NO-mediated cytotoxicity contributes to multiple low-dose streptozotocin-induced diabetes but not to NOD diabetes.
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.
Yasuda
Hisafumi
H
Department of Internal and Geriatric Medicine, Kobe University Graduate School of Medicine, Chuo-ku, Kobe, Japan. yasuda@med.kobe-u.ac.jp
Jin
Zhenzi
Z
Nakayama
Maki
M
Yamada
Katsumi
K
Kishi
Minoru
M
Okumachi
Yasuyo
Y
Arai
Takashi
T
Moriyama
Hiroaki
H
Yokono
Koichi
K
Nagata
Masao
M
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
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