Reduced sensitivity of inducible nitric oxide synthase-deficient mice to multiple low-dose streptozotocin-induced diabetes

被引:135
作者
Flodström, M
Tyrberg, B
Eizirik, DL
Sandler, S
机构
[1] Scripps Res Inst, Dept Immunol, La Jolla, CA 92037 USA
[2] Uppsala Univ, Dept Med Cell Biol, Uppsala, Sweden
[3] Free Univ Brussels, Diabet Res Ctr, Brussels, Belgium
关键词
D O I
10.2337/diabetes.48.4.706
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Nitric oxide (NO), synthesized by the inducible isoform of nitric oxide synthase (iNOS), has been proposed as a mediator of immune-induced beta-cell destruction in type I diabetes. To evaluate the role of iNOS for beta-cell dysfunction and death, we investigated the sensitivity of beta-cells from mice genetically deficient in this enzyme (iNOS(-/-), background C57BL/6x129SvEv, H-2(b)) both to interleukin (IL)-1 beta-induced beta-cell dysfunction in vitro and to multiple low-dose streptozotocin (MLDS)-induced diabetes in vivo. Exposure of islets isolated from C57BL/6 mice to IL-1 beta for 24 h in vitro resulted in an induction of iNOS mRNA expression, an increase in nitrite formation, and a decrease in insulin release and proinsulin biosynthesis as compared with untreated C57BL/6 islets, IL-1 beta failed to induce iNOS mRNA expression and increase nitrite formation by islets isolated from iNOS knockout mice (iNOS(-/-)), and no impairment in islet function was observed. The iNOS(-/-) mice showed a reduced incidence of hyperglycemia after treatment with MLDS as compared with wild-type C57BL/6 (H-2(b)) and 129 SvEv (H-2b) mice. On day 21 after the first streptozotocin (STZ) injection, 75% of the C57BL/6 mice and 100% of the 129SvEv mice had blood glucose levels >11 mmol/l, whereas the corresponding number for iNOS(-/-) mice was only 23%, This protection was not due to a delay in the onset of hyperglycemia, since no increase in number of hyperglycemic iNOS(-/-) mice was observed when the animals were followed up to 42 days, Moreover; islets isolated from iNOS(-/-) mice were susceptible to the in vitro deleterious effects of STZ, In conclusion, the present study provides evidence that iNOS may contribute to p-cell damage after exposure to IL-1 beta in vitro and treatment with MLDS in vivo.
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页码:706 / 713
页数:8
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