Genetic modifiers of the insulin resistance phenotype in mice

Insulin resistance can result from genetic interactions among susceptibilit y 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 ins ulin receptor gene mutation causes mild hyperinsulinemia. In contrast, on t he genetic background of 129/Sv mice, the same mutation causes severe hyper insulinemia, suggesting that the 129/Sv strain harbors alleles that interac t with the insulin receptor mutation and predispose to insulin resistance. As a first step to identify these alleles, we generated an F-2 intercross b etween insulin receptor heterozygous mutant mice on B6 and 129/Sv backgroun ds (B6(IR) x 129(IR)) and performed a genome-wide scan with polymorphic mar kers at a 20-cM resolution. me report the identification of loci on chromos omes 2 (logarithm of odds [LOD] 5.58) and 10 (LOD 5.58) that show significa nt evidence for linkage to plasma insulin levels as a quantitative trait. T hese findings indicate that targeted mutations in knockout mice can be used to unravel the complex genetic interactions underlying insulin resistance.