Journal
DIABETES RESEARCH AND CLINICAL PRACTICE
Volume 83, Issue 2, Pages 200-207Publisher
ELSEVIER IRELAND LTD
DOI: 10.1016/j.diabres.2008.11.029
Keywords
Nitric oxide (NO); iNOS; ONO-1714; STZ; NOD
Categories
Funding
- Ministry of Education, Culture, Sports, Science and Technology of Japan [18590990]
- Grants-in-Aid for Scientific Research [18590990] Funding Source: KAKEN
Ask authors/readers for more resources
Type 1 diabetes (T1D) is caused mostly by autoimmune destruction of pancreatic p-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 p-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-1 beta, 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. (C) 2008 Elsevier Ireland Ltd. All rights reserved.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available