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David J. Pettitt, MD Sansum Diabetes Research Institute

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. Studies on Long-term Implications for the Offspring of Women with Diabetes.

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David J. Pettitt, MD Sansum Diabetes Research Institute

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  1. Long-term Effects of The Hyperglycemic Intrauterine EnvironmentDiabetes, Obesity and Fetal ProgrammingPennington Biomedical Research CenterApril 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

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

  4. Are Pima Data Relevant forOther 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

  5. Subject Groups

  6. Subject Groups

  7. Subject Groups

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

  9. Relative weight at age 10-14 years by mother’s pregnancy glucose 155 145 Relative Weight (%) 135 125 < 5.6 5.6-6.6 6.7-7.7 7.8-11.0 Diabetes Mother's 2-hour glucose (mM)

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

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

  12. DPC Offspring of DM Pima offspring of DM Pima offspring of nonDM Symmetry Index in Offspring from theDiabetes in Pregnancy Center* in Chicagoand in Pima Indians from Arizona *Silverman et al. Diabetes 1991

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

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

  15. Prevalence of Overweight ( ) and Obesity ( ) in Offspring by Mother’s Diabetes Risk during Pregnancy * Clausen TD et al.:JClinEndocrinolMetab. April 2010

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

  17. 95% Confidence Interval Age-adjusted Diabetes Incidence by Body Mass Index 2

  18. 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 - ????

  19. Both Mother Father Neither Prevalence of Diabetes byAge and Parental Diabetes Parental Diabetes

  20. 2-hour Glucose by Age and Mother’s Diabetes Offspring of: 2-hour Glucose (mM)

  21. Adjusted 2-hour glucose at age 10-14 years by mother’s pregnancy glucose 8.0 7.0 2-Hour Glucose (mM) 6.0 5.0 < 5.6 5.6-6.6 6.7-7.7 7.8-11.0 Diabetes Mother's 2-hour glucose (mM)

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

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

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

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

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

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

  28. Age of Onset of Type 2 Diabetes by Exposure to Diabetes in Utero Data from SEARCH for Diabetes in Youth Study

  29. Age of Onset of Type 2 Diabetes by Paternal Diabetes Data from SEARCH for Diabetes in Youth Study

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

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

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

  33. Prevalence of Type 2 Diabetesby Age in 3 Time Periods

  34. Other Early Life Risk Factors

  35. Metabolic Syndrome by Birth Weightin Men aged 64 years p for trend < 0.001 Barker et al. Diabetologia 1993

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

  37. Prevalence of Diabetesby Birth Weight Birth Weight (kg)

  38. Prevalence of Diabetes by Birth Weightin 15-24 year old Women During Pregnancy

  39. Prevalence of Diabetes by Birth Weight in25-34 year old Pima Women During Pregnancy Pettitt & Knowler, Diabetes Care, 1998

  40. Prevalence of GDM by Birth Weightof African American Women in Washington State Williams et al. Ped & PerinatEpi, 1999

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

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

  43. Breast Fed* Bottle Fed Prevalence of Diabetesby Infant Feeding *  2 months

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

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

  46. Prevalence of DiabetesDuring Pregnancy Breast Fed Yes No

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

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

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