Maternal vitamin B12, folic acid and homocysteine as determinants of gestational diabetes, fetal growth and intergenerational programming of diabesity

Lead Research Organisation: University of Southampton
Department Name: Development Origin of Health and Disease

Abstract

There is a rapidly escalating epidemic of obesity and type 2 diabetes across the world, with the fastest rise occurring in low- and middle-income countries. India not only has one of the highest rates in the world, but the disease starts at a younger age and lower levels of body weight than in UK white caucasians. Among city-dwelling Indians, approximately 8% of people aged 30-40 years already have diabetes. This is creating a heavy burden of disease and disability, and an intolerable economic burden through medical costs and lost earnings. Until now, efforts to prevent diabetes have mainly focussed on modifying the diet, lifestyle and activity of at-risk adults (for example those who are overweight, have a family history of diabetes or already have high blood sugar). However, recent research has indicated that factors acting in early life (during development in the womb) place an individual at risk of later diabetes. These include maternal malnutrition and low birthweight, and diabetes in the mother during pregnancy. Our research has shown that Indian mothers often have low vitamin B12 levels, which in turn causes high blood levels of a harmful metabolite (homocysteine). We have shown that these mothers get more diabetes in pregnancy. Their children are more likely to born with a low birth weight, and develop more body fat and higher plasma insulin levels during childhood, which are signs of higher diabetes risk in later life. The risk is increased further if the mother has normal or high status for another B vitamin, folate. Thus, we have shown, for the first time a link between a specific nutritional deficiency in the mother and diabetes risk in the next generation. One possible mechanism for the effect of maternal nutrition on risk of diabetes in her children is through epigenetic effects, whereby the nutritional environment during early development affects the switches that control gene expression. Since these switches are passed on via either parent, we think it is possible that paternal vitamin B12 status could also be important.

Our proposed programme comprises 3 related projects in India and the UK:

1) A randomised controlled trial of vitamin B12 supplementation in a cohort of 700 rural Indian adolescents (Pune Maternal Nutrition Study) with the aim of improving their vitamin B12 status prior to marriage, conception and pregnancy.

The objectives are to determine

a) whether vitamin B12 supplementation of young Indian women improves the vitamin B12 status of their newborns.

b) whether vitamin B12 supplementation of young Indian women and men improves birth weight, neonatal body composition, and (beyond the time span of this grant) body composition and insulin sensitivity in the children.

2) A case-control study of mothers with gestational diabetes (N=700) and controls (N=1400) in a UK population with a high proportion of S Asians (Coventry, Nuneaton and Leicester).

The objective is to determine:

c) whether Indian and white caucasian women who develop GDM were more likely to have low vitamin B12 status, or an imbalance between B12 and folate (low B12, normal/high folate) in early pregnancy.

3) Measurement of vitamin B12, folate and homocysteine in stored maternal plasma samples from 3000 pregnancies in a UK birth cohort (Southampton Women's Survey) which has subsequently collected data on body composition in the newborns and children.

The objectives will be to determine:

d) whether lower maternal B12 status and higher homocysteine concentrations are associated with lower birthweight in a UK population.

e) whether B12-folate imbalance (low maternal B12 and normal/high folate status) are associated with a more adipose body composition at birth and during childhood.

We expect this unique research to have a major impact on future strategies to prevent diabetes.

Technical Summary

There is an escalating global epidemic of type 2 diabetes, with developing countries experiencing the most rapid increase. Current strategies for preventing the disease rely mainly on altering adult lifestyles. Recent research suggests that factors acting during early development, including fetal growth restriction, and exposure to gestational diabetes (GDM) in the mother, increase diabetes and obesity risk in later life. Our research in India has shown that maternal vitamin B12 deficiency and hyper-homocysteinaemia, in combination with normal/high folate status, is associated with an increased risk of GDM in the mother, growth restriction in her fetus, and adiposity and insulin resistance in her children. These effects could act through epigenetic mechanisms and occur in paternal as well as maternal B12 deficiency. Improving the B12 status of women and men preparing for pregnancy could be a scalable and affordable intervention to prevent diabetes in future generations. Our proposed programme includes an RCT of B12 supplementation in rural Indian adolescents who will marry and conceive within the next 4 years, aiming to improve newborn B12 status and body composition and reduce diabetes risk in their children. We will also carry out 2 observational studies in the UK, to replicate the earlier Indian findings and study their wider relevance. We will measure B12, folate and homocysteine in stored maternal samples from a UK birth cohort which has measured body composition in the children, and carry out a case-control study of mothers with and without GDM in a UK population at high risk and with a high S Asian population (W Midlands) to determine whether UK women who develop GDM have low B12 status, or B12/folate imbalance, in early pregnancy. Samples taken in all studies will be used for genetic studies, and future epigenetic research, relevant to our objectives. We expect this unique research to have a major impact on future strategies to prevent type 2 diabetes.

Planned Impact

This comprehensive programme will assess the impact of 2 B vitamins (B12 and folic acid) on metabolic risk of pregnant mothers, fetal growth and inter-generational programming of common chronic metabolic disorders (obesity and diabetes). We will assess impact in India, as well as in white Caucasians and South Asians living in the UK. We expect the work to have an influence on future strategies to prevent these disorders. This is important given the high burden of disease potentially caused by vitamin B12 deficiency and the scalable and affordable nature of widespread B12 supplementation. It is anticipated 15-20% of all pregnant mothers will develop GDM in the UK if the new International Association of Diabetes and Pregnancy Study Group (IADPSG) guidelines are adopted. Despite best efforts, childhood obesity is increasing along with the epidemic of metabolic disorders in adult life.

Apart from patients who develop GDM, the beneficiaries from this research will be: pregnant mothers of all ethnicities living in India, UK and elsewhere; diabetologists in the NHS and world-wide (if B12 deficiency predicts the risk of GDM); public health experts (involved in strategies to reduce childhood obesity); and policy makers (huge potential to reduce the burden of obesity and metabolic diseases of the next generation).

Publications


10 25 50
Krishnaveni GV (2015) Clinical Handbook of Diabesity
Fall CH (2013) Fetal malnutrition and long-term outcomes. in Nestle Nutrition Institute workshop series
Limaye TY (2016) High prevalence of cardiometabolic risk factors in young employees of Information Technology industry. in Indian journal of occupational and environmental medicine
 
Description Findings that have supported interventions in the first 1000 days
Geographic Reach Multiple continents/international 
Policy Influence Type Citation in other policy documents
Impact Caroline Fall and Clive Osmond are members of the COHORTS collaboration, which has carried out research that supports the targeting of nutritional interventions for the prevention of undernutrition in pregnancy and infancy.
 
Description Department of Biotechnology, Government of India, Centre of Excellence Grant to Diabetes Research Unit, Pune, India (co-applicant K Kumaran)
Amount रू 70,000,000 (INR)
Organisation Ministry of Science and Technology India 
Department Department of Biotechnology, India
Sector Public
Country India, Republic of
Start 12/2013 
End 11/2018
 
Description Translating cutting edge research from the University of Southampton into global health policy opportunities; a proposal to fund an intern to work with the World Health Organisation. KMG HI 2016
Amount £27,308 (GBP)
Organisation Economic and Social Research Council (ESRC) 
Sector Public
Country United Kingdom of Great Britain & Northern Ireland (UK)
Start 01/2016 
End 12/2016
 
Title Databases from 8 Indian birth cohorts 
Description Lifecourse data from 8 Indian birth cohorts. 
Type Of Material Database/Collection of data 
Provided To Others? Yes  
Impact Widening of research usage 
 
Description Maternal vitamin B12, folic acid and homocysteine as determinants of gestational diabetes, fetal growth and inter-generational programming of diabesity 
Organisation Council of Scientific and Industrial Research (CSIR)
Department Centre for Cellular and Molecular Biology (CCMB)
Country India, Republic of 
Sector Academic/University 
PI Contribution Epidemiological and statistical expertise, study design, training of field and scientific staff, data interprtetation.
Collaborator Contribution Multi-disciplinary collaboration (paediatrics, obstetrics, diabetes, epidemiology, statistics, nutrition, genetics, biochemistry)
Impact 27076577. Multi-disciplinary collaboration (paediatrics, obstetrics, diabetes, epidemiology, statistics, nutrition, genetics, biochemistry). Abstracts presented at conferences.
Start Year 2010
 
Description Maternal vitamin B12, folic acid and homocysteine as determinants of gestational diabetes, fetal growth and inter-generational programming of diabesity 
Organisation KEM Hospital Research Centre
Department Department of Diabetes
Country India, Republic of 
Sector Hospitals 
PI Contribution Epidemiological and statistical expertise, study design, training of field and scientific staff, data interprtetation.
Collaborator Contribution Multi-disciplinary collaboration (paediatrics, obstetrics, diabetes, epidemiology, statistics, nutrition, genetics, biochemistry)
Impact 27076577. Multi-disciplinary collaboration (paediatrics, obstetrics, diabetes, epidemiology, statistics, nutrition, genetics, biochemistry). Abstracts presented at conferences.
Start Year 2010
 
Description Maternal vitamin B12, folic acid and homocysteine as determinants of gestational diabetes, fetal growth and inter-generational programming of diabesity 
Organisation Medical Sciences Division
Department Department of Pharmacology
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Academic/University 
PI Contribution Epidemiological and statistical expertise, study design, training of field and scientific staff, data interprtetation.
Collaborator Contribution Multi-disciplinary collaboration (paediatrics, obstetrics, diabetes, epidemiology, statistics, nutrition, genetics, biochemistry)
Impact 27076577. Multi-disciplinary collaboration (paediatrics, obstetrics, diabetes, epidemiology, statistics, nutrition, genetics, biochemistry). Abstracts presented at conferences.
Start Year 2010
 
Description Maternal vitamin B12, folic acid and homocysteine as determinants of gestational diabetes, fetal growth and inter-generational programming of diabesity 
Organisation University of Warwick
Department Warwick Medical School
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Academic/University 
PI Contribution Epidemiological and statistical expertise, study design, training of field and scientific staff, data interprtetation.
Collaborator Contribution Multi-disciplinary collaboration (paediatrics, obstetrics, diabetes, epidemiology, statistics, nutrition, genetics, biochemistry)
Impact 27076577. Multi-disciplinary collaboration (paediatrics, obstetrics, diabetes, epidemiology, statistics, nutrition, genetics, biochemistry). Abstracts presented at conferences.
Start Year 2010
 
Description Pune Children's Study 
Organisation KEM Hospital, Pune
Department Department of Paediatrics
Country India, Republic of 
Sector Hospitals 
PI Contribution Contributions to study design, fieldwork training and quality control, data management, analysis and interpretation. Epidemiological, statistical and nutritional expertise.
Collaborator Contribution Expertise in long-term follow-up of birth cohorts, clinical and laboratory expertise. Day-to-day liaison with cohort members, fieldwork/data collection, data management, analysis and interpretation.
Impact Publications: 24874906, 25940643 and several abstracts presented at a major international meetings and published in peer-reviewed international journals.
Start Year 2006
 
Description Pune Maternal Nutrition Study 
Organisation KEM Hospital Research Centre
Department Department of Diabetes
Country India, Republic of 
Sector Hospitals 
PI Contribution Contributions to study design, fieldwork training and quality control, data management, analysis and interpretation.Epidemiological, statistical and nutritional expertise.
Collaborator Contribution Expertise in community-based research, including interventions, in rural and urban settings in a developing country. Day-to-day liaison with cohort subjects, fieldwork management, data management, analysis and interpretation.
Impact 16480528, 16735496, 17032446, 17116720, 17620450, 17653070, 17851649, 19005641, 19498084, 19636321, 19776185, 20090113, 20103791, 20216560, 20675085, 21682572, 21731039, 22109280, 22323413, 22829248, 22941936, 22941936, 22941936, 22323413, 23349157, 23757425, 23920141, 24162586, 24459167, 25052622, 26902699 Abstracts presented at major international meetings and published in peer-reviewed international journals. Multi-disciplinary study: diabetes, paediatrics, obstetrics, radiology, nutrition, epidemiology, statistics
Start Year 2006
 
Title Vitamin B12 
Description Physiological doses of vitamin B12 for women and men before conception and (women) during pregnancy, to prevent adverse fetal programming 
Type Preventative Intervention - Nutrition and Chemoprevention
Current Stage Of Development Early clinical assessment
Year Development Stage Completed 2010
Development Status Under active development/distribution
Clinical Trial? Yes
UKCRN/ISCTN Identifier ISRCTN32921044
Impact Trial ongoing. 
URL http://www.controlled-trials.com/ISRCTN32921044
 
Description 20th Annual Sneha Workshop, Feb 2017 (K Kumaran) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Indian meeting on DOHaD research attended by over 600 delegates and over 200 for the 2nd David Barker Memorial conference
Year(s) Of Engagement Activity 2017
 
Description Address to a school audience, Mysore, India March 3016 (K Kumaran) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact Chief guest: address to a school audience (students, teachers and parents) on the importance of early life nuturing to improve child development and later health. The school has subsequently asked Dr Kumaran to run regular sessions on adolescent health for the high school students
Year(s) Of Engagement Activity 2016
 
Description Annual Sneha conference, Lonavala, India, 2014 (K Kumaran) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Part of the organising team; attended by over 60 delegates for the main workshop and approx 150 for the David Barker Memorial Conference
Year(s) Of Engagement Activity 2014
 
Description Biostatistics and Epidemiology for Clinical and Public Health Research, Vellore, India, March 2016 and June 2016 (K Kumaran) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Professional Practitioners
Results and Impact Faculty on a course for multi-disciplinary professionals run by Christian Medical College, Vellore in March and again in June 2016
Year(s) Of Engagement Activity 2016
 
Description Caroline Fall, K Kumaran, Sarah Kehoe; Organisers and chairs; 19th Annual Workshop of SNEHA India 2016 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact Annual workshop in India on developmental origins of health and disease, under the aegis of SNEHA-INDIA (Society for natal effects on health in adults). This workshop brings senior researchers, multi-disciplinary research teams, under- and post-graduate students working on cohorts studies and trials from all over India together, along with international collaborators and invite speakers.
Year(s) Of Engagement Activity 2016
 
Description Caroline Fall: Interviews with journalists at FIGO conference, Rome 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Wide public dissemination. The presentation reaced a large number of international obstetricians at their major annual conference. Presentation has been posted on the website of C3 for Health, for longer term dissemination to everyone interested in global health issues.

Requests to give further talks!
Year(s) Of Engagement Activity 2012
 
Description Caroline Fall: MRC Life Magazine article (Jun 2014) 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact An article advertising the David Barker Commemorative meeting, "The Future of the Science David Barker Inspired", organised by MRC Lifecourse Epidemiology Unit and University of Southampton

Highlighting the commemorative event and work of the unit
Year(s) Of Engagement Activity
 
Description Clive Osmond: Inaugural lecture (May 2014) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact Clive Osmond gate his inaugural lecture on 29 May 2014. It was entitled "Painting with numbers: exploring life's wonders"

Increased awareness of the work of the MRC LEU
Year(s) Of Engagement Activity
 
Description Epidemiology for Clinicians course, Southampton, Jan 2017 (K Kumaran) 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact On the Faculty of Epidemiology for Clinicians course hosted by University of Southampton, aimed at delegates with both clinical and non-clinical backgrounds who are interested in a career in epidemiological research
Year(s) Of Engagement Activity 2017
 
Description Invited presentation at the 2nd annual PRIDE meeting, University of Warwick. Prof Caroline Fall "The Mumbai Maternal Nutrition Project" 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Invited presentation at the 2nd annual PRIDE meeting, University of Warwick. November 2014
Year(s) Of Engagement Activity 2014
 
Description Invited presentation at the annual review meeting of the GIFTS consortium. Prof Caroline Fall "The Mumbai Maternal Nutrition Project" 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Invited presentation at the annual review meeting of the GIFTS consortium, London, April 2014
Year(s) Of Engagement Activity 2014
 
Description K Kumaran: 9th World Congress on Developmental Origins of Health and Disease, Cape Town, South Africa. 8-11 November 2015. 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Four presentations to multi-disciplinary audience at 9th World Congress on Developmental Origins of Health and Disease, Cape Town, South Africa. 8-11 November 2015.
- Components of height and the intergenerational change in height as predictors of body composition and CVD risk in young Indian adults.
- Does change in components of childhood height influence cardiovascular risk and cognitive function in Indian adolescents?
- Stunting at 18 years is predicted by femur length in utero.
- Lifecourse evolution of diabetes related phenotypes.
Year(s) Of Engagement Activity 2015
 
Description Member Expert Panel to review MSC Nutrition and Dietetics at Symbiosis School of Biomedical Sciences, Pune (K Kumaran) 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Professional Practitioners
Results and Impact Contributed to curriculum review and modification of MSC course at Symbiosis International University
Year(s) Of Engagement Activity 2016
 
Description Newspaper and Magazine articles 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Type Of Presentation Paper Presentation
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Wide dissemination to a lay readership

Raised public awareness
Year(s) Of Engagement Activity 2010,2011,2012
 
Description PPI and stakeholder meeting - University of Warwick 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact 47 people (researchers, GPs, PPI representatives) attended the meeting which was help at University of Warwick. Emerging data from the UK GDM cohort was discussed alongside with the STRiDE study's rationale, plan and implementation
Year(s) Of Engagement Activity 2016
 
Description Prof Caroline Fall: Disentangling the effects of weight and height gain in early life on chronic disease risk and human capital; data from 5 cohorts in low- and middle-income countries; the COHORTS collaboration 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Presentation of the work of the COHORTS collaboration at the 17th Annual meeting of Sneha-India, Mysore, India, 2013
Year(s) Of Engagement Activity 2013
 
Description Public Health Platform Technical Advisory Group meeting, Pune, Mar 2016 (K Kumaran) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Professional Practitioners
Results and Impact Part of a public health platform in India aimed at capacity building in public health
Year(s) Of Engagement Activity 2016
 
Description Pune Public Health Conference 2014, School of Health Sciences, University of Pune and Joint State Conference of IPHA-IAPSM (K Kumaran) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Presentation to public health conference and IPHA-IAPSM on maternal health and pre-conceptional health
Year(s) Of Engagement Activity 2014
 
Description What is DOHaD and where is it going? 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Professional Practitioners
Results and Impact 2nd David Barker Memorial Symposium in India on Developmental Origins of Health and Disease, held at the Integrated Research School for Health Affairs, Bharati Vidyapeeth University, Pune, India. A lecture for clinicians on what DOHaD is all about, and its relevance for cinical care.
Year(s) Of Engagement Activity 2017