When does gestational diabetes mellitus leave an imprint on the child?

Gestational diabetes mellitus (GDM) is the most prevalent pregnancy complication world-wide (<18%) and predisposes a child for metabolic disease in adulthood. This developmental imprint on metabolism is mediated by epigenetic marks such as DNA methylation (DNAm). I was instrumental in showing that the first trimester is the key period in humans during which alterations in DNAm may occur. Using exposure to the Dutch Famine, likewise associated with later-life metabolic disease, I found differences in DNAm along metabolic genes. Studies on GDM found associations between maternal glucose levels and DNAm at some of these genes, but have yet to address when in gestation this imprint arises and link DNAm changes to metabolism. I hypothesize that maternal glucose levels alter DNAm levels during the first trimester, while currently diagnosis and treatment is in mid-gestation, and that these mediate cellular metabolic changes that predispose for obesity and type 2 diabetes in later-life. I will circumvent the inaccessibility of tissues for joint epigenetic and metabolic studies in infants by isolating mesenchymal stem cells from cord-blood (CB-MSCs) from a subset (N=80) of normal, mild hyperglycemic and GDM pregnancies in the ongoing GLIMP2 study (N=320). CB-MSCs are of an embryonic lineage and have a similar phenotype and epigenome as MSCs from adult tissues. Using CB-MSCs I will: 1. Assess when during gestation maternal glucose influences cellular metabolic output and glucose uptake and repeat measurements after the CB-MSCs are differentiated to white pre-adipocytes as proxies for such an inaccessible cell-type. 2. Assess when during gestation DNAm is altered in primary CB-MSCs and the differentiated CB-MSCs. 3. Relate DNAm differences to metabolic and gene-expression differences and validate DNAm differences in buccal swaps collected post-partum. This study will give detailed insight into disease mechanism and may help alter the focus to early gestation for GDM diagnosis and treatment.