Insulin resistance in human preeclamptic placenta is mediated by serine phosphorylation of insulin receptor substrate-1 and -2.
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.
Scioscia
Marco
M
Department of Obstetrics and Gynaecology, University of Bari, Policlinico di Bari, Piazza Giulio Cesare 11, 70125 Bari, Italy. marco.scioscia@tin.it
Gumaa
Khalid
K
Kunjara
Sirilaksana
S
Paine
Malcolm A
MA
Selvaggi
Luigi E
LE
Rodeck
Charles H
CH
Rademacher
Thomas W
TW
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
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