Insulin inhibits transcription of IRS-2 gene in rat liver through an insulin response element (IRE) that resembles IREs of other insulin-repressed genes

Recent data indicate that sustained elevations in plasma insulin suppress t he mRNA for IRS-2, a component of the insulin signaling pathway in liver, a nd that this deficiency contributes to hepatic insulin resistance and inapp ropriate gluconeogenesis. Here, we use nuclear run-on assays to show that i nsulin inhibits transcription of the IRS-2 gene in the livers of intact rat s. Insulin also inhibited transcription of a reporter gene driven by the hu man IRS-2 promoter that was transfected into freshly isolated rat hepatocyt es. The human promoter contains a heptanucleotide sequence, TGTTTTG, that i s identical to the insulin response element (IRE) identified previously in the promoters of insulin-repressed genes. Single base pair substitutions in this IRE decreased transcription of the IRS-2-driven reporter in the absen ce of insulin and abolished insulin-mediated repression. We conclude that i nsulin represses transcription of the IRS-2 gene by blocking the action of a positive factor that binds to the IRE. Sustained repression of IRS-2, as occurs in chronic hyperinsulinemia, contributes to hepatic insulin resistan ce and accelerates the development of the diabetic state.