Animal Experimentation system as an infrastructure to support translational progression of diabetes research to medical practice

该项目的目的是建立一个动物实验系统，以期推进2型糖尿病的转化研究。2型糖尿病被认为是其他生活方式相关疾病的多个危险因素之一，并且许多因素影响疾病，例如遗传和环境贡献。因此，我们建立了具有严格同源条件的遗传背景。将IRS 1基因和IRS 2基因敲除（KO）小鼠分别培育成C57 BU 6（B6）品系。我们还与129个品系的基因敲除小鼠进行了繁殖。B6-IRS 2基因敲除株出现高血糖、葡萄糖耐量试验（GTT）不耐受和胰岛素耐量试验（IR）抵抗等糖尿病症状的时间均早于原杂交株。B6-IRS 2 KO小鼠在6周龄时引起糖尿病。自然交配所产小鼠与体外受精-胚胎移植所产小鼠的表型无明显差异。B6-IRS 2基因敲除小鼠分别饲喂含5%、10%和15%脂肪的三种食物。在10%脂肪组的GTT中观察到疾病进展，在15%脂肪喂养组的GTT和ITT中都观察到疾病进展。129-IRS 2基因敲除小鼠GTT的临床价值比B6背景小鼠更差。另一方面，129-IRS 2 KO小鼠对胰岛素治疗显示出相对良好的应答。

The aim of this project is to establish an animal experimentation system expecting to progress translational research for type 2 diabetes disease. Type 2 diabetes considers as one of multiple risk factors for other lifestyle-related] diseases, and many factors influence for the disease such as genetic and environmental contribution. Therefore, we set up genetic background with strict congenic conditions. Knockout (KO) mice for IRS1 gene and IRS2 gene were bred into C57BU6 (B6) strain respectively. We also bred with 129 strains for those gene knockdown mice. The earlier onset of diabetic symptoms such as hyper blood glucose levels, intolerance in GTT (glucose tolerance test) and resistance in'Tr (insulin tolerant test) were observed in B6-IRS2 KO than original hybrid strain. B6-IRS2 KO mice caused diabetic in six weeks of age. There were any obvious phenotypic difference observed between mice delivered by natural mating and those by using in vitro fertilization and embryo transfer technology. B6-IRS2 KO mice were fed three types of foods containing with 5%, 10% and 15% of fat, respectively. Progression of the disease was observed on GTT in the group with 10% fat, and both on GTT and ITT in the 15% fat-feeding group. Clinical value of GTT was getting worse in 129-IRS2 KO mice than those of B6 background. On the other hand, 129-IRS2 KO mice showed relatively good response against insulin treatment.