Intergenerational Programming of Diabesity in Offspring of Women With Gestational Diabetes Mellitus

The DOHaD paradigm proposes that early life nutrition and growth influence health and disease risk across the life-course. Intrauterine period is the most crucial period in these events, and contributes to fetal programming. Fetal undernutrition as well as over-nutrition (maternal obesity and diabetes) increase risk of diabetes in the offspring. Current thinking is that fetal programming is an 'epigenetic' phenomenon and the most prominent mechanism may be methylation of DNA and histones that regulate gene expression in key pathways. The investigators have previously highlighted a role for maternal micronutrients in fetal programming of adiposity, insulin resistance, and prediabetes (nutrient mediated teratogenesis). Now, the investigators propose to study the impact of maternal hyperglycemia during pregnancy on the future risk of diabesity in the offspring (fuel mediated teratogenesis). This programme, first of its kind in India, will undertake 'OMICs' measurements (DNA methylation and targeted metabolomics) on cord blood samples of children born to women with gestation diabetes mellitus (GDM), in studies in Pune, Western India (Arm-1) and Punjab, North India (Arm-2). Markers identified in the discovery phase will be investigated for validity and stability in blood, cord blood and placenta samples from children born to GDM mothers in the older cohorts in Pune and Punjab. Danish investigators will perform complimentary measurements in the Danish National Birth Cohort which will allow comparison of epigenetic markers in these two populations with widely different prevalence of GDM, and ethnic and nutritional factors. Special attention will be given to role of nutritional and lifestyle factors of mothers which influence the programming of fetal epigenome during pregnancy. The biobank of maternal, cord and offspring samples will be available in future to test newer hypotheses. This study will benefit from technology transfer across two countries. The findings will add substantially to the evidence base of intergenerational transmission of diabetes in a diabetic pregnancy, and will inform policy-makers to help curb the escalating epidemic of diabetes in India.

Hypotheses

• The molecular mechanisms underlying the associations between gestational diabetes in the mother and diabesity in the offspring may involve permanent changes of DNA methylations in various tissues including blood cells obtained at birth and/or during childhood defining different trajectories.
• Epigenetic fingerprints linking GDM with risk of T2D among the offspring may or may not be influenced by tissue of origin, diet, life-style and ethnicity of population.
• Epigenetic changes in blood cells obtained at birth and/or during childhood associated with GDM in pregnancy may be used as bio-markers to predict later development of T2D in the offspring
• The risk of developing diabetes among offspring of GDM women may be influenced by maternal factors operating during pregnancy including degree of hyperglycemia, obesity, dietary factors including composition of macro- and micronutrients, and/or by the level of physical activity of the mother.

Inclusion criteria

Arm 1 and 2:

• GDM or NGT on 75g OGTT (IADPSG Criteria).
• Willing to participate and sign consent
• Planned delivery at study site
• Age > 18 years
• Singleton pregnancy.

Arm 3:

• Offspring of diabetic mothers and non diabetic mothers ( >2 years of age).

Exclusion criteria

Arm 1 and 2:

• Severe medical/ surgical illness detrimental to pregnancy or delivery (Severe liver, renal, cardiovascular, pulmonary, hematologic, endocrine disorder or long term steroid use for any reason)
• K/C/O Diabetes (Type 1 or Type 2 or any other type)
• Severe anemia (Hemoglobin< 9 gm% in first trimester and < 8 gm% in second or third trimester)
• IVF pregnancy.

Arm 3: None.