Diabetes Volume 64, February 2015 327 Anthony R. Angueira,1 Anton E. Ludvik,1 Timothy E. Reddy,2,3 Barton Wicksteed,4 William L. Lowe Jr.,1 and Brian T. Layden1,5 New Insights Into Gestational Glucose Metabolism: Lessons Learned From 21st Century Approaches Diabetes 2015;64:327–334 | DOI: 10.2337/db14-0877 Pregnancy presents a unique physiological challenge that gestational diabetes mellitus (GDM) (i.e., new-onset hyper- requires changes coordinated by placentally and non– glycemia that presents during pregnancy) (1). Exemplifying PERSPECTIVES IN DIABETES placentally derived hormones to prepare the mother for the importance of studying GDM is that hyperglycemia the metabolic stress presented by fetal development and during pregnancy not only increases the risk of maternal to ensure appropriate nutrient allocation between mother type 2 diabetes (T2D), but also predisposes the developing and fetus. Of particular importance is the maintenance of fetus to poor metabolic health later in life (2). In this Per- normal glucose metabolism during pregnancy. Here, we spectives in Diabetes article, we first highlight key aspects of describe physiological changes in glucose metabolism normal gestational glucose metabolism. We then describe during pregnancy and highlight new insights into these new findings that have emerged in recent years spurred by adaptations that have emerged over the past decade us- new technologies (genome-wide association studies [GWAS], ing novel methodologies, specifically genome-wide asso- metabolomics, and gut microbiota investigations). Finally, ciation studies (GWAS) and metabolomics. While GWAS fi fi we place these ndings in context with current knowledge have identi ed some novel associations with metabolic fi traits during pregnancy, the majority of the findings over- in the eld and emphasize new directions emerging from lap with those observed in nonpregnant populations and these investigations. individuals with type 2 diabetes (T2D). Metabolomics stud- GESTATIONAL GLUCOSE METABOLISM ies have provided new insight into key metabolites in- volved in gestational diabetes mellitus (GDM). Both of Maternal adaptations occur in multiple systems, including these approaches have suggested that a strong link exists cardiovascular, respiratory, and metabolic, throughout between GDM and T2D. Most recently, a role of the gut pregnancy. These maternal adaptations aim to maintain microbiome in pregnancy has been observed, with a healthy balance between the mother and fetus while changes in the microbiome during the third trimester hav- ensuring proper fetal development. In the context of ing metabolic consequences for the mother. In this Per- glucose metabolism, these adaptations occur to ensure spectives in Diabetes article, we highlight how these new adequate shunting of glucose to promote fetal develop- data have broadened our understanding of gestational ment while maintaining adequate maternal nutrition. metabolism, and emphasize the importance of future This balance in glucose regulation is paramount to studies to elucidate differences between GDM and T2D. maternal-fetal health during all trimesters of gestation. Initially during gestation, fasting blood glucose levels drop A major challenge in maternal fetal medicine over the due, in part, to dilutional effects as maternal blood volume past few decades has been the increasing prevalence of increases, remain constant in the second trimester, and 1Division of Endocrinology, Metabolism and Molecular Medicine, Northwestern Corresponding author: Brian T. Layden, [email protected]. University Feinberg School of Medicine, Chicago, IL Received 3 June 2014 and accepted 2 September 2014. 2Department of Biostatistics and Bioinformatics, Duke University Medical Center, © 2015 by the American Diabetes Association. Readers may use this article as Durham, NC long as the work is properly cited, the use is educational and not for profit, and 3Institute of Genome Science and Policy, Duke University, Durham, NC the work is not altered. 4Kovler Diabetes Center, The University of Chicago, Chicago, IL 5Jesse Brown Veterans Affairs Medical Center, Chicago, IL 328 Metabolism and Pregnancy Diabetes Volume 64, February 2015 further decrease during the third trimester (3,4). Increased changes is decreased insulin sensitivity, which helps to glucose utilization by the fetal-placental unit throughout maintain normal glucose homeostasis in a manner that pregnancy, removing glucose from the maternal circula- is suitable for both mother and offspring. One direct con- tion, also contributes to the decline (3). During this pe- sequence of the marked decline in insulin sensitivity is riod of increased glucose utilization by the fetal-placental that circulating insulin levels, and consequently the secre- unit, maternal insulin sensitivity decreases. To compensate tory capacity of pancreatic b-cells, are increased as gesta- for these changes, both maternal hepatic gluconeogenesis tion progresses to maintain adequate maternal and fetal and fatty acid levels increase (3). While gravid fasting blood nutrition (9). glucose levels remain lower than pregravid fasted levels, Pancreatic b-Cell Adaptations postprandial glucose levels are elevated relative to the pre- Pancreatic b-cell adaptation is critical for the response to gravid state (5). This elevation is likely a result of impaired the decline in maternal insulin sensitivity. This response insulin action, leading to diminished postprandial glucose is mediated, at least in part, by maternal and placental utilization by the mother (3). Other contributing factors hormones such as prolactin and human placental lacto- may include altered pancreatic b-cell–mediated insulin se- gens, which have been shown to enhance insulin secretion cretion and hepatic gluconeogenesis (3). and also increase the size and number of pancreatic b-cells (11,12). Additionally, the activity and levels of Insulin Sensitivity glucokinase, the primary glucose sensor in b-cells, are in- As one of the key determinants of glucose homeostasis, creased in pancreatic b-cells during this insulin-resistant peripheral insulin sensitivity is dynamically altered through- phase of pregnancy, thus enhancing glucose-stimulated out pregnancy, initially increasing following embryonic insulin secretion at lower than normal blood glucose lev- implantation and decreasing markedly later in pregnancy. els (11). Interestingly, in addition to placental lactogens The mechanisms underlying the changes in insulin sensi- and glucokinase, paracrine and autocrine signaling by se- tivity have been detailed previously (6). rotonin may also contribute to b-cell adaptations to preg- In brief, during the first weeks of pregnancy, the nancy (13,14). Recently, the importance of microRNAs in presence of the fetal-placental unit causes a drop in growth regulating b-cell mass and function during pregnancy has hormone levels, resulting in enhanced insulin sensitivity been described. Specifically, miR-338-3p has been shown (6). After this period of increased sensitivity to insulin, to play a role in regulating b-cell proliferation during circulating levels of human placental lactogen, placentally gestation and is regulated by hormones such as estradiol derived human growth hormone (GH-V), progesterone, (15). The end result of these adaptations is increased cortisol, prolactin, and other hormones increase and con- pancreatic b-cell mass and a lower threshold for glucose- tribute to decreasing insulin sensitivity in peripheral tis- stimulated insulin secretion. sues such as adipocytes and skeletal muscle by interfering Of importance, the research described above has been with insulin receptor signaling (6). Elevated levels of these performed almost exclusively in rodent models, and there placentally and non–placentally derived hormones, partic- are likely differences in b-cell adaptations during preg- ularly progesterone, cortisol, and GH-V, lead to markedly nancy between humans and rodents, as has been previ- decreased insulin sensitivity during the second and third ously reported (12). For example, prolactin appears to trimesters of pregnancy, with the highest levels of insulin have a similar role in vitro in regulating pancreatic resistance occurring during the third trimester (3). The role b-cell function in humans and mice, but it is not clear of placentally derived hormones in mediating insulin re- whether the function of prolactin in vivo is similar (16). sistance is made evident by the marked decrease in insulin Likewise, it is not clear whether the action of other hor- resistance immediately postpartum (7). mones and receptors (e.g., GH-V and the prolactin recep- In addition to maternally and placentally derived hor- tor) differs between rodents and humans in mediating mones, changes in the production of inflammatory media- pregnancy-induced changes in b-cells (16). Additionally, tors by the placenta (e.g., tumor necrosis factor-a), and the focus of much of this past work has been on b-cell cytokines produced by adipose tissue also contribute to adaptation during the insulin-resistant phase, whereas, the decrease in insulin sensitivity in peripheral tissues the mechanisms underlying the increase in insulin sensi- (3,8,9). The role of cytokines during pregnancy has been tivity during early gestation as well as the return of pan- extensively reviewed previously (10). The levels of the creatic b-cell mass to prepregnancy levels during the adipocyte-derived hormone leptin, which acts as a sensor postpartum period remain