A common amino acid polymorphism in insulin receptor substrate-1 causes impaired insulin signaling. Evidence from transfection studies.

摘要: Insulin receptor substrates-1 (IRS-1) is the major cytoplasmic substrate of insulin and IGF-1 receptors. Recent studies have identified multiple sequence variants IRS-1, especially in patients with non-insulin-dependent diabetes mellitus. In present study, we examined insulin-stimulated processes 32D(IR) cells, a myeloid progenitor cell stably overexpressing receptor, transfected wild-type human-IRS-1 or most common human variant IRS-1 which glycine 972 replaced by arginine. As compared to stimulation cells mutant exhibited 32% decrease incorporation [3H]thymidine into DNA (P = 0.002), 36% associated phosphatidylinositol (PI) 3-kinase activity 0.004) 25% binding p85 regulatory subunit PI 0.002). There was also tendency for Grb2 mitogen-activated protein kinase activity, however, these were not statistically significant. The changes occurred no change tyrosine phosphorylation. These data indicate that mutation codon impairs signaling, along pathway, may contribute resistance normal diabetic populations.