones
Dec 25, 2002·Journal of Chromatography. a·Yasushi IshihamaMatthias Mann
Feb 15, 2003·Developmental Cell·Hiderou YoshidaKazutoshi Mori
Mar 18, 2003·Journal of Clinical Psychopharmacology·Juan Antonio CarrilloJulio Benítez
Oct 23, 2003·International Clinical Psychopharmacology·Johanna van BruggenDonald Linszen
Mar 11, 2004·Diabetic Medicine : a Journal of the British Diabetic Association·N TsuchiyamaT Takamura
Aug 10, 2005·The Journal of Clinical Psychiatry·Leslie Citrome, Jan Volavka
May 25, 2006·Nordic Journal of Psychiatry·M P Høiberg, B Nielsen
Jun 20, 2006·Human Psychopharmacology·Pinkhas SirotaEleonora Tchernichovsky
Apr 23, 2010·Neuropsychopharmacology : Official Publication of the American College of Neuropsychopharmacology·Patrick N McCormickAlan A Wilson
Jan 25, 2011·Journal of Proteome Research·Jürgen CoxMatthias Mann
Feb 3, 2011·The FEBS Journal·Masaki OkumuraYuji Hidaka
Mar 3, 2011·Nature Cell Biology·Ira Tabas, David Ron
May 11, 2011·Proceedings of the National Academy of Sciences of the United States of America·Ann-Hwee LeeLaurie H Glimcher
Jun 29, 2012·BMC Endocrine Disorders·Ekenechukwu E YoungChioma N Unachukwu
Sep 15, 2012·Annual Review of Physiology·Patrik Rorsman, Matthias Braun
Sep 10, 2013·Endocrinology and Metabolism Clinics of North America·Chao Deng
Jul 6, 2014·BioMed Research International·Nevena DivacNatasa Cerovac
Aug 6, 2014·The Journal of Cell Biology·Satoshi NinagawaKazutoshi Mori
Nov 18, 2015·The Journal of Cell Biology·Satoshi NinagawaKazutoshi Mori

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Citations

Jan 12, 2021·The Australian and New Zealand Journal of Psychiatry·Takahiko Nagamine
Dec 15, 2020·Biochimica Et Biophysica Acta. General Subjects·Satoshi NinagawaKazutoshi Mori

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Methods Mentioned

BETA
SGA
protein folding
ELISA
in
immunoprecipitation
isothermal titration calorimetry
nucleotide exchange
protein assay

Software Mentioned

MaxQuant
Andromeda
Leica

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