Pregnancy Serum DLK1 Concentrations Are Associated With Indices of Insulin Resistance and Secretion.

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Burling, Keith A 
Barker, Peter 
Hughes, Ieuan A 
Ong, Ken K 

CONTEXT: Delta like noncanonical notch ligand 1 (DLK1) is a paternally expressed imprinted gene that encodes an epidermal growth factor repeat-containing transmembrane protein. A bioactive, truncated DLK1 protein is present in the circulation and has roles in development and metabolism. OBJECTIVE: We sought to investigate links between maternal pregnancy circulating DLK1 concentrations and: (1) maternal and fetal DLK1 genotypes, (2) maternal insulin resistance and secretion, and (3) offspring size at birth. PATIENTS, DESIGN, AND SETTING: We measured third-trimester maternal serum DLK1 concentrations and examined their associations with parentally transmitted fetal and maternal DLK1 genotypes, indices of maternal insulin resistance and secretion derived from 75-g oral glucose tolerance tests performed around week 28 of pregnancy, and offspring size at birth in 613 pregnancies from the Cambridge Baby Growth Study. RESULTS: Maternal DLK1 concentrations were associated with the paternally transmitted fetal DLK1 rs12147008 allele (P = 7.8 × 10-3) but not with maternal rs12147008 genotype (P = 0.4). Maternal DLK1 concentrations were positively associated with maternal prepregnancy body mass index (P = 3.5 × 10-6), and (after adjustment for maternal body mass index) with both maternal fasting insulin resistance (Homeostatic Model Assessment of Insulin Resistance: P = 0.01) and measures of maternal insulin secretion in response to oral glucose (insulinogenic index: P = 1.2 × 10-3; insulin disposition index: P = 0.049). Further positive associations were found with offspring weight (P = 0.02) and head circumference at birth (P = 0.04). CONCLUSION: These results are consistent with a partial paternal or placental origin for the maternal circulating DLK1 which may lead to increased maternal circulating DLK1 concentrations, stimulation of maternal insulin resistance and compensatory hyperinsulinemia during pregnancy, and the promotion of fetal growth.

FA1, PREF1, fetal growth, imprinted, pregnancy, Adult, Birth Weight, Calcium-Binding Proteins, Diabetes, Gestational, Female, Fetal Development, Glucose Tolerance Test, Health Status Indicators, Humans, Hypertension, Pregnancy-Induced, Infant, Newborn, Insulin, Insulin Resistance, Longitudinal Studies, Male, Membrane Proteins, Pregnancy, United Kingdom
Journal Title
J Clin Endocrinol Metab
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The Endocrine Society
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National Institute for Health Research (NIHR) (unknown)
Wellbeing of Women (RG1644)
Cambridge University Hospitals NHS Foundation Trust (CUH) (146281)
Wellcome Trust (100574/Z/12/Z)
Medical Research Council (MC_UU_12012/5)
Wellcome Trust (100574/B/12/Z)
Medical Research Council (MC_UU_12015/2)
MRC (MC_UU_00006/2)
Medical Research Council (G1001995)
Medical Research Council (MC_U106179472)
Diabetes UK (11/0004241)
This analysis was funded by the Wellbeing of Women (the Royal College of Obstetricians and Gynaecologists, U.K.) (RG1644) and Diabetes UK (11/0004241). Core funding for the Cambridge Baby Growth Study has come from the Medical Research Council (7500001180, G1001995, U106179472); European Union Framework 5 (QLK4-1999-01422); the Mothercare Charitable Foundation (RG54608); Newlife Foundation for Disabled Children (07/20) and the World Cancer Research Fund International (2004/03). We also acknowledge support from National Institute for Health Research Cambridge Biomedical Research Centre, including that for the Cambridge Biochemical Assay Laboratory. KO is supported by the Medical Research Council (Unit Programme numbers: MC_UU_12015/2 and MC_UU_00006/2).
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