Metabolic Culprits in Obese Pregnancies and Gestational Diabetes Mellitus: Big Babies, Big Twists, Big Picture : The 2018 Norbert Freinkel Award Lecture.

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 β-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 two-and possibly, for the next generation.