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 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

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

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

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

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

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

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

Relative weight at age years by mother’s pregnancy glucose < Diabetes Mother's 2-hour glucose (mM) Relative Weight (%)

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

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

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

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

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

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

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

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

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 - ????

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

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

Adjusted 2-hour glucose at age years by mother’s pregnancy glucose < Diabetes Mother's 2-hour glucose (mM) 2-Hour Glucose (mM)

Prevalence of Diabetes by Maternal Diabetes During Pregnancy Offspring of:

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

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

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

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

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

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

Age of Onset of Type 2 Diabetes by Paternal Diabetes Father’s Diabetes Age of onset Before BirthAfter Birth n%n% < χ 2 =0.20, p=0.91 Data from SEARCH for Diabetes in Youth Study

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

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

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

Prevalence of Type 2 Diabetes by Age in 3 Time Periods

Other Early Life Risk Factors

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

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

Prevalence of Diabetes by Birth Weight Birth Weight (kg)

Prevalence of Diabetes by Birth Weight in year old Women During Pregnancy

Prevalence of Diabetes by Birth Weight in year old Pima Women During Pregnancy Pettitt & Knowler, Diabetes Care, 1998

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

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

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

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

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.= )

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

Prevalence of Diabetes During Pregnancy Breast Fed Yes No

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

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

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

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

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

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

Adjusted* Prevalence of Diabetes by Breast and Bottle Feeding

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

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

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

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