title: Defective signaling through Akt-2 and -3 but not Akt-1 in insulin-resistant human skeletal muscle: potential role in insulin resistance.
abstract: Recent evidence has shown that activation of phosphatidyinositol-3-kinase (PI3K) and Akt, necessary for insulin stimulation of glucose transport, is impaired in insulin resistance. It is unknown, however, which Akt isoform shows impaired activation in insulin resistance. Additionally, related growth factors (epidermal or platelet-derived vascular) also stimulate PI3K, but it is unknown whether production of 3,4,5 phosphatidyinositol is sufficient to stimulate glucose transport in insulin-resistant muscle. Moreover, these studies were performed in rodents, and little data exists from humans. Hence, we investigated the stimulation of PI3K and Akt-1, -2, and -3 by insulin and epidermal growth factors (EGFs) in skeletal muscles from lean and obese insulin-resistant humans. Insulin activated all Akt isoforms in lean muscles, whereas only Akt-1 was activated in obese muscles. Insulin receptor substrate (IRS)-1 was associated with PI3K activity, which is necessary for Akt activation by insulin, and was reduced in obese muscles, and this was accompanied by decreased IRS-1 expression. In contrast, insulin- or EGF-stimulated phosphotyrosine-associated PI3K activity was not different between lean and obese muscles. These results show that a defect in the ability of insulin to activate Akt-2 and -3 may explain the impaired insulin-stimulated glucose transport in insulin resistance. Additionally, these data also show that different upstream or downstream signals may regulate the activity of the various Akt isoforms.
authors.affiliation: Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana, USA. brozinick_joseph_t@lilly.com
authors.forename: Joseph T
authors.initials: JT
authors.lastname: Brozinick
authors.forename: Brian R
authors.initials: BR
authors.lastname: Roberts
authors.forename: G Lynis
authors.initials: GL
authors.lastname: Dohm
mesh_terms: D000328:Adult; D015992:Body Mass Index; D003847:Deoxyglucose / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D004815:Epidermal Growth Factor / Q000494:pharmacology; D005260:Female; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D007328:Insulin / Q000494:pharmacology; D055504:Insulin Receptor Substrate Proteins; D007333:Insulin Resistance; D008297:Male; D018482:Muscle, Skeletal / Q000201:enzymology*; D009765:Obesity / Q000201:enzymology; D015513:Oncogene Proteins / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism; D019000:Phosphotyrosine / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D015398:Signal Transduction
chemical_list: D003847:Deoxyglucose; D004815:Epidermal Growth Factor; D038362:Glycogen Synthase Kinase 3; D000071679:Glycogen Synthase Kinase 3 beta; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D015513:Oncogene Proteins; D019869:Phosphatidylinositol 3-Kinases; D010750:Phosphoproteins; D019000:Phosphotyrosine; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; C526292:IRS1 protein, human; C494918:AKT1 protein, human; C494921:AKT2 protein, human; C491754:AKT3 protein, human