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) 亚品系之一。该小鼠是多基因 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。为了剖析 SMXA-5 的 A/J 衍生的糖尿病基因位点，该位点可导致糖耐量受损、高血糖、高胰岛素血症和肥胖等糖尿病相关性状，我们尝试分析高脂饮食喂养的 (SM/J x SAM-5)F2 杂交小鼠的数量性状基因座 (QTL)。体重指数、非空腹血糖浓度和葡萄糖耐量的主要 QTL 被定位在 Chr 2 上。该位点存在于 D2Mit15 附近，在腹膜内葡萄糖耐量试验 (IPGTT) 中，在 120 分钟时记录的葡萄糖浓度的对数 (LOD) 得分最高，为 12.5。我们将此 QTL 指定为 t2dm2sa，代表 SMXA RI 品系中的 2 型糖尿病 2。 SM.A-t2dm2sa 是一种将 A/J 衍生的 t2dm2sa 区域基因渗入 SM/J 的同源菌株，在高脂肪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 t2dm2sa 与除 t2dm2sa 存在之外的未知 SM/J 衍生基因座之间的相互作用会引起 SMXA-5 和 SM.A-t2dm2sa 小鼠的葡萄糖耐量受损。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.