Suppressors of cytokine signaling-1 and-6 associate with and inhibit the insulin receptor - A potential mechanism for cytokine-mediated insulin resistance

Insulin resistance contributes to a number of metabolic disorders, includin g type II diabetes, hypertension, and atherosclerosis. Cytokines, such as t umor necrosis factor-alpha, interleukin-1 beta, and interleukin-6, and horm ones, such as growth hormone, are known to cause insulin resistance, but th e mechanisms by which they inhibit the cellular response to insulin have no t been elucidated. One mechanism by which these agents could cause insulin resistance is by inducing the expression of cellular proteins that inhibit insulin receptor (IR) signaling. Suppressors of cytokine signaling (SOCS) p roteins are negative regulators of cytokine signaling pathways, the express ion of which is regulated by certain cytokines, SOCS proteins are therefore attractive candidates as mediators of cytokine-induced insulin resistance. We have found that SOCS-1 and SOCS-6 interact with the IR when expressed i n human hepatoma cells (HepG2) or in rat hepatoma cells overexpressing the human IR In SOCS-1-expressing cells, insulin treatment increases the extent of interaction with the IR, whereas in SOCS-6-expressing cells the associa tion with the IR appears to require insulin treatment. SOCS-1 and SOCS-6 do not inhibit insulin-dependent IR autophosphorylation, but both proteins in hibit insulin-dependent activation of ERK1/2 and protein kinase B in vivo a nd IR-directed phosphorylation of IRS-1 in vitro. These results suggest tha t SOCS proteins may be inhibitors of IR signaling and could mediate cytokin e-induced insulin resistance and contribute to the pathogenesis of type II diabetes.