title: Disruption of IRS-2 causes type 2 diabetes in mice.
abstract: Human type 2 diabetes is characterized by defects in both insulin action and insulin secretion. It has been difficult to identify a single molecular abnormality underlying these features. Insulin-receptor substrates (IRS proteins) may be involved in type 2 diabetes: they mediate pleiotropic signals initiated by receptors for insulin and other cytokines. Disruption of IRS-1 in mice retards growth, but diabetes does not develop because insulin secretion increases to compensate for the mild resistance to insulin. Here we show that disruption of IRS-2 impairs both peripheral insulin signalling and pancreatic beta-cell function. IRS-2-deficient mice show progressive deterioration of glucose homeostasis because of insulin resistance in the liver and skeletal muscle and a lack of beta-cell compensation for this insulin resistance. Our results indicate that dysfunction of IRS-2 may contribute to the pathophysiology of human type 2 diabetes.
authors.affiliation: Howard Hughes Medical Institute, Joslin Diabetes Center, Department of Medicine, Harvard Medical School, Boston, Massachusetts 02215, USA.
authors.forename: D J
authors.initials: DJ
authors.lastname: Withers
authors.forename: J S
authors.initials: JS
authors.lastname: Gutierrez
authors.forename: H
authors.initials: H
authors.lastname: Towery
authors.forename: D J
authors.initials: DJ
authors.lastname: Burks
authors.forename: J M
authors.initials: JM
authors.lastname: Ren
authors.forename: S
authors.initials: S
authors.lastname: Previs
authors.forename: Y
authors.initials: Y
authors.lastname: Zhang
authors.forename: D
authors.initials: D
authors.lastname: Bernal
authors.forename: S
authors.initials: S
authors.lastname: Pons
authors.forename: G I
authors.initials: GI
authors.lastname: Shulman
authors.forename: S
authors.initials: S
authors.lastname: Bonner-Weir
authors.forename: M F
authors.initials: MF
authors.lastname: White
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D003001:Cloning, Molecular; D003924:Diabetes Mellitus, Type 2 / Q000209:etiology* / Q000378:metabolism / Q000503:physiopathology; D005260:Female; D018390:Gene Targeting; D006801:Humans; D007328:Insulin / Q000378:metabolism; D055504:Insulin Receptor Substrate Proteins; D007333:Insulin Resistance; D047908:Intracellular Signaling Peptides and Proteins; D007515:Islets of Langerhans / Q000503:physiopathology; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018482:Muscle, Skeletal / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010750:Phosphoproteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D010766:Phosphorylation; D011972:Receptor, Insulin / Q000378:metabolism; D011995:Recombination, Genetic; D015398:Signal Transduction
chemical_list: D001786:Blood Glucose; C526292:IRS1 protein, human; C526297:IRS2 protein, human; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D047908:Intracellular Signaling Peptides and Proteins; C526295:Irs1 protein, mouse; C526298:Irs2 protein, mouse; D010750:Phosphoproteins; D019869:Phosphatidylinositol 3-Kinases; D011972:Receptor, Insulin