A new model of insulin-deficient diabetes:: male NOD mice with a single copy of Ins1 and no Ins2
A new model of insulin-deficient diabetes:: male NOD mice with a single copy of Ins1 and no Ins2
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DOI：
10.1007/s00125-006-0241-4
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发表时间：
2006-06-01
期刊：
影响因子：
8.2
通讯作者：
Eisenbarth, GS
中科院分区：
文献类型：
--
作者：
Babaya, N;Nakayama, M;Eisenbarth, GS
目的/假设：我们描述了一种新的胰岛素缺乏性糖尿病模型，其中编码胰岛素1 （Ins1）的基因拷贝单一，而没有编码胰岛素2 （Ins2）的基因拷贝。材料和方法：构建了5个品系：含有2个Ins1拷贝的小鼠（NODIns1+/+、Ins2-/-）、含有1个Ins1拷贝的小鼠（NODIns1+/-、Ins2-/-）、含有2个Ins1拷贝的小鼠（NODIns1-/-、Ins2+/+）、含有1个Ins1拷贝的小鼠（NODIns1-/-、Ins2+/-）和含有转基因编码B16:Ala原胰岛素的NOD（Ins1+/-、Ins2-/-）。结果：10周龄时，所有雄性NODIns1+/-、Ins2-/-小鼠均发生糖尿病，而所有雌性NODIns1+/-、Ins2-/-小鼠均未发生糖尿病（p < 0.0001）。相比之下，携带单个Ins2拷贝（而不是单个Ins1拷贝）的雄性和雌性NODIns1-/-、Ins2+/-小鼠都不会发生早期糖尿病，携带两个基因拷贝的小鼠也不会发生早期糖尿病。男性糖尿病患者NODIns1+/-、Ins2-/-的胰岛在这个早期没有淋巴细胞浸润。相反，胰岛细胞之间的胰岛素呈异质弱染色。虽然只有雄性NODIns1+/-、Ins2-/-小鼠发生糖尿病，但雄性和雌性NODIns1+/-、Ins2-/-小鼠的胰岛素含量均显著降低。NODIns1+/+、Ins2-/-小鼠胰岛素含量也明显降低，而NODIns1-/-、Ins2+/+小鼠，甚至NODIns1-/-、Ins2+/-小鼠胰岛素含量均正常。通过引入编码胰岛素原的转基因，雄性NODIns1+/-、Ins2-/-小鼠完全摆脱了糖尿病。在胰岛素耐量试验中，雄性小鼠与雌性小鼠相比出现胰岛素抵抗。结论/解释：这些结果表明，相对于Ins2而言，Ins1是一个“缺陷基因”，并且创建的小鼠系提供了一种性别二态胰岛素缺乏性糖尿病的新模型。
Aims/hypothesis: We describe a novel model of insulin-deficient diabetes with a single copy of the gene encoding insulin 1 (Ins1) and no gene encoding insulin 2 (Ins2). Materials and methods: We constructed five lines of mice: mice with two copies of Ins1 (NODIns1+/+,Ins2-/-), mice with a single copy of Ins1 (NODIns1+/-,Ins2-/-), mice with two copies of Ins2 (NODIns1-/-,Ins2+/+), mice with a single copy of Ins2 (NODIns1-/-,Ins2+/-) and NOD(Ins1+/-,Ins2-/-)mice with a transgene encoding B16:Ala proinsulin. Results: By 10 weeks of age, all male NODIns1+/-,Ins2-/- mice were diabetic, whereas all female NODIns1+/-,Ins2-/- were not diabetic (p < 0.0001). In contrast, neither male nor female NODIns1-/-,Ins2+/- with a single copy of Ins2 (rather than single copy of Ins1) developed early diabetes and no mice with two copies of either gene developed early diabetes. Islets of the diabetic male NODIns1+/-,Ins2-/- at this early age had no lymphocyte infiltration. Instead there was heterogeneous (between islet cells) weak staining for insulin. Although only male NODIns1+/-,Ins2-/- mice developed diabetes, both male and female NODIns1+/-,Ins2-/- mice had markedly decreased insulin content. In NODIns1+/+,Ins2-/-, there was also a significant decrease in insulin content, whereas NODIns1-/-,Ins2+/+ mice, and even NODIns1-/-,Ins2+/- mice, were normal. Male NODIns1+/-,Ins2-/- mice were completely rescued from diabetes by introduction of a transgene encoding proinsulin. On i.p. insulin tolerance testing, male mice had insulin resistance compared with female mice. Conclusions/interpretation: These results suggest that Ins1 is a 'defective gene' relative to Ins2, and that the mouse lines created provide a novel model of sex-dimorphic insulin-deficient diabetes.