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Nutritional Intervention Preconception and During Pregnancy to Maintain Healthy Glucose
Metabolism & OffspRing Health
Keith Godfrey, with Chan Shiao-Yng, Wayne Cutfield, Chong Yap Seng
Director, NIHR Southampton Biomedical Research Centre in Nutrition
Professor of Epidemiology & Human Development, MRC Lifecourse Epidemiology Unit & University of Southampton
Visiting Professor, National University of Singapore
Honorary Consultant, University Hospital Southampton NHS Foundation TrustTwitter @KeithMGodfreyFor Na
onsultant, UKeithMGo
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• Fat, muscle & bone• Heart, lungs & kidneys• Metabolic & stress responses• Mood & behaviour• Ability to learn & cognitive function• Timing of puberty, reproductive function• Immune responses
The effects can be subtle, but they have lifelong consequences, altering how a person responds to their later environment & lifestyle
A healthy start to life has lasting benefits for multiple organs & control systems in the offspring
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Men ( ) & women ( ) born after a famine period ( ) contribute an excess of diabetic patients - total population of Austria
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Developmental influences
Genotype
Uterine environmente.g. gestational
diabetes, mother’s diet, mother’s stress
Postnatal environmente.g. mode of delivery
early nutrition
Phenotypee.g.
Birth weightGestational age
Body composition
Phenotypee.g.
AdiposityGrowth
Neurodevelopment
Phenotypee.g.
HealthDisease
Epigenetic ModificationFor Fo
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“When scientists opened up the human genome, they expected to find the genetic components of common traits and diseases. But they were nowhere to be seen.
Brendan Maher shines a light on six places where the missing loot could be stashed away.”
Nature, 6th November 2008
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(DNA methylation, HDACi, miRNA)
Feeding bee larvae royal jelly for 6 days (vsthe usual 3 days) alters growth & development
How is the “memory” of early life experience held - epigenetics
The development & maintenance of plants & animals is orchestrated by reactions that switch parts of their DNA on & off at strategic times & locations. Epigenetics is the study of these reactions & the factors that influence them.*Plants & animals use epigenetic processes to adapt their development to the environment experienced in early life
*Adapted from http://learn.genetics.utah.edu/content/epigenetics/
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Epigenetics & the human genome
Human genome: 3.2 billion CGAT bases, 200 GB data, 30 million CpG sites3% protein coding (23,000 genes, ~half expressed in each cell)77% proposed to have functional elements (ENCODE)
Epigenetics underlies differences between cellsChanges in gene function that do not depend on DNA sequenceGene expression changed: methylation of CpG sites & chemical changes in the histone proteins alter “packaging” of DNA; non-coding RNAs have a variety of roles that alter gene transcription
Human body - 50 trillion cells: different but same DNA (2 metres /cell)
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Umbilical cord RXRASH amp1 CpG13 methylation
Umbilical cord RXRASH amp1 CpG13 methylation
Epigenetic “marks” in perinatal tissue: strong associations with childhood fat mass & % fat in 2 independent cohorts
Values are means + SEM Godfrey, et al. Diabetes 2011
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Changing the mother or father’s nutrition before/during pregnancycan result in fat & lazy “couch potato” offspring …
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Doyle, Heckman, et al. Economics & Human Biology 2009
Investment in human capital antenatally & preschool results in increased rates of return
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Maternal supplementation with 1000 IU Vitamin D: MAVIDOS multicentre RCT in 965 pregnancies
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…. and increases offspring bone mass in winter births
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Pregnancy low glycemic index diet reduced infant fatnessage 6 months
Reduction seen when3 or more months
exclusive breastfeeding
No reduction from prenatal intervention
if less than 3 months exclusive breastfeeding
Patel, Godfrey, Poston, et al, Int J Obesity 2017
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UPBEATUPBEAT
UPBEAT: UK Better Eating and Activity Trial
Beneficial effect of prenatal intervention dependent on prolonged breastfeeding:
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Iodine status of 30 countries in the EUthyroid project
Background colour refers to the iodine status in the general population; line colour represents the iodine status of pregnant women. Countries with solid colours have the same iodine status in both the general population and in pregnant women.
TLDE 2016
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Mother’s preconception urinary iodine:creatinine ratio μg/g
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*Adjusted for maternal IQ, maternal education and maternal pre-pregnancy BMI, breastfeeding duration, smoking in pregnancy (yes/no), sex, age & maternal iodine intakes in pregnancy
Robinson, Godfrey, et al. J Nutrition 2018
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Singapore: ideal for studying ethnic differences
• Total Population– 5 million (3.8 million citizens &
permanent residents)• Land Area
– 712 sq km• Literacy Rate
– 95.9%• Resident population living in
government-subsidized housing– 82%
• Home Ownership Rate– 87.2%
• Genetic– 3 distinct ethnic groups– Intermarriage rate of about 18%
• Nutritional– Distinct ethnic cuisines– Shared by all ethnic groups
• Cultural– Distinct cultural practices– Increasingly globalized
• Environmental– Very similar– >80% stay in similar
government-subsidized housing
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Rank Country / Territory
Population % of World population
World 6.96 billion 100%
1 China 1.34 billion 19.24%
2 India 1.21 billion 17.38%
3 United States 0.31 billion 4.48%
4 Indonesia 0.24 billion 3.41%
5 Brazil 0.19 billion 2.74%
36.6%
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Indian, 9.2
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Prevalence of type 2 diabetes in Singapore has risen from 1.9% in 1975 to 11.3% in 2010
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1. Excessive (& inadequate) pregnancy weight gain, maternal overweight/obesity, high dietary glycemic load & gestational diabetes are extremely common, with lasting effects on offspring adiposity
2. Low quality diets are extremely common among the population, & relate to how the baby grows in the womb & to growth & body fatness in childhood
3. Maternal vitamin insufficiencies/poor status (notably of particular B-group vitamins & vitamin D) are highly prevalent & are associated with postnatal gain in fatness +/- impaired bone development
Developmental influences on childhood growth
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Not just gestational diabetes, but normal higher fasting glucose levels lead to increased birthweight & adiposity
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2-hour plasma glucose (OGTT 2-hr)
Birthweight% body fatsum of skinfolds
(<4.2) (≥5.3 mmol/L) (<5.1) (≥8.8mmol/L)
GUSTO cohort - significant linear trend for fasting glucose for all 3 adiposity outcomes (p<0.0005) but not for 2h glucose
Aris et al, JCEM 2014
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Recruitment completed 1731 women age 18-38 y
UK (CI Godfrey), NZ, SG
n=~865 n=~550 (up to 12 months)
PRECONCEPTION PREGNANCYDELIVERY
n=~865
n=~300
n=~300
BABY FOLLOW-UP
Primary objective:Randomised to determine the effect of a myo-inositol, probiotic & micronutrient nutritional drink preconception & during pregnancy on the maintenance of healthy glucose metabolism, with the goal of promoting maternal & offspring wellbeing, with particular focus on offspring body composition & adiposity.
Outcomes:Primary outcome is maintenance of healthy glucose tolerance during pregnancy (28 wk oral glucose tolerance test), with secondary outcomes including infant adiposity, epigenetics & microbiome development.
Randomisation
First trial of its type, plus major discovery platform (deep phenotypingof mother, father & offspring, >800,000 biosamples)
NiPPeR: Nutritional Intervention Preconception & During Pregnancy to Maintain Healthy Glucose Metabolism & OffspRing Health
Godfrey, et al, Trials 2017;18:131
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The nutritional drink
Ingredient Daily dose (2 servings)
Vitamin D (ug) 10Vitamin B2 (mg) 1.8Vitamin B6 (mg) 2.6Vitamin B12 (ug) 5.2
Zinc (mg) 10Myo-inositol (g) 4
Probiotic blend 109 cfu each
Folic Acid (ug) 400Iron (mg) 12
Calcium (mg) 150 Iodine (ug) 150
Beta-carotene (RE) 120 (720ug)
ACTIVE
CON
TROL
• Taken twice a day during pre-conception and pregnancy• Time period of consumption:
– Min : 4 weeks (+/- protocol window) + pregnancy– Max: 12 months + pregnancy
• Standard dietary adviceFor +/-2 months + pr
d dietary aPers
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Review of 12 clinical trials treating - mild GI side effects reported only with doses of ≥12 g/day
Previous trials: myo-inositol may enhance fertility if taken before conception, and may reduce the chance of gestational diabetes
myo-inositol
myo-inositol may increase insulin sensitivity by making more phosphatidylinositol available
Naturally produced in the body in the kidney & by the action of gut bacteria on dietary fibres
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Probiotics
Two “friendly” bacteria associated with improved glucose metabolism: • Lactobacillus rhamnosus• Bifidobacterium animalis sp. lactis
Study: Pregnant women treated from first trimester
Laitinen et.al. Br J Nut 2009; Luoto et.al. Br J Nut 2010
Control n=85
Diet/Placebo n= 86
Diet/Probioticsn=85
P value
GDM at 26w
Odds of GDM (95% CI)
25/73 (34%)
1.0
27/76 (36%)
1.08 (0.55, 2.12)
10/76 (13%)
0.27 (0.11, 0.62)
0.003
12 months post-deliveryblood glucose in mother(base-adjusted means; mmol/L)
5.02 5.01 4.87 0.025
Proposed mechanism of anti-diabetic effect: microbial-derived products (e.g. fatty acids) exert immunomodulatory effects, reduce oxidative stress, modify nutrient absorption and gut microbiota (Tilg & Moschen. Gut 2014)
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• Systematic review indicates a significant inverse relation of serum 25OHD & the incidence of gestational diabetes
Eur J Intern Med. 2012;23:465-9F
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Studying the biosamplesBlood chemistryIncluding micronutrients
Genotyping 1,000,000 genetic variants - Omniexpress+ arrays
Epigenetic assessment450,000 CpGs - Infinium 450K arrays6 million CpGs – Reduced representation bisulfite sequencing (RRBS)Whole genome - 80 million reads - MeDIP-seq
Transcriptome assessment45,000 transcripts – Infinium HT12 v4 arraysWhole transcriptome – 25 million reads – RNAseq
Chromatin and histone assessmentWhole genome – 80 million reads - DNAaseprotection Whole genome – 25 million reads – ChIP-seq
Microbiome assessment16S RNA sequencing – 30K reads - 454sequencingMetagenomics - 4.5 GB - shotgun sequencing
Umbilical cord and placenta
Maternal and fetal blood
Longitudinal buccal swabs
Cord derived cells
Longitudinal microbiota sampling For microbiota
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Fleming, Godfrey, et al. Lancet 2018
Preconception maternal overnutrition & obesity, maternal undernutrition, related paternal factors, & assisted reproductive treatments all may change the phenotype & potential ofgametes & early embryos, with enduring consequences.
Our new data reveal that suboptimal maternal & paternal nutrition around conceptionhave similar effects on offspring weight, but differing effects on offspring blood pressure.
The NiPPeR Study & Preconception Health
Evidence exists for developmental origins on later disease throughout pregnancy & beyond, but there is a growing consensus that a critical period is around conception.
This emerging knowledge has significant societal & medical implications. In particular, it provides the basis for a new emphasis on preparation for pregnancy, before conception, to safeguard public health & as a means of disease prevention.
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LifeLab Southampton - science & health literacy Dedicated teaching programme at the heart of a major teaching hospital enables 4000 students per year to:• Experience for themselves exciting
developments in science: focus on understanding how our early lives have effects on our later health
• Learn how they can improve their own health & the health of their future children under a framework of ‘Me, my health & my children’s health’
• Become enthusiastic about science such that they consider further study & careers in scientific disciplines
LifeLab cluster randomised trial
For husiastic abhey consid
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Trial Management Group members
Professor Keith Godfrey
University of Southampton, UK
most recently as Chief strategy, venture investment
and most recently as
JProfessor Wayne Cutfield
University of Auckland, New Zealand
, M.D
Professor Chong Yap Seng
Singapore Institute of Clinical Sciences &
National University of Singapore
Associate Professor Chang Shiao-yng
National University of Singapore
-
Heidi NieldClinical Trial Operations
Director (CTOD)
University of Southampton, UK
For Pers
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Persklandland rso
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Chang
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