Banting Lecture 1980: of Pregnancy and Progeny

Abstract

A profile characteristic of fuel economy in the mother during normal pregnancy has been delineated. The evidence indicates that pregnancy changes the metabolism of every class of foodstuff. The mechanisms by which the conceptus may be implicated are reviewed. The gestational interactions create a pattern of "accelerated starvation" whenever food is withheld, especially in late pregnancy, and they tend to "facilitate anabolism" when food is ingested. The consequent heightened metabolic oscillations during the shuttlings from fed to fasted state provide a basis for more aggressive therapy with exogenous insulin when endogenous insulin is lacking in pregnancy. It is emphasized that developing fetal structures may be exquisitely attuned to fine alterations in maternal fuel economy and that pregnancy complicated by diabetes may merely exaggerate these normal dependencies since maternal insulin affects all maternal fuels. The manifest changes in the offspring of mothers with even the mildest limitations in insulin reserve, i.e., gestational diabetes, attest to the sensitivity of the relationships. It is suggested that concepts of teratogenesis should be expanded to include alterations occurring subsequent to organogenesis during the differentiation and proliferation of fetal cells. Such changes could cause long-range effects upon behavioral, anthropometric, and metabolic functions. It is hypothesized that all of these could constitute expressions of fuel-mediated teratogenesis and that the potentialities should be incorporated into any evaluation of the outcome of pregnancy in gestations attended by disturbances in maternal fuel metabolism.

Transmission of Obesity-Adiposity and Related Disorders from the Mother to the Baby

“…Insulin is a major growth hormone in utero and promotes the growth of insulin-sensitive tissues and organs, leading to fetal adiposity and macrosomia at birth. Freinkel [4] expanded this idea to suggest that the increased risk of postnatal obesity and diabetes was a ‘fuel-mediated teratogenesis' by comparing these common long-term outcomes with rare disfiguring birth defects (for example, neural tube defects). He proposed that this was mediated by a ‘stable change in gene expression', which we now call epigenetic programming, and not on the inherited genetic trait (fig.…”

“…This thought started with the demonstration that those exposed to the Dutch Hunger Winter in utero had an altered risk of obesity as adults [3]. This was followed by the ‘fuel-mediated teratogenesis' idea in diabetic pregnancies [4] and was finally established with the ‘thrifty phenotype' hypothesis from Southampton (UK) [5,6]. Recent ideas have focused on the ‘first 1,000 days' of life as the most important window in the programming of health and disease and offer hope that an intervention in early life could help prevent these disorders.…”

“…6 ‘Fuel-mediated teratogenesis' refers to an excess transfer of fuels (glucose, amino acids and fatty acids) across the placenta to the developing fetus which causes ‘stable change in gene expression' affecting not only perinatal but also long-term outcomes in the offspring (obesity and diabetes) [4,31]. IGT = Impaired glucose tolerance; DM = diabetes mellitus.…”

Intrauterine Adiposity and BMI in 4- to 5-Year-Old Offspring from Diabetic Pregnancies

“…As children, adolescents and adults, offspring from women with diabetes are at risk for obesity, type 2 diabetes, and the metabolic syndrome [4,5,6,7,8,9,10]. The fuel-mediated teratogenesis described by Pedersen and later extended by Freinkel [11] states that maternal hyperglycemia leads to increased transplacental transfer of glucose, lipids, and amino acids which in turn lead to fetal hyperinsulinism and increased growth. Maternal insulin itself does not cross the placenta.…”

“…Maternal insulin itself does not cross the placenta. The effect of maternal metabolic abnormalities is reflected in wide-ranging changes in fetal islets, fat stores, and muscles, and perhaps even changes in habitus [11]. This cascade, set off by an abnormal intrauterine environment, may lead to changes in offspring phenotype [12].…”