Nutritional Intervention Preconception and Metabolism ...

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

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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

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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

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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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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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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Beneficial effect of prenatal intervention dependent on prolonged breastfeeding:

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Public Health Canada – Preconception Health Recommendations

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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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*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

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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%

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Malay, 13.4

Indian, 9.2

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Singapore’s socioeconomic & nutritional transition:a model of precipitous prosperity ynly

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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

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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)

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• Taken twice a day during pre-conception and pregnancy• Time period of consumption:

– Min : 4 weeks (+/- protocol window) + pregnancy– Max: 12 months + pregnancy

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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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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)

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12 months post-deliveryblood glucose in mother(base-adjusted means; mmol/L)

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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

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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

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WHO 2106 Science & Evidence Working GroupChair Mark Hanson

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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

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Heidi NieldClinical Trial Operations

Director (CTOD)

University of Southampton, UK

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