Intergenerational Programming of Diabesity in Offspring of Women With Gestational Diabetes Mellitus (InDiaGDM)
|The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.|
|ClinicalTrials.gov Identifier: NCT03388723|
Recruitment Status : Recruiting
First Posted : January 3, 2018
Last Update Posted : January 3, 2018
|Condition or disease|
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.
- 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.
|Study Type :||Observational|
|Estimated Enrollment :||1200 participants|
|Official Title:||The Role of Epigenetics in the Vicious Cycle of Diabetes and Pregnancy (VICYDIP)|
|Actual Study Start Date :||September 2, 2014|
|Estimated Primary Completion Date :||June 30, 2018|
|Estimated Study Completion Date :||June 30, 2018|
Arm 1: Discovery phase
Approximately 150 women with Gestational Diabetes Mellitus (GDM) and 150 controls, and their offspring will be recruited in Pune (from KEM Hospital and Vadu). The objective will be:
Arm 2: Validation phase
Approximately 200 women with Gestational Diabetes Mellitus (GDM) and 200 controls, and their offspring will be recruited in Punjab, and 150 stored cord blood samples of GDM offspring in Pune will be investigated to validate the epigenetic signatures discovered in Arm 1.
Arm 3: Stability phase
Approximately 500 offspring of women with Gestational Diabetes Mellitus (GDM) from Pune (~ half below 10 years and the rest over 10 years) will be investigated to study:
- Epigenetic signatures in the cord blood of the offspring of GDM mothers. [ Time Frame: Upto 3 years from the start of the study ]The Illumina Infinium Human Methylation 450K array will be used for DNA methylation study. It generates a quantitative measurement of DNA methylation for >480,000 CpG sites spanning all annotated genes and other functional motifs. Markers influencing risk of diabetes and obesity will be of special interest. Approximately 150 GDM and 150 normal glucose tolerant pregnancies will contribute the samples.
- Association of the genotype with differentially methylated DNA regions. [ Time Frame: Upto 3.5 years from the start of the study ]The Human OmniExpress Exome BeadChip will be used for generating genome wide data. It provides a backbone of >700,000 genome-wide markers (SNPs >5% minor allele frequencies) and 240,000 coding SNPs of all frequencies. This will allow to identify the variants that act as meQTLS.
- Validation of the epigenetic signatures generated in Primary Outcome 1. [ Time Frame: Upto 3.5 years from the start of the study ]Quantitative profile of DNA methylation at specific CpG sites will be done using Bisulfite Pyrosequencing [Sequenom EpiTYPER], in cord blood samples obtained in Pune and in Ludhiana.
- Stability of epigenetic signatures discovered in the cord blood in offspring GDM mothers from childhood through adolescence. [ Time Frame: Upto 4 years from the start of the study ]The cord blood differential epigenetic signatures will be investigated in the blood sample of the offspring of GDM mothers during childhood and adolescence. These children were born to GDM patients attending the diabetes clinic at KEM hospital, Pune over last 2 decades.
- Association between epigenetic signatures and offspring phenotype at birth , and in childhood and adolescence. [ Time Frame: Upto 4 years from the start of the study ]
Following phenotype measures will be tested :
- Weight (Kg)
- Height (cm)
- BMI (Kg/m^2)
- Waist circumference (cm)
- Hip circumference (cm)
- Skinfolds (mm)
- DXA [ body composition measures: fat, lean and bone]
- Plasma Glucose concentration (mg/dl) in the cord blood and during an OGTT in childhood and adolescence.
- Plasma Insulin (mU/L) in the cord blood and during an OGTT in childhood and adolescence
- Glucose and insulin indices (HOMA measures) in 8, 9.
- Blood lipids (Cholesterol, HDL, LDL and Triglycerides) in the cord blood and during an OGTT in childhood and adolescence.
- Qualitative and quantitative comparison of epigenetic signatures in the offspring of GDM mothers [Indian and Danish cohort]. [ Time Frame: Upto 4.5 years from the start of the study ]
Epigenetic signatures from Indian and Denmark cohorts will be compared, taking into account differences in genetic background, nutrition and lifestyle.
Comparison will focus on the direction and strength of associations, and the metabolic pathways implicated in the above analysis.
Biospecimen Retention: Samples With DNA
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03388723
|Contact: Chittaranjan Yajnik, MD FRCPfirstname.lastname@example.org|
|Pune, Maharashtra, India, 411011|
|Contact: Chittaranjan Yajnik, MD FRCP 0091-020-26061958 email@example.com|
|Principal Investigator:||Chittaranjan Chittaranjan, MD FRCP||Director, Diabetes Unit, KEM Hospital Research Centre|