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

NCT03388723 | Completed

• 1 other identifier: KEMHRC ID No. 1404
• Study Type: observational
• Target: 1,178
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Gestational Diabetes

Keywords

Epigenetics; Cardiometabolic risk factors

Outcome Measures

Primary Outcomes (1)

• Epigenetic signatures in the cord blood of the offspring of GDM mothers.

  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.

  Upto 3 years from the start of the study

Secondary Outcomes (5)

• Association of the genotype with differentially methylated DNA regions.

  Upto 3.5 years from the start of the study

• Validation of the epigenetic signatures generated in Primary Outcome 1.

  Upto 3.5 years from the start of the study

• Stability of epigenetic signatures discovered in the cord blood in offspring GDM mothers from childhood through adolescence.

  Upto 4 years from the start of the study

• Association between epigenetic signatures and offspring phenotype at birth , and in childhood and adolescence.

  Upto 4 years from the start of the study

• Qualitative and quantitative comparison of epigenetic signatures in the offspring of GDM mothers [Indian and Danish cohort].

  Upto 4.5 years from the start of the study

Study Arms (3)

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: 1. Identification of epigenetic signatures 2. Measurements of B vitamins and 1-C metabolites in mothers' blood and cord blood 3. Glucose, insulin and lipids in mothers during pregnancy 4. Anthropometry and blood pressure

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: 1. Stability of epigenetic signatures in offspring through childhood and adolescence 2. Relation of these signatures with phenotype

Eligibility Criteria

• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)
• Sampling Method: Non-Probability Sample

Study Population

Arm 1 and Arm 2: GDM women (diagnosed on OGTT) and women with normal glucose tolerance on OGTT and their offspring. Arm 3: Offspring of diabetic mothers and non diabetic mothers

You may qualify if:

• 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).

You may not qualify if:

• 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.

Sponsors & Collaborators

• Kem Hospital, Pune, India: lead
• Centre for Cellular and Molecular Biology, Hyderabad, India: collaborator

Study Sites (1)

KEM Hospital

Pune, Maharashtra, 411011, India

Location

Related Publications (9)

• Dabelea D, Pettitt DJ. Intrauterine diabetic environment confers risks for type 2 diabetes mellitus and obesity in the offspring, in addition to genetic susceptibility. J Pediatr Endocrinol Metab. 2001 Sep-Oct;14(8):1085-91. doi: 10.1515/jpem-2001-0803.

  PMID: 11592564 BACKGROUND

• Petitt DJ, Bennett PH, Knowler WC, Baird HR, Aleck KA. Gestational diabetes mellitus and impaired glucose tolerance during pregnancy. Long-term effects on obesity and glucose tolerance in the offspring. Diabetes. 1985 Jun;34 Suppl 2:119-22. doi: 10.2337/diab.34.2.s119.

  PMID: 3996763 BACKGROUND

• Gluckman PD, Hanson MA, Cooper C, Thornburg KL. Effect of in utero and early-life conditions on adult health and disease. N Engl J Med. 2008 Jul 3;359(1):61-73. doi: 10.1056/NEJMra0708473. No abstract available.

  PMID: 18596274 BACKGROUND

• Wu L, Cui L, Tam WH, Ma RC, Wang CC. Genetic variants associated with gestational diabetes mellitus: a meta-analysis and subgroup analysis. Sci Rep. 2016 Jul 29;6:30539. doi: 10.1038/srep30539.

  PMID: 27468700 BACKGROUND

• Ma RC, Tutino GE, Lillycrop KA, Hanson MA, Tam WH. Maternal diabetes, gestational diabetes and the role of epigenetics in their long term effects on offspring. Prog Biophys Mol Biol. 2015 Jul;118(1-2):55-68. doi: 10.1016/j.pbiomolbio.2015.02.010. Epub 2015 Mar 16.

  PMID: 25792090 BACKGROUND

• Yajnik CS. Fetal programming of diabetes: still so much to learn! Diabetes Care. 2010 May;33(5):1146-8. doi: 10.2337/dc10-0407. No abstract available.

  PMID: 20427687 BACKGROUND

• Kale SD, Yajnik CS, Kulkarni SR, Meenakumari K, Joglekar AA, Khorsand N, Ladkat RS, Ramdas LV, Lubree HG. High risk of diabetes and metabolic syndrome in Indian women with gestational diabetes mellitus. Diabet Med. 2004 Nov;21(11):1257-8. doi: 10.1111/j.1464-5491.2004.01337.x. No abstract available.

  PMID: 15498096 BACKGROUND

• Kale SD, Kulkarni SR, Lubree HG, Meenakumari K, Deshpande VU, Rege SS, Deshpande J, Coyaji KJ, Yajnik CS. Characteristics of gestational diabetic mothers and their babies in an Indian diabetes clinic. J Assoc Physicians India. 2005 Oct;53:857-63.

  PMID: 16459528 BACKGROUND

• Yajnik CS. Transmission of obesity-adiposity and related disorders from the mother to the baby. Ann Nutr Metab. 2014;64 Suppl 1:8-17. doi: 10.1159/000362608. Epub 2014 Jul 23.

  PMID: 25059801 BACKGROUND

Biospecimen

Retention: SAMPLES WITH DNA

The following biospecimens will be stored appropriately (at -80 degree C): Maternal blood in pregnancy, offspring's cord blood and placental tissue In the follow up study, samples from children born to diabetic and non diabetic mothers will be stored: blood, urine

MeSH Terms

Conditions

Diabetes, Gestational

Condition Hierarchy (Ancestors)

Pregnancy Complications; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Diabetes Mellitus; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Endocrine System Diseases

Study Officials

• Chittaranjan Chittaranjan, MD FRCP

  Director, Diabetes Unit, KEM Hospital Research Centre

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Director, Diabetes Unit

Study Record Dates

• First Submitted: October 26, 2017
• First Posted: January 3, 2018
• Study Start: September 2, 2014
• Primary Completion: November 30, 2018
• Study Completion: November 30, 2018
• Last Updated: April 1, 2019

Record last verified: 2019-03

Locations

IN (1)