Gonzalez C, Cuvellier S, Hue-Beauvais C, Lévi-Strauss M
Institut National de la Santé et de la Recherche Médicale, Hôpital Necker, Paris, France.
Diabetologia. 2003 Sep;46(9):1291-5. doi: 10.1007/s00125-003-1168-7. Epub 2003 Jul 15.
AIMS/HYPOTHESIS: Streptozotocin is a monofunctional alkylating agent that induces diabetes in a large variety of mammals. While multiple low doses of streptozotocin induce immune-mediated diabetes, a single high dose of streptozotocin causes a strictly toxic diabetes. Among mouse strains, non-obese diabetic (NOD) mice are characterized by an extreme susceptibility to high dose of streptozotocin-induced diabetes whereas C3H/Or mice are particularly resistant. We hypothesized that NOD genes involved in high dose streptozotocin-induced diabetes could be also involved in the autoimmune destruction of pancreatic beta cells that characterizes this mouse strain which is a model of Type 1 diabetes.
We carried out a whole genome linkage scan on a population of (C3H/Or x NOD) x NOD backcross 1 mice in order to identify the genetic loci involved in NOD susceptibility to high dose of streptozotocin-induced diabetes.
Two loci, in chromosome 9 (D9Mit135 marker, 48 cM) and in chromosome 11 (D11Mit286 marker, 52 cM), were associated with NOD susceptibility to high dose streptozotocin-induced diabetes, the latter being co-localized with the autoimmune diabetes-predisposing idd4 locus. Moreover, we report here that C57BL/6 mice deficient in Nitric Oxide Synthase 2 were as sensitive as wild-type C57BL/6 mice to high dose streptozotocin-induced diabetes.
CONCLUSION/INTERPRETATION: Although the Nitric Oxide Synthase 2 ( Nos2) gene, localized at 45.6 cM in chromosome 11, is a good candidate gene, our results suggest that Nitric Oxide Synthase 2 activation might not be a crucial event for streptozotocin-induced destruction of pancreatic beta cells.
目的/假设：链脲佐菌素是一种单功能烷化剂，可在多种哺乳动物中诱发糖尿病。虽然多次低剂量链脲佐菌素可诱发免疫介导的糖尿病，但单次高剂量链脲佐菌素会导致严重的毒性糖尿病。在小鼠品系中，非肥胖糖尿病（NOD）小鼠对高剂量链脲佐菌素诱发的糖尿病极为敏感，而C3H/Or小鼠则具有特别的抗性。我们推测，参与高剂量链脲佐菌素诱发糖尿病的NOD基因可能也参与了胰腺β细胞的自身免疫性破坏，而这种自身免疫性破坏是该作为1型糖尿病模型的小鼠品系的特征。
我们对（C3H/Or×NOD）×NOD回交1代小鼠群体进行了全基因组连锁扫描，以确定参与NOD对高剂量链脲佐菌素诱发糖尿病易感性的基因座。
9号染色体（D9Mit135标记，48 cM）和11号染色体（D11Mit286标记，52 cM）上的两个基因座与NOD对高剂量链脲佐菌素诱发糖尿病的易感性相关，后者与自身免疫性糖尿病易感idd4基因座共定位。此外，我们在此报告，缺乏一氧化氮合酶2的C57BL/6小鼠对高剂量链脲佐菌素诱发的糖尿病与野生型C57BL/6小鼠一样敏感。
结论/解读：尽管位于11号染色体45.6 cM处的一氧化氮合酶2（Nos2）基因是一个很好的候选基因，但我们的结果表明，一氧化氮合酶2的激活可能不是链脲佐菌素诱导胰腺β细胞破坏的关键事件。
