title: NO-mediated cytotoxicity contributes to multiple low-dose streptozotocin-induced diabetes but not to NOD diabetes.
abstract: Type 1 diabetes (T1D) is caused mostly by autoimmune destruction of pancreatic beta-cells, the precise mechanism of which remains unclear. Two major effector mechanisms have been proposed: direct cell-mediated and indirect cytokine-mediated cytotoxicity. Cytokine-mediated beta-cell destruction is presumed mainly caused by NO production. To evaluate the role of iNOS expression in T1D, this study used a novel iNOS inhibitor ONO-1714. ONO-1714 significantly reduced cytokine-mediated cytotoxicity and NO production in both MIN6N9a cells and C57BL/6 islets in the presence of IL-1beta, TNF-alpha, and IFN-gamma. To evaluate whether NO contributes to diabetes progression in vivo, ONO-1714 was administered to four different mouse models of autoimmune diabetes: multiple low-dose STZ (MLDS)-induced C57BL/6, CY-induced, adoptive transfer and spontaneous NOD diabetes. Exposure to STZ in vitro induced NO production in MIN6N9a cells and C57BL/6 islets, and in vivo injection of ONO-1714 to MLDS-treated mice significantly reduced hyperglycemia and interestingly, led to complete suppression of cellular infiltration of pancreatic islets. In contrast, when ONO-1714 was injected into spontaneous NOD mice and CY-induced and adoptive transfer models of NOD diabetes, overt diabetes could not be inhibited in these models. These findings suggest that NO-mediated cytotoxicity significantly contributes to MLDS-induced diabetes but not to NOD diabetes.
authors.affiliation: Department of Internal and Geriatric Medicine, Kobe University Graduate School of Medicine, Chuo-ku, Kobe, Japan. yasuda@med.kobe-u.ac.jp
authors.forename: Hisafumi
authors.initials: H
authors.lastname: Yasuda
authors.forename: Zhenzi
authors.initials: Z
authors.lastname: Jin
authors.forename: Maki
authors.initials: M
authors.lastname: Nakayama
authors.forename: Katsumi
authors.initials: K
authors.lastname: Yamada
authors.forename: Minoru
authors.initials: M
authors.lastname: Kishi
authors.forename: Yasuyo
authors.initials: Y
authors.lastname: Okumachi
authors.forename: Takashi
authors.initials: T
authors.lastname: Arai
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Moriyama
authors.forename: Koichi
authors.initials: K
authors.lastname: Yokono
authors.forename: Masao
authors.initials: M
authors.lastname: Nagata
mesh_terms: D000578:Amidines / Q000494:pharmacology; D000818:Animals; D002478:Cells, Cultured; D003603:Cytotoxins / Q000037:antagonists & inhibitors / Q000494:pharmacology; D003921:Diabetes Mellitus, Experimental / Q000139:chemically induced* / Q000473:pathology; D003922:Diabetes Mellitus, Type 1 / Q000473:pathology*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005260:Female; D006574:Heterocyclic Compounds, 2-Ring / Q000494:pharmacology; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D009569:Nitric Oxide / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D013311:Streptozocin
chemical_list: C407360:7-chloro-3-imino-5-methyl-2-azabicyclo(4.1.0)heptane; D000578:Amidines; D003603:Cytotoxins; D006574:Heterocyclic Compounds, 2-Ring; D009569:Nitric Oxide; D013311:Streptozocin; D019001:Nitric Oxide Synthase