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Developmental Programming

Developmental Programming. The transgenerational effect of an abnormal situation during fetal and early neonatal life. F A Van Assche EBCOG congress ANTALYA May 2017.

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Developmental Programming

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  1. Developmental Programming The transgenerational effect of an abnormal situation during fetal and early neonatal life. F A Van Assche EBCOG congress ANTALYA May 2017.

  2. Developmental programming is a process of an insult in utero and/or in early postnatal life, inducing a permanent response in the fetus and the newborn, leading to enhanced suceptibility to later diseases.Environmental influences on function and behaviour. This is certainly the case during the developmental phase of life.Developmental programming and inheritance ? Is there a transgenerational effect ?

  3. Examples of environmental influencesLamarck JBP (1744-1829)“Some characteristics acquired during one’s lifetime can be passed to subsequent generations”Darwin CR (1809-1892)“The phenotype is the result of many discrete traits that are individually and exquisetely selected”“Detecting the smallest grain in the balance of fitness”Lorenz KZ (1903-1989)“Imprinting behaviour”

  4. Developmental programming Working mechanisms. Historical background. Future directions .

  5. MATERNAL DIABETES INCREASED SUPPLY OF GLUCOSE AND OTHER NUTRIENTS Fetus : macrosomia islet hypertrophy B-cell hyperplasia hyperglycaemia hyperinsulinemia Note : symmetric and asymmetric type Human studies

  6. Human studies Volume density ofPercentage endocrine tissueof B-cells Normal controls (n=40) 5.1 ± 1.6 40 ± 7.5 ---------------------------------------------------------------------------------------- Maternal diabetes (n=18) 12.9 ± 4.2 63.8 ± 8.9 ---------------------------------------------------------------------------------------- Anencephalics without 5.0 ± 1.6 38 ± 9.7 a functional HH-system Maternal diabetes ---------------------------------------------------------------------------------------- Anencephalics with 11.6 ± 4.9 59.2 ± 6.9 a functional HH-system Maternal diabetes MORPHOMETRIC DATA OF THE HUMAN FETAL ENDOCRINE PANCREAS (MEAN ± SD)

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  8. Human studies Reduced uteroplacental circulation Maternal malnutrition Pancreatic agenesis (Neonatal diabetes) (Diabetes with vasculopathy) INTRA-UTERINE GROWTH RESTRICTION

  9. MORPHOMETRIC DATA OF THE HUMAN PANCREAS (MEAN ± SD) Intra-uterine growth restriction Volume density ofPercentage endocrine tissueof B-cells Normal controls (n=20) 4.8 ± 1.3 42 ± 6.3 ---------------------------------------------------------------------- IUGR (n=20) 2.6 ± 0.6 26 ± 4.1 Human studies

  10. HUMAN FETUS Maternal diabetes : Hyperglycaemia Islet hypertrophy B-cell hyperplasia Hyperinsulinism Macrosomia Overstimulation - exhaustion B-cells ? Long term effect Human studies

  11. HUMAN FETUS Intra-uterine growth restriction : Hypoglycaemia Islet hypotrophy B-cell hypoplasia Hypoinsulinism Microsomia Underdevelopment ? Long term effect

  12. DIABETIC INTRA-UTERINE ENVIRONMENT Increased risk for diabetes Knowler et al, 1985 Increased risk for gestational diab Martin et al, 1985 Increased risk for diabetes/obesity Pettitt et al, 1988 Effect on different generations Dörner et al, 1984 Breast carcinoma Van Assche, 1997Transgenerational Dabela/ Crume, 2011 Prediction of adiposity Ai Kubo et al, 2014 Human studies

  13. Human studies There is overwhelming evidence that long-term consequences are related to low birth weight “Fetal origin of adult diseases” Barker “The thrifty phenotype” Hales Type II diabetes - Insulin resistance - Cardiovascular diseases “Metabolic syndrome” INTRA-UTERINE GROWTH RESTRICTION

  14. Animal models may unravel the specific effects of an exposure to an abnormal intrauterine environment independent of inherited trails Experimental

  15. Experimental studies BACKGROUND RAT DATA Pregnant animalFetus / neonate Mild diabetes Macrosomia Islet hypertrophy B-cell hyperplasia Hyperglycaemia Hyperinsulinism

  16. Experimental studies BACKGROUND RAT DATA Pregnant animalFetus / neonate Starvation Microsomia Low protein diet Islet hypotrophy Reduced uteroplacental B-cell hypoplasia circulation Hypoinsulinism Hypoglycaemia Severe Diabetes

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  20. CONSEQUENCES FOR OFFSPRING IN LATER LIFE Experimental studies

  21. IS GESTATIONAL DIABETES AN ACQUIRED CONDITION ?J. Dev. Physiol., 1979 First generation : mild diabetes during pregnancy Second generation : fetus : hyperglycaemia islet hypertrophy B-cell hyperplasia hyperinsulinism macrosomia adult : gestational diabetes Experimental studies

  22. IS GESTATIONAL DIABETES AN ACQUIRED CONDITION ?J. Dev. Physiol., 1979 Third generation : fetus : hyperglycaemia islet hypertrophy B-cell hyperplasia hyperinsulinism macrosomia Not of genetic origin Experimental studies

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  24. TRANSGENERATIONAL EFFECT ? Experimental studies

  25. Experimental studies FIRST GENERATION INDUCTION OF MILD DIABETES SECOND GENERATION FETUS: MACROSOMIA ADULT: REDUCED INSULIN SECRETION PREGNANT: “GESTATIONAL DIABETES” THIRD GENERATION FETUS: MACROSOMIA ADULT: REDUCED INSULIN SECRETION PREGNANT: “GESTATIONAL DIABETES” FOURTH GENERATION FETUS: MACROSOMIA

  26. Fetal overgrowthFetal hyperinsulism- overstimulation of the fetal B-cells- morphological and functional alterations in the hypothalamus-LeptinFetal growth restrictionFetal hypoinsulinism- underdevelopment of the fetal B-cells and insulin receptor system- catch up growth/ leptin charge

  27. Further working mechanisms- Match – mismatch (succesfull and unsuccesfull adaptation) Plasticity- Epigenetics DNA methylation and various histone modifications “the study of mitotically and/or meiotically heritable changes in gene function that cannot be explained by changes in DNA sequence- Stochastic epigenetic variation

  28. Maternal obesity(Human data) Maternal obesity and increased weight gain during pregnancy are associated with increased risk of high birthweight, congenital malformations, stillbirths and have a transgenerational effect, inducing obesity and diabetes in the next generations. Devlieger, Van Assche, Mahmood; EBCOG position paper EJOG, 2016.

  29. DIET-INDUCED OBESITY IN THE RAT : A MODEL FOR GESTATIONAL DIABETES MELLITUS K. HOLEMANS, S. CALUWAERTS, L. POSTON, F.A. VAN ASSCHE Am J Obstet Gynecol (2004) 190:858-865

  30. Insulin Sensitivity

  31. Inflammation on hepatic glucose production and insulin signaling. ( obesity, diabetes and pregnancy). CELL 2016: May issue pag 264 and 434.

  32. Low adinopectin and insulin resistance. Qiao H et al. Diabetes .May 2017, 1126-35. Ravi R. Diabetes ; may 2017 ,1121-1122.

  33. Growth Curves

  34. Obesity in pregnancyEffect for the offspring. Fetal Hyperglycaemia and hyperinsulinism

  35. Developmental Programming Inceased risk for Diabetes , Obesity and Cardiovascular problems related to fetal overgrowth and fetal undergrowth.

  36. Developmental programming (new insights) Maternal and or paternal line Epigenetics overrulers genetics.

  37. Maternal developmental programming Maternal obesity has an effect on its own ( abnormal intrauterine environment). Obesogenic influence in the offspring has an additional effect.

  38. Paternal developmental programming Paternal obesity has only an effect , when the offspring receive an obesogenic diet.

  39. Developmental Programming(New insights) Epigenetics overrules genetics. High-Fat Diet During Mouse Pregnancy and Lactation Targets GIP-regulated Metabolic Pathways in Adult Male Offspring. Diabetes March 2016 ;Michael Kruse et al.

  40. Gastric inhibitory polypeptide(GIP) • GIP is released from the duodenum after nutrient intake and regulates postprandial insulin secretion. • GIP has anabolic effects in adipocytes, leading to obesity.

  41. Gastric inhibitory polypeptide High fat diet ( HFD) in mice induces obesity and insulin resistance. Genetic ablation of GIP receptor (GIPR) protects from high fat diet induced obesity and insulin resistance. GIPR-/- are protected from obesity when exposed to a postweaning HFD.

  42. Gastric inhibitory polypeptide (GIP). • What will happen to the offspring ,when GIPR-/- mice are exposed to HFD during pregnancy (IU) and lactation( L).

  43. Gastric inhibitory polypeptide - Male offspring from GIPR-/- mice exposed to an HFD during pregnancy( IU) and lactation (L); and also exposed to a postweaning HFD develop Obesity. - Abnormal methylation indicates an epigenetic effect. -The protection from a diet induced obesity in GIPR-/- mice is overruled by deleterious and persistent developmental programming

  44. CONCLUSION Developmental programming = prevention Prevention of diseases in later life during the perinatal period of life.

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