Impact of gestational diabetes on fetal precursors and lipoprotein profile: effects on offspring

La diabetis mellitus gestacional (DMG) és una de les complicacions més comunes de l'embaràs i s'ha associat amb alteracions metabòliques i nutricionals maternes que pertorben les adaptacions metabòliques d'ell mateix. Aquests trastorns s'han associat amb patrons de creixement alterats i una major predisposició a desenvolupar malalties posteriors a la vida per la programació fetal. Les cèl·lules precursores fetals i el metabolisme dels lípids són components clau de la programació fetal que es poden veure directament afectats per la DMG. Aquest treball estudia l'impacte de la DMG en la funcionalitat de les cèl·lules precursores fetals trobades en la membrana amniòtica i en les característiques morfològiques i funcionals de les lipoproteïnes fetals, i també si aquestes alteracions potencials podrien programar el metabolisme fetal i contribuir directament a la major predisposició a malalties metabòliques i cardiovasculars durant el desenvolupament de la vida adulta. Portem a terme dos estudis observacionals cas-control amb DMG i embarassades amb tolerància normal a la glucosa. Vam demostrar que la DMG indueix canvis en les característiques biològiques de les cèl·lules mare mesenquimàtiques de la membrana amniòtica (AMSC), moltes de les quals estan relacionades amb paràmetres metabòlics fetals, el que suggereix que l'entorn de la DMG podria programar les cèl·lules mare i posteriorment afavorir la disfunció metabòlica més endavant en la vida. D'altra banda, trobem un contingut alterat de triglicèrids i lipoproteïnes de colesterol a la descendència de mares amb DMG dividida per categories de naixement. Concretament, els nounats amb pes adequat per a l'edat gestacional (AGA) mostren un perfil més similar als adults amb dislipidèmia i aterosclerosi que els nascuts de mares DMG. A més, trobem que les partícules de lipoproteïnes de baixa densitat (LDL) són biomarcadors potencials d'obesitat futura.La diabetes mellitus gestacional (DMG) es una de las complicaciones más comunes del embarazo y se ha asociado con alteraciones metabólicas y nutricionales maternas que perturban las adaptaciones metabólicas del mismo. Estos trastornos se han asociado con patrones de crecimiento alterados y una mayor predisposición a desarrollar enfermedades posteriores en la vida por la programación fetal. Las células precursoras fetales y el metabolismo de los lípidos son componentes clave de la programación fetal que pueden verse directamente afectados por la DMG. Este trabajo estudia el impacto de la DMG en la funcionalidad de las células precursoras fetales encontradas en la membrana amniótica y en las características morfológicas y funcionales de las lipoproteínas fetales, y también si estas alteraciones potenciales podrían programar el metabolismo fetal y contribuir directamente a la mayor predisposición a enfermedades metabólicas y cardiovasculares durante el desarrollo de la vida adulta. Llevamos a cabo dos estudios observacionales caso-control con DMG y embarazadas con tolerancia normal a la glucosa. Demostramos que la DMG induce cambios en las características biológicas de las células madre mesenquimatosas de la membrana amniótica (AMSC), muchas de las cuales están relacionadas con parámetros metabólicos fetales, lo que sugiere que el entorno de la DMG podría programar las células madre y posteriormente favorecer la disfunción metabólica más adelante en la vida. Por otro lado, encontramos un contenido alterado de triglicéridos y lipoproteínas de colesterol en la descendencia de madres con DMG dividida por categorías de nacimiento. Concretamente, los neonatos con peso adecuado para la edad gestacional (AGA) muestran un perfil más similar a los adultos con dislipidemia y aterosclerosis que los nacidos de madres DMG. Además, encontramos que las partículas de lipoproteína de baja densidad (LDL) son biomarcadores potenciales de obesidad futura

Relationship between the Ingestion of a Polyphenol-Rich Drink, Hepcidin Hormone, and Long-Term Training

The effects of polyphenol-rich foods on the iron status of athletes, as well as the effect of physical training on the hormone hepcidin, implicated in iron metabolism, are not clear. We investigated the influence on iron metabolism of a long-term training intervention of 120 days, measuring the hepcidin concentration in the plasma of 16 elite triathletes, and the effect of the ingestion of 200 mL of either aronia-citrus juice or a placebo drink for 45 days, in a crossover design. The highest plasma hepcidin concentrations were observed at the beginning of the study (116 ± 63 nM) and levels steadily decreased until the end of the intervention (final value 10 ± 7.5 nM). Long-term training might reduce inflammation and, hence, could be responsible for the decrease in hepcidin in triathletes. Polyphenols from aronia-citrus juice did not interfere in iron absorption, as we did not observe significant differences between the intake of the placebo drink or juice with regard to hepcidin levels. Further studies are required to ascertain the time and conditions necessary to restore hepcidin levels, which reflect the iron status of triathletes.The study received financial support from the National Funding Agencies, through the Project AGL2011-23690 (CICYT). Sonia Medina is grateful to the CICYT for a research contract (AGL2011-23690). This work has been partially funded by the “Fundación Séneca de la Región de Murcia” Grupo de Excelencia 19900/GERM/15

Anti-TNF Therapies Suppress Adipose Tissue Inflammation in Crohn's Disease

Anti-TNF biologics have been shown to markedly improve the quality of life for patients with Crohn's disease (CD), yet one-third of patients fail to benefit from this treatment. Patients with CD develop a characteristic wrapping of visceral adipose tissue (VAT) in the inflamed intestinal area, termed creeping fat, and it is known that adipose tissue expansion influences the efficacy of anti-TNF drugs. We questioned whether anti-TNF therapies impact the creeping fat in CD, which might affect the outcome of the disease. Adipose tissue biopsies were obtained from a cohort of 14 patients with CD that received anti-TNF drugs and from 29 non-anti-TNF-treated patients (control group) matched by sex, age, and body mass index undergoing surgical interventions for symptomatic complications. We found that anti-TNF therapies restored adipose tissue morphology and suppressed immune cell infiltration in the creeping fat. Additionally, anti-TNF treatments appeared to markedly improve the pro-inflammatory phenotype of adipose-tissue macrophages and adipose-tissue-derived stem cells. Our study provides evidence that anti-TNF medications influence immune cells and progenitor cells in the creeping of patients with CD, suppressing inflammation. We propose that perilesional VAT should be considered when administering anti-TNF therapy in patients with C

Impact of gestational diabetes on fetal precursors and lipoprotein profile: effects on offspring

La diabetis mellitus gestacional (DMG) és una de les complicacions més comunes de l'embaràs i s'ha associat amb alteracions metabòliques i nutricionals maternes que pertorben les adaptacions metabòliques d'ell mateix. Aquests trastorns s'han associat amb patrons de creixement alterats i una major predisposició a desenvolupar malalties posteriors a la vida per la programació fetal. Les cèl·lules precursores fetals i el metabolisme dels lípids són components clau de la programació fetal que es poden veure directament afectats per la DMG. Aquest treball estudia l'impacte de la DMG en la funcionalitat de les cèl·lules precursores fetals trobades en la membrana amniòtica i en les característiques morfològiques i funcionals de les lipoproteïnes fetals, i també si aquestes alteracions potencials podrien programar el metabolisme fetal i contribuir directament a la major predisposició a malalties metabòliques i cardiovasculars durant el desenvolupament de la vida adulta. Portem a terme dos estudis observacionals cas-control amb DMG i embarassades amb tolerància normal a la glucosa. Vam demostrar que la DMG indueix canvis en les característiques biològiques de les cèl·lules mare mesenquimàtiques de la membrana amniòtica (AMSC), moltes de les quals estan relacionades amb paràmetres metabòlics fetals, el que suggereix que l'entorn de la DMG podria programar les cèl·lules mare i posteriorment afavorir la disfunció metabòlica més endavant en la vida. D'altra banda, trobem un contingut alterat de triglicèrids i lipoproteïnes de colesterol a la descendència de mares amb DMG dividida per categories de naixement. Concretament, els nounats amb pes adequat per a l'edat gestacional (AGA) mostren un perfil més similar als adults amb dislipidèmia i aterosclerosi que els nascuts de mares DMG. A més, trobem que les partícules de lipoproteïnes de baixa densitat (LDL) són biomarcadors potencials d'obesitat futura.La diabetes mellitus gestacional (DMG) es una de las complicaciones más comunes del embarazo y se ha asociado con alteraciones metabólicas y nutricionales maternas que perturban las adaptaciones metabólicas del mismo. Estos trastornos se han asociado con patrones de crecimiento alterados y una mayor predisposición a desarrollar enfermedades posteriores en la vida por la programación fetal. Las células precursoras fetales y el metabolismo de los lípidos son componentes clave de la programación fetal que pueden verse directamente afectados por la DMG. Este trabajo estudia el impacto de la DMG en la funcionalidad de las células precursoras fetales encontradas en la membrana amniótica y en las características morfológicas y funcionales de las lipoproteínas fetales, y también si estas alteraciones potenciales podrían programar el metabolismo fetal y contribuir directamente a la mayor predisposición a enfermedades metabólicas y cardiovasculares durante el desarrollo de la vida adulta. Llevamos a cabo dos estudios observacionales caso-control con DMG y embarazadas con tolerancia normal a la glucosa. Demostramos que la DMG induce cambios en las características biológicas de las células madre mesenquimatosas de la membrana amniótica (AMSC), muchas de las cuales están relacionadas con parámetros metabólicos fetales, lo que sugiere que el entorno de la DMG podría programar las células madre y posteriormente favorecer la disfunción metabólica más adelante en la vida. Por otro lado, encontramos un contenido alterado de triglicéridos y lipoproteínas de colesterol en la descendencia de madres con DMG dividida por categorías de nacimiento. Concretamente, los neonatos con peso adecuado para la edad gestacional (AGA) muestran un perfil más similar a los adultos con dislipidemia y aterosclerosis que los nacidos de madres DMG. Además, encontramos que las partículas de lipoproteína de baja densidad (LDL) son biomarcadores potenciales de obesidad futura

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

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

The Genetic Diversity and Dysfunctionality of Catalase Associated with a Worse Outcome in Crohn’s Disease

Chronic gut inflammation in Crohn’s disease (CD) is associated with an increase in oxidative stress and an imbalance of antioxidant enzymes. We have previously shown that catalase (CAT) activity is permanently inhibited by CD. The purpose of the study was to determine whether there is any relationship between the single nucleotide polymorphisms (SNPs) in the CAT enzyme and the potential risk of CD associated with high levels of oxidative stress. Additionally, we used protein and regulation analyses to determine what causes long-term CAT inhibition in peripheral white mononuclear cells (PWMCs) in both active and inactive CD. We first used a retrospective cohort of 598 patients with CD and 625 age-matched healthy controls (ENEIDA registry) for the genotype analysis. A second human cohort was used to study the functional and regulatory mechanisms of CAT in CD. We isolated PWMCs from CD patients at the onset of the disease (naïve CD patients). In the genotype-association SNP analysis, the CAT SNPs rs1001179, rs475043, and rs525938 showed a significant association with CD (p < 0.001). Smoking CD patients with the CAT SNP rs475043 A/G genotype had significantly more often penetrating disease (p = 0.009). The gene expression and protein levels of CAT were permanently reduced in the active and inactive CD patients. The inhibition of CAT activity in the PWMCs of the CD patients was related to a low concentration of CAT protein caused by the downregulation of CAT-gene transcription. Our study suggests an association between CAT SNPs and the risk of CD that may explain permanent CAT inhibition in CD patients together with low CAT gene and protein expression