1. Long-term Effects of The Hyperglycemic Intrauterine Environment Diabetes, Obesity and Fetal Programming Pennington Biomedical Research Center April 22, 2010 David J. Pettitt, MD Sansum Diabetes Research Institute

2. Studies on Long-term Implications for the Offspring of Women with Diabetes Pima Indian Study - Type 2 in mothers –Obesity, IGT, type 2 in offspring Chicago Diabetes in Pregnancy Center - Type 1 or GDM in mothers –Obesity, IGT in offspring Danish Offspring of Diabetic Women - Type 1 or GDM in mothers –Obesity, IFG, IGT, type 2 in offspring Exeter Studies - HNF-1α MODY in mother –Earlier age of onset of HNF-1α in offspring SEARCH for Diabetes in Youth Study – Unspecified type in mother –Earlier age of onset of type 2 in offspring

5. Weight for Height for Pima Children in 1908 and 1985 1908* Males Females Height (centimeters) Weight (kg) *Hrdlicka, 1908 1985 and 1985

6. Are Pima Data Relevant for Other Populations? In 1965 they were thought to be unique Now it’s clear that they were just showing us our future Many other ethnic groups have followed the same pattern of progression through obesity to diabetes All “unique” Pima findings have been replicated in other populations

7. Subject Groups Offspring ofMother’s 2-hour Glucose Nondiabetic < 7.8 mM (140 mg/dl) ≥ 5 year follow up Future diabetic < 7.8 mM before delivery ≥ 11.1 mM (200 mg/dl) later Diabetic ≥ 11.1 mM before delivery

8. Subject Groups Offspring ofMother’s 2-hour Glucose Nondiabetic < 7.8 mM (140 mg/dl) ≥ 5 year follow up Future diabetic < 7.8 mM before delivery ≥ 11.1 mM (200 mg/dl) later Diabetic ≥ 11.1 mM before delivery

9. Subject Groups Offspring ofMother’s 2-hour Glucose Nondiabetic < 7.8 mM (140 mg/dl) ≥ 5 year follow up Future diabetic < 7.8 mM before delivery ≥ 11.1 mM (200 mg/dl) later Diabetic ≥ 11.1 mM before delivery

10. Mean Relative Weight (%) Mean Relative Weight for Height by Age and Mother’s Diabetes Mean Relative Weight (%) Normal Birth Weight (90-110 %) Offspring of: Nondiabetic Future diabetic Diabetic

11. Relative weight at age 10-14 years by mother’s pregnancy glucose 125 135 145 155 < 5.65.6-6.66.7-7.77.8-11.0Diabetes Mother's 2-hour glucose (mM) Relative Weight (%)

12. Prevalence of Obesity* by Maternal Diabetes During Pregnancy * ≥ 140 % standard Offspring of: Nondiabetic Future diabetic Diabetic

13. Exposure to Diabetes In utero Mean BMI in Siblings by exposure to diabetes In Utero

14. Symmetry Index in Offspring from the Diabetes in Pregnancy Center* in Chicago and in Pima Indians from Arizona DPC Offspring of DM Pima offspring of DM Pima offspring of nonDM *Silverman et al. Diabetes 1991

15. Amniotic Fluid Insulin Concentration and Symmetry Index at Birth in Offspring of Diabetic Women (n=56) p < 0.05 Metzger et al. Arch Dis Child 1990;65:1050 n=7 n=21 n=28

16. Amniotic Fluid Insulin Concentration and Symmetry Index at Age 6 Years in Offspring of Diabetic Women (n=56) n=13 n=14 n=29 p < 0.05 Metzger et al. Arch Dis Child 1990;65:1050 p < 0.05

17. Prevalence of Overweight ( ) and Obesity ( ) in Offspring by Mother’s Diabetes Risk during Pregnancy * Clausen TD et al.:J Clin Endocrinol Metab. April 2010

18. Magnetic Resonance Image of Pregnancy Complicated by Diabetes Tight Control Poorly Controlled Jovanovic-Peterson L et al. Am J Perinatol. 1993;10:432-437

19. Age-adjusted Diabetes Incidence by Body Mass Index 95% Confidence Interval 2

20. Increasing Diabetes Prevalence 1905 – Diabetes not mentioned (Russell) 1908 – One diabetic Pima (Hrdlicka) 1940 – Diabetes frequency similar in Indians And general U.S. population (Joslin) 1954 – Diabetes more common in Pimas (Cohen) 1978 – Diabetes common. Affects ½ of Pimas  35 years old (Knowler) Today – Diabetes prevalence increasing. Affects Children and adolescents. Childhood onset Type 2 diabetes in other U.S. groups Tomorrow - ????

21. Prevalence of Diabetes by Age and Parental Diabetes Parental Diabetes Both Neither Mother Father

22. 2-hour Glucose (mM) Offspring of: 2-hour Glucose by Age and Mother’s Diabetes

23. Adjusted 2-hour glucose at age 10-14 years by mother’s pregnancy glucose 5.0 6.0 7.0 8.0 < 5.65.6-6.66.7-7.77.8-11.0Diabetes Mother's 2-hour glucose (mM) 2-Hour Glucose (mM)

24. Prevalence of Diabetes by Maternal Diabetes During Pregnancy Offspring of:

25. Sib Pairs Discordant for Diabetes and for Intrauterine Exposure to Diabetes Dabelea et al. Diabetes 2000

26. Prevalence of IGT in Offspring of Diabetic Mothers Diabetes in Pregnancy Center* in Chicago * Silverman: Diabetes Care. 1995 10 to 16

27. Prevalence of Type 2 Diabetes/IGT/IFG in Offspring by Mother’s Diabetes Risk during Pregnancy * Clausen TD et al.: Diabetes Care. Feb 2008

28. Mother p<0.0001 Stride & Hattersley, Diabetes Care 2002;25 Mean age of MODY (HNF-1α) diagnosis by maternal diabetes in pregnancy

29. Mean age of MODY (HNF-1α) diagnosis by maternal diabetes in pregnancy or paternal age of diagnosis. Mother Father p<0.0001 p=0.77 Stride & Hattersley, Diabetes Care 2002;25

30. Age of Onset of Type 2 Diabetes by Exposure to Diabetes in Utero Mother’s Diabetes Age of onset Before BirthAfter Birth n%n% < 10466.7233.3 10-142938.24761.8 15-19412.12987.9 OR=4.3, 95% CI= 1.1-16.9, p=0.0351, controlled for mother’s age at diagnosis and for race/ethnicity Data from SEARCH for Diabetes in Youth Study

31. Age of Onset of Type 2 Diabetes by Paternal Diabetes Father’s Diabetes Age of onset Before BirthAfter Birth n%n% < 10001100 10-14716.33683.7 15-19415.42284.6 χ 2 =0.20, p=0.91 Data from SEARCH for Diabetes in Youth Study

32. Diabetes in Pregnancy: Vicious Cycle Child or Woman With Diabetes Infant of Diabetic Mother Mother with Diabetes

33. Abnormal GTT During Pregnancy According to The Mother’s Pregnancy Glucose Diabetes Impaired Glucose Tolerance

34. Increasing Diabetes During Pregnancy in Pima Indians: Percent exposed Dabelea et al. Diabetologia 1998 (Left) & Attributable Risk (Right)

35. Prevalence of Type 2 Diabetes by Age in 3 Time Periods

36. Other Early Life Risk Factors

37. Metabolic Syndrome by Birth Weight in Men aged 64 years Barker et al. Diabetologia 1993 p for trend < 0.001

38. Age-adjusted Diabetes Prevalence By Birth Weight (age 20-39 years) McCance DR et al. BMJ, 1994

39. Prevalence of Diabetes by Birth Weight Birth Weight (kg)

40. Prevalence of Diabetes by Birth Weight in 15-24 year old Women During Pregnancy

41. Prevalence of Diabetes by Birth Weight in 25-34 year old Pima Women During Pregnancy Pettitt & Knowler, Diabetes Care, 1998

42. Prevalence of GDM by Birth Weight of African American Women in Washington State Williams et al. Ped & Perinat Epi, 1999

43. Prevalence of GDM by Birth Weight in Norwegian Women (n=138,714) Egeland et al. BMJ, 2000

44. Prevalence of GDM by Birth Weight of Women in New York State (n=23,314) Innes et al. JAMA, 2002

45. Prevalence of Diabetes by Infant Feeding Breast Fed* Bottle Fed *  2 months

46. Adjusted* Prevalence of Diabetes *Adjusted for age, birth date, sex, obesity, birth weight parental diabetes and maternal diabetes in pregnancy Odds ratio=0.42 (95% c.i.=0.18-0.96)

47. Percent of youth (age 15 ± 2.7 yr) Ever Breastfed Type 2 diabetes Control Mayer-Davis EJ et al. Diabetes Care 2008.

48. Prevalence of Diabetes During Pregnancy Breast Fed Yes No

49. Adjusted* Prevalence of Diabetes *Adjusted for age, birth date, sex, birth weight, parental diabetes Breast Fed Yes No

50. Adjusted* Prevalence of Diabetes *Adjusted for age, sex, parental diabetes Breast Fed Yes No

51. Diabetes in Pregnancy: Vicious Cycle Child or Woman With Diabetes Infant of Diabetic Mother Mother with Diabetes New Diabetes Sources

52. Summary Diabetes in Pregnancy has long-lasting effects on the offspring: –More obesity –More diabetes –More gestational diabetes Vicious Cycle –Diabetes begets Diabetes –Diabetes from other sources enter the cycle

55. Labayen I et al. Diabetes Care, April 2010 BMI in Offspring according to whether Mother, Father or Both are overweight.

56. Labayen I et al. Diabetes Care, April 2010 Skin Fold Thickness in Offspring according to whether Mother, Father or Both are overweight.

57. Adjusted* Prevalence of Diabetes by Breast and Bottle Feeding

58. Adjusted* Prevalence of Diabetes by Duration of Breast Feeding *Adjusted for age, sex, birth weight, parental diabetes and maternal diabetes in pregnancy

59. Fuel-Mediated Effects in Utero Organ Behavioral Body Size- Metabolic Weeks of Pregnancy Adapted from Freinkel: Diabetes 1980;29:1023 Type 1 & Type 2 DiabetesGestational Diabetes

60. Studies with Data on Long-term Implications for the Offspring Obesity & Diabetes –Pima Indian Study Obesity & IGT/Diabetes –Chicago Diabetes in Pregnancy Center –Offspring of Danish Women Age of onset –Exeter MODY Studies –SEARCH for Diabetes in Youth Study

61. Labayen I et al. Diabetes Care, April 2010 Waist Circumference in Offspring according to whether Mother, Father or Both are overweight.