title: Insulin resistance in human preeclamptic placenta is mediated by serine phosphorylation of insulin receptor substrate-1 and -2.
abstract: BACKGROUND
  Preeclampsia is a severe complication of human pregnancy often associated with maternal risk factors. Insulin resistance represents a major risk for developing preeclampsia during pregnancy.
  
  
  OBJECTIVE
  A putative second messenger of insulin, inositol phosphoglycan P type (P-IPG), was previously shown to be highly increased during active preeclampsia. Its association with insulin resistance was investigated.
  
  
  METHODS
  A cross-sectional study was carried out in a referral center.
  
  
  METHODS
  Nine preeclamptic (PE) and 18 healthy women were recruited and matched for maternal age, body mass index, parity, and ethnicity in a 1:2 ratio. Placental specimens were collected immediately after delivery.
  
  
  METHODS
  Placental tissue was incubated with insulin and P-IPG production assessed. Insulin signaling proteins were subsequently studied by immunoblotting.
  
  
  RESULTS
  P-IPG extracted from human term placentas upon incubation with insulin was found to be far lower in those with preeclampsia than controls (P < 0.001). Immunoblotting studies revealed serine phosphorylation of insulin receptor substrate-1 and -2 in PE placentas (P < 0.001) with downstream impairment of insulin signaling. The activation of the p85 regulatory subunit of phosphatidylinositol 3- kinase was markedly decreased in PE samples (P < 0.001).
  
  
  CONCLUSIONS
  These findings highlight the importance of P-IPG in active preeclampsia and demonstrate a substantially different response to the insulin stimulus of human PE placentas. Acquired alterations in activation of proteins involved in insulin signaling may play a role in the complex pathogenesis of preeclampsia, probably as a consequence of the immunological dysfunction that occurs in this syndrome. These results seem to confirm an insulin-resistant state in PE placenta and shed a different light on its role in the pathogenesis of this disease with potential therapeutic implications.
authors.affiliation: Department of Obstetrics and Gynaecology, University of Bari, Policlinico di Bari, Piazza Giulio Cesare 11, 70125 Bari, Italy. marco.scioscia@tin.it
authors.forename: Marco
authors.initials: M
authors.lastname: Scioscia
authors.forename: Khalid
authors.initials: K
authors.lastname: Gumaa
authors.forename: Sirilaksana
authors.initials: S
authors.lastname: Kunjara
authors.forename: Malcolm A
authors.initials: MA
authors.lastname: Paine
authors.forename: Luigi E
authors.initials: LE
authors.lastname: Selvaggi
authors.forename: Charles H
authors.initials: CH
authors.lastname: Rodeck
authors.forename: Thomas W
authors.initials: TW
authors.lastname: Rademacher
mesh_terms: D000328:Adult; D015153:Blotting, Western; D003430:Cross-Sectional Studies; D004789:Enzyme Activation; D005260:Female; D006801:Humans; D007295:Inositol Phosphates / Q000096:biosynthesis; D055504:Insulin Receptor Substrate Proteins; D007333:Insulin Resistance / Q000502:physiology*; D047908:Intracellular Signaling Peptides and Proteins; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism*; D010766:Phosphorylation; D010920:Placenta / Q000378:metabolism*; D011134:Polysaccharides / Q000096:biosynthesis; D011225:Pre-Eclampsia / Q000378:metabolism*; D011247:Pregnancy; D011446:Prospective Studies; D012694:Serine / Q000378:metabolism; D015398:Signal Transduction
chemical_list: C526292:IRS1 protein, human; C526297:IRS2 protein, human; D007295:Inositol Phosphates; D055504:Insulin Receptor Substrate Proteins; D047908:Intracellular Signaling Peptides and Proteins; D010750:Phosphoproteins; D011134:Polysaccharides; C028039:inositol phosphate glycan; D012694:Serine; D019869:Phosphatidylinositol 3-Kinases