The Pedersen hypothesis was formulated more than 50 years ago. Jorgen Pedersen primarily cared for women with type 1 diabetes. He suggested that fetal overgrowth was related to increased transplacental transfer of glucose, stimulating the release of insulin by the fetal beta cell and subsequent macrosomia. Optimal maternal glucose control decreased perinatal mortality and morbidity. However, over the ensuing decades, there have been increases in maternal obesity and subsequently gestational diabetes mellitus (GDM) and type 2 diabetes. The underlying pathophysiology of type 1 and GDM/type 2 diabetes are fundamentally different, type 1 diabetes being primarily a disorder of beta cell failure and type 2 diabetes/GDM including both insulin resistance and beta cell dysfunction. As such the metabolic milieu in which the developing fetus is exposed may be quite different in type 1 diabetes and obesity. In this review we examine the metabolic environment of obese diabetic women and lipid metabolism affecting fetal adiposity. The importance of understanding these issues relates to the increasing trends of obesity worldwide with perinatal programming of metabolic dysfunction in the offspring.
Over the last 2 decades, there has been a significant increase in obesity in the general population of industrialized countries and a growing concern in the developing world as well. In the United States in 2009, approximately 68% of the population is overweight (body mass index [BMI], kilograms per square meter) defined as a BMI greater than 25 kg/m 2 . Thirty-five percent of the adult female population is obese with a BMI greater than 30 kg/m 2 , and fully 7.2% have significant or class III obesity (ie, a BMI >40 kg/m 2 ).
The increase in obesity is not limited to adults but affects 15-25% of children as young as 2 years of age. The increase in obesity has disproportionately affected minority populations. How do the changes in the demographics of the population affect the manner in which we care for pregnant women?
We clearly recognize that the maternal metabolic environment of women with poorly controlled diabetes at conception increases the risk of congenital anomalies (ie, fuel mediated teratogenesis). However, we often pay little heed to the periconceptual environment in the woman who is overweight or obese. Obese women are at risk for early pregnancy loss and congenital anomalies, such as neural tube defects. There is also increasing evidence that the maternal metabolic environment may have long-term effects on the developing fetus (ie, perinatal metabolic programming).
The effects of this obesogenic environment on long-term childhood development may be more subtle than phenotypic congenital anomalies. For example, epigenetic changes in the fetoplacental unit affecting the risk of chronic disease such as hypertension, diabetes, and cardiovascular dysfunction may become clinically manifest only decades later. Hence, this review will focus on how the obesity epidemic has altered our understanding of the maternal metabolic environment, causing us to rethink and critically examine our beliefs and practices relating to fetal growth.
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?
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