Insulin resistance and growth retardation in mice lacking insulin receptor substrate-1 and identification of insulin receptor substrate-2.
To clarify the physiological roles of insulin receptor substrate-1 (IRS-1) in vivo, we made mice with a targeted disruption of the IRS-1 gene locus. Mice homozygous for targeted disruption of the IRS-1 gene were born alive but were retarded in embryonal and postnatal growth. They also had resistance to the glucose-lowering effects of insulin, insulin-like growth factor-1 (IGF-1) and factor-2 (IGF-2). These data suggest the existence of both IRS-1-dependent and IRS-1-independent pathways for signal transduction of insulin and IGFs. Moreover, we identified tyrosine phosphorylation of a 190-kDa protein (pp 190) as a novel substrate (IRS-2) for insulin receptor kinase in livers of IRS-1 deficient mice which can bind both P13-kinase and Ash/Grb2.
Third Department of Internal Medicine, Faculty of Medicine, University of Tokyo, Japan.
T
T
Kadowaki
H
H
Tamemoto
K
K
Tobe
Y
Y
Terauchi
K
K
Ueki
Y
Y
Kaburagi
T
T
Yamauchi
S
S
Satoh
H
H
Sekihara
S
S
Aizawa
Y
Y
Yazaki
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D002678:Chimera; D017931:DNA Primers; D005317:Fetal Growth Retardation / Q000235:genetics; D005951:Glucose Tolerance Test; D006130:Growth Disorders / Q000235:genetics*; D006720:Homozygote; D007328:Insulin / Q000097:blood / Q000378:metabolism*; D055504:Insulin Receptor Substrate Proteins; D007333:Insulin Resistance / Q000235:genetics*; D000078790:Insulin Secretion; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D010750:Phosphoproteins / Q000096:biosynthesis* / Q000172:deficiency* / Q000235:genetics; D016133:Polymerase Chain Reaction; D015183:Restriction Mapping
D001786:Blood Glucose; D017931:DNA Primers; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D047908:Intracellular Signaling Peptides and Proteins; C526295:Irs1 protein, mouse; C526298:Irs2 protein, mouse; D010750:Phosphoproteins