Shc protein phosphorylation has been extensively characterized as the initial step that activates a complex mitogenic pathway through its association with Grb2. In the present study, we investigated the adrenergic control of insulin-induced Shc phosphorylation and Shc-Grb2 association, and the modulating effect of streptozotocin-induced diabetes mellitus on Shc phosphorylation and Shc/Grb2 association. Acute treatment with epinephrine, which leads to a normoglycemic insulin-resistant state, does not affect insulin-induced Shc tyrosine phosphorylation or Shc-Grb2 association in liver, muscle, or fat. By contrast, a significant increase in insulin-induced Shc phosphorylation is observed in liver and muscle of rats treated with streptozotocin. The association of Shc/Grb2 is also increased in both tissues following insulin treatment. These data suggest that while epinephrine preserves the insulin-induced phosphorylation of Shc and the mitogenic pathway stimulated by Shc-Grb2 association, treatment with streptozotocin leads to a tissue-specific increase in the activity of the initial step that ultimately results in the activation of the Shc/Grb2 mitogenic pathway.14295-302