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Several mechanisms could account for the greater than expected degree of insulin resistance in these individuals. First, because the insulin receptor precursor can form hybrids, the mutant receptor might function in a dominant-interfering manner, inhibiting the function of the normal allele. However, an interesting alternative model has emerged from the study of Insr knockout mice. The developmental characteristics of homozygous insulin receptor null mice are different from those of the compound receptor mutations in humans, and these mice die shortly after birth owing to extreme insulin resistance (4, 5). Heterozygous mice, carrying only one disrupted Insr allele are phenotypically normal, with no apparent defects in insulin signaling. Similarly, heterozygous knockout mice lacking a single allele of the gene for the insulin receptor substrate protein IRS1 lack any significant phenotype, whereas homozygous …