Genetic Analysis of Diabetes in a Spontaneously Diabetic Non-obese Torii Rat, a Newly Established Animal Model

自发性糖尿病鸟（SDT）大鼠是人类非肥胖型2型糖尿病的动物模型。雄性大鼠在30周龄时糖尿病的累积发病率为100%，而雌性大鼠在65周龄时糖尿病的累积发病率仅为33.3%（Int.J Exp Diab Res，1：89-100，2000）。我们使用回交板{（BN x SDT）F1 x SDT}进行病理和生理表征以及QTL分析。所有的F1后代在20周龄时没有表现出葡萄糖耐受不良的迹象，在25周龄时也没有表现出高血糖的迹象。在319只雄性回交大鼠中，只有27只（8.5%）在20周龄时表现出葡萄糖耐受不良或在25周龄时表现出高血糖。利用SSLP标记对该菌株进行了首次全基因组扫描，定位了5个葡萄糖耐量QTL，分别位于第1、2、11、18和X染色体上，分别为Niddm/sdt 1、Niddm/sdt 2、Niddm/sdt 3、Niddm/sdt 4和Niddm/sdt 5。它们被定位在与人类糖尿病易感基因位点不同源的染色体区域上。对于这些QTL，SDT等位基因的流行显着加剧葡萄糖耐受不良。此外，这些QTL之间的协同作用有助于葡萄糖耐受不良的发生。这些遗传位点是SDT大鼠葡萄糖耐受不良的原因。

A spontaneously diabetic Torii (SDT) rat is an animal model for type 2 diabetes with non-obese in humans. A cumulative incidence of diabetes of 100% was noted by 30weeks of age in male rats, while it was only 33.3% even by 65 weeks of age in the female rats (Int.J Exp Diab Res, 1 : 89-100, 2000). We performed pathological and physiological characterizations and QTL analysis using a backcross panel {(BN x SDT) F1 x SDT}. All of the F1 progenies showed no sign of glucose intolerance at 20 weeks of age and hyperglycemia at 25 weeks of age. Only 27 rats (8.5%) out of 319 male backcrosses showed glucose intolerance at 20 weeks of age or hyperglcemia at 25 weeks of age. By the first genome-wide scan for responsible genes in this strain using SSLP markers, we mapped five QTLs for glucose intolerance ; these were Niddm/sdt 1, Niddm/sdt2, Niddm/sdt3, Niddm/sdt4, and Niddm/sdt5 on chromosomes 1, 2, 11, 18 and X, respectively. They were mapped on chromosomal regions that were not homologous to human diabetes-susceptibility loci already reported. For these QTLs, prevalence of SDT alleles significantly exacerbated glucose intolerance. Furthermore, a synergistic interaction among these QTLs contributed to the onset of glucose intolerance. These genetic loci are responsible for glucose intolerance in the SDT rat.