DIABETES

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 Bytautiene1

1The University of Texas Medical Branch, Obstetrics & Gynecology,Galveston, TX, 2The University of Texas Medical Branch, InternalMedicine, Galveston, TX, 3The University of Texas MedicalBranch, Center for Biomedical Engineering, Galveston, TXOBJECTIVE: Pioglitazone(PL),ananti-diabeticdrugofthethiazolidinedionefamily, improvesglucoseandlipidmetabolisminthemuscles,adiposetissue,and liver by increasing insulin sensitivity via peroxisome proliferator-acti-vated receptor gamma (PPAR�) activation. PPAR� mRNA expression is in-creased in adipose tissue from offspring born to obese mothers. We hypoth-esize that activation of PPAR� receptors by PL will improve the metabolicstatus of the offspring exposed to maternal obesity in a previously validatedmouse model of the fetal origin of metabolic syndrome.STUDY DESIGN: CD-1 mice were placed on high fat diet for 3 months priorto, and during pregnancy. The resulting pups were weaned to regular diet.Pupswererandomlyassignedtoreceive40mg/kgofPLbyoralgavagein0.5%of methyl cellulose (PL group, n�10), or the same amount of 0.5% methylcellulose (CTR group, n�8). Treatment was given once daily from 10 to 12weeksofage.Immediatelybeforeandafterthetreatmentperiod,theoffspringwere weighed, their visceral adipose tissue (VAT) was evaluated using com-puted-tomography, blood was collected for fasting glucose (GL) and triglyc-eride(TRG)analysis,andintraperitonealglucosetolerance(IGTT)testswereperformed. Data was analyzed as change from pre-treatment using Studentt-test (significance: P�0.05).RESULTS: PL therapy significantly attenuated the increase in bodyweight (BW) seen in the control mice (mean increase: PL 1.25% vs.CTR 9.56%; Figure, P�0.02). TRG levels increased by 15% in the CTRvs a 24% decrease in PL (Figure, P�0.004). There was also a trendtowards lower VAT and improvement in GL (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 Reece2

1University of Maryland School of Medicine, Department of Obstetrics,Gynecology, and Reproductive Sciences, Baltimore, MD, 2University ofMaryland School of Medicine, Obstetrics, Gynecology & ReproductiveSciences and Biochemistry & Molecular Biology, Baltimore, MDOBJECTIVE: We and others have shown that maternal 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 (60 mg/kg), before being matedwith 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 Ross1

1LABioMed at Harbor-UCLA Med. 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

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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, p�0.05). 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�/�4 mg/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-Riz3

1University of North Carolina School of Medicine, 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-ated with 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 of �0.05 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 and HOMA-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 and GDM amongAfrican 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, 2GeorgeMason University, Global and Community Health, Fairfax, VAOBJECTIVE: A few small studies have investigated maternal hypergly-cemia and neonatal respiratory morbidity by the impact of gestationalfrom pregestational diabetes. Our objective was 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 prematurity was the biggest risk factor for respiratory mor-bidity, and obstetrical and physician characteristics effect timing ofdelivery, we calculated a propensity to deliver at term versus pretermand stratified by the propensity.RESULTS: Gestational and pregestational diabetes complicated 4.1%and 1.3% of pregnancies, respectively. Maternal diabetes was associ-ated with a significantly elevated risk of neonatal respiratory morbid-ities. Resuscitation with CPAP or intubation occurred in 1.8% and2.2% of gestational and pregestational diabetes versus 1.2% of non-diabetics. NICU admission occurred 13.4% and 25.8%, versus 9.7%.The associations between diabetes and respiratory morbidity werestronger at term (�37 weeks) than preterm, indicating that prematu-rity was the more important predictor at earlier gestational ages. Risksof respiratory morbidities were stronger with pregestational versusgestational diabetes (Table).CONCLUSION: In this contemporary cohort with detailed respiratoryinformation, neonatal morbidity was increased with maternal diabe-tes even among term pregnancies. The association was stronger forpregestational versus gestational diabetes, indicating a potential dosedependent association between maternal hyperglycemia and neonatalrespiratory morbidity.

76 Pre-pregnancy maternal body mass index,physical activity, nutrition, and preterm deliveryAli Khatibi1, Verena Sengpiel2, Marian Kacerovsky3, NilsHalvdan Morken4, Ronny Myhre5, Nina Gunnes5,Anne Lise Brantsaeter6, Bo Jacobsson7

1Sahlgrenska University Hospital, Department of Obstetrics and Gynecology,Goteborg, Sweden, 2Sahlgrenska University Hospital, Department ofObstetrics and Gynecology, Goteborg, Sweden, 3University Hospital HradecKralove, Department of Obstetrics and Gynecology, Hradec Kralove, CzechRepublic, 4Department of Obstetrics and Gynecology, Haukeland UniversityHospital, Department of Obstetrics and Gynecology, Haukeland UniversityHospital, Bergen, Norway, 5Norwegian Institute of Public Health, Divisionof Epidemiology, Oslo, Norway, 6Norwegian Institute of Public Health,Division of Environmental Medicine, Oslo, Norway, 7Sahlgrenska UniversityHospital, Department of Obstetrics and Gynecology, Gothenburg, SwedenOBJECTIVE: To determine the influence of maternal pre-pregnancybody mass index (BMI) on preterm delivery (PTD) adjusting for var-ious variables regarding maternal lifestyle.

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