| Description |
A neomycin resistance cassette replaced bases -77 to + 179
of the gene, deleting the start codon and producing a shift
in the reading frame. Western blots of liver and muscle
extracts showed no detectable protein.
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| Phenotype Description |
Although IRS-1 (insulin receptor substrate-1) is widely
expressed, including in the developing fetus, disruption of
the IRS-1 gene did not result in significant embryonic
lethality. Homozygous IRS-1 (-/-) mice showed a birth weight
between 40 and 60% of that of the heterozygotes or
homozygous unaffected littermates. The homozygous IRS-1
knockouts grew in proportion to their smaller size and
maintained body weights between 50 and 60% of wild-type
littermates up to age 4 months. Histological examination of
long bones at birth, two and four months of age, as well as
differential staining of cartilage and bone in whole
skeletons of neonatal mice, showed a normal progression of
ossification. Adult IRS-1-knockout mice of both sexes were
fertile, litter size was normal, and females were capable of
nursing their young. IRS-1 (-/-) mice were insulin- and
IGF-1-resistant and showed abnormal glucose tolerance. Thus,
although there was no significant difference in fasting
glucose levels between wild-type IRS-1 (+/+), heterozygote
IRS-1 (+/-) and homozygote IRS-1-deficient mice,
intraperitoneal glucose-tolerance tests in the
IRS-1-knockout mice revealed significant levels of
hyperglycaemia at 15-60 min compared with control; fasting
plasma insulin levels were increased 2.3-fold in IRS-1 (-/-)
mice.
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