developmental origins of health and disease: inter ... · inter-generational programming of...
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Maternal nutrition and offspring metabolic health
in India: inter-generational
programming of diabesity
K Kumaran MRC Lifecourse Epidemiology Unit, University of Southampton
Diabetes Unit, KEM Hospital Research Centre, Pune
CSI Holdsworth Memorial Hospital, Mysore
Holdsworth Memorial Hospital Mysore
Mysore Studies
Stein et al, Lancet 1996
Mysore Birth Records Study
KEM Hospital Pune
Pune Studies
Insulin Resistance
0.5
1
1.5
2
3 2 1 3
2
1
8y weight
HOMAResistance
Birth weight
Bavdekar et al, Diabetes, 1999
Pune Children’s Study
20,755 married women
8,181 live births
2,584 re-traced living in or near Delhi
1,526 studied
1969-1972
1998-2002
survey of defined area of New Delhi
weight and length measured at birth
weight and height measured 6-monthly up
to age 21 years
infancy
childhood
adolescence
Age 26-32 years
anthropometryOGTT
blood pressurefasting lipids
Delhi studies
Childhood BMI of men and women
who developed diabetes or pre-diabetes,
Bhargava et al, New Eng J Med 2004
BMI SD score
0 5 10 15 20 25 30 Age (years)
-0.3
0
0.5
Cohort average
• In childhood: • Less than 1% were obese (IOTF 30 kg/m2) Mean BMI ranged from –0.4 to –1.0 SD (CDC) • At 26-32 years: • 10% obese (BMI >30 kg/m2) • 10% impaired glucose tolerance (pre-diabetes) 4% type 2 diabetes 25% Metabolic Syndrome
New Delhi Birth Cohort
Pune Maternal Nutrition Study
Preconception Intrauterine Birth Postnatal 6 and12 y 18 y
Maternal Size
Nutrition Metabolism Paternal size
Metabolic variables Fetal growth (USG)
814
Children & parents
Size, body composition
IR CVD risk markers
Cognition 698
Maternal Size
Hemo- globin 2675
Size Phenotype
770
Growth every
6 months 743
Children & parents
Size, body composition
IR CVD risk markers
Genetics and Epigenetics
663
1993 1994-96 2000-03 2006-08 2013
Freq of green leafy veg
p<0.005 Mean
Maternal Nutrition & offspring size, metabolism
Rao et al, J Nutr2001 Yajnik et al, Int J Obes 2003 Yajnik et al, Diabetologia 2008
Mysore Parthenon Study
~6% gestational diabetes; mean age 24 yrs; mean BMI 23 kg/m2
Birth weight: GDM 3.3 kg; non-GDM 2.9 kg; increased adiposity
Hill et al, Acta Obstet Gynecol Scand 2005 Krishnaveni et al, Diabetologia 2009
Effects of Gestational Diabetes on the Children
Krishnaveni et al Diabetes Care 2010
Mumbai Maternal Nutrition Project Randomised controlled trial of pre-conceptional micronutrient supplementation
Mumbai Trial Randomised 6513; pregnancies 2291; singleton livebirths 1962
Birth size effect +48g overall, more in heavier
mothers
Low birth weight reduced (34 v 41%)
GDM reduced in mothers (7 v 13%)
Bir
th w
eig
ht
(g)
ALL WOMEN
CONTROL
TREATMENT
Mother’s pre-pregnant BMI (kg/m2)
<18.6 18.6-21.8 >21.8
+ 48g - 7g + 79g + 113g
Mean and 95% confidence intervals
p=0.05 p=0.84 p=0.07 p=0.008
Pune Intervention Study ICMR-MRC
Pre-intervention screening (n=690)•Exclusion (n=133)
Newborn•Cord bloodB12, DNA•Anthro• Follow up
*Iron and folate tablets as per Government of India guidelines to all
InterventionIndividual Randomisation (n=557)
1) B12 (2mcg)2) MMN + B12 + milk3) Placebo*
• Adolescent girls and boys• Physiological doses• 3y/till first delivery
PROSPECTIVE COHORTS
TRIALS Pre-conceptional:
Food-based micronutrients (Mumbai) Vitamin B12 +/- MMN and protein (Pune)
HISTORIC COHORTS
INSULIN RESISTANCE DIABETES
CVD RISK FACTORS CVD
COGNITION
Maternal size, diet, micronutrient status, fuels Maternal pre-eclampsia Child growth
Intermediate outcomes: Fetal development
PUBLIC HEALTH IMPACT
MECHANISMS Epigenetics, metabolomics,
cellular/molecular, MR studies
PILOT WORK Acceptability Absorption
Dose-response
Birth weight Child/adult BMI
Indian multiple birth cohort Biobank
Other pre- and post-natal interventions
Funding The Wellcome Trust Medical Research Council Dept of Biotechnology ICMR Parthenon Trust ICICI Wessex Medical Trust DfID Nestle Foundation IAEA Firodiya family Bajaj family EU NIH
Acknowledgements
Participants
Research teams Pune,
Mysore, Delhi, Mumbai,
Hyderabad, Vellore,
Soton
Team of collaborators: India and UK