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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.

the journal of clinical endocrinology and metabolism/journal of clinical endocrinology and metabolism

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<sup>1</sup>

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 I1

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 I¹