title: Chronically increased S6K1 is associated with impaired IRS1 signaling in skeletal muscle of GDM women with impaired glucose tolerance postpartum.
abstract: BACKGROUND
  The rapidly increasing prevalence of gestational diabetes mellitus (GDM) globally places a growing population at risk for developing type 2 diabetes mellitus (T2DM), particularly those with persistent impaired glucose tolerance (IGT) postpartum.
  
  
  OBJECTIVE
  We sought to 1) identify dynamic insulin signaling abnormalities in vivo in a prospective, longitudinal study of GDM women compared to weight-matched pregnant controls both antepartum and postpartum; and 2) determine abnormalities that might distinguish GDM women who normalize their glucose tolerance postpartum from those with persistent IGT.
  
  
  METHODS
  Skeletal muscle biopsies were obtained before and after a 75-g glucose load in nine overweight to obese GDM women and 10 weight-matched pregnant controls antepartum and postpartum. Postpartum biopsies were collected in five weight-matched GDM women with IGT (GDM/IGT).
  
  
  RESULTS
  GDM women had decreased skeletal muscle insulin-stimulated insulin receptor and insulin receptor substrate 1 (IRS1) tyrosine activation and reduced IRS1, concomitant with increased basal IRS1 serine phosphorylation and basal p70 S6-kinase (S6K1) activation, which resolved postpartum. However, GDM/IGT subjects had a persistent impairment in IRS1 activation and increased S6K1 phosphorylation compared to GDM subjects with normal glucose tolerance.
  
  
  CONCLUSIONS
  This study reveals that women with GDM demonstrate impaired IRS1 signaling associated with increased S6K1 activation in skeletal muscle in vivo. This defect is maintained postpartum in GDM/IGT subjects, despite similar body weights and cytokine levels. Given that GDM women with persistent IGT are at a high risk of developing T2DM, understanding how the nutrient-sensitive mammalian target of rapamycin/S6K1 pathway is chronically activated in GDM may lead to important therapies that could prevent the progression to T2DM.
authors.affiliation: Department of Medicine, Division of Endocrinology, Metabolism, and Diabetes, University of Colorado Denver, Aurora, Colorado 80045, USA.
authors.forename: Linda A
authors.initials: LA
authors.lastname: Barbour
authors.forename: Carrie E
authors.initials: CE
authors.lastname: McCurdy
authors.forename: Teri L
authors.initials: TL
authors.lastname: Hernandez
authors.forename: Jacob E
authors.initials: JE
authors.lastname: Friedman
mesh_terms: D000328:Adult; D015415:Biomarkers / Q000097:blood; D001786:Blood Glucose / Q000378:metabolism; D015153:Blotting, Western; D016640:Diabetes, Gestational / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D005260:Female; D018149:Glucose Intolerance / Q000235:genetics* / Q000503:physiopathology*; D005951:Glucose Tolerance Test; D006801:Humans; D007231:Infant, Newborn; D007328:Insulin / Q000502:physiology; D055504:Insulin Receptor Substrate Proteins / Q000235:genetics* / Q000502:physiology*; D007333:Insulin Resistance / Q000235:genetics / Q000502:physiology; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000473:pathology; D010766:Phosphorylation; D049590:Postpartum Period / Q000235:genetics; D011247:Pregnancy; D012313:RNA / Q000096:biosynthesis / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000096:biosynthesis* / Q000235:genetics*; D012694:Serine / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D014443:Tyrosine / Q000378:metabolism
chemical_list: D015415:Biomarkers; D001786:Blood Glucose; C526292:IRS1 protein, human; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D014443:Tyrosine; D012694:Serine; D012313:RNA; D038762:Ribosomal Protein S6 Kinases, 70-kDa; C448901:ribosomal protein S6 kinase, 70kD, polypeptide 1