Medical University Graz

Clinic of Obstetrics and Gynaecology, Medical University of Graz, Austria

Gernot Desoye

Intrauterine Hyperinsulinemia as Major Determinant of Neonatal

Adiposity

Neonatal Phenotype in Diabesity

Maternal obesity is associated with more subcutaneous fat in the newborn

Whitelaw AGL, BMJ 1:985, 1976

Normal (10-90th centile) n=179 Obese (> 90th centile) n=61

28.6 ± 5.7 32.2 ± 6.1 p<0.001

Mean skinfold thickness (sum of 8 skinfolds)

syncytiotrophoblast endothelium

Fetal hyperinsulinism

compartments

FFA

Glucose

2015 25 30 35

2

1.8

1.6

1.4

1.2

1

0.8

0.6

0.4

0.2

0

First trimester maternal BMI (kg/m²)

Cor

d bl

ood

c-pe

ptid

e (

ng/

ml)

Valsamkis G. et al, Hormones 13:87-94, 2014

Cord blood C-peptide correlateswith1st trimester maternal BMI

p = 0.035r = 0.74

P. Catalano et al Am J Clin Nutr 2009; 90:1303-13

Body fat at birth correlates with body fat at 9 years of age

Elevated amniotic fluid insulin associates with obesity and IGT in childhood

Silvermann et al, Diabetes Care 18: 611 (1995)

IGT10 – 16 years

Weiss et al, Diabetes Care 23: 905 (2000)

Obesity5 – 15 years

syncytiotrophoblast endothelium

fetal

maternal

stroma

Fetal hyperinsulinism

compartments

glucose glucose insulin

Transplacental Glucose Fluxat end of gestation

Depends on the MATERNAL-FOETAL concentration gradient

syncytiotrophoblast endothelium

fetal

maternal

stroma

Fetal hyperinsulinism leads to multiple changes

compartments

glucose glucose insulin

Glucose uptake

Metabolism

glucose steal

glucose

syncytiotrophoblast endothelium

fetalmaternal stroma

compartments

glucose glucose insulin

oxygen

Fetal hyperinsulinism leads to multiple changes

Vascularization

Glucose uptake

Metabolism

Liver / Skeletal muscle

ProliferationTG storage

Adipocyte

Brain/Hypothalamus

GrowthOrexigenicNPY/ AGRP

ARC neurons

Differentiation Anorexigenic

Ventromedial nucleus

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

GDM risk

9-10 weeks N=6129

13-14 weeks N=17,186

GDM Development LGA and/or Macrosomia

Riskin-Mashia S et al Diabetes Care 32: 1639, 2009 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

Pregnancy

Adipocyte number

Hypothalamus

TG deposition

ChildhoodAdulthood

Diabesity risk

2nd & 3rd trimester

InsulinInsulin

Glucose Glucose

Placenta

First trimester

placental development placental development

?ß-cell changes

Desoye & van Poppel, 2014

Maternal – Placental – Fetal Dialogue

Pregnancy

Adipocyte number

Hypothalamus

TG deposition

ChildhoodAdulthood

Diabesity risk

2nd & 3rd trimester

InsulinInsulin

Glucose Glucose

Placenta

First trimester

placental development placental development

?ß-cell changes

Desoye & van Poppel, 2014

Maternal – Placental – Fetal Dialogue

InsulinInsulin

Glucose

Pregnancy

Adipocyte number

Hypothalamus

TG deposition

2nd & 3rd trimester

Glucose

Placenta

First trimester

placental development placental development

?ß-cell changes

Desoye & van Poppel, 2014

Insulin resistanceObesity

IGT/T2D

Stress

Environmental pollutants

GWG

‚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