title: Antiinsulin receptor autoantibodies induce insulin receptors to constitutively associate with insulin receptor substrate-1 and -2 and cause severe cell resistance to both insulin and insulin-like growth factor I.
abstract: We report here that antiinsulin receptor (anti-IR) autoantibodies (AIRs) from a newly diagnosed patient with type B syndrome of insulin resistance induced cellular resistance not only to insulin but also to insulin-like growth factor I (IGF-I) for the stimulation of phosphatidylinositol 3-kinase and mitogen-activated protein kinase activities and of glycogen and DNA syntheses. The molecular mechanisms of this dual resistance were investigated. Patient AIRs bound the IR at the insulin-binding site and caused insulin resistance at the IR level by inducing a 50% decrease in cell surface IRs and a severe defect in the tyrosine kinase activity of the residual IRs, manifested by a loss of insulin-stimulated IR autophosphorylation and IR substrate-1 (IRS-1)/IRS-2 phosphorylation. In contrast, cell resistance to IGF-I occurred at a step distal to IGF-I receptors (IGF-IRs), as AIRs altered neither IGF-I binding nor IGF-I-induced IGF-IR autophosphorylation, but inhibited the ability of IGF-IRs to mediate tyrosine phosphorylation of IRS-1 and IRS-2 in response to IGF-I. Coimmunoprecipitation assays showed that in AIR-treated cells, IRs, but not IGF-IRs, were constitutively associated with IRS-1 and IRS-2, strongly suggesting that AIR-desensitized IRs impeded IGF-I action by sequestering IRS-1 and IRS-2. Accordingly, AIRs had no effect on the stimulation of mitogen-activated protein kinase activity or DNA synthesis by vanadyl sulfate, FCS, epidermal growth factor, or platelet-derived growth factor, all of which activate signaling pathways independent of IRS-1/IRS-2. Thus, AIRs induced cell resistance to both insulin and IGF-I through a novel mechanism involving a constitutive and stable association of IRS-1 and IRS-2 with the IR.
authors.affiliation: INSERM Unité 402, Faculté de Médecine Saint-Antoine, Paris, France.
authors.forename: M
authors.initials: M
authors.lastname: Auclair
authors.forename: C
authors.initials: C
authors.lastname: Vigouroux
authors.forename: C
authors.initials: C
authors.lastname: Desbois-Mouthon
authors.forename: J
authors.initials: J
authors.lastname: Deibener
authors.forename: P
authors.initials: P
authors.lastname: Kaminski
authors.forename: O
authors.initials: O
authors.lastname: Lascols
authors.forename: G
authors.initials: G
authors.lastname: Cherqui
authors.forename: J
authors.initials: J
authors.lastname: Capeau
authors.forename: M
authors.initials: M
authors.lastname: Caron
mesh_terms: D000368:Aged; D000818:Animals; D001323:Autoantibodies / Q000494:pharmacology*; D016466:CHO Cells; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D006224:Cricetinae; D004247:DNA / Q000096:biosynthesis; D005260:Female; D006003:Glycogen / Q000096:biosynthesis; D006801:Humans; D007074:Immunoglobulin G / Q000494:pharmacology; D055504:Insulin Receptor Substrate Proteins; D007333:Insulin Resistance / Q000276:immunology*; D007334:Insulin-Like Growth Factor I / Q000378:metabolism / Q000494:pharmacology*; D047908:Intracellular Signaling Peptides and Proteins; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism*; D010766:Phosphorylation; D011972:Receptor, Insulin / Q000276:immunology* / Q000378:metabolism*; D017968:Vanadium Compounds / Q000494:pharmacology
chemical_list: D001323:Autoantibodies; C526292:IRS1 protein, human; C526297:IRS2 protein, human; D007074:Immunoglobulin G; D055504:Insulin Receptor Substrate Proteins; D047908:Intracellular Signaling Peptides and Proteins; D010750:Phosphoproteins; D017968:Vanadium Compounds; D007334:Insulin-Like Growth Factor I; C034028:vanadyl sulfate; D006003:Glycogen; D004247:DNA; D019869:Phosphatidylinositol 3-Kinases; D011972:Receptor, Insulin; D017871:Calcium-Calmodulin-Dependent Protein Kinases