alimentazione del bambino con basso peso alla nascita e ...old.iss.it/binary/inte/cont/04 - stefano...

Alimentazione del bambino Alimentazione del bambino con basso peso alla nascita con basso peso alla nascita e metabolismo in ete metabolismo in etàà adultaadulta

Stefano CianfaraniStefano Cianfarani““RinaRina BalducciBalducci”” Centre of Pediatric Endocrinology Centre of Pediatric Endocrinology

Department of Public Health & Cell BiologyDepartment of Public Health & Cell BiologyTorTor VergataVergata University, RomeUniversity, Rome

““ThereThere are more are more thingsthings in in heavenheaven and and earthearth, , HoratioHoratio,,thanthan are are dreamtdreamt of in of in youryour philosophyphilosophy……””

William William ShakespeareShakespeare, , HamletHamlet

http://www.uniroma2.it/

OddsOdds ratio ratio forfor impairedimpairedglucoseglucose tolerancetolerance or or typetype 2 2 diabetesdiabetes accordingaccording toto birth birth weightweight amongamong 370 370 menmenagedaged 64 64 yearsyears bornborn in in HertfordshireHertfordshire ((adjustedadjusted forforadultadult body mass body mass indexindex). ).

MetabolicMetabolic riskrisk

HalesHales CN & CN & BarkerBarker DJP DJP BrBr MedMed Bull 60:5Bull 60:5--20,200120,2001

Hales, C N. et al. Br Med Bull 2001 60:5-20; doi:10.1093/bmb/60.1.5

OddsOdds ratio ratio forfor the the metabolicmetabolicsyndromesyndrome accordingaccording toto birth birth weightweight amongamong 407 407 menmenbornborn in in HertfordshireHertfordshire((adjustedadjusted forfor adultadult body body mass mass indexindex). ).


Gluckman PD & Hanson MA Science 305:1733-1736,2004


Glucose and Insulin Concentrations and the Insulin-ResistanceIndex (HOMA-IR) in Young Adults with Very Low Birth Weight(VLBW) and a Comparison Group of Young Adults Born at Term.

Hovi P et al. N Engl J Med 2007;356:2053-63.

Hales & Barker 1992:Thrifty Phenotype Hypothesis

Intrauterine MalnutritionIntrauterine Malnutrition

Limited nutrient supplyLimited nutrient supplyi.e. glucosei.e. glucose

Vital organsVital organsi.e. braini.e. brain

GrowthGrowth IUGRIUGR

ββ--cellscells

MechanismsMechanisms

Programming

EmbryoEmbryo FoetusFoetus NewbornNewborn

Critical periods

PermanentPermanent metabolicmetabolic changeschangesi.e. i.e. insulininsulin resistanceresistance

IntrauterineIntrauterine MalnutritionMalnutrition


Fowden, A. L. et al. Physiology 21: 29Fowden, A. L. et al. Physiology 21: 29--37 200637 2006

Causes and consequences of intrauterine programmingCauses and consequences of intrauterine programming

Maternal constraint

Cellular processes that may be programmed by intrauterine manipuCellular processes that may be programmed by intrauterine manipulation of the lation of the nutritional or hormonal environment nutritional or hormonal environment

Fowden, A. L. et al. Physiology 21: 29Fowden, A. L. et al. Physiology 21: 29--37 200637 2006

ModifiedModified fromfrom GodfreyGodfrey KM KM etet al.al. PediatrPediatr Res Res 61: 5R61: 5R––10R, 200710R, 2007

NutritionalsupplementationGrowth promoters


MaternalMaternal dietarydietary methylmethyl supplementationsupplementationand and coatcoat--colorcolor phenotypephenotype of of A/aA/a offspringoffspring. . (A) (A) IsogenicIsogenic A/aA/a animalsanimals representingrepresenting the the fivefive coatcoat--colorcolor classesclasses usedused toto classifyclassifyphenotypephenotype. The . The AA allelesalleles of yellow of yellow micemiceare are hypomethylatedhypomethylated, , allowingallowing maximal maximal ectopicectopic agoutiagouti expressionexpression. . AAhypermethylationhypermethylation silencessilences ectopicectopic agoutiagoutiexpressionexpression in in pseudopseudo--agoutiagouti animalsanimals, , recapitulatingrecapitulating the the agoutiagouti phenotypephenotype. (B) . (B) CoatCoat--colorcolor distributiondistribution of of allall A/aA/a offspringoffspringbornborn toto 9 9 nonnon--supplementedsupplemented (30 (30 offspringoffspring, , graygray barsbars) and 10 ) and 10 supplementedsupplemented damsdams(39 (39 offspringoffspring, black , black barsbars). ). The The coatcoat--colorcolordistributiondistribution of of supplementedsupplemented offspringoffspring isisshiftedshifted towardtoward the the pseudopseudo--agoutiagoutiphenotypephenotype relative relative toto thatthat of of nonnon--supplementedsupplemented offspringoffspring ((PP = 0.008). = 0.008).

Waterland RA et al. Nutrition 20:63-68, 2004

SummarySummary of of epigeneticepigenetic changeschanges at at Pdx1 Pdx1 in in IUGR IUGR ratsrats duringduring the the developmentdevelopment of of typetype 2 2 diabetesdiabetes. In . In pancreaticpancreatic ββ--cellscells (top (top rowrow), the ), the Pdx1 Pdx1 proximalproximal promoter promoter isis normallynormally foundfoundin in anan unmethylatedunmethylated (open (open circlescircles) open ) open chromatinchromatin state, state, allowingallowing access access tototranscriptiontranscription factorsfactors suchsuch asas USFUSF--1 and 1 and associatedassociated withwith nucleosomesnucleosomes characterizedcharacterizedbyby acetylatedacetylated ((AcAc, , octagonsoctagons) ) histoneshistones H3 and H3 and H4 and H4 and withwith H3K4me3 (Me3, H3K4me3 (Me3, hexagonshexagons). In ). In IUGR IUGR fetalfetal and 2 and 2 weekweek isletsislets ((secondsecond and and thirdthird rowsrows), ), histonehistone acetylationacetylation isisprogressivelyprogressively lostlost through through associationassociation withwith a a mSin3AmSin3A--HDAC1HDAC1--DNMT1 DNMT1 repressorrepressorcomplexcomplex, , withwith H3K4me3 H3K4me3 disappearingdisappearingand H3K9me2 (Me2, and H3K9me2 (Me2, trianglestriangles) ) appearingappearingafter birth. IUGR after birth. IUGR adultadult isletsislets ((fourthfourth rowrow) ) are are characterizedcharacterized byby inactiveinactive chromatinchromatin withwithH3K9me2 and H3K9me2 and extensiveextensive DNA DNA methylationmethylation((filledfilled circlescircles) ) lockinglocking in the in the transcriptionallytranscriptionallysilentsilent state of state of Pdx1Pdx1..

Park JH Park JH etet al.al. J J ClinClin Invest Invest doidoi:10.1172/JCI33655, 2008:10.1172/JCI33655, 2008

The The hypothalamushypothalamus isis emergingemerging asas a a criticalcritical site site forfor the the integrationintegration of of nutritionalnutritional, endocrine, and , endocrine, and neuralneural cuescues signalingsignaling the the bodybody’’s s metabolicmetabolicand and nutritionalnutritional status.status.

ElmquistElmquist JK & JK & MarcusMarcus JN JN NatNat MedMed 9:6459:645--647,2003647,2003


Aim of the studyAim of the studyWe asked whether hypothalamus lipid We asked whether hypothalamus lipid sensing programming might be present in an sensing programming might be present in an animal model of IUGR obtained by uterine animal model of IUGR obtained by uterine artery artery ligationligation, a procedure which mimics , a procedure which mimics uteroplacentaluteroplacental insufficiency.insufficiency.

On day 19 of gestation SpragueOn day 19 of gestation Sprague--DawleyDawley pregnant rats underwent pregnant rats underwent uterine artery uterine artery ligationligation. Pregnant . Pregnant rats were allowed to deliver rats were allowed to deliver spontaneously. Hypothalamus, spontaneously. Hypothalamus, cerebellum, hippocampus and cerebellum, hippocampus and cortex were dissected at birth and cortex were dissected at birth and analyzed by Realanalyzed by Real--Time PCR. Time PCR.


AnimalAnimal Model Model SpragueSprague--DawleyDawley ratsrats

ControlControlIUGRIUGR-30%


Sham: n=30 Sham: n=30 IUGR: n=30IUGR: n=30

0

30

60

90

mg/dL

Sham Iugr

Glucose

00.10.20.30.40.50.6

ng/ml

sham iugr

Insulin

0

0.1

0.2

0.3

0.4

mg/dL

sham iugr

NEFA

*

p<0.0001

Serum AssaysSerum AssaysMechanismsMechanisms

Prodi, E. et al. Endocrinology 2006;147:2664Prodi, E. et al. Endocrinology 2006;147:2664--26692669

Gene Gene expressionexpression analysisanalysis (RT(RT--PCR)PCR)MechanismsMechanisms

FOOD INTAKEFOOD INTAKE

ExpressionExpression of CPT1 of CPT1 isoformsisoforms in in differentdifferent brain brain regionsregions of of shamsham--operatedoperated(n=15) and IUGR (n=15) and IUGR ratsrats (n=15)(n=15)

0.000.200.400.600.801.001.201.401.60

Fold

change

Hypothalamus Cerebellum Hippocampus Cortex

CPT1ACPT1BCPT1C

**

*p*p< 0.01< 0.01**p< 0.05**p< 0.05

****

Puglianiello A. Puglianiello A. etet al.al. PediatrPediatr Res Res 61: 43361: 433––437, 2007437, 2007

0

0.25

0.5

0.75

1

Fold Increase

SHAM IUGR

*

* p=0* p=0.005.005

AcetylAcetyl CoACoA CarboxylaseCarboxylase ββAcetylAcetyl CoACoA CarboxylaseCarboxylase αα

0

0.25

0.5

0.75

1

Fold Increase

SHAM IUGR* p<0.05* p<0.05

*

Sham: n=14 Sham: n=14 IUGR: n=14IUGR: n=14

ExpressionExpression of ACCof ACCαα and and ACCACCββ in in hypothalamushypothalamus of of shamsham--operatedoperated(n=15) and IUGR (n=15) and IUGR ratsrats (n=15)(n=15)



Model of neuronal integration of metabolic and endocrine signalsModel of neuronal integration of metabolic and endocrine signalsinvolved in regulation of glucose productioninvolved in regulation of glucose production


FOOD INTAKEFOOD INTAKE

Weights of IUGR ( diamonds) Weights of IUGR ( diamonds) and shamand sham--operated control operated control (squares ) rats from birth until 4 (squares ) rats from birth until 4 weeks of age (weeks of age (AA) and from 5 to ) and from 5 to 26 weeks of age (26 weeks of age (BB). Values are ). Values are the means the means ±± SE from 55 animals SE from 55 animals from each group followed from each group followed sequentially from birth until 26 sequentially from birth until 26 weeks of age. *weeks of age. *PP < 0.05 vs. < 0.05 vs. shamsham--operated control rats. operated control rats.

Simmons RA et al. Diabetes 2001;50:2279Simmons RA et al. Diabetes 2001;50:2279--22862286


ConclusionsConclusions

NEFA circulating levels are increased in IUGR animals.NEFA circulating levels are increased in IUGR animals.CPTCPT--11γγ expression is specifically expression is specifically downregulateddownregulated in the hypothalamus in the hypothalamus

and and upregulatedupregulated in the hippocampus of IUGR animals.in the hippocampus of IUGR animals.ACC expression is ACC expression is downregulateddownregulated in the hypothalamus of IUGR animals.in the hypothalamus of IUGR animals.

CPTCPT--11γγ downregulationdownregulation LCFALCFA--CoACoA FI & GPFI & GPACC ACC downregulationdownregulation LCFALCFA--CoACoA FI & GPFI & GP

TimingTimingEnvironment Environment

Genetic PredispositionGenetic Predisposition



IntrauterineIntrauterine nutrientnutrient deficiencydeficiency

Central (Central (hypothalamushypothalamus) ) programmingprogramming

CPTCPT--11γγ & ACC& ACC

ΔΔFood Food intakeintake

ΔΔGlucoseGlucose productionproduction


Background

Circulating free fatty acids (FFAs) represent important nutrientCirculating free fatty acids (FFAs) represent important nutrientand oxidative fuel for skeletal muscle. and oxidative fuel for skeletal muscle. InsulinInsulin resistanceresistance and and typetype 2 2 diabetesdiabetes are are characterizedcharacterized bybyhyperglycemiahyperglycemia withwith hyperinsulinemiahyperinsulinemia, , elevatedelevated plasma FFA plasma FFA levelslevels, a , a reducedreduced abilityability toto oxidizeoxidize fatfat, and , and anan accumulationaccumulation of of fatfat withinwithin skeletalskeletal musclemuscle..ThisThis increaseincrease in in musclemuscle fatfat contentcontent isis highlyhighly associatedassociated withwithinsulininsulin resistanceresistance. . Growing evidence indicates that elevated Growing evidence indicates that elevated plasma FFAs induce insulin resistance through inhibition of plasma FFAs induce insulin resistance through inhibition of glucose transport activityglucose transport activityMiceMice lackinglacking the ACC the ACC enzymeenzyme (and (and thusthus havinghaving no no malonylmalonyl--CoACoA) ) havehave elevatedelevated ratesrates of of fatfat oxidationoxidation and and reducedreduced fatfatstoragestorage, , suggestingsuggesting thatthat ACC and ACC and malonylmalonyl--CoACoA play play ananimportantimportant rolerole in in overalloverall energyenergy balancebalance..

Kiens, B. Physiol. Rev. 86: 205Kiens, B. Physiol. Rev. 86: 205--243 2006.243 2006.

Mechanisms whereby intramuscular lipids may interfere with the iMechanisms whereby intramuscular lipids may interfere with the insulin signaling pathway nsulin signaling pathway and glucose metabolism in human skeletal muscleand glucose metabolism in human skeletal muscle

Aim of the Study

The objective of this study was to investigate The objective of this study was to investigate the effects of uterine artery ligation, a the effects of uterine artery ligation, a procedure which mimics procedure which mimics uteroplacentaluteroplacentalinsufficiency, on the skeletal muscle insufficiency, on the skeletal muscle expression of key enzymes of LCFA expression of key enzymes of LCFA metabolism.metabolism.

* P<0.05

SHAMLIG

Muscle Genes Relative Quantification

****

AC

CA

CC αα

AC

CA

CC ββ

AC

SA

CS

AM

PKA

MPK

CPT

1C

PT1 ββ

MC

DM

CD

Germani Germani etet al.al. Cardiovascular DiabetologyCardiovascular Diabetology 2008 2008 77:14 :14 doidoi:10.1186/1475:10.1186/1475--28402840--77--1414

MuscleMuscle InsulinInsulin ReceptorReceptor Western Western ImmunoImmuno BlottingBlotting

SHAM LIG

LIGSHAM

0

20

40

60

80

100

SHAM LIG

*p = 0.03

*

N=6 N=6


**

ConclusionsConclusions

UteroplacentalUteroplacental insufficiencyinsufficiency maymay affectaffectskeletalskeletal musclemuscle metabolismmetabolism down down regulatingregulatinginsulininsulin receptorreceptor and and reducingreducing the the expressionexpressionof of keykey enzymesenzymes involvedinvolved in LCFA in LCFA formationformationand and oxidationoxidation. .

WeWe speculate speculate thatthat decreaseddecreased intramuscularintramuscularlipidlipid accumulationaccumulation maymay representrepresent a a transienttransientcompensatorycompensatory mechanismmechanism toto counteractcounteractinsulininsulin resistanceresistance..


WHO Technical Consultation on the Global Strategy on Optimal Fetal Development, Southampton, UK, November 2-4, 2005

Factors affecting fetal development

Endocrine disrupters

EDCsEDCs

Endocrine disrupters(endocrine disruptor, endocrine modulators, endocrine toxicants, hormonally active chemicals, hormone mimics)

Kavlock et al., 1996: “an exogenous agent that interferes with the production, release, transport, metabolism, binding, action or elimination of natural hormones in the body responsible for the maintenance of homeostasis and the regulation of developmental processes”

WHO, 2002: “an exogenous substance or mixture that alters function(s) of the endocrine system and consequently causes adverse health effects in an intact organism, or its progeny, or (sub)populations”

EDCsEDCs

Putative endocrine disrupting chemicals

EndocrineEndocrine disruptingdisrupting chemicalschemicals ((EDCsEDCs))EDCsEDCs

• >100,000 man-made chemicals

• 400 million tonnes yearly production

• 85% no safety information

• 300 synthetic chemicals in human blood(incl. in blood of EU Commissioners -WWF)

• Higher levels of “modern” chemicals in children in “three generations study” (WWF Detox)

• >200 chemicals in cord blood (www.ewg.org/reports/bodyburden2)

Global perspective on synthetic chemicals Global perspective on synthetic chemicals EDCsEDCs

http://www.ewg.org/reports/bodyburden2

EDCsEDCs may interfere with may interfere with nuclear hormone receptorsnuclear hormone receptors

••Estrogen receptors, EREstrogen receptors, ERαα & ER& ERββ••Androgen receptor, ARAndrogen receptor, AR••Thyroid hormone receptors, TRThyroid hormone receptors, TR••Orphan receptors?Orphan receptors?

Suggested mechanisms of action of Suggested mechanisms of action of EDCsEDCsEDCsEDCs

Nuclear receptors govern many critical physiological events Nuclear receptors govern many critical physiological events prenatallyprenatally, such as sex differentiation and brain development, such as sex differentiation and brain development

EDCsEDCs

Hypospadia

Declining sperm count Cryptorchidism

Testis dysgenesis syndrome(Skakkebaek)

Disorders of prenatal sex differention

Testicular cancer

BRAIN

Pre- and postnatal brain development

Gender specificbrain differentiation

Disorders:

Gender identity disorder?

Neurocognitive disorders:Developmental delayAttention deficit disorderLearning disability

TRs

EDCsEDCs

ARERs

http://arbl.cvmbs.colostate.edu/hbooks/pathphys/endocrine/hypopit/sagpitbig.jpg

Other concerns

Priming of metabolic patterns???Priming of metabolic patterns???

Immune system

♂ ♀

EDCsEDCs

AnAn animalanimal model of model of developmentaldevelopmental exposureexposure toto diethylstilbestroldiethylstilbestrol(DES), a (DES), a potentpotent perinatalperinatal endocrine endocrine disruptordisruptor withwith estrogenicestrogenicactivityactivity ((postnatalpostnatal growthgrowth))

NewboldNewbold RR RR etet al.al. ReprodReprod ToxicolToxicol 23:29023:290--6, 20076, 2007

AnAn animalanimal model of model of developmentaldevelopmental exposureexposure toto diethylstilbestroldiethylstilbestrol (DES), a (DES), a potentpotentperinatalperinatal endocrine endocrine disruptordisruptor withwith estrogenicestrogenic activityactivity ((intraperitonealintraperitoneal injectioninjection of of glucoseglucose solutionsolution, 2 g/kg body , 2 g/kg body weightweight, , 2 and 6 2 and 6 monthsmonths))

NewboldNewbold RR RR etet al.al. ReprodReprod ToxicolToxicol 23:29023:290--6, 20076, 2007

Grun, F. et al. Endocrinology 2006;147:s50-s55

Schematic depiction of the known and potential pathways through Schematic depiction of the known and potential pathways through which TBT might act to which TBT might act to modulate adipocyte differentiation and obesitymodulate adipocyte differentiation and obesity

Stress Stress ResponsivenessResponsiveness in in AdultAdult Life: Life: InfluenceInfluence of of MotherMother’’s s DietDiet in in LateLate PregnancyPregnancyRebecca M. Rebecca M. ReynoldsReynolds, , KeithKeith M. M. GodfreyGodfrey, Mary , Mary BarkerBarker, , CliveClive OsmondOsmond, and , and David I. David I. W.W. PhillipsPhillips. . J Clin Endocrinol Metab 92: 2208–2210, 2007

MaternalMaternal consumptionconsumption of a of a highhigh--meatmeat, , lowlow--carbohydratecarbohydrate dietdiet in in pregnancypregnancy hashas longlong--termterm consequencesconsequences forfor the the offspringoffspring.. ThisThisdietdiet isis knownknown toto reduce reduce fetalfetal growthgrowth and and hashas beenbeen associatedassociatedwithwith raisedraised adultadult bloodblood pressurepressure in the in the offspringoffspring of of mothersmothersattendingattending a a maternitymaternity hospital in hospital in MotherwellMotherwell, , ScotlandScotland, , betweenbetween1952 and 1976. 1952 and 1976. DuringDuring pregnancypregnancy, the , the mothersmothers in in MotherwellMotherwellwerewere advisedadvised toto eateat a a highhigh--meatmeat, , lowlow--carbohydratecarbohydrate dietdiet in in ananattemptattempt toto preventprevent preeclampsiapreeclampsia. The . The specificspecific adviceadvice waswas toto eateat1 1 poundpound (0.45 kg) of (0.45 kg) of redred meatmeat dailydaily duringduring pregnancypregnancy and and totoavoidavoid carbohydratecarbohydrate--richrich foodsfoods suchsuch asas potatoespotatoes, , breadbread, or , or cakescakes..In In subsequentsubsequent studiesstudies greatergreater maternalmaternal consumptionconsumption of of meatmeat and and fishfish in in latelate pregnancypregnancy waswas linkedlinked withwith higherhigher systolicsystolic bloodbloodpressurepressure in the in the adultadult offspringoffspring at 29 at 29 yryr of of ageage..

Reynolds, R. M. et al. J Clin Endocrinol Metab 2007;92:2208Reynolds, R. M. et al. J Clin Endocrinol Metab 2007;92:2208--22102210

Salivary cortisol concentrations in response to the Trier SocialSalivary cortisol concentrations in response to the Trier Social Stress Test in men and women Stress Test in men and women according to the mother's meat and fish consumption (portions peaccording to the mother's meat and fish consumption (portions per week) in late pregnancyr week) in late pregnancy

Reynolds, R. M. et al. J Clin Endocrinol Metab 2007;92:2208Reynolds, R. M. et al. J Clin Endocrinol Metab 2007;92:2208--22102210

Conclusions•• The The underlyingunderlying processesprocesses linkinglinking anan unbalancedunbalanced maternalmaternal dietdiet withwith offspringoffspring

cortisolcortisol responsesresponses toto stress are stress are notnot knownknown..•• A A highhigh--proteinprotein dietdiet isis knownknown toto stimulatestimulate the HPA the HPA axisaxis, possibly by means

of the direct neuroendocrine effects of ingested neurotransmittersubstrates including l-tyrosine and l-tryptophan. Because cortisol maycross the incomplete placental glucocorticoid barrier, the fetus may beexposed to excess cortisol, thereby reprogramming the developing fetalHPA axis by altering the expression of glucocorticoid receptor populationsin limbic structures within the brain.

• Alternatively, the type of diet consumed by pregnant women in Motherwellmay have imposed a direct metabolic stress on both mother and fetus as a result of the reducedreduced availabilityavailability of of nonessentialnonessential amino amino acidsacids.. Meat and fish are rich in essential amino acids that must be either used for proteinsynthesis or oxidized. Oxidation consumes nonessential amino acidswhose synthesis requires cofactors including folate and vitamin B6 that are likely to have been low in the diet consumed by the pregnant women in Motherwell.

• Finally, the mother’s diet may have altered HPA axis regulation by meansof the epigeneticepigenetic modificationmodification of glucocorticoid receptor expression.

Left panel: placental 11b-hydroxysteroid dehydrogenase (11b-HSD) activity correlates withbirth weight in rodents and, less certainly, in humans. This suggests that relative deficiency of this barrier to maternal glucocorticoids, but allowing active forms to cross to the foetus, correlates with foetal growth restraint. Centre panel: inhibition of 11b-HSD by maternaltreatment with carbenoxolone (CBX; filled bar/solid line) reduces birth weight compared withcontrol (open bar/broken line). Right panels: this produces higher blood pressure and plasma glucose levels across an oral glucose tolerance test (fasting and post-prandial) in the offspring.

SecklSeckl JR. EJE 151:U49JR. EJE 151:U49--U62, 2004U62, 2004

Soto, N. et al. J Clin Endocrinol Metab 2003;88:3645-3650

Catch up Catch up growthgrowth and and metabolicmetabolic riskrisk

0

2

4

6

8

10

12

14

16

M-Value (hyperinsulinemic euglycemic clamp)

AGA (n=24)

SGA (n29)

NCG-SGA (n=5)

CG-SGA BMI <17(n=18)CG-SGA BMI>17(n=6)

InsulinInsulin sensitivitysensitivity waswas calculatedcalculated fromfrom the the glucoseglucose infusioninfusion rate rate ((milligramsmilligrams per minute) per minute) betweenbetween 60 and 120 60 and 120 minmin of the of the euglycemiceuglycemicclampclamp, , divideddivided byby body body weightweight ((kilogramskilograms; ; MM--valuevalue).).

*

*P<0.001


Veening MA et al. JCEM 87:4657-4661,2002

Mean Z-scores forheight, weight and BMI duringchildhood in 290 people who laterdeveloped Type 2 diabetes within a cohort of 8760 menand women. At anyage, the mean Z-score for the cohortis set at 0 while the standard deviationis set at 1

Eriksson JG et al Diabetologia 46:190-194, 2003


Largedifferences in the incidence of Type 2 diabetesare associatedwith growthrates in utero, weight gain in infancy andage at adiposityrebound.

Eriksson JG et al Diabetologia 46:190-194, 2003

MeanMean BMI in 6060 BMI in 6060 childrenchildren accordingaccordingtoto the the ageage of of adiposityadiposity reboundrebound\\


Copyright ©2001 BMJ Publishing Group Ltd.

Eriksson, J G et al. BMJ 2001;322:949Eriksson, J G et al. BMJ 2001;322:949--953953

Growth of 357 boys who later developed coronary heartdisease in a cohort of 4630 boys born in Helsinki


MeanMean z z ScoresScores forfor Height, Height, WeightWeight, , and Bodyand Body--Mass Mass IndexIndex in the Firstin the First11 11 YearsYears after Birth after Birth amongamong BoysBoys and and GirlsGirls WhoWho HadHad CoronaryCoronary HeartHeartDiseaseDisease asas AdultsAdults..

The study cohort consisted of men and The study cohort consisted of men and women who were born at Helsinki women who were born at Helsinki University Central HospitalUniversity Central Hospitalfrom 1934 through 1944 and attended from 1934 through 1944 and attended childchild--welfare clinics in the city. Details of welfare clinics in the city. Details of the birth records, recordsthe birth records, recordsfromfrom the the childchild--welfarewelfare clinicsclinics, and , and schoolschoolhealthhealth recordsrecords havehave beenbeen describeddescribedpreviouslypreviously. . 4630 4630 menmen and 4130 and 4130 womenwomenwerewere identifiedidentified..

Barker DJP et al.N Engl J Med 2005;353:1802-9.


Metabolic parameters in AGA and SGA children with and without catch-up growth in BMI.

0

20

40

60

80

100

120

Glucose(mg/dL)

Insulin (mU/L) G/I ratio HOMA-IR(x100)

QUICKI (x100)

CG-SGA (n=26)NCG-SGA (n=26)AGA (n=26)

P<0.05P<0.05

Torre P Torre P etet al., J Endocrinol Invest 2008, in pressal., J Endocrinol Invest 2008, in press

Metabolic parameters in AGA and SGA children with and without catch-up growth in BMI.

020406080

100120140160180

Tot.Chol.(mg/dL) LDL-Chol. (mg/dL)HDL.Chol. (mg/dL) Triglycerides(mg/dL)

CG-SGA (n=26)NCG-SGA (n=26)AGA (n=26)

Torre P Torre P etet al., J Endocrinol Invest 2008, in pressal., J Endocrinol Invest 2008, in press

“Low nutrient intake and earlygrowth for later insulin resistancein adolescents born preterm”. SinghalSinghal A. A. etet al.al. LancetLancet 361:1089361:1089--1097, 20031097, 2003

Fasting 32–33 split proinsulin concentrationsaccording to quarters of the distribution of weightchange in the first 2 postnatal weeks in adolescents bornpreterm Data analysedby linear regression. Error bars are 95% CI.


Flow-mediated endothelium-dependent dilation inadolescence according to quarters of weight change in first 2 postnatal weeks. Analyzed by linear regression.

SinghalSinghal A et al. A et al. CirculationCirculation. 2004;109:1108. 2004;109:1108--11131113

Singhal A et al. Lancet 2001; 357: 413–19

Singhal A et al. Lancet 2004; 363: 1571–78

Regan, F. M. et al. Pediatrics 2006;118:1943-1949

Change in weight SDS from 40 weeks to current weight versus log SI (r2 = 0.53; P < .0001)

IntrauterineIntrauterine malnutritionmalnutrition ±± GeneticGenetic PredispositionPredisposition

Programming

InsulinInsulin ResistanceResistance

Obesity

Cardiovascular Cardiovascular riskrisk in in adulthoodadulthoodModified from Cianfarani S et al. Horm Res 55 (Suppl 1): 7-10, 2001

DegreeDegree and and timing of timing of adiposityadipositychangechange

NeonatalNeonatal LeptinLeptin Treatment Treatment ReversesReversesDevelopmentalDevelopmental ProgrammingProgramming

M. M. H.H. VickersVickers, P. D. , P. D. GluckmanGluckman, A. , A. H.H. CovenyCoveny, P. , P. L.L. HofmanHofman, , W.W. S. S. CutfieldCutfield, A. , A. GertlerGertler, B. , B. H.H. BreierBreier, and M. , and M. HarrisHarris

Endocrinology 146: 4211–4216, 2005

Vickers, M. H. et al. Endocrinology 2005;146:4211-4216

Change in body weight Change in body weight gain in leptingain in leptin--treated treated AD and UN neonates AD and UN neonates

relative to salinerelative to saline--treated animalstreated animals


Diet-induced weight gain ( high fat chow fed) at postnatal d 170 in AD and UN animals treated with either saline or leptin in the neonatal period. Neonatal leptinin UN animals normalized diet-induced weight gain to match that of AD animals. Neonatal leptin had no effect on diet-induced weight gain in AD animals.


Representative DEXA scans from adult UN offspring at postnatal d 170 treated as neonates with either saline (top) or leptin (bottom); total fat

mass as assessed by DEXA


A, Fasting plasma A, Fasting plasma insulin concentrations at insulin concentrations at

d 170 in AD and UN d 170 in AD and UN animals on either a chow animals on either a chow (C) or high(C) or high--fat (HF) diet fat (HF) diet after neonatal saline or after neonatal saline or

leptin treatmentleptin treatment

AcknowledgmentsTorTor Vergata University, Vergata University, RomeRomeCaterina GeremiaCaterina GeremiaDaniela GermaniDaniela GermaniChristini Christini LadakiLadakiArianna MaioranaArianna MaioranaAntonella PuglianielloAntonella PuglianielloGiuseppe ScirGiuseppe ScirèèGian Luigi SpadoniGian Luigi SpadoniPiera TorrePiera TorreS.EugenioS.Eugenio Hospital, Hospital, RomeRomeSergio BoemiSergio BoemiKarolinskaKarolinska Institute & University Hospital Institute & University Hospital Stockholm, SwedenStockholm, SwedenOlleOlle SSööderder

Grant: Italian Ministry of Scientific Research -COFIN 2003.

““ThereThere are more are more thingsthings in in heavenheaven and and earthearth, , HoratioHoratio,,thanthan are are dreamtdreamt of in of in youryour philosophyphilosophy……””

William William ShakespeareShakespeare, , HamletHamlet

alimentazione del bambino con basso peso alla nascita e ...old.iss.it/binary/inte/cont/04 - stefano...

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