Reduced sensitivity of inducible nitric oxide synthase-deficient mice to multiple low-dose streptozotocin-induced diabetes.
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 1 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-2b) both to interleukin (IL)-1beta-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-1beta 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-1beta 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-2b) 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 beta-cell damage after exposure to IL-1beta in vitro and treatment with MLDS in vivo.
Flodström
M
M
Department of Medical Cell Biology, Uppsala University, Sweden. malinf@scripps.edu
Tyrberg
B
B
Eizirik
D L
DL
Sandler
S
S
D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000139:chemically induced* / Q000473:pathology; D004198:Disease Susceptibility; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D007375:Interleukin-1 / Q000494:pharmacology; D007515:Islets of Langerhans / Q000378:metabolism; D051379:Mice; D008815:Mice, Inbred Strains; D009154:Mutation; D019001:Nitric Oxide Synthase / Q000172:deficiency* / Q000235:genetics; D052247:Nitric Oxide Synthase Type II; D009573:Nitrites / Q000378:metabolism; D010179:Pancreas / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism; D013311:Streptozocin / Q000008:administration & dosage*
D007375:Interleukin-1; D009573:Nitrites; D012333:RNA, Messenger; D013311:Streptozocin; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse