Identification of causative gene for type 2 diabetes in SMXA-5 mouse feeding a high fat diet.

SMXA-5小鼠是从非糖尿病SMIJ株和A/J株建立的26个SMXA重组近交系(RI)亚系之一。这只小鼠是一种多基因2型糖尿病模型，其特征是中度糖耐量受损和轻度高胰岛素血症。为了分析SMXA-5基因A/J衍生的糖尿病相关性状，如糖耐量减低、高血糖、高胰岛素血症和肥胖，我们试图分析(SM/J x SAM-5)F2杂交小鼠的数量性状基因座(QTL)。一个控制体重指数、非空腹血糖浓度和糖耐量的主效QTL被定位在Chr2上。该基因座位于D2Mit15附近，腹膜糖耐量试验(IPGTT)记录的120min血糖浓度的优势对数(LOD)值最高，为12.5。我们将该QTL命名为t2dm2sa，代表SMXA RI品系中的2型糖尿病。Sm.A-t2dm2sa是一种将A/J来源的t2dm2sa区域导入Sm/J的同源菌株，在高脂饮食下表现出明显的糖耐量受损和轻度的高胰岛素血症。这些结果表明，非糖尿病AM和SM/J小鼠的基因组中存在潜在的致糖尿病基因，并且t2dm2sa与除t2dm2sa以外的未知SM/J衍生基因之间的相互作用可引起SMXA-5和SM.A-t2dm2sa小鼠的糖耐量降低。对这些具有上位效应的糖尿病基因的剖析将有助于阐明人类2型糖尿病的复杂机制。

The SMXA-5 mouse is one of the 26 SMXA recombinant inbred (RI) substrains that have been established from nondiabetic SMIJ and A/J strains. This mouse is a model for polygenic type 2 diabetes characterized by both moderate impairment of glucose tolerance and mild hyperinsulinemia. To dissect A/J-derived diabetogenic loci of SMXA-5 contributing to diabetes-related traits such as impaired glucose tolerance, hyperglycemia, hyperinsulinemia, and obesity, we attempted to analyze the quantitative trait loci (QTL) in (SM/J x SAM-5)F2 intercross mice fed a high-fat diet. A major QTL for body mass index, nonfasting blood glucose concentration, and glucose tolerance was mapped on Chr 2. This locus existed near D2Mit15, with the highest logarithm of odds (LOD) score, 12.5, for glucose concentration being recorded at 120 min in an intraperitoneal glucose tolerance test (IPGTT). We designated this QTL as t2dm2sa, for type 2 diabetes mellitus 2 in the SMXA RI strains. SM.A-t2dm2sa, a congenic strain that introgressed the A/J-derived t2dm2sa region into SM/J, exhibited overt impaired glucose tolerance and mild hyperinsulinemia under a high-fat diet. These results suggested that latent diabetogenic genes exist in the genomes of nondiabetic AM and SM/J mice, and that interaction between t2dm2sa and an unknown SM/J-derived locus except where t2dm2sa exists, elicits impaired glucose tolerance in SMXA-5 and SM.A-t2dm2sa mice. The dissection of these diabetogenic genes that have epistatic effects will contribute to the elucidation of the complex mechanisms underlying human type 2 diabetes.