bluuebunny/crossref_metadata_2025_split huggingface dataset:
1324-P: GLP-1 Hypersecretion in Gestational Diabetes
Authors: FRITSCHE LOUISE , HENI MARTIN , ECKSTEIN SABINE S. , WINZENRIED MAREN J. , HUMMEL JULIA , BIRKENFELD ANDREAS L. , PREISSL HUBERT , HAERING HANS-ULRICH , PETER ANDREAS , FRITSCHE ANDREAS , WAGNER ROBERT 
Published: June 2020

Background and Aims: Incretins are crucial for an adequate insulin secretion in response to ingestions of nutrients. In patients with diabetes, prediabetes or a specific genetic background, this incretin effect is blunted. Data on incretin secretion and action during pregnancy are scarce. Here we investigated the incretin response during an oral glucose tolerance test (OGTT) in pregnant women with and without gestational diabetes.
Methods: Pregnant women from the ongoing PREG study underwent 5-point OGTT with 75 g glucose. We measured plasma glucose, insulin and C-peptide at all time points and total GLP-1 at minute 0, 30 and 120. Indices of insulin secretion and GLP-1 increase were calculated from the difference at min 0 and 30. We used linear regression to analyze the relation of GLP-1 and glucose with insulin secretion.
Results: We examined 163 women during gestational week 26.8 (±2.0 SD), GDM was present in 30 (18.4%) women. Insulin secretion was significantly lower in women with GDM (p=0.04, adjusted for BMI, age, week of gestation, insulin sensitivity). GLP-1 levels increased after glucose intake with a peak at 30 min. GLP-1 levels at minute 30 and AUCGLP-1 was significantly higher in women with GDM (by ∼20%, both p=0.03, adjusted for age, BMI and week of gestation). The GLP-1 increase was associated with insulin secretion only in GDM, but not in women with normal glucose tolerance. This association remained significant even after adjustment for increase of glucose and basal insulin levels (GDM group: p&lt;0.001, non GDM: p=0.69).
Conclusion: Women with GDM had lower insulin secretion despite increased GLP-1 levels during OGTT. The more pronounced GLP-1 increase in women with GDM could be part of a compensatory mechanism counteracting GLP-1 resistance. In addition to incretin resistance, this phenomenon suggests a dysfunction of glucose stimulated insulin secretion.

Disclosure
L. Fritsche: None. M. Heni: Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Sanofi. Speaker’s Bureau; Self; Novo Nordisk A/S. S.S. Eckstein: None. M.J. Winzenried: None. J. Hummel: None. A.L. Birkenfeld: None. H. Preissl: None. H. Haering: None. A. Peter: None. A. Fritsche: None. R. Wagner: Advisory Panel; Self; Novo Nordisk A/S. Speaker’s Bureau; Self; Novo Nordisk A/S. Other Relationship; Self; Eli Lilly and Company.

Funding
German Federal Ministry of Education and Research (01GI0925)
1326-P: Maternal HbA1c in Pregnancy Is Associated with Higher Placental DNA Methylation at CTNNA3
Authors: JUVINAO-QUINTERO DIANA L. , CARDENAS ANDRES , BOUCHARD LUIGI , PERRON PATRICE , HIVERT MARIE-FRANCE 
Published: June 2020

Adverse perinatal outcomes have been associated with exposure to maternal hyperglycemia during pregnancy, which can be assessed by glycated hemoglobin A1c (HbA1c) levels. Prior analyses in the Gen3G cohort revealed that maternal HbA1c measured at the 2nd rather than at the 1st trimester, was strongly associated with differences in DNA methylation in fetal tissues. Thus, in this study, we seek to identify novel epigenetic mechanisms of placental response to prolonged exposure to maternal hyperglycemia by conducting an Epigenome-Wide Association Study (EWAS) of maternal HbA1c measured at 2nd trimester and DNAm of full-term placentas in 448 mother-child pairs of the Gen3G cohort. We tested associations at 791,131 CpG sites, adjusting for age, gestational age, week at HbA1c measurement, gravidity, smoking, pre-pregnancy BMI, sex, and the first ten principal components from ReFACTor to account for cell-type admixture. We also examined consistency in the direction of associations between maternal 2nd trimester HbA1c, and 1st trimester HbA1c for top CpGs detected in EWAS at p&lt;10-7. We further investigated causality of CpGs with the smallest p-value in the EWAS using Mendelian Randomization (MR). In EWAS, we observed with Bonferroni significance (p&lt;6.3x10-8) the association between maternal HbA1c (per %-unit) and higher placenta DNAm at cg23886783 mapping to the SLC20A1 gene (effect=0.9%, 95% CI= 0.5% to 1.2%, p=6.1x10-8). No other CpG was observed with Bonferroni or FDR significance in the EWAS. In addition, we found consistency in the direction of associations between HbA1c measured at 1st trimester and placental DNAm for the top six CpGs with the smallest p-value discovered in the EWAS of 2nd trimester HbA1c. Among these top six CpGs, we found nominal evidence that maternal HbA1c was causally associated with higher DNAm at cg11963170 in CTNNA3 (MR effect=25.1% per 1 %-unit, 95% CI= 3.1% to 47%, p=0.04). Our findings help to reveal placental adaptations to long-term maternal hyperglycemia.

Disclosure
D.L. Juvinao-Quintero: None. A. Cardenas: None. L. Bouchard: None. P. Perron: None. M. Hivert: None.

Funding
American Diabetes Association (1-15-ACE-26 to M-F.H.)
1328-P: Infant Mesenchymal Stem Cell Insulin Sensitivity Is Associated with Maternal Plasma-Free Fatty Acids, Independent of Obesity Status: The Healthy Start Study
Authors: CHAVES ALEC B. , JOHNSON JONATHAN A. , ZHENG DONGHAI , DABELEA DANA , HOUMARD JOSEPH A. , BOYLE KRISTEN E. 
Published: June 2020

Introduction: Maternal obesity is associated with greater neonatal adiposity and increased offspring risk for type 2 diabetes (T2D) later in life. We have previously reported that mesenchymal stem cells (MSCs) isolated from umbilical cord tissue maintain similar metabolic phenotype to the infant, particularly when differentiated to adipocytes or myocytes. A well-established driver in the pathogenesis of T2D is skeletal muscle insulin resistance. Therefore, we hypothesized that MSCs from infants born to mothers with obesity would display insulin resistance when differentiated to myocytes.
Objectives: The objective was to determine the effect of maternal obesity on offspring MSC insulin sensitivity (Si).
Methods: MSCs were isolated from umbilical cord tissue from offspring born to either normal weight (BMI 21.1 ± 0.9, n = 9) or obese (BMI 32.9 ± 2.1, n = 10) mothers enrolled in the Healthy Start pre-birth cohort study in Colorado. Following differentiation into skeletal muscle myocytes, MSCs were serum starved and incubated with 14C-glucose, in the presence or absence of insulin. The rate of insulin-mediated 14C-glucose incorporation into glycogen, was used as an index of offspring Si.
Results: Offspring Si did not correlate with maternal BMI (r = 0.26), nor was BMI different between groups when median-stratified by offspring Si. However, maternal free fatty acid levels positively correlated with offspring Si (r = 0.63, p &lt; 0.05) and were significantly elevated in the high Si group (low Si vs. high Si; 332.1 ± 30.9 vs. 483.3 ± 48.7 uEq/L, p &lt; 0.05).
Conclusions: Offspring Si was not related to the BMI of the mother. Moreover, offspring Si was higher in cells from infants born to mothers with higher free fatty acids during pregnancy. Considering the role of insulin in somatic growth pathways, this phenomenon may serve to increase available nutrient storage capacity during early development.

Disclosure
A.B. Chaves: None. J.A. Johnson: None. D. Zheng: None. D. Dabelea: None. J.A. Houmard: None. K.E. Boyle: None.

Funding
American Heart Association (14PRE18230008); Nutrition Obesity Research Center (P30DK048520); National Institutes of Health (R01DK076648); Colorado National Center for Advancing Translational Sciences (UL1TR001082)
133-OR: Dyrk1b Is a Nutrient-Sensing Protein That Triggers De Novo Lipogenesis by Activating mTORC2 Complex: Implication for the Treatment of Type 2 Diabetes
Authors: BHAT NEHA 
Published: June 2020

The mechanisms underlying enhanced insulin-induced de novo lipogenesis (DNL) in an insulin resistant liver are not understood. Genetic studies in subjects with inherited metabolic syndrome, a cluster of phenotypes that includes dyslipidemia, glucose intolerance, central obesity and insulin resistance led to the identification of perfectly segregating mutations in the Dyrk1b gene. This work also revealed previously unknown function of Dyrk1b in glucose and lipid metabolism. In this study, we introduce Dyrk1b as the missing link between enhanced HGP and increased DNL. The liver specific Dyrk1b knockdown protected against hepatic steatosis, hyperlipidemia and diet induced insulin resistance, while AAV mediated Dyrk1b elevation enhanced DNL causing hepatic steatosis, hyperlipidemia and augmented hepatic Glucose Production (HGP), features characteristic of diabetic dyslipidemia. A comprehensive analysis revealed that Dyrk1b facilitates DNL by binding and activating the mTORC2 complex in a kinase independent fashion. Mechanistically, Dyrk1b displaces mTORC2 inhibitor Fkbp12 from the complex and induces auto-phosphorylation of the mTOR protein. Accordingly, the knockout of mTORC2 function, rescued hepatic steatosis, inflammation, and hyperlipidemia. The global relevance of this disease pathway is illustrated by increased hepatic Dyrk1b levels in mice and humans with hepatic steatosis. Altogether, our findings reveal Dyrk1b as a nutrient sensing protein that triggers DNL and hepatic insulin resistance and is an attractive therapeutic target for type 2 diabetes.

Disclosure
N. Bhat: None.

Funding
National Institutes of Health (RHL135767A, P30DK034989)
1333-P: The Adipokine Fatty Acid Binding Protein 4 Promotes Glucose Production in Gestational Diabetes Mellitus
Authors: MADAH RAGAD , RONEN IDIT RON , RATHAUS MORAN , ZEMET RONI , TOVI SHALI AMAZAKI , TIROSH AMIR 
Published: June 2020

Gestational diabetes mellitus (GDM) is characterized by maternal hyperglycemia and insulin resistance that develops during pregnancy. Altered secretion of adipokines that modulate insulin action during pregnancy has been implicated in GDM pathogenesis. FABP4 is an adipokine with an important role in promoting insulin resistance in various animal models. In humans, FABP4 was suggested to regulate systemic metabolism. Although elevated levels of circulating FABP4 were demonstrated in GDM, its differential contribution to GDM pathophysiology is unclear. In this study, we aimed to determine the tissue source of elevated circulating FABP4 levels and to assess FABP4 differential contribution in promoting hepatic glucose production in GDM. We included 71 pregnant women defined as normal glucose tolerant (NGT) and 31 diagnosed with GDM. Maternal level of FABP4 before delivery was measured using ELISA. FABP4 circulating levels were increased in GDM compared to NGT (14.1 IQR: 11.5-21.4 ng/ml vs.10.3 IQR: 6.6-12.4 ng/ml, respectively, p=0.0014), with a rapid post-partum decline in FABP4 levels observed in both groups. Using biopsies of placenta, sub-cutaneous (sWAT) and visceral (vWAT) adipose tissues, we observed that FABP4 is secreted from these tissues during pregnancy. FABP4 secretion from vWAT of GDM women was ? 2 fold higher than that of NGT women. Depletion of FABP4 from vWAT conditioned media of NGT or GDM women using monoclonal antibodies, significantly suppressed glucose production in primary hepatocytes by ? 20% and ? 36%, respectively (p&lt;0.05). Taken together, our data highlight the importance of FABP4 in the pathophysiology of enhanced hepatic glucose production in GDM.

Disclosure
R. Madah: None. I. Ron Ronen: None. M. Rathaus: None. R. Zemet: None. S. Amazaki Tovi: None. A. Tirosh: Advisory Panel; Self; Abbott, AstraZeneca, Merck Sharp & Dohme Corp., Novo Nordisk A/S, Sanofi-Aventis. Consultant; Self; DreaMed Diabetes. Research Support; Self; Medtronic.

Funding
Israeli Diabetes Association
1336-P: Trimethylamine N-Oxide Inhibits the Formation of Neutrophil Extracellular Traps to Regulate Placental Development in Gestational Diabetes Mellitus
Authors: LIN XIAOJING , HE XIAOLING , XIAO XIAOQIU 
Published: June 2020

Objective: Trimethylamine N-oxide (TMAO) is associated with risk of gestational diabetes mellitus (GDM), and TMAO levels in peripheral/cord blood of GDM mothers increased. Diabetes primes neutrophils to produce neutrophil extracellular traps (NETs), but it has not been reported in GDM. We determined the relationship between NETs and GDM, and explored potential role of TMAO.
Methods: Maternal peripheral blood was collected during OGTT tests, and cord blood and placenta were collected during delivery. Plasma concentrations of cell-free double-stranded DNA (dsDNA) were compared between GDM and control mothers and association analysis was performed. Expression of myeloperoxidase (MPO) in placental tissues of GDM and control mothers was examined. Neutrophils from the blood of healthy donors were used to observe effects of TMAO on NETs formation. The effect of TMAO on human placental extravillous trophoblast cell line HTR-8/Svneo was examined.
Results: Compared with controls, plasma concentrations of dsDNA in peripheral blood and cord blood were significantly increased in GDM mothers. Association analysis found that concentrations of dsDNA in peripheral and cord blood plasma were positively correlated with BMI and blood glucose levels, but not blood pressure. In addition, the placental thickness was positively correlated with dsDNA levels in cord blood plasma. MPO expression in the placental tissues of GDM mothers was also significantly higher than that of control mothers. TMAO-treated neutrophils could resist the formation of NETs stimulated by PMA or LPS, and TMAO promotes the proliferation, migration, invasion and angiogenesis of the cells.
Conclusion: The formation of NETs was increased in GDM, and was positively correlated with BMI and blood glucose. TMAO could inhibit NETs formation and promote invasion and angiogenesis of human placental trophoblast cells, which may be involved in the development of the placenta.

Disclosure
X. Lin: None. X. He: None. X. Xiao: None.
134-LB: Effectiveness and Safety of Empagliflozin in Routine Care Patients: Interim Results from the EMPagliflozin compaRative effectIveness and SafEty (EMPRISE) Study
Authors: PATORNO ELISABETTA , PAWAR AJINKYA , BESSETTE LILY G. , FRANKLIN JESSICA , NAJAFZADEH MEHDI , WEXLER DEBORAH J. , DERUAZ-LUYET ANOUK , BRODOVICZ KIMBERLY , SCHNEEWEISS SEBASTIAN 
Published: June 2020

EMPRISE studies the effectiveness, safety and healthcare utilization of empagliflozin (EMPA), using data from Medicare and 2 U.S. commercial claims datasets (2014-2019). In an interim analysis on data from 2014-2017, we identified 39,169 pairs of 1:1 propensity score-matched patients ≥18 years with type 2 diabetes initiating EMPA or a DPP-4 inhibitor (DPP-4i). Effectiveness outcomes of interest were HHF [defined as a HF discharge diagnosis in the primary (HHF-Specific) or in any position (HHF-Broad)], a composite of MI and stroke, and all-cause mortality (Medicare only). Safety outcomes were lower-limb amputations (LLA), bone fractures, diabetic ketoacidosis (DKA), and acute kidney injury (AKI). We estimated pooled HR and 95% CI adjusting for &gt;140 baseline covariates. Compared to DPP-4i, EMPA had a reduced risk of HHF [HHF-Specific: 0.46 (0.30-0.73); HHF-Broad: 0.63 (0.51-0.77)], a similar risk of MI or stroke [HR (95% CI) = 0.89 (0.73-1.09)], and a reduced risk of all-cause mortality [0.52 (0.36-0.76) in Medicare. Over a mean follow up of 178 days, EMPA was associated with a decreased risk of AKI [(0.64 (0.53-0.77)], an increased risk of DKA [1.56 (1.00-2.44)], and a similar risk of LLA and fractures (Table 1). In routine care, EMPA had an effectiveness profile consistent with RCT findings and safety outcomes in line with documented information.

Disclosure
E. Patorno: Other Relationship; Self; Boehringer Ingelheim International GmbH. A. Pawar: None. L.G. Bessette: None. J. Franklin: None. M. Najafzadeh: None. D.J. Wexler: Other Relationship; Self; Novo Nordisk A/S. A. Deruaz-Luyet: Employee; Self; Boehringer Ingelheim International GmbH. Employee; Spouse/Partner; Sanofi-Aventis Deutschland GmbH. K. Brodovicz: Employee; Self; Boehringer Ingelheim Pharmaceuticals, Inc. S. Schneeweiss: None.

Funding
Boehringer Ingelheim
1342-P: BMI from Birth to Age 10 Years by Types of Maternal Diabetes during Pregnancy
Authors: SIDELL MARGO A. , CHOW TING , MARTINEZ MAYRA P. , KOEBNICK CORINNA , PAGE KATHLEEN A. , BUCHANAN THOMAS A. , XIANG ANNY 
Published: June 2020

Limited studies have assessed longitudinal growth among children exposed to different types of diabetes in-utero. We assessed BMI from birth to age 10 years in offspring of mothers who had pre-existing type 1 (T1D) or type 2 (T2D), gestational diabetes mellitus (GDM) or no diabetes during pregnancy. GDM was further divided into GDM managed with (GDM with meds) or without (GDM no meds) diabetes medication. More than 3.5 million BMI measurements were obtained from medical records of 218,227 singleton children born at 28-44 weeks gestation from 2008 to 2015. Relationships between BMI, age and diabetes exposure were modelled using random effects mixed models with quadratic B splines adjusted for maternal age, race/ethnicity, education, household income, pre-pregnancy BMI, gestational weight gain, maternal comorbidity, and child’s sex. At birth, the adjusted BMI had small differences among groups except for T1D which had the highest BMI [diff=0.4; 95%CI 0.2-0.6 kg/m2 relative to no diabetes]. After birth, the adjusted BMIs were comparable between T1D and T2D exposed. At about 48 months, the growth pattern started separating with highest BMI in T1D and T2D groups, followed by GDM with meds, GDM no meds and no diabetes groups (Figure). Thus, despite standard diabetes management, there exists a hierarchical BMI pattern in offspring exposed to different types of diabetes even after adjusting for important covariates, starting as early as age 4.

Disclosure
M.A. Sidell: None. T. Chow: None. M.P. Martinez: None. C. Koebnick: None. K.A. Page: None. T.A. Buchanan: None. A. Xiang: None.
1344-P: Metabolomics Reveals Broad Scale Metabolic Changes in Gestational Diabetes
Authors: LIU YU , KUANG ALAN , BAIN JAMES R. , GEORGE TABITHA , ILKAYEVA OLGA , MINCEY ADAM , MUEHLBAUER MICHAEL , LOWE LYNN P. , METZGER BOYD E. , NEWGARD CHRISTOPHER B. , SCHOLTENS DENISE , LOWE WILLIAM 
Published: June 2020

Studies examining metabolites in GDM have been small with inconsistent results. To address this, we used targeted metabolomics to examine levels of 65 metabolites in a cohort of 3457 mothers from the Hyperglycemia and Adverse Pregnancy Outcome Study, of whom 547 were retrospectively diagnosed with GDM using IADPSG criteria. GDM was untreated. Metabolomics assays were performed on fasting and 1 hr serum samples collected during an oral glucose tolerance test (OGTT) at ∼28 weeks gestation. Differences in metabolite levels in women without and with GDM were determined using linear regression with adjustment for field center as well as maternal age, gestational age, height, mean arterial pressure, parity, smoking (yes/no), drinking (yes/no) and BMI at the OGTT and false discovery rate correction. Women with GDM had higher levels of a broad array of fasting metabolites, including branched chain amino acids (BCAA) and their metabolic byproducts, aromatic and other amino acids, triglycerides, non-esterified fatty acids and lipid byproducts, and medium- and long-chain acylcarnitines (ACs). Similar differences were seen 1 hr after a glucose load, except for higher levels of a broader array of ACs but lower levels of arachidonoyl carnitine in women with GDM. Prior studies categorizing women with GDM into those with normal and low insulin sensitivity demonstrated differences in maternal and newborn outcomes between groups. Compared to women with GDM and normal insulin sensitivity, women with GDM in the lowest quartile of insulin sensitivity had higher levels of BCAAs and their metabolic byproducts, aromatic amino acids, triglycerides, and lactate but lower levels of 3-hydroxybutyrate (3-HB) and multiple ACs. A generally a similar pattern was seen 1 hr after glucose except for no change in 3-HB. Together these data demonstrate broad scale perturbations in metabolites in women with GDM and differences across subgroups of women with GDM that may contribute to maternal and fetal complications related to GDM.

Disclosure
Y. Liu: None. A. Kuang: None. J.R. Bain: None. T. George: None. O. Ilkayeva: None. A. Mincey: None. M. Muehlbauer: None. L.P. Lowe: None. B.E. Metzger: None. C.B. Newgard: None. D. Scholtens: None. W. Lowe: None.
1355-P: Association between Glycated Hemoglobin and Glycemia during First Trimester of Pregnancy
Authors: FARO FERNANDA , RAMALHO RODRIGO F. , PRIETO WESLEY H. , PEREIRA MARIANA , SALLES JOAO E. , ROSA PEDRO S. , TELES MILENA G. , TAVARES RUSSO PEDRO DE SÁ 
Published: June 2020

Background: first trimester glycemia ≥ 92 mg/dL is a valid criterion for diagnosis of gestational diabetes mellitus (GDM), excluding the requirement of Oral Glucose Tolerant Test (OGTT) later in pregnancy. Glycated Hemoglobin (A1C), is well stablished for diagnosis of diabetes mellitus, however its utility in the screening of GDM is not certain. The aim of this study was to associate A1C and glycemia values in the first trimester of pregnancy.
Methods: this was an observational retrospective study that included Brazilian women screened with A1C until 20 weeks of gestation between January 2009 and March 2019. Data were collected from a laboratory center. A1C was estimated by high-performance liquid chromatography. Exclusion criteria were hemoglobin &lt; 11.0 and use of antidiabetic drugs or insulin. Women were divided into groups according to first trimester glycemia: &lt;70; 70-85; 85-92; 92-126; ≥ 126 mg/dL. Primary outcome was association between A1C and glycemia values.
Results: a total of 17.764 women were included. The majority was in the 70-85 mg/dL group (9.689), followed by 85-92 mg/dL (5.420), 92-126 mg/dL (2.178), &lt; 70 mg/dL (436) and ≥ 126 mg/dL (41). Means’ age were: 32.5 ± 4.79 (&lt;70 mg/dL); 33.8 ± 4.14 (70-85 mg/dL); 34.2 ± 3.9 (85-92 mg/dL); 34.7 ± 4.03 (92-126 mg/dL) and 31.4 ± 3.46 years (≥ 126 mg/dL). Means’ Body Mass Index (BMI): 24.5 ± 2.68 (&lt;70 mg/dL); 25.2 ± 3.88 (70-85 mg/dL); 25.8 ± 4.5 (85-92 mg/dL); 27.6 ± 4.83 (92-126 mg/dL) and 27.3 ± 2.59 years (≥ 126 mg/dL). A1C means were very similar in the first four groups: 4.92% ± 0.41 (&lt;70 mg/dL); 5.01% ± 0.32 (70-85 mg/dL); 5.15% ± 0.32 (85-92 mg/dL) and 5.33% ± 0.42 (92-126 mg/dL). The group with glycemia ≥ 126 mg/dL presented A1C mean of 7.08% ± 1.49, significantly higher than all the other groups (p &lt; 0.01 by Kruskal-Wallis test).
Conclusion: in this study, A1C values were not accurate to the screening of GDM in the first trimester of pregnancy. The main difference was in the group with glycemia ≥ 126 mg/dL, already defined as overt diabetes.

Disclosure
F. Faro: None. R.F. Ramalho: None. M. Pereira: None. J.E. Salles: Board Member; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Lilly Diabetes, Novo Nordisk Inc. P.S. Rosa: None. M.G. Teles: None. P. de Sá Tavares Russo: None.