Regulation of insulin-stimulated tyrosine phosphorylation of Shc and Shc/Grb2 association in liver, muscle, and adipose tissue of epinephrine- and streptozotocin-treated rats

Shc protein phosphorylation has been extensively characterized as the initi al step that activates a complex mitogenic pathway through its association with Grh2. In the present study, we investigated the adrenergic control of insulin-induced She phosphorylation and Shc-Grb2 association, and the modul ating effect of streptozotocin-induced diabetes mellitus on She phosphoryla tion and Shc/Grb2 association. Acute treatment with epinephrine, which lead s to a normoglycemic insulin-resistant state, does not affect insulin-induc ed She tyrosine phosphorylation or Shc-Grb2 association in liver, muscle, o r fat. By contrast, a significant increase in insulin-induced She phosphory lation is observed in liver and muscle of rats treated with streptozotocin. The association of Shc/Grb2 is also increased in both tissues following in sulin treatment, These data suggest that while epinephrine preserves the in sulin/induced phosphorylation of She and the mitogenic pathway stimulated b y Shc-Grb2 association, treatment with streptozotocin leads to a tissue-spe cific increase in the activity of the initial step that ultimately results in the activation of the Shc/Grb2 mitogenic pathway.