Growth hormone induces cellular insulin resistance by uncoupling phosphatidylinositol 3-kinase and its downstream signals in 3T3-L1 adipocytes

Growth hormone (GH) is well known to induce in vivo insulin resistance. How ever, the molecular mechanism of GH-induced cellular insulin resistance is largely unknown. In this study, we demonstrated that chronic GH treatment o f differentiated 3T3-L1 adipocytes reduces insulin-stimulated 2-deoxyglucos e (DOG) uptake and activation of Akt (also known as protein kinase B), both of which are downstream effects of phosphatidylinositol (PI) 3-kinase, des pite enhanced tyrosine phosphorylation of insulin receptor substrate (IRS)- 1, association of IRS-1 with the p85 subunit of PI 3-kinase, and IRS-1-asso ciated PI 3-kinase activity. In contrast, chronic GH treatment did not affe ct 2-DOG uptake and Akt activation induced by overexpression of a membrane- targeted form of the p110 subunit of PI 3-kinase (p110(CAAX)) or Akt activa tion stimulated by platelet-derived growth factor. Fractionation studies in dicated that chronic GH treatment reduces insulin-stimulated translocation of Akt from the cytosol to the plasma membrane. Interestingly, chronic GH t reatment increased insulin-stimulated association of IRS-1 with p85 and IRS -1-associated PI 3-kinase activity preferentially in the cytosol. These res ults indicate that cellular insulin resistance induced by chronic GH treatm ent in 3T3-L1 adipocytes is caused by uncoupling between activation of PI 3 -kinase and its downstream signals, which is specific to the insulin-stimul ated PI 3-kinase pathway. This effect of GH might result from the altered s ubcellular distribution of IRS-1-associated PI 3-kinase.