Department of Pediatrics, Human and Molecular Genetics Center and Children's Research Institute, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, USA.
Physiol Genomics. 2012 Nov 1;44(21):1013-26. doi: 10.1152/physiolgenomics.00040.2012. Epub 2012 Sep 4.
Type 2 diabetes (T2D) is a disease of relative insulin deficiency resulting from both insulin resistance and beta cell failure. We have previously used heterogeneous stock (HS) rats to fine-map a locus for glucose tolerance. We show here that glucose intolerance in the founder strains of the HS colony is mediated by different mechanisms: insulin resistance in WKY and an insulin secretion defect in ACI, and we demonstrate a high degree of variability for measures of insulin resistance and insulin secretion in HS rats. As such, our goal was to use HS rats to fine-map several diabetes-related traits within a region on rat chromosome 1. We measured blood glucose and plasma insulin levels after a glucose tolerance test in 782 male HS rats. Using 97 SSLP markers, we genotyped a 68 Mb region on rat chromosome 1 previously implicated in glucose and insulin regulation. We used linkage disequilibrium mapping by mixed model regression with inferred descent to identify a region from 198.85 to 205.9 that contains one or more quantitative trait loci (QTL) for fasting insulin and a measure of insulin resistance, the quantitative insulin sensitivity check index. This region also encompasses loci identified for fasting glucose and Insulin_AUC (area under the curve). A separate <3 Mb QTL was identified for body weight. Using a novel penalized regression method we then estimated effects of alternative haplotype pairings under each locus. These studies highlight the utility of HS rats for fine-mapping genetic loci involved in the underlying causes of T2D.
2 型糖尿病（T2D）是一种相对胰岛素缺乏症，由胰岛素抵抗和β细胞衰竭引起。我们之前曾使用异质种群（HS）大鼠来精细定位葡萄糖耐量的基因座。我们在这里表明，HS 群体中创始品系的葡萄糖耐量受损是由不同的机制介导的：WKY 存在胰岛素抵抗，ACI 存在胰岛素分泌缺陷，并且我们证明了 HS 大鼠的胰岛素抵抗和胰岛素分泌测量值具有高度的可变性。因此，我们的目标是使用 HS 大鼠在大鼠 1 号染色体上的一个区域内精细定位几个与糖尿病相关的特征。我们在 782 只雄性 HS 大鼠中测量了葡萄糖耐量试验后的血糖和血浆胰岛素水平。使用 97 个 SSLP 标记物，我们对先前涉及葡萄糖和胰岛素调节的大鼠 1 号染色体上的 68Mb 区域进行了基因分型。我们使用混合模型回归和推断血统的连锁不平衡作图来识别一个包含一个或多个定量性状基因座（QTL）的区域，该区域与空腹胰岛素和胰岛素抵抗的衡量标准，即定量胰岛素敏感性检查指数有关。该区域还包含鉴定为空腹血糖和胰岛素 AUC（曲线下面积）的基因座。另外还鉴定了一个独立的<3Mb QTL 用于体重。然后，我们使用一种新颖的惩罚回归方法来估计每个基因座下替代单倍型配对的影响。这些研究强调了 HS 大鼠在精细定位参与 T2D 根本原因的遗传基因座方面的实用性。
