title: Prevention of antipsychotic-induced hyperglycaemia by vitamin D: a data mining prediction followed by experimental exploration of the molecular mechanism.
abstract: Atypical antipsychotics are associated with an increased risk of hyperglycaemia, thus limiting their clinical use. This study focused on finding the molecular mechanism underlying antipsychotic-induced hyperglycaemia. First, we searched for drug combinations in the FDA Adverse Event Reporting System (FAERS) database wherein a coexisting drug reduced the hyperglycaemia risk of atypical antipsychotics, and found that a combination with vitamin D analogues significantly decreased the occurrence of quetiapine-induced adverse events relating diabetes mellitus in FAERS. Experimental validation using mice revealed that quetiapine acutely caused insulin resistance, which was mitigated by dietary supplementation with cholecalciferol. Further database analysis of the relevant signalling pathway and gene expression predicted quetiapine-induced downregulation of Pik3r1, a critical gene acting downstream of insulin receptor. Focusing on the phosphatidylinositol 3-kinase (PI3K) signalling pathway, we found that the reduced expression of Pik3r1 mRNA was reversed by cholecalciferol supplementation in skeletal muscle, and that insulin-stimulated glucose uptake into C2C12 myotube was inhibited in the presence of quetiapine, which was reversed by concomitant calcitriol in a PI3K-dependent manner. Taken together, these results suggest that vitamin D coadministration prevents antipsychotic-induced hyperglycaemia and insulin resistance by upregulation of PI3K function.
authors.affiliation: Department of Molecular Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29 Yoshida-Shimoadachi-cho, Sakyo-ku, Kyoto 606-8501, Japan.
authors.forename: Takuya
authors.initials: T
authors.lastname: Nagashima
authors.affiliation: Department of Molecular Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29 Yoshida-Shimoadachi-cho, Sakyo-ku, Kyoto 606-8501, Japan.
authors.forename: Hisashi
authors.initials: H
authors.lastname: Shirakawa
authors.affiliation: Department of Clinical Pharmacology and Therapeutics, Kyoto University Hospital, 54 Shogoin-Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Nakagawa
authors.affiliation: Department of Molecular Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29 Yoshida-Shimoadachi-cho, Sakyo-ku, Kyoto 606-8501, Japan.
authors.forename: Shuji
authors.initials: S
authors.lastname: Kaneko
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000009:adverse effects*; D002460:Cell Line; D002762:Cholecalciferol / Q000008:administration & dosage*; D058543:Class Ia Phosphatidylinositol 3-Kinase / Q000235:genetics*; D057225:Data Mining; D016208:Databases, Factual; D004195:Disease Models, Animal; D051275:Glucose Transporter Type 4 / Q000378:metabolism; D006801:Humans; D006943:Hyperglycemia / Q000139:chemically induced / Q000235:genetics / Q000517:prevention & control*; D007333:Insulin Resistance; D051379:Mice; D000069348:Quetiapine Fumarate / Q000009:adverse effects*; D015398:Signal Transduction / Q000187:drug effects; D014807:Vitamin D / Q000031:analogs & derivatives
chemical_list: D014150:Antipsychotic Agents; D051275:Glucose Transporter Type 4; C495693:Slc2a4 protein, mouse; D014807:Vitamin D; D002762:Cholecalciferol; D000069348:Quetiapine Fumarate; D058543:Class Ia Phosphatidylinositol 3-Kinase; C000622001:Pik3r1 protein, mouse