Metabolic Culprits in Obese Pregnancies and Gestational Diabetes Mellitus: Big Babies, Big Twists, Big Picture

Abstract

Pregnancy has been equated to a "stress test" in which placental hormones and growth factors expose a mother's predisposition toward metabolic disease, unleashing her previously occult insulin resistance (IR), mild b-cell dysfunction, and glucose and lipid surplus due to the formidable forces of pregnancy-induced IR. Although pregnancy-induced IR is intended to assure adequate nutrition to the fetus and placenta, in mothers with obesity, metabolic syndrome, or those who develop gestational diabetes mellitus, this overnutrition to the fetus carries a lifetime risk for increased metabolic disease. Norbert Freinkel, nearly 40 years ago, coined this excess intrauterine nutrient exposure and subsequent offspring developmental risk "fuel-mediated teratogenesis," not limited to only excess maternal glucose. Our attempts to better elucidate the causes and mechanisms behind this double-edged IR of pregnancy, to metabolically characterize the intrauterine environment that results in changes in newborn body composition and later childhood obesity risk, and to examine potential therapeutic approaches that might target maternal metabolism are the focus of this article. Rapidly advancing technologies in genomics, proteomics, and metabolomics offer us innovative approaches to interrogate these metabolic processes in the mother, her microbiome, the placenta, and her offspring that contribute to a phenotype at risk for future metabolic disease. If we are successful in our efforts, the researcher, endocrinologist, obstetrician, and health care provider fortunate enough to care for pregnant women have the unique opportunity to positively impact health outcomes not only in the short term but in the long run, not just in one life but in twodand possibly, for the next generation.

BMI growth trajectory from ages 2 to 6 years and its association with maternal obesity, diabetes during pregnancy, gestational weight gain, and breastfeeding

“…Potential biological mechanisms linking the association between maternal obesity and diabetes during pregnancy and growth trajectory involve “fuel‐mediated teratogenesis” that includes maternal glucose and lipids as well as amino acids . Maternal obesity per se is associated with high levels of glucose, lipids, amino acids, inflammatory changes, and insulin resistance beyond normal pregnancy and diabetes . These abnormalities in the intrauterine environment and the long‐term exposure starting from early prenatal period for the entire pregnancy may in part explain the greater effect of prepregnancy obesity or overweight on growth trajectory in offspring than diabetes or weight gain during pregnancy or postnatal breastfeeding.…”

Determinants of Maternal Insulin Resistance during Pregnancy: An Updated Overview

“…Likewise, studies have reported a causal link between maternal smoking and subsequent increased risk of insulin resistance, type 2 diabetes, and hypertension, although the evidence here is weaker than that for overweight/obesity [64]. At the other end of the spectrum, intrauterine exposure to hyperglycemia and/or maternal obesity also increases the risk of later life obesity and impaired glucose tolerance [22, 65, 66]. A recent study describes how intrauterine exposure to hyperglycemia affects the offspring in a sex-specific way, with females being more prone to the effects [67].…”

“…The hPGH may also have the same diabetogenic effects as pituitary growth hormone such as hyperinsulinemia, decreased insulin-stimulated glucose uptake and glycogen synthesis, and impairment of the ability of insulin to suppress hepatic gluconeogenesis. Some of these effects have been demonstrated in rodents in vitro [22], whereas the effects during human pregnancy are less evident [23]. It appears that hPGH is the driver of the levels of insulin-like growth factors (IGFs) during pregnancy [24, 25], thereby indicating an interplay between GH, hPGH, IGFs, and insulin-like growth factors binding proteins (IGF-BPs), which might be the pathway coupling insulin resistance and the growth hormone axis during pregnancy.…”

Exploration of the shared pathophysiological mechanisms of gestational diabetes and large for gestational age offspring

“…Finally, while many gaps remain in the current state of knowledge, techno-logical advancements are likely to be a key driver of developments in this space. Indeed, contributions from fields such as metabolomics are already shedding light on the mechanisms underlying GDM[50]. Analytical techniques such as mass spectrometry and nuclear magnetic resonance spectroscopy have been employed to investigate metabolic profiles associated with GDM and hence determine the pathways leading to insulin resistance[50].…”

“…Indeed, contributions from fields such as metabolomics are already shedding light on the mechanisms underlying GDM[50]. Analytical techniques such as mass spectrometry and nuclear magnetic resonance spectroscopy have been employed to investigate metabolic profiles associated with GDM and hence determine the pathways leading to insulin resistance[50]. Lipid and amino acid molecules have been most consistently identified by these processes thus far[51].…”