Cord Blood Advanced Lipoprotein Testing Reveals an Interaction between Gestational Diabetes and Birth-Weight and Suggests a New Early Biomarker of Infant Obesity

Abnormal lipid metabolism is associated with gestational diabetes mellitus (GDM) and is observed in neonates with abnormal fetal growth. However, the underlying specific changes in the lipoprotein profile remain poorly understood. Thus, in the present study we used a novel nuclear magnetic resonance (NMR)-based approach to profile the umbilical cord serum lipoproteins. Two-dimensional diffusion-ordered 1H-NMR spectroscopy showed that size, lipid content, number and concentration of particles within their subclasses were similar between offspring born to control (n = 74) and GDM (n = 62) mothers. Subsequent data stratification according to newborn birth-weight categories, i.e., small (n = 39), appropriate (n = 50) or large (n = 49) for gestational age (SGA, AGA and LGA, respectively), showed an interaction between GDM and birth-weight categories for intermediate-density lipoproteins (IDL)-cholesterol content and IDL- and low-density lipoproteins (LDL)-triglyceride content, and the number of medium very low-density lipoproteins (VLDL) and LDL particles specifically in AGA neonates. Moreover, in a 2-year follow-up study, we observed that small LDL particles were independently associated with offspring obesity at 2 years (n = 103). Collectively, our data demonstrate that GDM disturbs triglyceride and cholesterol lipoprotein content across birth-weight categories, with AGA neonates born to GDM mothers displaying a profile more similar to that of adults with dyslipidemia. Furthermore, an altered fetal lipoprotein pattern was associated with the development of obesity at 2 years

The ANGPTL3-4-8 Axis in Normal Gestation and in Gestational Diabetes, and Its Potential Involvement in Fetal Growth

Dyslipidemia in gestational diabetes has been associated with worse perinatal outcomes. The ANGPTL3-4-8 axis regulates lipid metabolism, especially in the transition from fasting to feeding. In this study, we evaluated the response of ANGPTL3, 4, and 8 after the intake of a mixed meal in women with normal glucose tolerance and gestational diabetes, and we assessed their gene expressions in different placental locations. Regarding the circulating levels of ANGPTL3, 4, and 8, we observed an absence of ANGPTL4 response after the intake of the meal in the GDM group compared to its presence in the control group. At the placental level, we observed a glucose tolerance-dependent expression pattern of ANGPTL3 between the two placental sides. When we compared the GDM pregnancies with the control pregnancies, a downregulation of the maternal side ANGPTL3 expression was observed. This suggests a dysregulation of the ANGPTL3-4-8 axis in GDM, both at the circulating level after ingestion and at the level of placental expression. Furthermore, we discerned that the expressions of ANGPTL3, 4, and 8 were related to birth weight and placental weight in the GDM group, but not in the control group, which suggests that they may play a role in regulating the transplacental passage of nutrients

Gestational diabetes impacts fetal precursor cell responses with potential consequences for offspring

Fetal programming has been proposed as a key mechanism underlying the association between intrauterine exposure to maternal diabetes and negative health outcomes in offspring. To determine whether gestational diabetes mellitus (GDM) might leave an imprint in fetal precursors of the amniotic membrane and whether it might be related to adverse outcomes in offspring, a prospective case-control study was conducted, in which amniotic mesenchymal stem cells (AMSCs) and resident macrophages were isolated from pregnant patients, with either GDM or normal glucose tolerance, scheduled for cesarean section. After characterization, functional characteristics of AMSCs were analyzed and correlated with anthropometrical and clinical variables from both mother and offspring. GDM-derived AMSCs displayed an impaired proliferation and osteogenic potential when compared with control cells, accompanied by superior invasive and chemotactic capacity. The expression of genes involved in the inflammatory response (TNFα, MCP-1, CD40, and CTSS) was upregulated in GDM-derived AMSCs, whereas anti-inflammatory IL-33 was downregulated. Macrophages isolated from the amniotic membrane of GDM mothers consistently showed higher expression of MCP-1 as well. In vitro studies in which AMSCs from healthy control women were exposed to hyperglycemia, hyperinsulinemia, and palmitic acid confirmed these results. Finally, genes involved in the inflammatory response were associated with maternal insulin sensitivity and prepregnancy body mass index, as well as with fetal metabolic parameters. These results suggest that the GDM environment could program stem cells and subsequently favor metabolic dysfunction later in life. Fetal adaptive programming in the setting of GDM might have a direct negative impact on insulin resistance of offspring