title: Dissecting the mechanism of insulin resistance using a novel heterodimerization strategy to activate Akt.
abstract: Insulin resistance can occur in response to many different external insults, including chronic exposure to insulin itself as well as other agonists such as dexamethasone. It is generally thought that such defects arise due to a defect(s) at an early stage in the insulin signaling cascade. One model suggests that this involves activation of the mammalian target of rapamycin/S6 kinase pathway, which inactivates insulin receptor substrate via Ser/Thr phosphorylation. However, we have recently shown that insulin receptor substrate is not a major node for insulin resistance defects. To explore the mechanism of insulin resistance, we have developed a novel system to activate Akt independently of its upstream effectors as well as other insulin-responsive pathways such as mitogen-activated protein kinase. 3T3-L1 adipocytes were rendered insulin-resistant either with chronic insulin or dexamethasone treatment, but conditional activation of Akt2 stimulated hemagglutinin-tagged glucose transporter 4 translocation to the same extent in these insulin-resistant and control cells. However, addition of insulin to cells in which Akt was conditionally activated resulted in a reversion to the insulin-resistant state, indicating a feedforward inhibitory mechanism activated by insulin itself. This effect was overcome with wortmannin, implicating a role for phosphatidylinositol 3-kinase in this inhibitory process. We conclude that in chronic insulin- and dexamethasone-treated cells, acute activation with insulin itself is required to activate a feedforward inhibitory pathway likely emanating from phosphatidylinositol 3-kinase that converges on a target downstream of Akt to cause insulin resistance.
authors.affiliation: Diabetes and Obesity Research Program, The Garvan Institute of Medical Research, Sydney, New South Wales 2010.
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Ng
authors.forename: Georg
authors.initials: G
authors.lastname: Ramm
authors.forename: David E
authors.initials: DE
authors.lastname: James
mesh_terms: D041721:3T3-L1 Cells; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D003907:Dexamethasone / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D051275:Glucose Transporter Type 4 / Q000378:metabolism; D006801:Humans; D007004:Hypoglycemic Agents / Q000378:metabolism / Q000494:pharmacology; D007328:Insulin / Q000378:metabolism* / Q000494:pharmacology; D007333:Insulin Resistance; D051379:Mice; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*
chemical_list: D000893:Anti-Inflammatory Agents; D051275:Glucose Transporter Type 4; D007004:Hypoglycemic Agents; D007328:Insulin; C495693:Slc2a4 protein, mouse; D003907:Dexamethasone; D019869:Phosphatidylinositol 3-Kinases; C494922:Akt2 protein, mouse; D051057:Proto-Oncogene Proteins c-akt