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

We report here that antiinsulin receptor (anti-IR) autoantibodies (AIRs) fr om a newly diagnosed patient with type B syndrome of insulin resistance ind uced cellular resistance not only to insulin but also to insulin-like growt h factor I (IGF-I) for the stimulation of phosphatidylinositol 3-kinase and mitogen-activated protein kinase activities and of glycogen and DNA synthe ses. The molecular mechanisms of this dual resistance were investigated. Pa tient AIRs bound the IR at the insulin-binding site and caused insulin resi stance 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, manifes ted by a loss of insulin-stimulated IR autophosphorylation and IR substrate -1 (IRS-1)/IRS-2 phosphorylation. In contrast, cell resistance to IGF-I occ urred at a step distal to IGF-I receptors (IGF-IRs), as AIRs altered neithe r 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 IR S-2 in response to IGF-I. Coimmunoprecipitation assays showed that in AIR-t reated cells, IRs, but not IGF-IRs, were constitutively associated with IRS -1 and IRS-8, strongly suggesting that AIR-desensitized IRs impeded IGF-I a ction by sequestering IRS-1 and IRS-2. Accordingly, AIRs had no effect on t he stimulation of mitogen-activated protein kinase activity or DNA synthesi s by vanadyl sulfate, FCS, epidermal growth factor, or platelet-derived gro wth factor, all of which activate signaling pathways independent of IRS-1/I RS-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.