Role of developmental overnutrition in pediatric obesity and type 2 diabetes

Introduction

Childhood obesity continues to be a significant public health burden, with almost one-third of children in the United States classified as overweight or obese (≥85^th percentile of weight for height).¹ The original “Barker hypothesis”² (also known as the fetal origins of adult disease hypothesis) postulated, based on epidemiological evidence available in the early 1990s, that fetal life was a critical period for the development of later, adult chronic diseases. Later on, empirical evidence began to accumulate identifying developmental pathways and mechanisms that increase the likelihood of excess adiposity and increased risk of type 2 diabetes (T2D) among offspring. Epidemiologic studies have demonstrated that both low- and high-birth weight offspring have increased obesity in later life, though this is likely through different mechanisms. Thus, intrauterine exposures resulting in both restricted and exacerbated fetal growth also lead to increased adiposity later in the life course.^3,4 Fetal growth restriction occurs as a result of inadequate fuel substrates and oxygenation, resulting in a phenotypically undernourished infant. Excessive fetal growth occurs when the fetus is overnourished by excess maternal fuels, which can deregulate the fetus' adipoinsular axis, resulting in altered energy and appetite regulation, and disordered adipocyte metabolism.⁵ The adipoinsular axis, which involves the hormones insulin and leptin, may play a significant role in the development of adiposity and diabetes. The pathway related to excess maternal fuels results in increased fetal and neonatal fat mass and subsequent childhood obesity, which increases the likelihood of cardiovascular disease (CVD), T2D, metabolic syndrome, and other morbidities later in life. Studies have shown that developmental overnutrition can occur as a result of the fetus being exposed to an excess of maternal fuels from maternal diabetes,^6,–8 maternal prepregnancy overweight and obesity,^9,10 and excess gestational weight gain (GWG).^11,–13 Based on this and other evidence reviewed herein, it appears that a transgenerational vicious cycle is set in motion, which perpetuates and likely contributes to the rise in the prevalence and risk for early-onset obesity and T2D.^14,15

The present review examines the evidence that an altered intrauterine environment results in long-term consequences for the offspring. It also explores the history and concept of developmental overnutrition along with the evidence of the effect it has on childhood adiposity and T2D, public health consequences, potential preventive approaches, and future directions for research.

Obesity and Type 2 Diabetes among Children and Adolescents in the United States

The potential roles of developmental overnutrition and the transgenerational vicious cycle must be seen in the context of current trends in obesity and T2D among children and adolescents in the United States. In recent decades, the prevalence of obesity (≥95^th percentile of weight for height) has increased dramatically among US children and adolescents.¹⁶ Currently, the prevalence of obesity is close to 20% in youth older than 6 years of age, which results in an enormous burden on health resources and overall population health. Furthermore, obese individuals often have comorbidities such as T2D, which is also on the rise.¹⁷ The most recent data come from the multicenter, population-based, prospective registry study SEARCH for Diabetes in Youth, where investigators explored the incidence of T2D by age and race-ethnicity among US youth.¹⁸ Native Americans had the highest incidence of T2D among both 10–14 and 15–19 year olds, followed by other minority youth; the lowest rates were seen among non-Hispanic white youth. Additionally, 15–19 year olds had a higher incidence of T2D than 10–14 year olds¹⁸ in all race/ethnic groups. Few data exist on trends for T2D in youth, though recent data from the SEARCH study suggest it is increasing among Hispanics and non-Hispanic whites.¹⁹

Concept of Developmental Overnutrition

The fuel-mediated teratogenesis hypothesis,²⁰ first proposed in the 1950s by Pederson, postulates that intrauterine fetal exposure to hyperglycemia in women with diabetes in pregnancy causes permanent fetal changes, leading to malformations, greater birth weight, and an increased risk of developing T2D and obesity in later life. A likely mechanism occurs through intrauterine exposure to a hyperglycemic environment, which induces hyperinsulinemia. Insulin is an adipogenic hormone; thus, this type of environment would catalyze excessive fetal growth, increasing the risk of macrosomia. In the 1980s, this hypothesis was broadened to include the possibility that other fuels, in addition to glucose, such as free fatty acids, ketone bodies, and amino acids also increase fetal growth.²⁰ More recently, it has been suggested that fetal overnutrition may also occur in nondiabetic but obese pregnancies, and that it has consequences on offspring that extend beyond those apparent at birth.²¹ Most recently, scientists have started to refer to this theory as “developmental overnutrition,”²² in recognition of the likelihood that overnutrition occurring during other developmentally sensitive periods, such as early postnatal life, may also have long-term consequences on offspring.

Effects on Childhood Adiposity

It is well known that infants born to mothers with diabetes have increased birth length and weight. However, it is less clear whether developmental overnutrition leads to increased adiposity later in life. Pettitt et al.²³ analyzed the weight of 5–19-year-old offspring of Pima Indian women, a population with one of the highest T2D risks in the world. A unique aspect of this study was that the investigators knew whether the offspring were the product of nondiabetic, prediabetic, or diabetic pregnancies from serial testing over many years. After adjusting for maternal and offspring characteristics, 5–9-, 10–14-, and 15–19-year-old offspring of mothers who were diabetic during pregnancy all had significantly greater relative weight compared to the offspring of women who were either prediabetic (P < 0.001) or nondiabetic during pregnancy (P < 0.002).²³ Because it was possible to determine a prediabetic pregnancy (i.e., a mother that did not have diabetes during pregnancy, but developed it after the birth of the child), it was possible to examine the in utero role of overnutrition independent of a genetic predisposition to later diabetes. At all ages from birth to 19 years, there was no difference in relative weight for offspring of prediabetic compared to nondiabetic mothers (P < 0.20).²³ Interestingly, no effect was seen among offspring aged 20 years and older; this is likely because obesity is extremely prevalent in this population during adulthood.²⁴ There is now substantial evidence that these effects are present in other populations with lower obesity and T2D risks than the Pima Indians.

The retrospective cohort study, Exploring Perinatal Outcomes among Children (EPOCH), consisted of 461 multiethnic offspring, 82 of whom were exposed to GDM and 379 youth who were unexposed.²⁵ The results showed that offspring exposed to GDM had significantly increased BMI, waist circumference, visceral and subcutaneous adipose tissue (by magnetic resonance imaging), and a more central subscapular-to-triceps skinfold thickness ratio, after adjusting for maternal and offspring characteristics.²⁵ Not only did the study confirm the relationships of exposure to diabetes in utero with increased adiposity during childhood and early adolescence, it also showed that adipose tissue is more centrally distributed in exposed offspring. Not surprisingly, the relationships were attenuated when adjustments were made for maternal prepregnancy BMI. Evidence described below shows that maternal obesity and maternal fuels, in addition to glucose, are also related to developmental overnutrition. Thus, it is likely that maternal obesity is part of a common causal pathway linking maternal obesity and diabetes, through elevated maternal fuels, to offspring outcomes. Therefore, adjustment for prepregnancy BMI is likely an overadjustment.

Childhood overweight and obesity are not the only morbidities associated with developmental overnutrition. Boney et al.²⁶ explored whether developmental overnutrition was associated with development of metabolic syndrome in a longitudinal cohort study of 179 children followed from birth to early adolescence. Of the participants, 84 were born large for gestational age (LGA) and 95 were average for gestational age (AGA). Compared with AGA offspring, those born LGA had a twofold increased hazard for metabolic syndrome by the age of 11 years. Additionally, independent of maternal diabetes, maternal obesity increased the risk of metabolic syndrome by 1.8-fold.²⁶ These findings provide evidence of metabolic factors that contribute to excess adiposity in childhood and early adolescence among offspring of obese pregnant women, independent of GDM presence.

Effects on Childhood Type 2 Diabetes

The first study of the long-term consequences of maternal diabetes in utero on risk of T2D in offspring again came from the Pima Indian study.²⁷ The results showed that the odds of being exposed to maternal diabetes in utero was 10.4 times greater (95% confidence interval [CI] 4.3–25.1) among offspring with T2D compared to offspring without such exposure. Furthermore, the researchers estimated that maternal diabetes was responsible for 35.4% of all T2D cases among exposed offspring.²⁷ More recently, the SEARCH case-control study tested if these associations existed in an ethnically diverse population of youth aged 10–22 years in Colorado and South Carolina. After adjusting for offspring age, sex, and race/ethnicity, the odds of exposure to diabetes in utero was 7.3 times greater (95% CI 3.2–16.8) among offspring with T2D than controls, with similar results in non-Hispanic whites, Hispanics, and African Americans.²⁸ Thus, the effects of developmental overnutrition on pediatric T2D are detectable in both high- and low-risk populations.

Associations Reflect Specific Intrauterine Effects

Clearly, fetal development takes place in an environment shaped both by parental genetics and environmental influences. What evidence is there that the associations described above reflect specific intrauterine effects and that the outcomes are not primarily due to parental genetics or shared familial behaviors? In an attempt to test this hypothesis of specificity of the intrauterine effects, Dabelea et al.⁶ selected nuclear Pima Indian families with at least one offspring born before and one after the mother was diagnosed with T2D. Siblings born after a maternal diagnosis of diabetes (exposed) had a BMI that was 2.6 kg/m² higher (P = 0.003) than that of siblings born before diabetes was diagnosed (unexposed). However, there were no significant differences in offspring BMI among those who were born before or after paternal diagnosis of diabetes (P = 0.50).⁶

Next, the researchers explored the presence of T2D among siblings who were born before and after maternal and paternal diagnosis of diabetes. Siblings exposed to maternal diabetes in utero were 3.0 times more likely to have T2D than those born before the mother developed diabetes (P = 0.02).⁶ No significant differences in T2D risk in the offspring were found between siblings born before or after the diagnosis of paternal T2D (odds ratio 1.3, P = 0.80).⁶ These results clearly indicate that exposure to an in utero diabetic environment (developmental overnutrition) increases the likelihood that the offspring will develop obesity and T2D, independent of genetic or familial factors.

Potential Mechanisms

While it is clear that developmental overnutrition increases the likelihood of excess adiposity and early-onset T2D among exposed offspring, and that these associations exist over and above genetic and familial factors, what are some of the potential mechanisms that may explain these intrauterine effects?

Role of maternal fuels

Pregnancy is a state of relative insulin resistance, which spares glucose, amino acids, and fatty acids for placental-fetal transport.²⁹ Therefore, obese or diabetic pregnant women, who have severe insulin resistance, transport an excess of nutrients, such as glucose, to the fetus.²⁰ Increased transfer of glucose across the placental barrier in obese or diabetic pregnancies results in the fetal pancreas secreting excess insulin, which acts as a growth hormone and may result in excessive growth or macrosomia in the offspring. This process is presumed to increase the risk of obesity later in life.

Several studies have explored specific maternal fuels, such as glucose and free fatty acids (FFA). In 2007, Hillier et al.³⁰ analyzed 9,439 multiethnic mother-offspring pairs. All mothers received a 50 g, 1-h glucose challenge test as screening for GDM, followed by a diagnostic test using a 3-h, 100 g oral glucose tolerance test. Offspring weight was measured at 5–7 years of age. Sex-specific weight-for-age percentiles were calculated and shown to be linearly associated with maternal glucose levels, even among mothers with a normal glucose challenge test during screening.³⁰ These results showed that maternal glucose may represent one of the important fuels involved in developmental overnutrition.

However, maternal glucose is not the only fuel believed to be involved. Schaffer-Graf et al.³¹ studied 150 pregnant women and their offspring to examine whether several maternal fuels, including FFA and triglyceride levels, were associated with neonatal outcomes. The authors found positive correlations between maternal FFA levels and fetal abdominal circumference (r = 0.22, P = 0.02), FFA in cord blood (r = 0.28, P = 0.004), and neonatal fat mass (r = 0.27, P = 0.01).³¹ Thus, maternal FFAs appear to be associated with neonatal adiposity. However, it is important to note that no studies have thus far explored whether maternal FFAs are associated with obesity or T2D later in life.

Role of the adipoinsular axis

The adipoinsular axis is a dual-hormone feedback loop based on the adipocytokine, leptin, and the adipogenic hormone insulin. The endocrine feedback loop links the brain (i.e., autonomic nervous system [ANS] and hypothalamus) and endocrine pancreas with other peripheral leptin- and insulin-sensitive tissues in the regulation of feeding behavior, metabolic regulation, and energy expenditure.^32,33 Leptin, which is produced and secreted by adipocytes, occurs at levels proportionate to the amount of fat stored. As adiposity and leptin levels concurrently increase, insulin secretion decreases due to central and direct actions on pancreatic β-cells.³³ When the adipoinsular axis is regulated appropriately, nutrient balance may be maintained; however, if dysregulation of the axis occurs, then obesity and hyperinsulinemia resulting in the development of diabetes may occur.³³ In animal^32,34 and human studies,^35,–37 increasing circulating leptin levels, which is a biologic indicator of leptin resistance, has been shown to be associated with CVD, hyperphagia, insulin resistance, and obesity.

Public Health Consequences

Historically, T2D was uncommonly diagnosed among children; however, an increase in T2D among children and adolescents has occurred in the past few decades.^17,38 In the first population-based study to explore the changes in T2D prevalence in youth, Dabelea et al.²⁷ analyzed 5,274 Pima Indian children from 1967 to 1996 to determine potential trends in the prevalence of early-onset T2D. The authors found that the prevalence of T2D increased almost threefold over the past three decades, especially among 15–19 year olds. They next explored the potential role of developmental overnutrition (exposure to maternal diabetes) in explaining these trends.²⁷ From 1967–1976 to 1987–1996, the prevalence of exposure to maternal diabetes in utero increased from 2% of all pregnancies to 7.5%. This was associated with a doubling of the population-attributable fraction (PAF), which represents the proportion of T2D in the population that may be due to exposure. This translated into a PAF of 35.4%, which means that over one-third of Pima Indian youth with T2D in 1987–1996 may have developed T2D because they were exposed to maternal diabetes in utero. Together, increasing weight and increasing frequency of exposure to diabetes in utero accounted for most of the increase in T2D prevalence in Pima Indian children over the past 30 years.²⁷

Dabelea et al.²⁸ later replicated these findings in a tri-ethnic population in the SEARCH case-control study. Here, they separately estimated the proportion of T2D in youth attributable to exposure to maternal diabetes, to maternal obesity, and to both. The results showed that 4.7% of T2D among youth aged 10–22 years was attributable to maternal diabetes (in the absence of obesity), 19.7% was attributable to maternal obesity (in the absence of diabetes), and 22.8% was attributable to exposure to both maternal morbidities. Overall, an estimated 47.2% of T2D in youth was attributable to intrauterine exposure to maternal diabetes and obesity,²⁸ which is similar to that seen among the Pimas. Clearly, developmental overnutrition has a significant public health impact. These results also support the idea of a vicious cycle of obesity and diabetes leading to obesity and its comorbidities in the next generation.

Postnatal Modification of Effects

The role of postnatal life in mediating or modifying the effects of developmental overnutrition has not been studied extensively. Recently, the EPOCH study explored growth trajectories after birth among offspring exposed and not exposed to maternal diabetes in utero.³⁹ During an in-person research visit, current height and weight of children aged 6–13 years were measured. Historical recumbent length (up to 2 years of age) and height and weight measures were abstracted from medical records. These data were used to estimate BMI and BMI growth trajectory.³⁹ On average, BMI growth trajectories during early stages of life (birth to 26 months of age) were not significantly different between exposed and unexposed offspring (P = 0.48). Although there were no immediate and consistently observed differences in mean BMI or growth trajectory up to the age of 26 months, both were significantly greater among exposed offspring from the age of 27 months to 13 years (P = 0.01; P = 0.008, respectively).³⁹ Furthermore, the difference in BMI based on maternal diabetes exposure status became much more evident around puberty. The largest difference in BMI growth trajectories between exposed and unexposed offspring was around 10–13 years of age (β = 1.05; P = 0.005). This highlights the fact that other developmentally sensitive periods, such as the pubertal period, may modify the long-term consequences of intrauterine exposures, supporting the concept of developmental overnutrition.

Other postnatal periods and factors must also be considered. One such period is early life and one such factor is breastfeeding, both of which are known to affect offspring obesity and T2D status.⁴⁰ The role of breastfeeding status as a potential moderator of the association between exposure to maternal diabetes in utero and childhood BMI, skinfold measures (subscapular and triceps), waist circumference, and visceral and subcutaneous fat was also explored in the EPOCH study.⁴¹ Breastfeeding status was calculated as breast milk-months (similar to pack-years with regard to smoking), which accounts for both the duration and exclusivity of breastfeeding. Analyses were stratified based on breastfeeding status categorized as low (<6 breast milk-months) or adequate (≥6 breast milk-months). Among offspring with low breastfeeding status, exposure to diabetes in utero was associated with significantly higher adiposity parameters in childhood. However, among offspring with adequate breastfeeding history, all of the statistically significant excesses of adiposity among offspring exposed to diabetes in utero were substantially attenuated and no longer statistically significant.⁴¹ Thus, breastfeeding appears to reduce the harmful influence of in utero exposure to maternal diabetes on offspring adiposity measures.

How Can These Effects be Prevented?

Although no studies have directly addressed preventing the vicious cycle, studies have suggested possible approaches. In a study by Hillier et al.³⁰ results suggested that maternal glucose levels above 122 mg/dL were associated with childhood overweight and obesity; however, levels below that were not significantly associated with offspring adiposity. Thus, if maternal glucose levels were carefully monitored and controlled during gestation, it might be possible to reduce the risk of later adiposity among offspring. The only evidence to date indicating whether directly reducing maternal glucose levels reduces offspring obesity is from a study conducted by Gillman et al.⁴² This was a follow-up of a multicenter randomized trial of treatment of mild GDM that randomized mothers to a group that received dietary advice, blood glucose monitoring, and insulin therapy (∼20% received insulin) or a control group. At birth, macrosomia was reduced in the treatment group compared to the control group, 5.3% to 21.9%, respectively. However, no significant differences in offspring BMI were observed at 4–5 years of age.⁴² Since the EPOCH study found no differences in BMI growth trajectories by in utero exposure status at these ages, but only later in life, it is possible that longer follow-up of these offspring will show that reducing maternal glucose levels has an impact on offspring adiposity. However, such follow-up may require years before the answer is known. Another possible reason for the negative findings in the Gillman study may be the need to control the effect of other fuels that are elevated in obese pregnancies, such as FFA and triglycerides, which may have long-term programming consequences. For example, controlling gestational weight gain in pregnancies of obese women may reduce the levels of elevated maternal fuels and represent another potential avenue for prevention. Based on the observational evidence that breastfeeding is associated with less adiposity among offspring exposed to maternal diabetes, a study directly testing this hypothesis could be undertaken.

Future Research Directions

First and foremost, an improved understanding of the biologic mechanisms involving developmental overnutrition must be a priority. This can be obtained through animal studies, followed by rapid translation to studies in humans. Specific biologic mechanisms that need to be better understood include the effects of fuels on fetal target tissues, appetite regulation in exposed offspring, and the potential role of epigenetics. Additionally, large, longitudinal prebirth cohort studies need to be initiated with specific aims involving the interaction of intrauterine effects with postnatal life.

Subsequent to improving understanding of the mechanisms involved, randomized clinical trials of interventions prior to or during pregnancy, including reduction of gestational weight gain, as well as optimizing early life nutrition, and later eating behaviors and physical activity patterns, need to be conducted to determine how the transgenerational cycle may be broken. Preventing this cycle may not only provide direct health benefits to the offspring, but should provide a cumulative positive effect for succeeding generations.

Conclusion

It is clear that fetal overnutrition results in increased risk of obesity and T2D in exposed offspring. These associations appear to be above and beyond those that might be due to genetic susceptibility for diabetes and obesity. Of the potential mechanisms studied, it appears that the theory of fuel-mediated teratogenesis has substantial support. Maternal diabetes and obesity account for almost 50% of T2D in youth and likely trigger a transgenerational vicious cycle of obesity and diabetes. It appears likely that postnatal life can modify the long-term consequences of fetal overnutrition, though the observation that breastfeeding may reduce risks requires careful testing. It appears that adiposity risks are amplified during obesogenic and insulin-resistant periods such as puberty. There is an urgent need to better understand how best to reverse the long-term impact of developmental overnutrition and to develop effective interventions that promote healthier pregnancies and healthy children.

Declaration of interest

The authors have no relevant interests to declare.

References