IRS1 and Hyperinsulinemia: For example, profound differences between phenotypic manifestations of double heterozygosity (DH) for targeted deletions of the insulin receptor and insulin receptor substrate-1 genes between C57BL/6 DH (hyperinsulinemia and diabetes) and129S6 DH mice (no diabetes, only mild insulin elevations) have been associated with distinct quantitative trait loci linked to hyperinsulinemia and hyperleptinemia [5].