Impact of gestational diabetes on fetal precursors and lipoprotein profileeffects on offspring

Resumen

This work study the impact of gestational diabetes mellitus (GDM) on the functionality of fetal precursor cells found in the amniotic membrane and on the morphological and functional characteristics of fetal lipoproteins, and also whether these potential disturbances could program the fetal metabolism and directly contribute to the higher predisposition to metabolic and cardiovascular diseases later in life. This work studies the impact of gestational diabetes mellitus (GDM) on the functionality of fetal precursor cells found in the amniotic membrane and on the morphological and functional characteristics of fetal lipoproteins, and also whether these potential disturbances could program the fetal metabolism and directly contribute to the higher predisposition to metabolic and cardiovascular diseases later in life. BACKGROUND AND OBJECTIVES Pregnancy is a dynamic state that encompasses changes in the metabolism of the mother to ensure an adequate growth and development of the fetus. GDM is one of the most common pregnancy complications and has been associated with maternal nutritional and metabolic alterations that disturbs the metabolic adaptations of pregnancy, including an exacerbated IR that favors an excessive nutrient availability and uptake by the fetus. These derangements have been associated with altered growth patterns and increased predisposition for developing later diseases in life by fetal programming. Fetal precursor cells and lipid metabolism are key components of fetal programming that can be directly affected by GDM. Several studies pointed the great impact of GDM on the functionality of mesenchymal stem cells (MSCs) from extraembryonic tissues and the umbilical cord lipoprotein profile. The amniotic membrane (AM) is in contact with the amniotic fluid and the fetus and, as such, its stem cell component might be a good indicator of how the intrauterine environment impacts the fetus. On the other hand, 1H-NMR-based lipoprotein tests have demonstrated higher detection capacity of subtle lipoprotein abnormalities and to have a greater ability to predict cardiovascular risk than classical cholesterol determinations. For these reasons, we decided to study the influence of GDM on the functional characteristics of the amniotic mesenchymal stem cells (AMSCs) and on the fetal advanced lipoprotein profile across birth weight categories, in order to explore a potential relationship with fetal parameters associated with adverse outcomes that may have a prognostic value. METHODS We carried out two observational case-control studies. In the first one, AMSCs and resident macrophages were isolated from eighteen pregnant (9 diagnosed with GDM and 9 with 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. In the second one, 62 GDM and 74 normal glucose tolerant pregnant and their offspring were included. Newborns were classified according to birth-weight as small, appropriate or large for gestational age (SGA, AGA and LGA, respectively). Advanced 1H-nuclear magnetic resonance (NMR)-based lipoprotein test was used to profile cord blood serum lipoproteins. Height and weight data of the offspring up to two years was used to estimate age- and sex-specific body mass index. RESULTS We observed that GDM induces a pro-inflammatory profile in AMSCs accompanied by a higher chemotactic and invasive activities, and it also modifies their plasticity, affecting proliferation and differentiation potential. Consistently, AM-resident macrophages also displayed a more pro-inflammatory phenotype. Moreover, genes involved in AMSCs inflammatory response were associated with maternal insulin sensitivity and pre-pregnancy body mass index, as well as with fetal metabolic parameters, suggesting that the GDM environment could program stem cells and subsequently favor metabolic dysfunction later in life. On the other hand, using advanced 1H-NMR-based lipoprotein test we found a disturbed triglyceride and cholesterol lipoprotein content in offspring of GDM mothers across birth categories. Concretely, AGA neonates born to GDM mothers showed a profile more similar to adults with dyslipidemia and atherosclerosis than to those born to control women. In addition, lipoprotein parameters were independently associated with offspring obesity at two years old, indicating a possible implication of an altered fetal lipoprotein profile in the greater predisposition to future adverse outcomes. CONCLUSIONS We demonstrate that GDM induces changes in the biological characteristics of AMSCs, many of which are related to fetal metabolic parameters, suggesting that the GDM environment could program stem cells and subsequently favor metabolic dysfunction later in life. On the other hand, we found a disturbed triglyceride and cholesterol lipoprotein content in offspring of GDM mothers across birth categories, with AGA neonates showing a profile more similar to adults with dyslipidemia and atherosclerosis than those born to control women. Moreover, we find that LDL particles are potential biomarkers of obesity later in life.