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Maternal malnutrition programmes a prediabetic phenotype
in the progeny
Brigitte Reusens
Institut des Sciences de la vie, Université catholique de Louvain,
Louvain-la-Neuve, Belgium
The Power of ProgrammingMunich, 5-8 Mai 2010
Note: for non-commercial purposes only
Florence Florence BieswalBieswalVanesaVanesa BolBolSamira Samira BoujendarBoujendarHananeHanane CherifCherifSalouaSaloua DahriDahriOlivier Olivier DumortierDumortierIlhamIlham El El KhattabiKhattabiKKevinevin GoosseGoosseSihamSiham MerezakMerezakPierre Pierre RomanusRomanusAnne Anne SnoeckSnoeckNicolas TheysNicolas Theys
University of LouvainUniversity of Louvain
Claude Claude RemacleRemacle
Thomas BouckenoogheThomas BouckenoogheLuise Luise KalbeKalbeCCééline line MorrensMorrensPierre Pierre NivoitNivoit
DeptDept of of ClinicalClinical BiochemistryBiochemistryUniversity of Cambridge, UKof Cambridge, UKSuzanSuzan OzanneOzanne
INSERM U457, ParisINSERM U457, ParisBernadette BrBernadette Brééantant
Lawson Institute, London, OntariLawson Institute, London, OntariooDavid HillDavid HillEdith AranyEdith Arany
StenoSteno Institute, Institute, CopenhagenCopenhagen, DK, DKJorn Jorn NerupNerupTomas Tomas SparreSparre
Early Nutrition Programming & HealthOutcomes in Later Life: Obesity & Beyond
Budapest, April 20-21, 2007
BUDAPEST, HUNGARY
Impaired insulin secretion versus sensitivity:
cause and effect?
Brigitte Reusens
The beta cells
or
the insulin-sensitive target tissues
What is first programmed?
Sequence of the key pathologicalfeatures of type 2 diabetes
Leahy JL, 2005
Aquired organ abnormalities
Protein RestrictionCalorie Restriction
Uterine Artery Ligation
Gestational DiabetesHigh Fat / (High saccharide) DietMaternal Obesity
Animal modelsof early food manipulation
Other specific dietary manipulation
Intrauterine Programmingof the
foetal endocrine pancreas?
Glucagon
Insulin
Mass of ββββ cells
Apoptosis or necrosis
Neogenesis from precursors(Ngn3, Pdx1= differentiation)
Proliferation ofdifferentiated ββββ cells
Low Calorie and Low Protein Diets
0
C 20% protein20% protein
20% protein20% protein
20% protein20% protein 8% protein8% protein
8% protein8% protein
F15 F21
LCLLC
LPL
LP
50% cal.
50% cal.
Dumortier et al., 2007
Gestation
ββββ cell mass (mg)
C LCLCL LPLPL
1
0
*
***
**
Beta cell mass and proliferationF 21.5
Image analysis
Dumortier et al., 2007
0
4
8
12
C LCLCL LPLPL
******
Proliferation (%)
BrdU labelling
Cell differentiation
(after the notch-delta lateral
specification)
NGN3NGN3
Differentiation of the endocrine pancreas
Beta 2
Pax 4
?
Brn 4
MafB
Pax 6
? MafA
Acinar cell
Ptf1a
Mist1
Hnf 6
Duct cell
PP δδδδ αααα
Pdx-1
ββββ
Nkx2.2
Nkx6.1
Pdx-1
Endocrine cells
10th -15th day
NGN3NGN3
Differentiation of the endocrine pancreas
Beta 2
Pax 4
?
Brn 4
MafB
Pax 6
? MafA
Acinar cell
Ptf1a
Mist1
Hnf 6
Duct cell
PP δδδδ αααα
Pdx-1
ββββ
Nkx2.2
Nkx6.1
Pdx-1
Endocrine cells
Cell differentiation
(after the notch-delta lateral specification)
10th -15th days
NGN3 / duct area (µm 2 x100)
*
0
0.1
0.2
C LC LP
0
2
4
6
8
C LC LP
**
PDX-1 / duct area (µm 2 x104)
10
Beta cell markers of differentiation(day 15)
Du
mo
rtie
r e
t a
l.,
20
07
NGN3
PDX1
Numerical density (# /104µm2)
0
4
8
12
16
C LCL LC LPL LP
**
0
1
2
3
4
5
C LCL LC LPL LP
*
Volume density (%)Islet vascularizationD
um
ort
ier
et
al.
, 2
00
7
Reduced ββββ cells Mass
Apoptosis or necrosis
Neogenesis Proliferation
Apoptosis or necrosis
Neogenesis Proliferation
Low calorie Low protein
Islet vascularizationGlucocorticoids
Taurine
Islet vascularizationGlucocorticoids
Taurine
1/2
Insulin secretion by fetal islets in vitro
G5.6 G16.7 +Leu +Arg +Tau +Met0
5
10
15
Insu
lin r
elea
se (
%)
Cherif et al, 1998
Insulin secretion by fetal islets in vitro
G5.6 G16.7 +Leu +Arg +Tau +Met0
5
10
15
Insu
lin r
elea
se (
%)
Islet from LP foetuses secrete less insulin in response to secretagogues
Cherif et al, 1998
Foetal islet cell sensitivityto cytotoxic molecules
Apo
ptos
is (
%)
0
5
10
15
20
- + IL1 + SNP (NO)Merezak et al, 2001
Foetal islet cell sensitivityto cytotoxic molecules
Apo
ptos
is (
%)
**
0
5
10
15
20
**
**
- + IL1 + SNP (NO)Merezak et al, 2001
Beta cells from LP foetuses are more susceptible to cytokines
Acquired cell sensitivityto cytotoxic molecules in vitro
Apo
ptos
is(%
)
0
5
- + IL1+ TNF+IFNMerezak et al, 2004
Acquired cell sensitivityto cytotoxic molecules in vitro
Apo
ptos
is(%
)
0
5
**
- + IL1+ TNF+IFNMerezak et al, 2004
Beta cells from LP adult remain more susceptible to cytokines
General Nutritional Molecular Programming ?
• Epigenetic programming • Mitochondrial programming
Nutritional Mitochondrial Programming ?
IUGR afteruterine artery ligation(Islets)
ATP production
Mitochondrial copy number
Simmons & al., 2005
Nutritional Mitochondrial Programming ?
1,299 / 10,343genes
Genes Microarray, AffymetrixGeneChip Rat Expression 230A probe array
C LP
20 % 8 %
Neoformed islets
Significance Analysis of Microarray (SAM)
7 days in vitro in standard culture medium
Fetal pancreata
Reusens et al, 2008
Nutritional Mitochondrial Programming ?
11% of the genes of which the expression was modified
encode for mitochondrial proteinsReusens et al, 2008
Energy derivation by oxidation of organic
Compounds (19)[9.5% of 196]Chi Sq: 31.2
Energy reserve metabolism (3)[4.9% of 61]Chi Sq: 0.80
Main path of carbohydrate (15)
[11.5% of 130]Chi Sq: 33.41
Cellular respiration (12)[29.2% of 41]Chi Sq: 98.63
Glycogen met.(3)[6.5% of 46]Chi Sq:2.01
Glycolysis (6)[10% of 60]Chi Sq: 10.3
Gluconeogenesis (1)[4% of 25]
Chi Sq: 0.09
TCA cycle intermediate metabolism (3)[11.1% of 27]Chi Sq: 6.2
Pentose-phosphate shunt (1)[10.1% of 10]Chi Sq: 1.71
Aerobic respiration (11)[30.5 of 36]
Chi Sq:95.26
Glycogen catabolism (1)[16.6 of 6]Chi Sq: 3.9
Regulation of glycolysis (1)[20% of 5]
Chi Sq: 5.03
Fumarate metabolism (1)[100% of 1]
Chi Sq: 32.65
Citrate metabolism (1)[20% of 5]
Chi Sq: 5.03
Malate metabolism (1)[11.1% of 9]Chi Sq: 2.1
TCA Cycle (10)[31.2% of 32]Chi Sq: 88.96
Low protein diet targeted the Krebs cycleof the beta cells
Reusens et al, 2008
gestation lactation
3 monthsweaning birth
LP
Maternal malnutrition
LC
20%
8%
50%
C
HF
ATP production in islets of LP adult progeny
3.3 mM16.7 mM
Glucose
0
50
100
150
200
250
300
350
C LP
% o
f con
trol
3.3
mM
**
0
50
100
150
200
250
C LP
% o
f con
trol
3.3
mM
Theys et al, 2009