title: Insulin signalling and insulin actions in the muscles and livers of insulin-resistant, insulin receptor substrate 1-deficient mice.
abstract: We and others recently generated mice with a targeted disruption of the insulin receptor substrate 1 (IRS-1) gene and demonstrated that they exhibited growth retardation and had resistance to the glucose-lowering effect of insulin. Insulin initiates its biological effects by activating at least two major signalling pathways, one involving phosphatidylinositol 3-kinase (PI3-kinase) and the other involving a ras/mitogen-activated protein kinase (MAP kinase) cascade. In this study, we investigated the roles of IRS-1 and IRS-2 in the biological action in the physiological target organs of insulin by comparing the effects of insulin in wild-type and IRS-1-deficient mice. In muscles from IRS-1-deficient mice, the responses to insulin-induced PI3-kinase activation, glucose transport, p70 S6 kinase and MAP kinase activation, mRNA translation, and protein synthesis were significantly impaired compared with those in wild-type mice. Insulin-induced protein synthesis was both wortmannin sensitive and insensitive in wild-type and IRS-1 deficient mice. However, in another target organ, the liver, the responses to insulin-induced PI3-kinase and MAP kinase activation were not significantly reduced. The amount of tyrosine-phosphorylated IRS-2 (in IRS-1-deficient mice) was roughly equal to that of IRS-1 (in wild-type mice) in the liver, whereas it only 20 to 30% of that of IRS-1 in the muscles. In conclusion, (i) IRS-1 plays central roles in two major biological actions of insulin in muscles, glucose transport and protein synthesis; (ii) the insulin resistance of IRS-1-deficient mice is mainly due to resistance in the muscles; and (iii) the degree of compensation for IRS-1 deficiency appears to be correlated with the amount of tyrosine-phosphorylated IRS-2 (in IRS-1-deficient mice) relative to that of IRS-1 (in wild-type mice).
authors.affiliation: Third Department of Internal Medicine, Faculty of Medicine, University of Tokyo, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Yamauchi
authors.forename: K
authors.initials: K
authors.lastname: Tobe
authors.forename: H
authors.initials: H
authors.lastname: Tamemoto
authors.forename: K
authors.initials: K
authors.lastname: Ueki
authors.forename: Y
authors.initials: Y
authors.lastname: Kaburagi
authors.forename: R
authors.initials: R
authors.lastname: Yamamoto-Honda
authors.forename: Y
authors.initials: Y
authors.lastname: Takahashi
authors.forename: F
authors.initials: F
authors.lastname: Yoshizawa
authors.forename: S
authors.initials: S
authors.lastname: Aizawa
authors.forename: Y
authors.initials: Y
authors.lastname: Akanuma
authors.forename: N
authors.initials: N
authors.lastname: Sonenberg
authors.forename: Y
authors.initials: Y
authors.lastname: Yazaki
authors.forename: T
authors.initials: T
authors.lastname: Kadowaki
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D001693:Biological Transport, Active; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D051380:GRB2 Adaptor Protein; D005947:Glucose / Q000378:metabolism; D007328:Insulin / Q000378:metabolism* / Q000494:pharmacology*; D055504:Insulin Receptor Substrate Proteins; D007333:Insulin Resistance / Q000235:genetics / Q000502:physiology*; D047908:Intracellular Signaling Peptides and Proteins; D008099:Liver / Q000187:drug effects* / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases; D010750:Phosphoproteins / Q000737:chemistry / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011506:Proteins / Q000378:metabolism; D011972:Receptor, Insulin / Q000378:metabolism; D019893:Ribosomal Protein S6 Kinases; D014157:Transcription Factors / Q000737:chemistry / Q000378:metabolism; D014443:Tyrosine / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D051380:GRB2 Adaptor Protein; D005947:Glucose; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D047908:Intracellular Signaling Peptides and Proteins; D019869:Phosphatidylinositol 3-Kinases; D010750:Phosphoproteins; D017853:Phosphotransferases (Alcohol Group Acceptor); D017346:Protein Serine-Threonine Kinases; D011506:Proteins; D011972:Receptor, Insulin; D019893:Ribosomal Protein S6 Kinases; D014157:Transcription Factors; D014443:Tyrosine; C495949:Grb2 protein, mouse; C526295:Irs1 protein, mouse; C526298:Irs2 protein, mouse