1. Medical University Graz Clinic of Obstetrics and Gynaecology, Medical University of Graz, Austria Gernot Desoye Intrauterine Hyperinsulinemia as Major Determinant of Neonatal Adiposity

2. Neonatal Phenotype in Diabesity

3. 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 ± 5.732.2 ± 6.1 p<0.001 Mean skinfold thickness (sum of 8 skinfolds)

4. syncytiotrophoblast endothelium Fetal hyperinsulinism compartments FFA Glucose

5. 20 15 2530 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) Cord blood c-peptide (ng/ml) Valsamkis G. et al, Hormones 13:87-94, 2014 Cord blood C-peptide correlates with1st trimester maternal BMI p = 0.035 r = 0.74

6. 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

7. Elevated amniotic fluid insulin associates with obesity and IGT in childhood Silvermann et al, Diabetes Care 18: 611 (1995) IGT 10 – 16 years Weiss et al, Diabetes Care 23: 905 (2000) Obesity 5 – 15 years

8. syncytiotrophoblastendothelium fetalmaternal stroma Fetal hyperinsulinism compartments glucose insulin

9. Transplacental Glucose Flux at end of gestation Depends on the MATERNAL-FOETAL concentration gradient

10. syncytiotrophoblastendothelium fetalmaternal stroma Fetal hyperinsulinism leads to multiple changes compartments glucose insulin Glucose uptake Metabolism glucose steal glucose

11. syncytiotrophoblastendothelium fetal maternal stroma compartments glucose insulin oxygen Fetal hyperinsulinism leads to multiple changes Vascularization Glucose uptake Metabolism Liver / Skeletal muscle Proliferation TG storage Adipocyte Brain/Hypothalamus Growth Orexigenic NPY/ AGRP ARC neurons Differentiation Anorexigenic Ventromedial nucleus

12. At what time in gestation will fetal hyperinsulinism begin ?

13. Insulin in Human Fetal Pancreas 9 weeks 14 weeks 24 weeks In t‘ Veld Diabetologia 35, 272 (1992)

14. 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)

15. Fasting Glycemia Early in Gestation Correlates with GDM Risk GDM risk 9-10 weeks N=6129 13-14 weeks N=17,186 GDM DevelopmentLGA and/or Macrosomia Riskin-Mashia S et al Diabetes Care 32: 1639, 2009 Zhu et al, Diabetes Care 36:586, 2013

16. 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

17. 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 TNF  upregulate MMP14 in first trimester trophoblasts in vitro (Hiden et al, Diabetes 2008)

18. Maternal – Placental – Fetal Dialogue Pregnancy Adipocyte number Hypothalamus TG deposition Childhood Adulthood Diabesity risk 2nd & 3rd trimester Insulin Glucose Placenta First trimester placental development ? ß-cell changes Desoye & van Poppel, 2014

19. Maternal – Placental – Fetal Dialogue Pregnancy Adipocyte number Hypothalamus TG deposition Childhood Adulthood Diabesity risk 2nd & 3rd trimester Insulin Glucose Placenta First trimester placental development ? ß-cell changes Desoye & van Poppel, 2014

20. Maternal – Placental – Fetal Dialogue Insulin Glucose Pregnancy Adipocyte number Hypothalamus TG deposition 2nd & 3rd trimester Glucose Placenta First trimester placental development ? ß-cell changes Desoye & van Poppel, 2014 Insulin resistance Obesity IGT/T2D Stress Environmental pollutants GWG

21. ‚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)

22. The Team