233: Hexosamine biosynthetic pathway: does it contribute to insulin resistance of pregnancy?

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Clinical Obstetrics, Neonatology, Physiology-Endocrinology

tracings with a baseline 90 - 100 bpm and apparent early decelerations could be maternal in origin. 2nd stage tracings that show repetitive accelerations with contractions (especially with ⌬ ⬎ 20 bpm) should be considered MHR until proven otherwise. 0002-9378/$ – see front matter • doi:10.1016/j.ajog.2009.10.245

231 The effect of low dose oxytocin infusion on cerebral hemodynamics in pregnant women Teelkien R. Van Veen1, Michael A Belfort2, Gerda G. Zeeman1 1 University Medical Center, Groningen, Netherlands, 2HCA, St. Mark‘s Hospital, and University of Utah School of Medicine, Salt Lake City, Utah

OBJECTIVE: Oxytocin is known to have a vasodilator effect on porcine cerebral blood vessels. If true in humans, oxytocin may increase cerebral perfusion pressure (CPP), potentially endangering women in whom increased CPP is contraindicated. Our aim was to investigate the cerebrovascular effects of a continuous infusion of low dose oxytocin in normal pregnant women undergoing induction of labor. STUDY DESIGN: Prospective observational study. Middle cerebral artery (MCA) velocity was measured with transcranial Doppler (TCD) ultrasound in 25 healthy, normotensive, non-smoking patients undergoing induction of labor. No vasoactive drugs were used before or during the study period. Measurements were made at baseline, 15, 30, 60 and 120 minutes after oxytocin initiation. Mean arterial pressure (MAP), CPP, resistance index, resistance area product and cerebral flow index at the different time points were analyzed. CPP was estimated as: MeanVelocity/(MeanVelocity-DiastolicVelocity) x (MAPDiastolicBP). Statistics: 1-way ANOVA for repeated measures or Friedman Repeated Measures ANOVA as appropriate. P ⬍ 0.05 significant. RESULTS: Mean cumulative dose at 120 minutes was 467⫾ 133 mU. No systemic or cerebrovascular changes were noted after oxytocin initiation and there was no correlation between the dosage administered and any hemodynamic parameter. Oxytocin did not increase the CPP (CPP baseline: 52 ⫾ 7; CPP 120 minutes: 52 ⫾ 9; P⫽0.83). CONCLUSION: Induction dose oxytocin does not significantly effect selected cerebral hemodynamic parameters in the first two hours after initiation. Specifically oxytocin infusion, at least at these low doses, does not increase CPP in normal pregnant women and is unlikely to endanger parturients at risk from high cerebral perfusion pressure (preeclamptics, women with an AVM or aneurysm). 0002-9378/$ – see front matter • doi:10.1016/j.ajog.2009.10.246

232 The influence of maternal obesity and diabetes on placental fatty acid transporters Christina Scifres1, Baosheng Chen2, D. Michael Nelson3, Yoel Sadovsky4 1

University of Pittsburgh School of Medicine, Department of Obstetrics, Gynecology and Reproductive Sciences, Pittsburgh, Pennsylvania, 2 Washington University in St. Louis, St. Louis, Missouri, 3Washington University in St. Louis, OBGYN and Cell Biology & Physiology, St. Louis, Missouri, 4University of Pittsburgh, Pittsburgh, Pennsylvania

OBJECTIVE: Maternal diabetes is associated with increased placental free fatty acid content. Exposure of cultured primary human trophoblasts to fatty acids in the presence or absence of insulin enhances neutral lipid droplet formation. We hypothesized that hyperinsulinemia, hyperlipidemia, or both regulate the expression of fatty acid transport proteins (FATP) responsible for uptake of fatty acids in cells. STUDY DESIGN: Placental villi samples were collected from healthy, normal weight controls (BMI ⬍25, n⫽10), obese women (BMI ⬎30, n⫽10), or obese women with gestational or type-2 diabetes mellitus (n⫽10) who underwent term elective cesarean delivery without labor. Primary human trophoblasts were exposed to insulin (10 nM), 1200 microM fatty acids, both or vehicle control. Expression of the FATPs in villi and cells was assessed by RT-qPCR and total neutral lipids in cultured human trophoblasts were visualized by microscopy and quantified using BODIPY immunofluorescence.

Poster Session I

RESULTS: Obesity plus diabetes was associated with a significant increase in the expression of FAT/CD36 (2.2-fold, p ⬍0.05, ANOVA with Bonferroni correction), but no differences in the expression of FATP 1,2,3,4, and 6 when compared to placental villi samples from normal or obese women. Using cultured primary trophoblasts we found that FAT/CD36 expression was increased in cells exposed to fatty acids (4-fold, p⬍0.05) or fatty acids plus insulin (6.4-fold, p⬍0.05) compared to vehicle control. There were no differences in expression of FATP 1,2,3,4, and 6 in cultured human trophoblasts. Exposure of the cells to fatty acids or fatty acids plus insulin resulted in increased intracellular lipid accumulation as assessed using BODIPY immunofluorescense (p⬍0.05). CONCLUSION: Placentas from women with diabetes and obesity exhibit higher expression of FAT/CD36 compared to control or obese women. Our data suggest that fatty acids play a central role in trophoblast up regulation of FAT/CD36 expression. 0002-9378/$ – see front matter • doi:10.1016/j.ajog.2009.10.247

233 Hexosamine biosynthetic pathway: does it contribute to insulin resistance of pregnancy? Hye Heo1, Roopali Donepudi2, Reshmi Madankumar3, Derek M. Huffman4, Radhika Muzumdar5, Nir Barzilai4, Francine H. Einstein1 1 Albert Einstein College of Medicine/Montefiore Medical Center, Obstetrics & Gynecology and Women’s Health, Bronx, New York, 2University of Tennessee Health Science Center, Obstetrics & Gynecology and Women’s Health, Tennessee, 3North Western University, Illinois, 4Albert Einstein College of Medicine, Department of Medicine, Bronx, New York, 5Albert EInstein College of Medicine, Department of Pediatrics, Bronx, New York

OBJECTIVE: With positive energy balance, intrinsic nutrient-sensing

pathways can limit cellular uptake of nutrients by rapid induction of insulin resistance via hexosamine biosynthetic pathway (HBP). Covalent modification of the transcription factor, Sp1 by GlcNAc, has been implicated as the link between HBP activation and insulin signaling regulation. Because pregnancy is associated with insulin resistance and positive energy balance, we sought to determine if alteration of glucose flux through the HPB contributes to the insulin resistance of normal pregnancy. STUDY DESIGN: Three groups of age-matched SD rats were studied: 1)Non-pregnant (NP; n⫽6), 2)Pregnant (day 19) non-obese, glucose tolerant (P; n⫽6), and 3) Pregnant (day 19) after surgical removal of visceral fat 1 month prior to mating(PVF⫺; n⫽6). We used pre-conception removal of visceral fat as a tool to improve insulin sensitivity. Western blot was performed using rabbit polyclonal anti-Sp1 antibody and used to measure protein concentration in hind limb muscle as a representative marker for GlcNAc modifications dependent on increased glucose flux through HPB. Skeletal muscle glucose uptake was measured after 2-[U-14C]deoxyglucose (20 ␮Ci) was administered over the final 30 minutes of 3mU/kg/min hyperinsulinemiceuglycemic clamp. RESULTS: Glucose uptake in muscle was greater in NP compared to P (27.6⫾4 v 13.5⫾3.4 ug/g/min, p⬍0.05) and intermediate in PVF⫺ (23.8⫾6.3 ug/g/min, p⫽NS compared to other groups) demonstrating the predicted variation in peripheral insulin action in the 3 groups. However, Sp1 glycosylation was similar in all groups (P 27,646 ⫾3408, NP 35,337 ⫾5064, PVF⫺ 34846 ⫾6070 AU, p⫽NS compared to others) and was not consistent with the degree of insulin resistance. CONCLUSION: Cellular nutrient-sensing with HBP in maternal skeletal muscles does not contribute greatly to pregnancy-related insulin resistance. Future studies will need to determine if the placental/pup unit diverts glucose from the mother during transient periods of relative hyperglycemia, minimizing flux through the HPB. 0002-9378/$ – see front matter • doi:10.1016/j.ajog.2009.10.248

Supplement to DECEMBER 2009 American Journal of Obstetrics & Gynecology

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