Long-term outcome in offspring of women with diabetes in pregnancy - what is the role of intrauterine hyperglycemia?

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1 Long-term outcome in offspring of women with diabetes in pregnancy - what is the role of intrauterine hyperglycemia? Tine Dalsgaard Clausen Consultant, Associate Professor, PhD Department of Gynaecology and Obstetrics, Nordsjællands Hospital Hillerød, Denmark

2 Background Different studies Future 2

3 Background 3

4 Why bother about the offspring? Genes Epigenetics Postnatal environment Intrauterine environment Possible effect of intrauterine hyperglycemia??? 4

5 5

6 Gestationel diabetes - Denmark % % India 10-15% Danish National Patient Registry 2010

7 Diabetes in pregnancy Pregestational - and Gestational diabetes Jørgen Pedersen theory (1952) 7

8 Short-term implications Severe pre-gestational diabetes - Congenital malformations - Perinatal mortality - Prematurity - Neonatal hypoglycaemia - Shoulder dystocia - Macrosomia Mild GDM 8

9 Long-term implications - animal studies Vicious cycle Aerts, Holemans Belgium Rats Severe maternal diabetes ~ offspring - Microsomia - Insulin - Cardiovascular risk factors - GDM Mild maternal diabetes ~ offspring - Macrosomia - Insulin secretion - GDM 9

10 Long-term implications - animal studies Plagemann, Harder Germany Rats Maternal diabetes ~ offspring - Obesity - Insulin - Structual changes in hypothalamus Insulin-induced central insulin resistance Neuroendocrine malprogramming 10

11 Human studies - type 2 diabetes, overweight and the metabolic syndrome - Different types of maternal diabetes - Different offspring age groups 11

12 Long-term implications - maternal Type 2 diabetes Pima, Arizona - Prospective % Offspring Type 2 diabetes Non-diabetic mother 35 Pre-diabetic mother 30 Diabetic mother Pettitt et al., Diabetes 1988 Offspring age 12

13 Long-term implications - maternal Type 2 diabetes Pima, Arizona - Prospective % Offspring Type 2 diabetes Non-diabetic mother 35 Pre-diabetic mother 30 Diabetic mother Pettitt et al., Diabetes

14 Pima, Arizona - Prospective Long-term implications - maternal Type 2 diabetes % Offspring Type 2 diabetes Non-diabetic mother 35 Pre-diabetic mother 30 Diabetic mother Sibling-studies: Offspring of mothers vs. fathers with diabetes ~ - Type 2 diabetes (OR 3.7) - Overweight BMI 2.6 kg/m Pettitt et al., Diabetes

15 Long-term implications - maternal diabetes (Type1, Type2, GDM) Mixed group 90 Type1+2 /100 GDM / 35 controls Follow-up: 0 16 years Maternal diabetes ~ offspring - Glucose + insulin + overweight + BP Maternal glucose ~ adverse offspring outcome Silverman, Rizzo, Cho, Metzger, Diabetes Care

16 Long-term implications - maternal Type 1 diabetes 22 year old offspring Mothers with Type 1 (n=15) Fathers with Type 1 (n=16) Sobngwi et al, Lancet 2003 Maternal Type 1 diabetes ~ IGT Insulin secretion BMI, fat mass, waist/hip ratio, blood pressure, insulin sensitivity 16

17 Long-term implications - maternal Type 1 diabetes + GDM 160 Type 1 /168 GDM / 128 BP Follow-up: years Kelstrup et al., JCEM 2013, 2015 Kelstrup et al., Diab Res Clin Prac 2012 Clausen et al., JCEM 2009 Clausen et al., Diabetes Care 2008 Type 1 DM + GDM ~ offspring - Type 2 diabetes, overweight and the metabolic syndrome - Insulin-resistance - Relative insulin secretion - Low-grade inflammation - Incretin function.. Maternal glucose-estimates ~ Adverse outcome 17

18 Long-term implications - human studies (children) RCT GDM intensive treatment (n=94) GDM routine care (n=105) Intensive treatment ~ Macrosomia Offspring follow-up: 4-5 years BMI Crowther, N Engl J Med, 2005 Gillman, Crowther, Diabetes Care,

19 Human studies - cognitive function - Small studies - Several different cognitive tests 19

20 Long-term implications CNS - maternal diabetes (Type 1, Type 2, GDM) Diabetes exposed offspring Followed 0-7 years - Newborn behavior - Psychomotor development - IQ Maternal glucose ~ cognitive function Silverman, Rizzo, Cho, Metzger, Diabetes Care

21 Long-term implications CNS - maternal Type I diabetes Temple et al., Diabetic Medicine, 2011 Offspring of Type 1 (n=40) UK-standards Follow-up: 6-12 years Offspring exposed to Type 1 IQ Working memory (<37GA ~ digit span ) No associations with maternal HbA1c Hypoglycaemia DM duration 21

22 Long-term implications CNS - GDM 221 GDM / 2,612 controls Singletons and twins in both groups Follow-up: 18 months 7 years GDM offspring ~ Scores (6/15 tests) Risk of language impairment x 2 (no adjustment for SES or education) The effect of GDM moderated by: Genes Maternal education (short education) Dionne et al., Pediatrics,

23 Long-term implications CNS - GDM 32 GDM / 483 controls Follow-up: 10 years GDM offspring ~ - IQ Among controls: - Maternal 2-h ~ offspring IQ GDM mothers ~ SES and education Veena et al., Diabetologia,

24 Long-term implications CNS - maternal Type 1 diabetes + GDM Type 1 DM vs. BP - Cognitive score Diet-treated GDM vs. BP - Cognitive score Maternal glucose ~ - Cognitive score Clausen et al., Diabetic Medicine 2011 Clausen et al., PLOSone 2013 GA<34weeks - Cognitive score - Maternal glucose levels But when No interaction adjusted for with SES SESand education 24

25 Changes in: Pancreas Muscles Fat Blood vessels Liver Heart Pathogenesis - what do we know? Changes are preventable!!? Maternal hyperglycaemia Fetal glucose Fetal insulin Placental barrier Jørgen Pedersen theory Overweight Type 2 diabetes Insulin resistance Blood pressure Cognitive function 25

26 Pathogenesis Maternal hyperglycaemia Placental barrier Fetal glucose Blood-brain barrier Fetal insulin Neuroendocrine malprogramming Changes are preventable!! and inducible!! Overweight Type 2 diabetes Insulin resistance Blood pressure Cognitive function? Brain Changes in: Hypothalamus - Food intake - Weight - Insulin secretion 26

27 Pathogenesis Maternal hyperglycaemia Changes in: Pancreas Muscles Fat Blood vessels Liver Heart Fetal glucose Overweight Type 2 diabetes Insulin resistance Blood pressure Cognitive function Placental barrier Changes are preventable!! Blood-brain barrier Brain Changes in: Hypothalamus Electrophysiological Human studies - Food intake - Weight - Insulin secretion Hippocampus - Memory - Learning 27

28 Pathogenesis Changes in: Pancreas Muscles Fat Blood vessels Liver Heart Cortisol Leptin Adiponectin Other hormones Blood-brain barrier Brain 28

29 Pathogenesis Other risk factors: Maternal overweight Genetics Neonatal weight gain Breast feeding Lifestyle Other. Overweight Type 2 diabetes Insulin resistance Blood pressure Cognitive function 29

30 Pathogenesis Maternal hyperglycaemia Missing link epigenetics Placental barrier? Changes in: Fetal glucose Pancreas Blood-brain barrier Muscles Fetal insulin Fat Maternal hyperglycemia Cortisol ~ Blood vessels Leptin Liver Brain - DNA-Methylation in hypothalamic Adiponectin insulin-receptor genes Heart Other hormones (Plagemann et al. 2009, 2010) - DNA-Methylation in placental adiponectine-genes Changes in: Other risk factors: Hypothalamus (Buchard et al. 2012, 2015) Maternal overweight - Food intake - Methylation other genes Genetics Overweight - Weight Neonatal - Other weight epigenetic gain mechanisms? Type 2 diabetes - Insulin secretion Breast feeding Insulin resistance Hippocampus Lifestyle Blood pressure - Memory Cognitive function - Learning 30 Other.

31 Future 31

32 Clinical implications World-wide GDM Diabetes in pregnancy ~ Vicious circle Offspring targets for preventive strategies Does tight glycaemic control help? 32

33 Take home message Pregestational - and Gestational diabetes Maternal glucose ~ adverse metabolic outcome ~? Cognitive function Patogenesis Follow-up RCT 33

34 Thank you Collaborators: Peter Damm, Center for pregnant women with diabetes, Rigshospitalet, Copenhagen Elisabeth Mathiesen, Center for pregnant women with diabetes, Rigshospitalet, Copenhagen Torben Hansen, The Novo Nordisk Foundation Center for Basic Metabolic Research Erik Lykke Mortensen, Section of environmental health, Public Health, University of Copenhagen Dorte Møller Jensen, Department of endocrinology, Odense University Hospital Lone Schmidt, Section of Social Medicine, Department of Public Health, University of Copenhagen Jeannet Lauenborg, Department of obstetrics and gynecology, Herlev Hospital Oluf Borbye Pedersen, The Novo Nordisk Foundation Center for Basic Metabolic Research Louise Kelstrup, Center for pregnant women with diabetes, Rigshospitalet, Copenhagen Funding: The Copenhagen University, The Danish Medical recearch Council, The Lundbeck Foundation, The Aase and Ejnar Danielsens Foundation, The Gangsted Foundation, The Civilingeniør H.C. Bechgaards Foundation, The AP Møller Foundation for the Advancement of Medical Science, The Danish Diabetes Association 34

35 Thank you 35

36 Collaboration: Peter Damm, Center for pregnant women with diabetes, Rigshospitalet, Copenhagen Elisabeth Mathiesen, Center for pregnant women with diabetes, Rigshospitalet, Copenhagen Torben Hansen, The Novo Nordisk Foundation Center for Basic Metabolic Research Erik Lykke Mortensen, Section of environmental health, Public Health, University of Copenhagen Dorte Møller Jensen, Department of endocrinology, Odense University Hospital Lone Schmidt, Section of Social Medicine, Department of Public Health, University of Copenhagen Jeannet Lauenborg, Department of obstetrics and gynecology, Herlev Hospital Oluf Borbye Pedersen, The Novo Nordisk Foundation Center for Basic Metabolic Research Louise Kelstrup, Center for pregnant women with diabetes, Rigshospitalet, Copenhagen Funding: The Copenhagen University, The Danish Medical recearch Council, The Lundbeck Foundation, The Aase and Ejnar Danielsens Foundation, The Gangsted Foundation, The Civilingeniør H.C. Bechgaards Foundation, The AP Møller Foundation for the Advancement of Medical Science, The Danish Diabetes Association 36

37 Pima, Arizona - conclusions Maternal diabetes ~ Offspring Type 2 diabetes Overweight Hyperinsulinaemia Relative insulin secretion Maternal 2-H BG ~ Offspring - type 2 diabetes - overweight - waist - HbA1c 37