Over 100,000 pregnant women with overt type 2 diabetes (T2DM) give birth in the United States every year and this number is expected to double by 2030. Medical treatment of T2DM in pregnancy is generally restricted to insulin because data on the safety and efficacy of oral hypoglycemic agents (e.g., metformin) for T2DM are limited. However, over one-third of infants born to women with T2DM experience an adverse outcome, such as premature delivery, large-for-gestational age (LGA), hypoglycemia, hyperbilirubinemia, or birth trauma, suggesting that current treatment regimens fall short of optimizing outcomes. The lack of clinical trials enrolling pregnant women limits our knowledge about the critical role of the placenta in pregnancy outcomes. The placenta is a temporary organ in pregnancy that supplies the fetus with nutrition, protects the fetus from toxins, and eliminates waste from the fetus. This barrier function is maintained by placental drug transport proteins (e.g., MultiDrug Resistance protein, MDR1; Breast Cancer Resistance Protein, BCRP; Organic Anion Transporting Polypeptide, OATP2A1 and OATP2B1; Organic Cation Transporter, OCT3). In addition, glucose transporters (GLUT) are responsible for the transplacental movement of glucose, which is essential in T2DM pregnant women. These placental transport proteins are not well-characterized in pregnant women with T2DM treated with insulin alone or with insulin plus metformin. The long-term goal in the parent award is to optimize maternal and infant outcomes in T2DM complicating pregnancy with metformin treatment. The goal in this administrative supplement is to measure T2DM- and metformin-mediated effects on placental transport proteins. The central hypothesis is that key placental drug and GLUT transport proteins are upregulated in women with T2DM treated with insulin alone compared to healthy women, which could lead to increased exposure of the fetus to medications and a higher supply of glucose to the fetus. Importantly, we hypothesize that metformin treatment of pregnant women with T2DM will result in downregulation of key placental drug and GLUT transport proteins to normal levels. We will test these hypotheses by quantitative targeted proteomic analyses of some of the placental tissue collected for the parent study. We propose the following specific aims: 1) Quantify protein levels of key placental transporters in pregnant women with and without T2DM, and 2) Determine the effect of metformin on protein levels of key placental transporters. Completion of these studies will provide critical information on the role of placental transport proteins in drug safety and efficacy in pregnant women.
Predicting drug safety and efficacy in the large number of pregnant women in the United States who have type 2 diabetes mellitus (T2DM) treated with insulin, or insulin plus metformin, is critical for optimizing pregnancy outcomes. There is currently a dearth of information on T2DM- and drug-mediated effects on placental transport proteins, which regulate fetal exposure to nutrients, medications and toxins. This study will elucidate these effects and provide critical information needed to predict the safety and efficacy of pharmacologic treatments in pregnant women with T2DM including medication exposure to unborn babies.
