Pregnancy Serum DLK1 Concentrations are associated with Indices of Insulin Resistance and Secretion.

CONTEXT: DLK1 (delta like non-canonical notch ligand 1) 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 75g 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=7.8x10 -3) but not with maternal rs12147008 genotype (p=0.4). Maternal DLK1 concentrations were positively associated with maternal pre-pregnancy BMI (p=3.5x10 6), and (after adjustment for maternal BMI) with both maternal fasting insulin resistance (HOMA IR: p=0.01) and measures of maternal insulin secretion in response to oral glucose (insulinogenic index: p=1.2x10 -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.