Kido Y, Philippe N, Schäffer A A, Accili D
Developmental Endocrinology Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA.
Diabetes. 2000 Apr;49(4):589-96. doi: 10.2337/diabetes.49.4.589.
Insulin resistance can result from genetic interactions among susceptibility alleles. To identify genetic loci predisposing to insulin resistance, we used crosses between different strains of mice with a targeted null allele of the insulin receptor gene. On the genetic background of B6 mice, the insulin receptor gene mutation causes mild hyperinsulinemia. In contrast, on the genetic background of 129/Sv mice, the same mutation causes severe hyperinsulinemia, suggesting that the 129/Sv strain harbors alleles that interact with the insulin receptor mutation and predispose to insulin resistance. As a first step to identify these alleles, we generated an F2 intercross between insulin receptor heterozygous mutant mice on B6 and 129/Sv backgrounds (B6IR x 129IR) and performed a genome-wide scan with polymorphic markers at a 20-cM resolution. We report the identification of loci on chromosomes 2 (logarithm of odds [LOD] 5.58) and 10 (LOD 5.58) that show significant evidence for linkage to plasma insulin levels as a quantitative trait. These findings indicate that targeted mutations in knockout mice can be used to unravel the complex genetic interactions underlying insulin resistance.
胰岛素抵抗可能源于易感等位基因之间的遗传相互作用。为了确定易导致胰岛素抵抗的基因位点，我们利用胰岛素受体基因靶向无效等位基因的不同品系小鼠进行杂交。在B6小鼠的遗传背景下，胰岛素受体基因突变会导致轻度高胰岛素血症。相比之下，在129/Sv小鼠的遗传背景下，相同的突变会导致严重的高胰岛素血症，这表明129/Sv品系携带与胰岛素受体突变相互作用并易导致胰岛素抵抗的等位基因。作为鉴定这些等位基因的第一步，我们在B6和129/Sv背景下的胰岛素受体杂合突变小鼠之间产生了F2代杂交（B6IR×129IR），并使用多态性标记以20厘摩的分辨率进行全基因组扫描。我们报告了在2号染色体（优势对数[LOD] 5.58）和10号染色体（LOD 5.58）上鉴定到的位点，这些位点显示出与作为数量性状的血浆胰岛素水平存在显著连锁证据。这些发现表明，基因敲除小鼠中的靶向突变可用于揭示胰岛素抵抗背后复杂的遗传相互作用。
