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和A/J品系建立的26个SMXA重组近交（RI）亚系之一。该小鼠是多基因2型糖尿病的模型，其特征在于葡萄糖耐量的中度损害和轻度高胰岛素血症。为了分析SMXA-5中A/J基因的致糖尿病基因座对糖耐量异常、高血糖、高胰岛素血症和肥胖等糖尿病相关性状的影响，我们试图分析高脂饲料喂养的（SM/J x SAM-5）F2杂交小鼠的数量性状基因座（QTL）。一个主要的QTL的体重指数，非空腹血糖浓度，和葡萄糖耐量被定位在第2章。该位点存在于D2 Mit 15附近，在腹膜内葡萄糖耐量试验（IPGTT）中，在120 min时记录到葡萄糖浓度的最高对数比值（LOD）评分为12.5。我们将SMXA RI菌株中2型糖尿病的该QTL命名为t2 dm 2sa。SM. A-t2 dm 2sa是一个将A/J衍生的t2 dm 2sa区域渗入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高胰岛素血症。这些结果表明，潜在的致糖尿病基因存在于非糖尿病AM和SM/J小鼠的基因组中，并且t2 dm 2sa与除了t2 dm 2sa存在之外的未知SM/J衍生位点之间的相互作用导致SMXA-5和SM. A-t2 dm 2sa小鼠的糖耐量受损。这些具有上位效应的致糖尿病基因的解剖将有助于阐明人类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.