title: γ-Oryzanol protects pancreatic β-cells against endoplasmic reticulum stress in male mice.
abstract: Endoplasmic reticulum (ER) stress is profoundly involved in dysfunction of β-cells under high-fat diet and hyperglycemia. Our recent study in mice showed that γ-oryzanol, a unique component of brown rice, acts as a chemical chaperone in the hypothalamus and improves feeding behavior and diet-induced dysmetabolism. However, the entire mechanism whereby γ-oryzanol improves glucose metabolism throughout the body still remains unclear. In this context, we tested whether γ-oryzanol reduces ER stress and improves function and survival of pancreatic β-cells using murine β-cell line MIN6. In MIN6 cells with augmented ER stress by tunicamycin, γ-oryzanol decreased exaggerated expression of ER stress-related genes and phosphorylation of eukaryotic initiation factor-2α, resulting in restoration of glucose-stimulated insulin secretion and prevention of apoptosis. In islets from high-fat diet-fed diabetic mice, oral administration of γ-oryzanol improved glucose-stimulated insulin secretion on following reduction of exaggerated ER stress and apoptosis. Furthermore, we examined the impact of γ-oryzanol on low-dose streptozotocin-induced diabetic mice, where exaggerated ER stress and resultant apoptosis in β-cells were observed. Also in this model, γ-oryzanol attenuated mRNA level of genes involved in ER stress and apoptotic signaling in islets, leading to amelioration of glucose dysmetabolism. Taken together, our findings demonstrate that γ-oryzanol directly ameliorates ER stress-induced β-cell dysfunction and subsequent apoptosis, highlighting usefulness of γ-oryzanol for the treatment of diabetes mellitus.
authors.affiliation: Division of Endocrinology, Diabetes and Metabolism, Hematology, Rheumatology (Second Department of Internal Medicine) (C.K., S.S., R.U., M.H., H.T., M.S., H.M.), Graduate School of Medicine, University of the Ryukyus, Okinawa 903-0215, Japan; The Diabetes and Life-Style Related Disease Center (M.H.), Tomishiro Central Hospital, Okinawa 901-0243, Japan; Tanaka Clinic (H.T.), Okinawa 901-0244, Japan; Department of Molecular Anatomy (C.S.-O., C.T.), Graduate School of Medicine, University of the Ryukyus, Okinawa 903-0215, Japan; Department of Neurosurgery (S.I.), Graduate School of Medicine, University of the Ryukyus, Okinawa 903-0215, Japan; Department of Molecular and Cellular Physiology (M.M.), Graduate School of Medicine, University of the Ryukyus, Okinawa 903-0215, Japan; Department of Pharmacology (M.T.), Graduate School of Medicine, University of the Ryukyus, Okinawa 903-0215, Japan; Division of Stem Cell Regulation Research (J.-i.M.), Osaka University Graduate School of Medicine, Osaka 565-0871, Japan; Institute for Genome Research (S.O.), University of Tokushima, Tokushima 770-8506, Japan; and Department of Cardio-Diabetes Medicine (M.S.), University of Tokushima Graduate School of Health Biosciences, Tokushima 770-8503, Japan.
authors.forename: Chisayo
authors.initials: C
authors.lastname: Kozuka
authors.forename: Sumito
authors.initials: S
authors.lastname: Sunagawa
authors.forename: Rei
authors.initials: R
authors.lastname: Ueda
authors.forename: Moritake
authors.initials: M
authors.lastname: Higa
authors.forename: Hideaki
authors.initials: H
authors.lastname: Tanaka
authors.forename: Chigusa
authors.initials: C
authors.lastname: Shimizu-Okabe
authors.forename: Shogo
authors.initials: S
authors.lastname: Ishiuchi
authors.forename: Chitoshi
authors.initials: C
authors.lastname: Takayama
authors.forename: Masayuki
authors.initials: M
authors.lastname: Matsushita
authors.forename: Masato
authors.initials: M
authors.lastname: Tsutsui
authors.forename: Jun-ichi
authors.initials: J
authors.lastname: Miyazaki
authors.forename: Seiichi
authors.initials: S
authors.lastname: Oyadomari
authors.forename: Michio
authors.initials: M
authors.lastname: Shimabukuro
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Masuzaki
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D059305:Diet, High-Fat; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D007328:Insulin / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D010666:Phenylpropionates / Q000494:pharmacology*
chemical_list: D007328:Insulin; D010666:Phenylpropionates; C013172:gamma-oryzanol