The Pedersen hypothesis

Although first formulated in the 1920s, Jorgen Pedersen is generally given credit for the hyperglycemia-hyperinsulinemia hypothesis or, as it is more commonly referred to today, the Pedersen hypothesis. The hypothesis as stated by Pedersen is as follows: “Maternal hyperglycemia results in fetal hyperglycemia and, hence, in hypertrophy of fetal islet tissue with insulin hypersecretion. This again means a greater fetal utilization of glucose. This phenomenon will explain several abnormal structure and changes found in the newborn.” Today the Pedersen hypothesis is most commonly associated with the concept of fetal overgrowth or macrosomia.

There are abundant data to support the Pedersen hypothesis. For example, umbilical cord insulin concentrations are strongly correlated with fetal growth in both human and animal studies. Schwartz et al reported that fetal size was significantly correlated with umbilical total insulin, free insulin, and C-peptide. The recently completed Hyperglycemia and Adverse Pregnancy Outcome Study (HAPO) showed a linear relationship between increasing maternal glucose and cord C-peptide with birthweight.

Several in vivo animal models also support the Pedersen hypothesis. Twelve hours after injection of insulin into rat fetuses, total fetal weight, both wet and dry mass, significantly increased as compared with saline-injected controls. In an elegant experiment, using in utero insulin infusion via an osmotic pump implanted into a fetal rhesus monkey for 21 days, Susa et al reported a 34% increase in body weight, particularly in the liver, heart, and spleen in the experimental model as compared with controls despite maternal euglycemia. Interestingly, there was no significant increase in the lipid, protein, and deoxyribonucleic acid and ribonucleic acid concentrations. The authors concluded that increased fetal insulin, even in the presence of normal maternal substrate concentrations, was growth promoting in the nonhuman primate. Lastly, the corollary experiment with injecting streptozocin to the fetal sheep resulted in beta cell destruction with subsequent hypoinsulinemia. Fetal body weight was decreased by 21%, particularly protein content in carcass, liver, and kidney. There were no significant changes in fetal lipid accretion. Hence, based on the available data, it has become widely accepted that fetal insulin is a primary in utero growth factor. However, is the concept developed by Pedersen reflecting the entire story?

The metabolic environment of pregnant women is evolving

In the 1950s when Pedersen cared for pregnant women with preexisting diabetes, the overwhelming majority of these women had type 1 diabetes. One of the primary goals of management was to maintain optimal glucose control and decrease the risk of ketoacidosis. Hence, these women were treated using insulin along with a diet of between 1800-2000 calories (90 g of protein, 80 g of fat, and 180-200 g of carbohydrate) distributed over 6 meals. Many of these women were quite thin because this was the common phenotype of women with type 1 diabetes at that time.

Concurrent with the current epidemic of obesity, there is also increasing incidence of type 2 diabetes. The Center for Disease Control and Prevention estimates that in 2007, 23.6 million people, or 7.8% of the population, had diabetes. The majority of women of reproductive age with preexisting diabetes now consist of women with type 2 rather than type 1 diabetes ( Figure 1 ). Along with the increase of type 2 diabetes in the population, Reaven coined the term, metabolic syndrome, to describe the constellation of symptoms associated with this increase in obesity and diabetes in the nonpregnant population. The metabolic syndrome encompasses a myriad of seemingly unrelated disorders such as hypertension, hyperlipidemia, atherosclerosis, and inflammation. During pregnancy these disorders may be referred to using different names, such as gestational diabetes mellitus (GDM), pregnancy-associated hypertension, and preeclampsia, but most likely represent a similar pathophysiology. The common metabolic thread being increased insulin resistance and hyperinsulinemia.

Longitudinal trends of the diabetes and obesity epidemics, encompassing the 20th and 21st centuries

Trends in obesity and diabetes from 1990 through 2030, the projected numbers showing a parallel increase from the last century through 2030. Black bars indicate overweight individuals (BMI >25 kg/m ² ) including obese (BMI >30 kg/m ² ). Gray bars indicate obese individuals. Red bars indicate type 2 and type 1 individuals with diabetes, with type 2 representing greater than 90 % of all the population with diabetes.

BMI , body mass index.

Catalano. Pedersen hypothesis revisited. Am J Obstet Gynecol 2011.

Adapted, with permission. from Haffner ; Shaw et al ; and www.iotf.org/database .

As this concept has developed, research has shown that adipose tissue, originally thought to be simply a storage depot for triglycerides, actually serves a wide array of metabolic functions. The current understanding is that the adipocyte and adjacent stroma are metabolically active tissues, having metabolic, endocrine, and immune functions (reviewed elsewhere ). In short, with increasing obesity there evolves an inflammatory milieu, in which cytokine production by macrophages in the adipose tissue affects postreceptor insulin signaling. This disturbance of insulin signaling results in increased insulin resistance.

Pregnancy is also in and of itself an inflammatory condition, very possibly initiated to allow immunotolerance of the fetus by the mother. Inflammation therefore has become an important factor for our understanding of the mechanism for the increased insulin resistance of pregnancy.

In summary, the obese woman begins pregnancy with greater insulin resistance as compared with her normal-weight counterpart. The 50-60% increase in insulin resistance of pregnancy further increases this metabolic stress in these women. These metabolic changes create a metabolic environment of excess nutrients and cytokines in which the fetoplacental unit develops.

Fetal macrosomia despite excellent glucose control: a role for maternal lipids?

Clinically, despite what is apparently excellent glucose control, some pregnant women with diabetes of any classification, GDM, type 1 or type 2, have a large or macrosomic fetus. We often attribute this to unrecognized hyperglycemia despite intermittent home blood glucose monitoring values within the normal range. Continuous glucose monitoring in pregnant women with diabetes has provided data supporting the concept that improved glucose control, as estimated by hemoglobin A1c in later pregnancy, can decrease the risk of macrosomia when compared with frequent glucose self-monitoring. However, although rates of macrosomia have been decreased with continuous glucose monitoring, they remain 3.5 times higher than in the general population.

Additionally, Langer and Yogev have shown that the risk of having a macrosomic baby in women with well-controlled GDM was a function of their pregravid BMI. Overweight women with well-controlled GDM on diet alone had a 50% greater risk of having a macrosomic baby as compared with normal-weight woman with GDM. The risk of macrosomia increased 2-fold if the women was obese. In women with poorly controlled GDM, the risk of macrosomia increased 3-fold. Of interest, overweight or obese women with well-controlled GDM on insulin had no increased risk of macrosomia in comparison with the reference group. This effect of insulin to decrease the risk of macrosomia may be related to the effects of insulin on lipid as well as glucose metabolism. Whether oral agents would have a similar effect on fetal growth is not known and remains speculative.

It is critical to remember that insulin resistance or diabetes per se are disorders affecting more than just glucose metabolism. Increased free fatty acids and triglycerides are hallmarks of insulin resistance, particularly in the obese individual. In this context, whether factors other than glucose modulate fetal overgrowth and adiposity in overweight and obese women is a relevant question.

Is macrosomia or increased birthweight a sufficient measure of fetal overgrowth?

In the past 5 years, there has emerged solid clinical data based, on randomized clinical trials, that treatment of women with GDM can improve outcomes, in particular limiting fetal overgrowth. Both the Australian Carbohydrate Intolerance Study in Pregnant Women and the Maternal-Fetal Medicine Network (MFMU) trials have shown that treatment of GDM with lifestyle measures such as diet decreases the rate of macrosomia and in the case of the MFMU decreased fetal adiposity.

At birth, the human has one of the largest percentage of body fat in comparison with other mammalian species, approximately 12-15%, depending on the methodology used. In contrast, murine models have on the order of 1-3% body fat at birth. Even the nonhuman primate, such as the rhesus monkey, has only 3-5% body fat. As such, factors that are well known to affect fetal growth may differentially affect the various components of fetal body composition. The in utero metabolic environment is thought to primarily affect fetal fat mass and not lean body mass.

Previous studies have reported that neonates of women with well-controlled GDM have significantly increased fat mass but not lean body mass. This increase in fat mass persists, even when birthweights are appropriate for gestational age, race, and gender. Similarly, it is well recognized that neonates of overweight and obese women are significantly heavier at birth as compared with lean or average-weight women. These neonates are heavier because of an increase in fat and not lean body mass.

In summary, the in utero metabolic environment affects primarily growth of adipose and not lean body mass. The increase in birthweight in overweight/obese women, and even in women with well-controlled GDM, is because of increased fat and not lean body mass. Because increased adiposity at birth is related to both obesity and metabolic dysfunction, even in children, it is imperative to understand which factors are related to and amenable to preventive treatment during pregnancy.

Metabolic adaptations to pregnancy: role of lipids

There is a decreased ability of insulin to suppress lipolysis in late pregnancy. In addition to the increase in glucose after an oral glucose challenge or after a meal, there are significant increases in circulating lipids during human pregnancy ( Table ). In the third trimester, obese women have higher triglyceride, very low density lipoproteins (VLDL)-cholesterol, and lower high-density lipoprotein (HDL) concentrations as compared with lean women. Similarly, women with GDM have significantly higher triglyceride concentrations as compared with women with normal glucose tolerance.

Additional evidence for the insulin resistance relating to lipid metabolism during pregnancy was reported using euglycemic clamp studies. Infused insulin in women with GDM does not decrease free fatty acids (FFAs) to the degree observed in a weight-matched normal glucose-tolerant group. This is a mechanism that may increase the availability of FFA available for placental transport to the fetus.

Several clinical studies have suggested the contribution of maternal lipids to fetal growth in particular adiposity. Knopp et al, in 1985 reported that triglycerides hydrolyzed by placental lipoprotein lipase to FFAs were able to cross the placenta. These FFAs become incorporated into fetal lipids in normal pregnancy and exaggerated in women with GDM. Circulating triglyceride concentrations had a significant positive correlation with birthweight, independent of maternal obesity and glucose concentrations.

Similarly the serum triglycerides and prepregnancy BMI of women with a positive glucose screen but normal glucose tolerance both correlate with birthweight at term. Nonfasting maternal triglycerides measured at 9-12 weeks’ gestation were significantly correlated with neonatal birthweight ratio.

Lastly, in a well-controlled GDM population, maternal FFA concentrations were correlated with ultrasound estimates of neonatal abdominal circumference and neonatal fat mass at birth. Taken together, these data suggest that in women with evidence of decreased insulin sensitivity, increased maternal lipids, in particular triglycerides, may account for a significant proportion of fetal adiposity.

These data support the original work by Freinkel that although glucose was an important component relating to fetal growth, fetal overgrowth is a function multiple nutritional factors in addition to glucose.

Perinatal metabolic programming

Why is it important to investigate issues related to maternal obesity and fetal overgrowth? Certainly from a clinical perspective, fetal macrosomia affects our clinical management of the obese pregnant women. There is the increased risk of spontaneous abortion, congenital anomalies, stillbirth, shoulder dystocia, and cesarean delivery in obese pregnant women. Furthermore, because of the increased prevalence of obesity, as many as 15-20% of pregnant women may soon be classified as having GDM. These data are based on the results of the HAPO study and recommendations of the International Association of Diabetes in Pregnancy Study Groups. Obese women are also at increased risk to develop the chronic medical diseases associated with the metabolic syndrome, both during pregnancy and later in life.

However, from a public health perspective, an equal and potentially more important issue is the increased risk for the offspring of these women. Offspring of obese women have an increased risk of developing obesity and metabolic dysfunction in childhood, thereby perpetuating a vicious cycle of obesity and diabetes.

There are now multiple studies reporting that the infants of women diabetes are at increased risk of obesity and glucose intolerance as children and adolescents. Hillier et al also reported that increased glucose concentrations, less than currently used to define GDM, are associated with an increased risk of childhood obesity in a Kaiser population. Maternal pregravid obesity, even in women with well-controlled GDM, is the strongest risk factor for childhood obesity and metabolic dysfunction. The next steps in this review are to investigate the potential mechanisms relating to fetal obesity to develop prevention and treatment strategies.

Molecular mechanisms accounting for metabolic programming of the offspring

Based on the clinical evidence reviewed in the aforementioned text, changes in maternal lipid metabolism in pregnancy may account for an increased availability of lipid substrates for fetal growth and nutrition. The question then is what are the mechanisms that make the fetus fatter when maternal homeostasis becomes unbalanced, as with diabetes and obesity? Can increased fetal fat accretion be solely a result of excess maternal derived energy substrates? Are other factors increased in obesity such as inflammatory mediators facilitating fetal fat accretion?