title: Disruption of insulin receptor substrate 2 causes type 2 diabetes because of liver insulin resistance and lack of compensatory beta-cell hyperplasia.
abstract: To investigate the role of insulin receptor substrate (IRS)-2 in vivo, we generated IRS-2-deficient mice by gene targeting. Although homozygous IRS-2-deficient mice (IRS-2-/- mice) had a body weight similar to wild-type mice, they progressively developed type 2 diabetes at 10 weeks. IRS-2-/- mice showed insulin resistance and a defect in the insulin-stimulated signaling pathway in liver but not in skeletal muscle. Despite insulin resistance, the amount of beta-cells was reduced to 83% of that in wild-type mice, which was in marked contrast to the 85% increase in the amount of beta-cells in IRS-1-deficient mice (IRS-1-/- mice) to compensate for insulin resistance. Thus, IRS-2 plays a crucial role in the regulation of beta-cell mass. On the other hand, insulin secretion by the same number of cells in response to glucose measured ex vivo was significantly increased in IRS-2-/- mice compared with wild-type mice but was decreased in IRS-1-/- mice. These results suggest that IRS-1 and IRS-2 may play different roles in the regulation of beta-cell mass and the function of individual beta-cells.
authors.affiliation: Department of Metabolic Disease, Graduate School of Medicine, University of Tokyo, Japan.
authors.forename: N
authors.initials: N
authors.lastname: Kubota
authors.forename: K
authors.initials: K
authors.lastname: Tobe
authors.forename: Y
authors.initials: Y
authors.lastname: Terauchi
authors.forename: K
authors.initials: K
authors.lastname: Eto
authors.forename: T
authors.initials: T
authors.lastname: Yamauchi
authors.forename: R
authors.initials: R
authors.lastname: Suzuki
authors.forename: Y
authors.initials: Y
authors.lastname: Tsubamoto
authors.forename: K
authors.initials: K
authors.lastname: Komeda
authors.forename: R
authors.initials: R
authors.lastname: Nakano
authors.forename: H
authors.initials: H
authors.lastname: Miki
authors.forename: S
authors.initials: S
authors.lastname: Satoh
authors.forename: H
authors.initials: H
authors.lastname: Sekihara
authors.forename: S
authors.initials: S
authors.lastname: Sciacchitano
authors.forename: M
authors.initials: M
authors.lastname: Lesniak
authors.forename: S
authors.initials: S
authors.lastname: Aizawa
authors.forename: R
authors.initials: R
authors.lastname: Nagai
authors.forename: S
authors.initials: S
authors.lastname: Kimura
authors.forename: Y
authors.initials: Y
authors.lastname: Akanuma
authors.forename: S I
authors.initials: SI
authors.lastname: Taylor
authors.forename: T
authors.initials: T
authors.lastname: Kadowaki
mesh_terms: D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D018390:Gene Targeting; D006965:Hyperplasia; D007328:Insulin / Q000378:metabolism / Q000494:pharmacology; D055504:Insulin Receptor Substrate Proteins; D007333:Insulin Resistance; D000078790:Insulin Secretion; D047908:Intracellular Signaling Peptides and Proteins; D007515:Islets of Langerhans / Q000378:metabolism / Q000473:pathology*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism; D010750:Phosphoproteins / Q000172:deficiency* / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D047908:Intracellular Signaling Peptides and Proteins; C526298:Irs2 protein, mouse; D010750:Phosphoproteins