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 1985
70
Females
Males
60
50
1985
1908*
40
30
20
125
135
145
155
165
125
135
Height (centimeters)
*Hrdlicka, 1908
145
155
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 of
Mother’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 of
Mother’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 of
Mother’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 for Height
by Age and Mother’s Diabetes
Normal Birth Weight (90-110 %)
170
170
160
160
150
150
140
140
Offspring of:
Nondiabetic
Future diabetic
Diabetic
130
130
120
120
110
110
100
100
Birth
Birth
5-9
10-14
15-19
5-9
10-14
15-19
Age at Examination (years)
Age at Examination (years)
Relative weight at age 10-14 years
by mother’s pregnancy glucose
Relative Weight (%)
155
145
135
125
< 5.6
5.6-6.6
6.7-7.7
7.8-11.0
Mother's 2-hour glucose (mM)
Diabetes
Prevalence of Obesity* by Maternal Diabetes
During Pregnancy
Prevalence (%)
90
80
70
60
50
40
30
20
10
0
Offspring of:
Nondiabetic
Future diabetic
Diabetic
5-9
* ≥ 140 % standard
10-14
15-19
20-24
Age (years)
25-29
30-34
Mean BMI in Siblings by exposure to diabetes In Utero
45
Exposure to
Diabetes In utero
Mean BMI (kg/m2)
No
Yes
35
25
15
6-9
9-12
12-15
15-18
Age (years)
18-21
21-24
Symmetry Index in Offspring from the
Diabetes in Pregnancy Center* in Chicago
and in Pima Indians from Arizona
Symmetry Index
1.6
DPC Offspring of DM
Pima offspring of DM
Pima offspring of nonDM
1.5
1.4
1.3
1.2
1.1
1.0
0
1
2
3
4
5
6
7
Age in Years
*Silverman et al. Diabetes 1991
8
9
10
11
12
Amniotic Fluit Insulin (pM)
Amniotic Fluid Insulin Concentration and Symmetry Index at
Birth in Offspring of Diabetic Women (n=56)
p < 0.05
150
100
50
n=7
n=28
n=21
< 1.0
1.0-1.2
> 1.2
0
Symmetry Index
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)
p < 0.05
Amniotic Fluit Insulin (pM)
p < 0.05
150
100
50
n=13
n=29
n=14
< 1.0
1.0-1.2
> 1.2
0
Symmetry Index
Metzger et al. Arch Dis Child 1990;65:1050
Percent
Prevalence of Overweight ( ) and Obesity ( ) in
Offspring by Mother’s Diabetes Risk during Pregnancy
40
35
30
25
20
15
10
5
0
Normal
Type 1 DM
Genetic Risk
Mother's Status During Pregnancy
* Clausen TD et al.:J Clin Endocrinol Metab. April 2010
GDM
Magnetic Resonance Image
of Pregnancy Complicated by Diabetes
Tight Control
Poorly Controlled
Jovanovic-Peterson L et al. Am J Perinatol. 1993;10:432-437
Incidence: cases per 1000
person-years
Age-adjusted Diabetes Incidence by
Body Mass Index
100
95% Confidence Interval
80
60
40
20
0
< 20
20-25
25-30
30-35
Body Mass Index (Kg/m2 )
35-40
40+
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
Prevalence (%)
Parental
Diabetes
60
50
40
30
20
10
0
5-14
Both
Mother
Father
Neither
15-14
25-34
Age (years)
35-44
2-hour Glucose by Age and Mother’s Diabetes
2-hour Glucose (mM)
21.0
Offspring of:
Diabetic
Pre-diabetic
17.7
Non-diabetic
14.4
11.1
7.8
4.5
5-9
10-14
15-19
Age at Examination (years)
20-24
2-Hour Glucose (mM)
Adjusted 2-hour glucose at age 10-14 years
by mother’s pregnancy glucose
8.0
7.0
6.0
5.0
< 5.6
5.6-6.6
6.7-7.7
7.8-11.0
Mother's 2-hour glucose (mM)
Diabetes
Prevalence of Diabetes by Maternal Diabetes
During Pregnancy
70 Offspring of:
Prevalence (%)
60
50
NonDiabetic
Future Diabetic
Diabetic
40
30
20
10
0
5-9
10-14
15-19
20-24
Age (years)
25-29
30-34
Sib Pairs Discordant for Diabetes and for
Intrauterine Exposure to Diabetes
25
Number of Sib Pairs
21
20
15
10
7
5
0
Born Before Mother's
Diagnosis
Dabelea et al. Diabetes 2000
Born After Mother's
Diagnosis
Prevalence of IGT in Offspring of Diabetic Mothers
Diabetes in Pregnancy Center* in Chicago
20
Percent
15
10
5
0
<5
5 to 9
10 to 16
Age (years)
* Silverman: Diabetes Care. 1995
Control
10 to 16
Prevalence of Type 2 Diabetes/IGT/IFG in Offspring
by Mother’s Diabetes Risk during Pregnancy
Percent
20
15
10
5
0
Normal
Type 1 DM
Genetic Risk
Mother's Status During Pregnancy
* Clausen TD et al.: Diabetes Care. Feb 2008
GDM
Mean age of MODY (HNF-1α) diagnosis by maternal
diabetes in pregnancy
Mean age of diabetes diagnosis
p<0.0001
30
25
20
15
10
5
0
Diabetic
Future
Diabetic
Mother
Stride & Hattersley, Diabetes Care 2002;25
Mean age of MODY (HNF-1α) diagnosis by maternal
diabetes in pregnancy or paternal age of diagnosis.
Mean age of diabetes diagnosis
p<0.0001
p=0.77
30
25
20
15
10
5
0
Diabetic
Future
Diabetic
Mother
Stride & Hattersley, Diabetes Care 2002;25
<=33 yrs.
>33 yrs.
Father
Age of Onset of Type 2 Diabetes by
Exposure to Diabetes in Utero
Mother’s Diabetes
Age of
Before Birth
After Birth
onset
n
%
n
%
< 10
4
66.7
2
33.3
10-14
29
38.2
47
61.8
15-19
4
12.1
29
87.9
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
Age of Onset of Type 2 Diabetes by
Paternal Diabetes
Father’s Diabetes
Age of
Before Birth
After Birth
onset
n
%
n
%
< 10
0
0
1
100
10-14
7
16.3
36
83.7
15-19
4
15.4
22
84.6
χ2 =0.20, p=0.91
Data from SEARCH for Diabetes in Youth Study
Diabetes in Pregnancy:
Vicious Cycle
Mother with
Diabetes
Child or Woman
With Diabetes
Infant of
Diabetic Mother
Prevalence (%)
Abnormal GTT During Pregnancy According
to The Mother’s Pregnancy Glucose
70
60
50
40
30
20
10
0
Impaired Glucose Tolerance
Diabetes
< 5.6
5.6-6.6
6.7-7.7
7.8-11.0 Diabetes
Maternal Pregnancy Glucose (mM)
Increasing Diabetes During Pregnancy in Pima Indians:
Percent exposed (Left) & Attributable Risk (Right)
40
Attributable Risk (%)
Percent Exposed
8
6
4
2
0
67-76
77-86
87-96
Time Period (years)
Dabelea et al. Diabetologia 1998
30
20
10
0
67-76
77-86 87-96
Time Period (years)
Prevalence of Type 2 Diabetes
by Age in 3 Time Periods
Prevalence (%)
4
3
2
67-76
77-86
87-96
1
0
5-9
10-14
Age (years)
15-19
Other Early Life Risk Factors
Prevalence (%)
Metabolic Syndrome by Birth Weight
in Men aged 64 years
30
25
20
15
10
5
0
p for trend < 0.001
< 5.5 5.5-6.5 6.5-7.5 7.5-8.5 8.5-9.5 > 9.5
Birth weight (pounds)
Barker et al. Diabetologia 1993
Age-adjusted Diabetes Prevalence
By Birth Weight (age 20-39 years)
Prevalence (%)
40
30
20
10
0
< 2.5
2.5-3.0
3.0-3.5
3.5-4.0
Birth weight (Kg)
McCance DR et al. BMJ, 1994
4.0-4.5
≥ 4.5
Prevalence of Diabetes
by Birth Weight
Prevalence (%)
25
Birth Weight (kg)
< 2.5
2.5-3.5
3.5-4.5
≥ 4.5
20
15
10
5
0
5-9
10-14
15-19
Age (years)
20-29
Prevalence of Diabetes by Birth Weight
in 15-24 year old Women During Pregnancy
Prevalence (%)
20
15
10
5
0
< 2.5 2.5-3.0 3.0-3.5 3.5-4.0 4.0-4.5 ≥ 4.5
Birth weight (kg)
Prevalence of Diabetes by Birth Weight in
25-34 year old Pima Women During Pregnancy
Prevalence (%)
25
20
15
10
5
0
< 2.5 2.5-3.0 3.0-3.5 3.5-4.0 4.0-4.5 ≥ 4.5
Birth weight (kg)
Pettitt & Knowler, Diabetes Care, 1998
Prevalence (%)
Prevalence of GDM by Birth Weight
of African American Women in Washington State
5.0
4.0
3.0
2.0
1.0
0.0
< 2.0
2.0-2.5
2.5-3.0
3.0-4.0
Birth weight (kg)
Williams et al. Ped & Perinat Epi, 1999
4.0+
Prevalence of GDM by Birth Weight
in Norwegian Women (n=138,714)
Prevalence (%)
5
4
3
2
1
0
< 2.5 2.5-3.0 3.0-3.5 3.5-4.0 4.0-4.5 ≥ 4.5
Birth weight (kg)
Egeland et al. BMJ, 2000
Prevalence (%)
Prevalence of GDM by Birth Weight
of Women in New York State (n=23,314)
3.0
2.5
2.0
1.5
1.0
0.5
0.0
< 2.0 2.0-2.5 2.5-3.0 3.0-3.5 3.5-4.0 4.0-4.5
Birth weight (kg)
Innes et al. JAMA, 2002
Prevalence of Diabetes
by Infant Feeding
Prevalence (%)
15
10
Breast Fed*
Bottle Fed
5
0
10-14
15-19
Age (years)
*  2 months
20-24
Adjusted* Prevalence of Diabetes
Prevalence (%)
10
8
Odds ratio=0.42
(95% c.i.=0.18-0.96)
6
4
2
0
Yes
No
Breast fed
*Adjusted for age, birth date, sex, obesity, birth weight
parental diabetes and maternal diabetes in pregnancy
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
Prevalence (%)
5
Breast Fed
Yes
No
4
3
2
1
0
15-19
20-24
Age (years)
Adjusted* Prevalence of Diabetes
Breast Fed
Yes
No
Prevalence (%)
40
30
20
10
0
No
Yes
Maternal Diabetes in Pregnancy
*Adjusted for age, birth date, sex, birth weight, parental diabetes
Adjusted* Prevalence of Diabetes
Breast Fed
Yes
No
Prevalence (%)
30
20
10
0
< 2.5
2.5-3.5
3.5-4.5
Birth Weight (Kgs)
*Adjusted for age, sex, parental diabetes
> 4.5
Diabetes in Pregnancy:
Vicious Cycle
Mother with
Diabetes
New Diabetes
Sources
Child or Woman
With Diabetes
Infant of
Diabetic Mother
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
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.
Labayen I et al. Diabetes Care, April 2010
Adjusted* Prevalence of Diabetes
by Breast and Bottle Feeding
Prevalence (%)
10
8
6
4
2
0
No
Yes - with bottle
Breast fed (> 2 months)
Yes - Breast
Adjusted* Prevalence of Diabetes
by Duration of Breast Feeding
Prevalence (%)
10
8
6
4
2
0
None
0-2
2-4
>4
Duration (months)
*Adjusted for age, sex, birth weight, parental diabetes and maternal diabetes in pregnancy
Fuel-Mediated Effects in Utero
Organ
Body SizeMetabolic
Behavioral
Type 1 & Type 2 Diabetes
Gestational Diabetes
Weeks of Pregnancy
Adapted from Freinkel: Diabetes 1980;29:1023
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
Waist Circumference in Offspring according to whether
Mother, Father or Both are overweight.
Labayen I et al. Diabetes Care, April 2010