73: In utero exposure to maternal obesity programs offspring insulin resistance
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Abstracts 71 78Moderators: Thomas Moore, MD; Yvonne Chang, MD
71 Pioglitazone therapy in offspringexposed to maternal obesityArshag Kalanderian1, Nicola Abate2, Igor Patrikeev3, MonicaLongo1, Massoud Motamedi3, George R. Saade1, Egle Bytautiene11The University of TexasMedical Branch, Obstetrics &Gynecology,Galveston, TX, 2The University of TexasMedical Branch, InternalMedicine, Galveston, TX, 3The University of TexasMedicalBranch, Center for Biomedical Engineering, Galveston, TXOBJECTIVE: Pioglitazone(PL),ananti-diabeticdrugofthethiazolidinedionefamily, improvesglucoseandlipidmetabolisminthemuscles,adiposetissue,and liver by increasing insulin sensitivity via peroxisome proliferator-acti-vated receptorgamma(PPAR) activation.PPARmRNAexpression is in-creased in adipose tissue fromoffspringborn toobesemothers.Wehypoth-esize that activation of PPAR receptors by PL will improve the metabolicstatus of the offspring exposed tomaternal obesity in a previously validatedmousemodel of the fetal origin ofmetabolic syndrome.STUDY DESIGN: CD-1mice were placed on high fat diet for 3months priorto, and during pregnancy. The resulting pups were weaned to regular diet.Pupswererandomlyassignedtoreceive40mg/kgofPLbyoralgavagein0.5%ofmethyl cellulose (PL group, n10), or the same amount of 0.5%methylcellulose (CTR group, n8). Treatment was given once daily from10 to 12weeksofage.Immediatelybeforeandafterthetreatmentperiod,theoffspringwereweighed, their visceral adipose tissue (VAT)was evaluated using com-puted-tomography, bloodwas collected for fastingglucose (GL) and triglyc-eride(TRG)analysis,andintraperitonealglucosetolerance(IGTT)testswereperformed. Data was analyzed as change frompre-treatment using Studentt-test (significance: P0.05).RESULTS: PL therapy significantly attenuated the increase in bodyweight (BW) seen in the control mice (mean increase: PL 1.25% vs.CTR9.56%; Figure, P0.02). TRG levels increased by 15% in theCTRvs a 24% decrease in PL (Figure, P0.004). There was also a trendtowards lowerVAT and improvement inGL (fasting and IGTT) levelsin the offspring that received PL.CONCLUSION: Short therapy with PL in the offspring of obese mothersmitigates the weight and metabolic changes associated with develop-mental programming.Our data are novel and propose a potential rolefor drugs that activate PPAR receptors in the prevention of meta-bolic syndrome in adult offspring of obese mothers.
72 Oral treatment with anti-oxidant N-acetylcysteinereduces maternal diabetes-inducedembryonic neural tube defectsYuanning Cao1, Zhiyong Zhao2, E. Albert Reece21University ofMaryland School ofMedicine, Department of Obstetrics,Gynecology, and Reproductive Sciences, Baltimore,MD, 2University ofMaryland School ofMedicine, Obstetrics, Gynecology & ReproductiveSciences and Biochemistry &Molecular Biology, Baltimore,MDOBJECTIVE: We and others have shown thatmaternal diabetes inducesembryonic malformations, including neural tube defects (NTDs), byincreasing oxidative and endoplasmic reticulum (ER) stress. The aimsof this study are to explore antioxidative approaches, using antioxi-dant N-acetylcysteine (NAC), to reduce NTDs and investigate theunderlying mechanisms.STUDY DESIGN: Diabetes mellitus in female mice was induced by in-travenous injection of streptozotocin (60mg/kg), before beingmatedwith normal male mice At embryonic day (E) 7.5, the mice weretreated with NAC (100 mg/kg, b.i.d) or vehicle through oral gavagefeeding for 3 days. At E10.5, the embryos were examined and neuraltube tissues were collected for protein assays.RESULTS: NAC treatment significantly reduced NTD rate in the em-bryos of diabetic mice (2.5%), compared with that in vehicle-treatedgroup (17.8%). Oxidative stress in the neural tubes was alleviated byNAC treatment, indicated by decreased levels of oxidative stressmarkers, 3-nitrotyrosine and 4-hydroxynonenal. In addition, the lev-els of ER stress factors (CHOP, calreticulin, p-PERK, and p-eIF2),which are increased in the embryos, were significantly reduced byNAC treatment.CONCLUSION: Pharmacological treatment with NAC ameliorates oxi-dative stress and reduces NTDs in the embryos of diabetic mice. Theantioxidant effects are associated with reduction in ER stress.
73 In utero exposure to maternal obesityprograms offspring insulin resistanceMina Desai1, Diana Wolfe1, Thomas Magee1, Michael Ross11LABioMed at Harbor-UCLAMed. Ctr., Obstetricsand Gynecology, Torrance, CAOBJECTIVE: Epidemiological studies and animal models confirm thedevelopmental origins of obesity. Offspring born to obese or diabeticmothers are often larger at birth, and show increased adipose tissuemass and obesity and diabetes risk in later life. As the prevalence ofobesity among pregnant women continues to rise, increasing numberof children are exposed to an obese intrauterine environment duringdevelopment. We investigated whether exposure to maternal obesityduring pregnancy impacts on obesity and diabetes in the offspring.STUDY DESIGN: Rats were fed a high fat (HF; 60% k/cal) or control diet(10% k/cal) prior to and thoughout pregnancy. At 1 day of age, bloodwas collected from pups. Offspring litter size was standardized, andboth HF and Control offspring were cross-fostered and nursed by
Oral Concurrent Session 7 www.AJOG.orgSaturday, February 11, 2012 8:00 am 10:00 am LandmarkB,DallasHyatt Regency
S46 American Journal of Obstetrics& Gynecology Supplement to JANUARY 2012
Control dams. At 3 weeks of age, female offspring underwent DEXAscan and were fasted overnight for GTT and blood samples.RESULTS: At 1 day of age, HF female newborns had similar bodyweight (7.1/0.2 vs 6.8/0.1 g) and comparable glucose levels toControls, though notably increased plasma insulin levels (0.68/0.06 vs 0.44/0.04 ng/ml, p0.05). After nursing by Controldams, 3 week old HF females continued to have similar body weightsand body fat as Controls. HF females maintained significantly higherplasma insulin levels (0.82/0.03 vs 0.50/0.02 ng/ml), thoughnow demonstrated elevated blood glucose (116/5 vs 90/4mg/dl) and an impaired GTT (AUC 2.8/0.2 vs 2.3/0.1).CONCLUSION: Maternal obesity programs offspring insulin resistanceindependent of offspring body weight. Nutrition interventions mustoccur during pregnancy, not the neonatal period, to prevent trans-generational programming of obesity and diabetes.
74 Maternal genotype and gestational diabetesAlison Stuebe1, Amy Herring2, AlisonWise2, Anna Maria Siega-Riz31University of North Carolina School ofMedicine, Obstetricsand Gynecology, Chapel Hill, NC, 2Gillings School of GlobalPublic Health, Biostatistics, Chapel Hill, NC, 3Gillings Schoolof Global Public Health, Epidemiology, Chapel Hill, NCOBJECTIVE: To determine whether maternal genetic variants associ-atedwith glucose homeostasis in genome-wide association studies areassociated with gestational diabetes (GDM).STUDY DESIGN: We genotyped 830 self-identified Caucasian womenand 372 self-identified African-American women in the Pregnancy,Infection and Nutrition (PIN) Studies cohorts for 37 ancestry-infor-mative markers and for 20 single-nucleotide polymorphisms (SNPs)associated with glucose homeostasis in European populations. Weused logistic regression to model the effect of genotype on GDM risk.All models were adjusted for pregravid BMI, pregravid BMI squared,maternal age and probability of Yoruban ancestry. Self-identifiedCaucasian and African-American women were analyzed separately. Pvalues of0.05 were considered statistically significant.RESULTS: GDM was diagnosed among 55/830 (6.63%) Caucasianand 23/372 (6.18%) African-American women. Among Caucasianwomen, we found a direct association between carriage of theMTNR1B rs10830963 risk allele and GDM (per-allele OR 1.55, 95%CI 1.03-2.34). In non-pregnant populations, this risk allele is associ-ated with impaired early insulin secretion and progression to T2DM.We similarly found a direct association between carriage of the GCKRrs780094 variant and GDM risk (per allele OR 1.51, 95% CI 1.02-2.24). This risk allele is associated with fasting glucose andHOMA-IRin non-pregnant populations. We also found an association betweencarriage of the rs243021 SNP and GDM risk (per allele OR 1.59, 95%CI 1.03-2.46). This SNP is adjacent to BCL11A, a zinc finger proteinimplicated in regulation of hematopoietic cell differentiation. Wefound no associations between the genotyped SNPs andGDMamongAfrican American participants in our study population.CONCLUSION: We found three SNPs that are strongly associated withGDM risk in our cohort. These variants have been previously associ-ated with glucose homeostasis and T2DM risk in non-pregnant pop-ulations. Further studies of these genetic loci may identify mecha-nisms leading to gestational glucose intolerance.
75 Increased neonatal respiratory Morbidity associatedwith gestational and pregestational diabetesS. Katherine Laughon1, Sahel Hazrati2, KatherineBowers1, Cuilin Zhang1, Una Grewal11NIH/NICHD, Epidemiology Branch, Bethesda,MD, 2GeorgeMasonUniversity, Global and Community Health, Fairfax, VAOBJECTIVE: A few small studies have investigated maternal hypergly-cemia and neonatal respiratorymorbidity by the impact of gestationalfrompregestational diabetes. Our objectivewas to explore risk of neo-
natal respiratory morbidity by diabetes type in a large, contemporaryU.S. population.STUDY DESIGN: The Consortium on Safe Labor was a retrospectivestudy using patient electronic medical records. We included 141,415women with first delivery in the database, singletons, delivering at 240/7-41 6/7 weeks, between 2002-2008, from 9 clinical centers. Out-comes from neonatal records were supplemented with detailed chartreview. Multivariable logistic regressions were performed and ad-justed for maternal characteristics, precursor for delivery (spontane-ous labor, rupture of membranes, indicated, elective/unknown) andsite. Since pr