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

SMXA-5小鼠是由非糖尿病型SMIJ和A/J菌株建立的26个SMXA重组近交（RI）亚株之一。这只小鼠是多基因2型糖尿病的模型，其特征是中度糖耐量损伤和轻度高胰岛素血症。为了解剖A/J来源的SMXA-5的糖尿病基因座对糖耐量受损、高血糖、高胰岛素血症和肥胖等糖尿病相关性状的影响，我们试图分析（SM/J x SAM-5）F2杂交小鼠喂食高脂肪饮食的数量性状位点（QTL）。体重指数、非空腹血糖浓度和葡萄糖耐量的主要QTL定位在Chr 2上。该位点位于D2Mit15附近，在腹腔葡萄糖耐量试验（IPGTT）中记录120分钟葡萄糖浓度时，LOD评分最高，为12.5。我们将这个QTL命名为t2dm2sa，用于SMXA RI株的2型糖尿病。SM。a -t2dm2sa是一种同源菌株，它将a /J衍生的t2dm2sa区域渗透到SM/J中，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，在非糖尿病AM和SM/J小鼠的基因组中存在潜在的糖尿病基因，并且t2dm2sa与SM/J衍生的未知位点之间的相互作用导致SMXA-5和SM的糖耐量受损。A-t2dm2sa老鼠。这些具有上位性作用的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.