title: Evidence against a role for insulin-signaling proteins PI 3-kinase and Akt in insulin resistance in human skeletal muscle induced by short-term GH infusion.
abstract: Prolonged growth hormone (GH) excess is known to be associated with insulin resistance, but the underlying mechanisms remain unknown. The aim of this study was to assess the impact of GH on insulin-stimulated glucose metabolism and insulin signaling in human skeletal muscle. In a cross-over design, eight healthy male subjects (age 26.0 +/- 0.8 yr and body mass index 24.1 +/- 0.5 kg/m2) were infused for 360 min with either GH (Norditropin, 45 ng.kg(-1).min(-1)) or saline. During the final 180 min of the infusion, a hyperinsulinemic euglycemic clamp was performed (insulin infusion rate: 1.2 mU.kg(-1).min(-1)). Muscle biopsies from vastus lateralis were taken before GH/saline administration and after 60 min of hyperinsulinemia. GLUT4 content and insulin signaling, as assessed by insulin receptor substrate (IRS)-1-associated phosphatidylinositol 3-kinase and Akt activity were determined. GH levels increased to a mean (+/-SE) level of 20.0 +/- 2.3 vs. 0.5 +/- 0.2 microg/l after saline infusion (P < 0.01). During GH infusion, the glucose infusion rate during hyperinsulinemia was reduced by 38% (P < 0.01). In both conditions, free fatty acids were markedly suppressed during hyperinsulinemia. Despite skeletal muscle insulin resistance, insulin still induced a similar approximately 3-fold rise in IRS-1-associated PI 3-kinase activity (269 +/- 105 and 311 +/- 71% compared with baseline, GH vs. saline). GH infusion did not change Akt protein expression, and insulin caused an approximately 13-fold increase in Akt activity (1,309 +/- 327 and 1,287 +/- 173%) after both GH and saline infusion. No difference in total GLUT4 content was noted (114.7 +/- 7.4 and 107.6 +/- 16.7 arbitrary units, GH vs. saline, compared with baseline). In conclusion, insulin resistance in skeletal muscle induced by short-term GH administration is not associated with detectable changes in the upstream insulin-signaling cascade or reduction in total GLUT4. Yet unknown mechanisms in insulin signaling downstream of Akt may be responsible.
authors.affiliation: Medical Research Laboratory, Medical Department M (Endocrionology and Diabetes), University Hospital of Aarhus, Denmark. Niels.Jessen@Joslin.Harvard.edu
authors.forename: Niels
authors.initials: N
authors.lastname: Jessen
authors.forename: Christian B
authors.initials: CB
authors.lastname: Djurhuus
authors.forename: Jens O L
authors.initials: JO
authors.lastname: Jørgensen
authors.forename: Lasse S
authors.initials: LS
authors.lastname: Jensen
authors.forename: Niels
authors.initials: N
authors.lastname: Møller
authors.forename: Sten
authors.initials: S
authors.lastname: Lund
authors.forename: Ole
authors.initials: O
authors.lastname: Schmitz
mesh_terms: D000328:Adult; D001786:Blood Glucose / Q000378:metabolism; D005230:Fatty Acids, Nonesterified / Q000378:metabolism; D051275:Glucose Transporter Type 4; D019382:Human Growth Hormone / Q000008:administration & dosage*; D006801:Humans; D007328:Insulin / Q000378:metabolism; D055504:Insulin Receptor Substrate Proteins; D007333:Insulin Resistance / Q000502:physiology*; D008297:Male; D009004:Monosaccharide Transport Proteins / Q000378:metabolism; D009124:Muscle Proteins / Q000378:metabolism; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010750:Phosphoproteins / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*
chemical_list: D001786:Blood Glucose; D005230:Fatty Acids, Nonesterified; D051275:Glucose Transporter Type 4; D019382:Human Growth Hormone; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D009004:Monosaccharide Transport Proteins; D009124:Muscle Proteins; D019869:Phosphatidylinositol 3-Kinases; D010750:Phosphoproteins; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; C526292:IRS1 protein, human; C495692:SLC2A4 protein, human; C494918:AKT1 protein, human