Medical University Graz
Intrauterine Hyperinsulinemia as
Major Determinant of Neonatal
Adiposity
Gernot Desoye
Clinic of Obstetrics and Gynaecology, Medical University of Graz, Austria
Neonatal Phenotype in Diabesity
Maternal obesity is associated with more
subcutaneous fat in the newborn
Mean skinfold thickness (sum of 8 skinfolds)
Normal (10-90th centile) n=179
28.6 ± 5.7
Obese (> 90th centile) n=61
32.2 ± 6.1 p<0.001
Whitelaw AGL, BMJ 1:985, 1976
Fetal hyperinsulinism
compartments
Glucose
FFA
syncytiotrophoblast
endothelium
Cord blood c-peptide (ng/ml)
Cord blood C-peptide correlates
with1st trimester maternal BMI
p = 0.035
r = 0.74
2
1.8
1.6
1.4
1.2
1
0.8
0.6
0.4
0.2
0
15
20
25
30
35
First trimester maternal BMI (kg/m²)
Valsamkis G. et al, Hormones 13:87-94, 2014
Body fat at birth correlates with
body fat at 9 years of age
P. Catalano et al Am J Clin Nutr 2009; 90:1303-13
Elevated amniotic fluid insulin associates
with obesity and IGT in childhood
Obesity
IGT
5 – 15 years
10 – 16 years
Weiss et al,
Diabetes Care 23: 905 (2000)
Silvermann et al,
Diabetes Care 18: 611 (1995)
Fetal hyperinsulinism
compartments
maternal
stroma
glucose
syncytiotrophoblast
fetal
glucose
endothelium
insulin
Transplacental Glucose Flux
at end of gestation
Depends on the MATERNAL-FOETAL
concentration gradient
Fetal hyperinsulinism leads to multiple changes
compartments
maternal
stroma
glucose
fetal
glucose
insulin
glucose
Glucose
uptake
glucose steal
Metabolism
syncytiotrophoblast
endothelium
Fetal hyperinsulinism leads to multiple changes
compartments
maternal
stroma
fetal
Brain/Hypothalamus
Growth
Differentiation
Orexigenic
NPY/ AGRP
ARC neurons
Anorexigenic
Ventromedial nucleus
Adipocyte
glucose
glucose
insulin
Proliferation
TG storage
Vascularization
Liver / Skeletal muscle
Glucose
uptake
oxygen
syncytiotrophoblast
endothelium
Metabolism
At what time in gestation will
fetal hyperinsulinism begin ?
Insulin in Human Fetal Pancreas
9 weeks
14 weeks
24 weeks
In t‘ Veld Diabetologia 35, 272 (1992)
AF insulin at 14-20 wks gestation
(n=247)
Higher AF insulin (by 1 MOM)
associated with
3-fold risk for
Fetal birth weight > 90th centile
Carpenter MW Diabetes Care 24: 1259 (2001)
Fasting Glycemia Early in Gestation
Correlates with GDM Risk
9-10 weeks
13-14 weeks
N=6129
N=17,186
GDM Development
LGA and/or Macrosomia
Riskin-Mashia S et al
Diabetes Care 32: 1639, 2009
GDM risk
Zhu et al, Diabetes Care 36:586, 2013
Fetal anthropometric parameters*
directly associated with:
• Placental volume at week 14 of gestation
• Rate of placental growth between week 14
and 17 of gestation
*abdominal circumference, femoral length, head circumference, biparietal diameter
Thame et al Eur J Clin Nutr 58: 894, 2004
Effects of a diabesogenic environment on
early placental development
Lower levels of human placental lactogen in
T1DM in the first trimester
(Pedersen et al, Acta Obstet Gynecol Scand 1998)
High glucose levels reduce proliferation of first
trimester trophoblasts in vitro
(Fröhlich et al, Am J Pathol 2012)
Insulin and TNFa upregulate MMP14 in first
trimester trophoblasts in vitro
(Hiden et al, Diabetes 2008)
Maternal – Placental – Fetal Dialogue
Desoye & van Poppel, 2014
Adipocyte
number
Placenta
Insulin
Glucose
Insulin
placental
development
?
TG
deposition
Diabesity
risk
Hypothalamus
Glucose
First trimester
ß-cell changes
2nd & 3rd trimester
Pregnancy
Childhood
Adulthood
Maternal – Placental – Fetal Dialogue
Desoye & van Poppel, 2014
Adipocyte
number
Placenta
Insulin
Glucose
Insulin
placental
development
?
TG
deposition
Diabesity
risk
Hypothalamus
Glucose
First trimester
ß-cell changes
2nd & 3rd trimester
Pregnancy
Childhood
Adulthood
Maternal – Placental – Fetal Dialogue
Desoye & van Poppel, 2014
Insulin resistance
Obesity
IGT/T2D
Placenta
Insulin
Stress
Environmental
pollutants
Adipocyte
number
Glucose
Insulin
placental
development
?
TG
deposition
Hypothalamus
Glucose
ß-cell changes
GWG
First trimester
2nd & 3rd trimester
Pregnancy
‚Diabetes in pregnant women shall be
carefully managed in EARLY gestation in
the hope of preventing excessive body fat
deposition in the conceptus‘
Poissonnet CM et al Early Hum Dev 10: 1-11 (1984)
The Team