Chronically increased S6K1 is associated with impaired IRS1 signaling in skeletal muscle of GDM women with impaired glucose tolerance postpartum

J Clin Endocrinol Metab. 2011 May;96(5):1431-41. doi: 10.1210/jc.2010-2116. Epub 2011 Feb 2.


Context: 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.

Design: 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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adult
  • Biomarkers / blood
  • Blood Glucose / metabolism
  • Blotting, Western
  • Diabetes, Gestational / genetics
  • Diabetes, Gestational / metabolism*
  • Diabetes, Gestational / pathology
  • Female
  • Glucose Intolerance / genetics*
  • Glucose Intolerance / physiopathology*
  • Glucose Tolerance Test
  • Humans
  • Infant, Newborn
  • Insulin / physiology
  • Insulin Receptor Substrate Proteins / genetics*
  • Insulin Receptor Substrate Proteins / physiology*
  • Insulin Resistance / genetics
  • Insulin Resistance / physiology
  • Muscle, Skeletal / metabolism*
  • Muscle, Skeletal / pathology
  • Phosphorylation
  • Postpartum Period / genetics
  • Pregnancy
  • RNA / biosynthesis
  • RNA / genetics
  • Reverse Transcriptase Polymerase Chain Reaction
  • Ribosomal Protein S6 Kinases, 70-kDa / biosynthesis*
  • Ribosomal Protein S6 Kinases, 70-kDa / genetics*
  • Serine / metabolism
  • Signal Transduction / physiology
  • Tyrosine / metabolism


  • Biomarkers
  • Blood Glucose
  • IRS1 protein, human
  • Insulin
  • Insulin Receptor Substrate Proteins
  • Tyrosine
  • Serine
  • RNA
  • Ribosomal Protein S6 Kinases, 70-kDa
  • ribosomal protein S6 kinase, 70kD, polypeptide 1