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Metabolic Networks and Metabolites Underlie Associations Between Maternal Glucose During Pregnancy and Newborn Size at Birth

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      Abstract

      Maternal metabolites and metabolic networks underlying associations between maternal glucose during pregnancy and newborn birth weight and adiposity demand fuller characterization. We performed targeted and nontargeted gas chromatography/mass spectrometry metabolomics on maternal serum collected at fasting and 1 h following glucose beverage consumption during an oral glucose tolerance test (OGTT) for 400 northern European mothers at ∼28 weeks' gestation in the Hyperglycemia and Adverse Pregnancy Outcome Study. Amino acids, fatty acids, acylcarnitines, and products of lipid metabolism decreased and triglycerides increased during the OGTT. Analyses of individual metabolites indicated limited maternal glucose associations at fasting, but broader associations, including amino acids, fatty acids, carbohydrates, and lipids, were found at 1 h. Network analyses modeling metabolite correlations provided context for individual metabolite associations and elucidated collective associations of multiple classes of metabolic fuels with newborn size and adiposity, including acylcarnitines, fatty acids, carbohydrates, and organic acids. Random forest analyses indicated an improved ability to predict newborn size outcomes by using maternal metabolomics data beyond traditional risk factors, including maternal glucose. Broad-scale association of fuel metabolites with maternal glucose is evident during pregnancy, with unique maternal metabolites potentially contributing specifically to newborn birth weight and adiposity.

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      KEGG as a reference resource for gene and protein annotation

      KEGG (http://www.kegg.jp/ or http://www.genome.jp/kegg/) is an integrated database resource for biological interpretation of genome sequences and other high-throughput data. Molecular functions of genes and proteins are associated with ortholog groups and stored in the KEGG Orthology (KO) database. The KEGG pathway maps, BRITE hierarchies and KEGG modules are developed as networks of KO nodes, representing high-level functions of the cell and the organism. Currently, more than 4000 complete genomes are annotated with KOs in the KEGG GENES database, which can be used as a reference data set for KO assignment and subsequent reconstruction of KEGG pathways and other molecular networks. As an annotation resource, the following improvements have been made. First, each KO record is re-examined and associated with protein sequence data used in experiments of functional characterization. Second, the GENES database now includes viruses, plasmids, and the addendum category for functionally characterized proteins that are not represented in complete genomes. Third, new automatic annotation servers, BlastKOALA and GhostKOALA, are made available utilizing the non-redundant pangenome data set generated from the GENES database. As a resource for translational bioinformatics, various data sets are created for antimicrobial resistance and drug interaction networks.
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        Random Forests

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          Hyperglycemia and adverse pregnancy outcomes.

          It is controversial whether maternal hyperglycemia less severe than that in diabetes mellitus is associated with increased risks of adverse pregnancy outcomes. A total of 25,505 pregnant women at 15 centers in nine countries underwent 75-g oral glucose-tolerance testing at 24 to 32 weeks of gestation. Data remained blinded if the fasting plasma glucose level was 105 mg per deciliter (5.8 mmol per liter) or less and the 2-hour plasma glucose level was 200 mg per deciliter (11.1 mmol per liter) or less. Primary outcomes were birth weight above the 90th percentile for gestational age, primary cesarean delivery, clinically diagnosed neonatal hypoglycemia, and cord-blood serum C-peptide level above the 90th percentile. Secondary outcomes were delivery before 37 weeks of gestation, shoulder dystocia or birth injury, need for intensive neonatal care, hyperbilirubinemia, and preeclampsia. For the 23,316 participants with blinded data, we calculated adjusted odds ratios for adverse pregnancy outcomes associated with an increase in the fasting plasma glucose level of 1 SD (6.9 mg per deciliter [0.4 mmol per liter]), an increase in the 1-hour plasma glucose level of 1 SD (30.9 mg per deciliter [1.7 mmol per liter]), and an increase in the 2-hour plasma glucose level of 1 SD (23.5 mg per deciliter [1.3 mmol per liter]). For birth weight above the 90th percentile, the odds ratios were 1.38 (95% confidence interval [CI], 1.32 to 1.44), 1.46 (1.39 to 1.53), and 1.38 (1.32 to 1.44), respectively; for cord-blood serum C-peptide level above the 90th percentile, 1.55 (95% CI, 1.47 to 1.64), 1.46 (1.38 to 1.54), and 1.37 (1.30 to 1.44); for primary cesarean delivery, 1.11 (95% CI, 1.06 to 1.15), 1.10 (1.06 to 1.15), and 1.08 (1.03 to 1.12); and for neonatal hypoglycemia, 1.08 (95% CI, 0.98 to 1.19), 1.13 (1.03 to 1.26), and 1.10 (1.00 to 1.12). There were no obvious thresholds at which risks increased. Significant associations were also observed for secondary outcomes, although these tended to be weaker. Our results indicate strong, continuous associations of maternal glucose levels below those diagnostic of diabetes with increased birth weight and increased cord-blood serum C-peptide levels. Copyright 2008 Massachusetts Medical Society.
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            Author and article information

            Affiliations
            1Feinberg School of Medicine, Northwestern University, Chicago, IL
            2Sarah W. Stedman Nutrition and Metabolism Center, Duke University Medical Center, Durham, NC
            3Duke Molecular Physiology Institute, Durham, NC
            4Duke University School of Medicine, Durham, NC
            Author notes
            Corresponding author: Denise M. Scholtens, dscholtens@ 123456northwestern.edu .
            Journal
            Diabetes
            Diabetes
            diabetes
            diabetes
            Diabetes
            Diabetes
            American Diabetes Association
            0012-1797
            1939-327X
            July 2016
            05 April 2016
            : 65
            : 7
            : 2039-2050
            27207545 4915585 1748 10.2337/db15-1748
            © 2016 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.
            Counts
            Figures: 5, Tables: 3, Equations: 0, References: 50, Pages: 12
            Product
            Funding
            Funded by: National Institute of Diabetes and Digestive and Kidney Diseases http://dx.doi.org/10.13039/100000062
            Award ID: R01-DK-095963
            Funded by: National Institute of Child Health and Human Development http://dx.doi.org/10.13039/100000071
            Award ID: R01-HD-34242
            Award ID: R01-HD-34243
            Categories
            Genetics/Genomes/Proteomics/Metabolomics

            Endocrinology & Diabetes

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