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

Overview

India is one of the diabetes capitals in the world. Indians are susceptible to develop diabetes at a younger age and at a lower BMI compared to Europeans. Current prevention strategies focus on reducing risk in those with the established disease or risk factors. The Developmental Origins of Health and Disease (DOHaD) hypothesis suggests that chronic non-communicable diseases (NCDs) are programmed by disturbances in maternal and fetal undernutrition. This offers an alternative primordial prevention strategy to reduce NCDs in future generations by improving health and nutrition of young women. Previous work in the Diabetes Unit, KEM Hospital, Pune has described the role of maternal micronutrients affecting 1-Carbon metabolism in the fetal programming of diabesity. In this application, the investigators offer to study other pathways of fetal programming i.e. maternal hyperglycemia and gestational diabetes mellitus (GDM) using an 'OMICs' approach. It is believed that epigenetic changes may be the main driver of programming. The investigators hypothesize that offspring of diabetic mothers will have different epigenetic signatures in cord blood and placenta compared to offspring of non-diabetic mothers. The investigators propose to study the effect of gestational hyperglycemia on newborn epigenetic signatures using the most appropriate technologies available and associate them with the underlying genotype. This will be performed on cord blood of 150 offspring of women with GDM and compared with a similar number of offspring of non-diabetic mothers recruited at Pune. The differentially methylated regions (DMRs) identified will then be validated by pyrosequencing in \~300 stored GDM cord blood samples in Pune. The investigators from Pune will also validate these markers in 200 newly recruited offspring of GDM and 200 controls from a different cohort in Punjab which has a different diet and lifestyle. The DMRs will also be validated in placental samples from both Pune and Punjab. The investigators will further test the stability of these markers and their associations with phenotype in a follow-up study of offspring of GDM mothers in upto 500 individuals. The investigators will compare the findings with the DNBC-GDM cohort in Denmark, allowing for differences in age, genetic make up, nutritional status and lifestyle. This study will help understand contribution of maternal diabetes to the current epidemic of diabesity and its molecular basis.

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 1. 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. 2. 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. 3. 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 4. 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.