RESUMEN
BACKGROUND AND AIMS: Pregnant women have significant morbidity and mortality due to COVID-19 infection. Pregnancy and diabetes are known risk factors for severe COVID 19 infection. Understanding the interactions between COVID-19 and diabetes in pregnancy is crucial in developing appropriate therapeutic approaches. India, like many other countries, has a very high prevalence of diabetes and COVID-19 infected cases. Such studies are minimal worldwide and none from India to the best of our knowledge. MATERIALS AND METHODS: We did a retrospective cross-sectional study. 856 COVID-19 infected pregnant women were included in the study. We estimated the impact of diabetes on the severity of COVID-19 infected pregnant women and compared the outcomes with the non-diabetic group. RESULTS: Prevalence of diabetes in pregnancy in the present study was 15.43%(n = 132/856). Prevalence of diabetes in non-severe infection was 14%(n = 115/818), severe infection was 44.73%(n = 17/38), and in maternal deaths was 75% (n = 6/8). The age-adjusted odds ratio for diabetes for severe infection was 4.492 (95% CI = 2.277-8.865, p < 0.001). COVID-19 infected pregnant women with diabetes were at higher risk for Cesarean section (78.3%) and ICU admission for newborns (14.81%) CONCLUSION: Diabetes in pregnant women is strongly associated with the severity of COVID-19 infection. The prevalence of diabetes in pregnancy increases as the severity of COVID-19 infection increases. Diabetes is associated with more adverse outcomes in mothers and newborns. It is necessary to identify pregnant women with diabetes and prioritize them in public health interventions like vaccination.
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COVID-19/epidemiología , COVID-19/patología , Diabetes Gestacional/epidemiología , Complicaciones Infecciosas del Embarazo , Embarazo en Diabéticas/epidemiología , Adolescente , Adulto , COVID-19/complicaciones , Comorbilidad , Estudios Transversales , Diabetes Gestacional/patología , Femenino , Humanos , India/epidemiología , Recién Nacido , Masculino , Gravedad del Paciente , Embarazo , Complicaciones Infecciosas del Embarazo/epidemiología , Complicaciones Infecciosas del Embarazo/patología , Resultado del Embarazo/epidemiología , Embarazo en Diabéticas/patología , Prevalencia , Estudios Retrospectivos , SARS-CoV-2/fisiología , Adulto JovenRESUMEN
Atomic force microscopy is not very popular in practical health care, therefore, its potential is not studied enough, for example, in obstetrics when studying the "mother-placenta-fetus" system. Our study summarizes the possibilities of using atomic force microscopy for detection of various circulatory disorders and vascular changes at the microscopic level in the uterus (endometrium and myometrium), placenta, and umbilical cord in the main variants of obstetric and endocrine pathology. For instance, in the case of endocrine pathologies, changes in the form of stasis, sludge, diapedesis, ischemia, destruction and separation of endotheliocytes in villous blood vessels were found in the mother. The oxygen content in erythrocytes also naturally decreased in pathologies; poikilo- and anisocytosis were observed.
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Microscopía de Fuerza Atómica , Complicaciones del Embarazo/diagnóstico , Diagnóstico Prenatal/métodos , Adulto , Estudios de Casos y Controles , Vellosidades Coriónicas/irrigación sanguínea , Vellosidades Coriónicas/diagnóstico por imagen , Vellosidades Coriónicas/patología , Vellosidades Coriónicas/ultraestructura , Diabetes Mellitus Tipo 1/sangre , Diabetes Mellitus Tipo 1/diagnóstico , Diabetes Mellitus Tipo 1/diagnóstico por imagen , Diabetes Mellitus Tipo 1/patología , Diabetes Gestacional/sangre , Diabetes Gestacional/diagnóstico , Diabetes Gestacional/diagnóstico por imagen , Diabetes Gestacional/patología , Femenino , Feto/irrigación sanguínea , Feto/diagnóstico por imagen , Pruebas Hematológicas/métodos , Humanos , Relaciones Materno-Fetales , Microscopía Electrónica de Rastreo , Miometrio/diagnóstico por imagen , Miometrio/patología , Miometrio/ultraestructura , Placenta/irrigación sanguínea , Placenta/diagnóstico por imagen , Placenta/patología , Placenta/ultraestructura , Preeclampsia/sangre , Preeclampsia/diagnóstico , Preeclampsia/diagnóstico por imagen , Preeclampsia/patología , Embarazo , Complicaciones del Embarazo/sangre , Complicaciones del Embarazo/diagnóstico por imagen , Complicaciones del Embarazo/patología , Embarazo en Diabéticas/sangre , Embarazo en Diabéticas/diagnóstico , Embarazo en Diabéticas/diagnóstico por imagen , Embarazo en Diabéticas/patología , Enfermedades de la Tiroides/sangre , Enfermedades de la Tiroides/diagnóstico , Enfermedades de la Tiroides/diagnóstico por imagen , Enfermedades de la Tiroides/patología , Cordón Umbilical/irrigación sanguínea , Cordón Umbilical/diagnóstico por imagen , Cordón Umbilical/ultraestructura , Útero/irrigación sanguínea , Útero/diagnóstico por imagen , Útero/ultraestructuraRESUMEN
In spite of the huge progress in the treatment of diabetes mellitus, we are still in the situation that both pregestational (PGDM) and gestational diabetes (GDM) impose an additional risk to the embryo, fetus, and course of pregnancy. PGDM may increase the rate of congenital malformations, especially cardiac, nervous system, musculoskeletal system, and limbs. PGDM may interfere with fetal growth, often causing macrosomia, but in the presence of severe maternal complications, especially nephropathy, it may inhibit fetal growth. PGDM may also induce a variety of perinatal complications such as stillbirth and perinatal death, cardiomyopathy, respiratory morbidity, and perinatal asphyxia. GDM that generally develops in the second half of pregnancy induces similar but generally less severe complications. Their severity is higher with earlier onset of GDM and inversely correlated with the degree of glycemic control. Early initiation of GDM might even cause some increase in the rate of congenital malformations. Both PGDM and GDM may cause various motor and behavioral neurodevelopmental problems, including an increased incidence of attention deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD). Most complications are reduced in incidence and severity with the improvement in diabetic control. Mechanisms of diabetic-induced damage in pregnancy are related to maternal and fetal hyperglycemia, enhanced oxidative stress, epigenetic changes, and other, less defined, pathogenic mechanisms.
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Diabetes Gestacional/epidemiología , Complicaciones del Embarazo/epidemiología , Embarazo en Diabéticas/epidemiología , Adulto , Trastorno por Déficit de Atención con Hiperactividad/epidemiología , Trastorno por Déficit de Atención con Hiperactividad/etiología , Trastorno por Déficit de Atención con Hiperactividad/patología , Trastorno del Espectro Autista/epidemiología , Trastorno del Espectro Autista/etiología , Trastorno del Espectro Autista/patología , Diabetes Gestacional/patología , Femenino , Humanos , Embarazo , Complicaciones del Embarazo/fisiopatología , Resultado del Embarazo , Embarazo en Diabéticas/patologíaRESUMEN
During the first days of development the preimplantation embryo is supplied with nutrients from the surrounding milieu. Maternal diabetes mellitus affects the uterine microenvironment, leading to a metabolic adaptation processes in the embryo. We analysed embryonic fatty acid (FA) profiles and expression of processing genes in rabbit blastocysts, separately in embryoblasts (EBs) and trophoblasts (TBs), to determine the potential consequences of maternal diabetes mellitus on intracellular FA metabolism. Insulin-dependent diabetes was induced by alloxan in female rabbits. On Day 6 post coitum, FA profiles in blastocysts (EB, TB and blastocoel fluid) and maternal blood were analysed by gas chromatography. The expression levels of molecules involved in FA elongation (fatty acid elongases, ELOVLs) and desaturation (fatty acid desaturases, FADSs) were measured in EB and TB. Maternal diabetes mellitus influenced the FA profile in maternal plasma and blastocysts. Independent from metabolic changes, rabbit blastocysts contained a higher level of saturated fatty acids (SFAs) and a lower level of polyunsaturated fatty acids (PUFAs) compared to the FA profile of the maternal plasma. Furthermore, the FA profile was altered in the EB and TB, differently. While SFAs (palmitic and stearic acid) were elevated in EB of diabetic rabbits, PUFAs, such as docosahexaenoic acid, were decreased. In contrast, in the TB, lower levels of SFAs and higher levels of oleic acid were observed. EB and TB specific alterations in gene expression were found for ELOVLs and FADSs, key enzymes for FA elongation and desaturation. In conclusion, maternal diabetes mellitus alters embryonic FA metabolism differently in EB and TB, indicating a lineage-specific metabolic adaptive response.
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Diabetes Mellitus Experimental/metabolismo , Embrión de Mamíferos/metabolismo , Ácidos Grasos/metabolismo , Embarazo en Diabéticas/metabolismo , Aloxano , Animales , Blastocisto/metabolismo , Diabetes Mellitus Experimental/inducido químicamente , Diabetes Mellitus Tipo 1/inducido químicamente , Diabetes Mellitus Tipo 1/metabolismo , Femenino , Metabolismo de los Lípidos/fisiología , Embarazo , Embarazo en Diabéticas/inducido químicamente , Embarazo en Diabéticas/patología , Embarazo en Diabéticas/veterinaria , Conejos , Trofoblastos/metabolismoRESUMEN
Diabetes is an increasingly common diagnosis among pregnant women. Pregestational diabetes is associated with an increase in many adverse pregnancy outcomes, which impact both on the woman and her fetus. The models of pregnancy care for women with diabetes are based largely on observational data or consensus opinion. Strategies for aneuploidy screening and monitoring for fetal well-being should be modified in women with diabetes. There is an increasing understanding of the mechanisms by which congenital anomalies and disorders of fetal growth occur, involving epigenetic modifications, changes in gene expression in critical developmental pathways, and oxidative stress. This knowledge may lead to pathways for improved care for these high-risk pregnancies.
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Embarazo en Diabéticas/etiología , Embarazo en Diabéticas/terapia , Progresión de la Enfermedad , Femenino , Humanos , Recién Nacido , Monitoreo Fisiológico/métodos , Embarazo , Resultado del Embarazo/epidemiología , Embarazo en Diabéticas/patología , Embarazo de Alto Riesgo/fisiología , Atención Prenatal/métodos , Diagnóstico Prenatal/métodos , Factores de RiesgoRESUMEN
Pregnant women with diabetes mellitus (DM) are at high risk for hypertensive disorder of pregnancy (HDP). Women with poor control DM sometimes have heavy-for-dates infants. However, women with HDP sometimes have light-for-dates infants. We aim to clarify the relationship between glycemic control and fetal growth in women with DM and/or subsequent HDP. Of 7893 women gave singleton birth at or after 22 gestational weeks, we enrolled 154 women with type 1 DM (T1DM) or type 2 DM (T2DM) whose infants did not have fetal abnormalities. Among women with T1DM or T2DM, characteristics of the three groups (with HDP, without HDP, and with chronic hypertension [CH]) were compared. No women with T1DM had CH, but 19 (17.4%) of 109 with T2DM did. HDP incidence was similar between women with T1DM (22.2%) and T2DM without CH (16.7%). Among women with T1DM, the incidences of fetal growth restriction (FGR) with and without HDP were similar. However, among women with T2DM without CH, this incidence was significantly higher among those with HDP (33.3%) than among those without HDP (5.3%), was significantly more common with HbA1c levels at first trimester ≥ 7.2% (33.3%) than with those < 7.2% (5.6%), and significantly more numerous without pre-pregnancy therapies for DM (23.3%) than with them (3.3%). Among women with T2DM and HDP, those with FGR had smaller placenta SDs and higher insulin dosages at delivery than those without light-for-dates. In multivariate analysis, the presence of diabetic nephropathy was a predictor of T1DM and HDP (P = 0.0105), whereas HbA1c levels ≥ 7.2% before pregnancy was a predictor of T2DM and HDP (P = 0.0009). Insulin dosage ≥ 50U/day at delivery (P = 0.0297) and the presence of HDP (P = 0.0116) independently predicted T2DM, HDP, and FGR development. Insufficient pre-pregnancy treatment of DM increased the risk of HDP.
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Glucemia/metabolismo , Diabetes Mellitus Tipo 1 , Diabetes Mellitus Tipo 2 , Retardo del Crecimiento Fetal , Insulina/administración & dosificación , Preeclampsia , Embarazo en Diabéticas , Adulto , Enfermedad Crónica , Diabetes Mellitus Tipo 1/sangre , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Diabetes Mellitus Tipo 1/epidemiología , Diabetes Mellitus Tipo 1/patología , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/epidemiología , Diabetes Mellitus Tipo 2/patología , Femenino , Retardo del Crecimiento Fetal/sangre , Retardo del Crecimiento Fetal/tratamiento farmacológico , Retardo del Crecimiento Fetal/epidemiología , Retardo del Crecimiento Fetal/patología , Humanos , Placenta/metabolismo , Placenta/patología , Preeclampsia/sangre , Preeclampsia/tratamiento farmacológico , Preeclampsia/epidemiología , Preeclampsia/patología , Embarazo , Embarazo en Diabéticas/sangre , Embarazo en Diabéticas/tratamiento farmacológico , Embarazo en Diabéticas/epidemiología , Embarazo en Diabéticas/patología , Estudios Retrospectivos , Factores de RiesgoRESUMEN
Diabetes in the mother during pregnancy is a risk factor for birth defects and perinatal complications and can affect long-term health of the offspring through developmental programming of susceptibility to metabolic disease. We previously showed that Streptozotocin-induced maternal diabetes in mice is associated with altered cell differentiation and with smaller size of the placenta. Placental size and fetal size were affected by maternal diet in this model, and maternal diet also modulated the risk for neural tube defects. In the present study, we sought to determine the extent to which these effects might be mediated through altered expression of nutrient transporters, specifically glucose and fatty acid transporters in the placenta. Our results demonstrate that expression of several transporters is modulated by both maternal diet and maternal diabetes. Diet was revealed as the more prominent determinant of nutrient transporter expression levels, even in pregnancies with uncontrolled diabetes, consistent with the role of diet in placental and fetal growth. Notably, the largest changes in nutrient transporter expression levels were detected around midgestation time points when the placenta is being formed. These findings place the critical time period for susceptibility to diet exposures earlier than previously appreciated, implying that mechanisms underlying developmental programming can act on placenta formation.
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Diabetes Mellitus Experimental/metabolismo , Dieta Alta en Grasa/efectos adversos , Proteínas de Transporte de Membrana/metabolismo , Nutrientes/metabolismo , Placenta/patología , Embarazo en Diabéticas/metabolismo , Animales , Diabetes Mellitus Experimental/inducido químicamente , Diabetes Mellitus Experimental/patología , Ácidos Grasos/metabolismo , Femenino , Desarrollo Fetal , Glucosa/metabolismo , Humanos , Ratones , Embarazo , Embarazo en Diabéticas/etiología , Embarazo en Diabéticas/patología , Estreptozocina/toxicidadRESUMEN
OBJECTIVES: To determine whether: 1) retinal vessel diameters in pregnant and non-pregnant women with type 1 diabetes (T1D) alter the relationship of pregnancy to severity of diabetic retinopathy (DR); and 2) retinal vessel diameters in early pregnancy alter the relationship of severity of DR in the mother to severe adverse outcome in the infant. METHODS: Two cohorts of women with T1D, one composed of pregnant women and the other of non-pregnant women of child-bearing age, were recruited in Wisconsin. Baseline examinations (including retinal photography and collection of diabetes-related characteristics) were conducted, with follow-up approximately one year later. Retinal images were graded according to the modified Airlie House classification protocol, and retinal vessel diameters were measured from digitized images. The latter were included in analyses as central retinal arteriolar equivalent (CRAE) and central retinal venular equivalent (CRVE). RESULTS: In multivariate models: 1) Pregnancy was significantly associated with both incidence (ORâ¯=â¯4.43, CIâ¯=â¯1.42-13.79) and progression (ORâ¯=â¯2.62, CIâ¯=â¯1.52-4.51) of DR. Neither CRAE nor CRVE were significant, but their addition modestly altered the associations of pregnancy to worsening DR; 2) Baseline retinopathy (ORâ¯=â¯1.28, CIâ¯=â¯1.05-1.57) was associated with severe adverse outcome in the infant. This association was unchanged by adjustment for retinal vessel diameters. CONCLUSIONS: Pregnancy is associated with worsening DR in women with T1D. DR severity in early pregnancy is associated with severe adverse outcome in the infant. The retinal vessel diameters CRAE and CRVE were not associated with these outcomes but were modest confounders of the association of pregnancy to worsening DR.
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Diabetes Mellitus Tipo 1/complicaciones , Retinopatía Diabética/epidemiología , Resultado del Embarazo , Embarazo en Diabéticas/patología , Vasos Retinianos/patología , Aborto Espontáneo/epidemiología , Adulto , Arteriolas/patología , Retinopatía Diabética/patología , Retinopatía Diabética/fisiopatología , Progresión de la Enfermedad , Femenino , Humanos , Oportunidad Relativa , Embarazo , Mortinato/epidemiología , Vénulas/patologíaRESUMEN
BACKGROUND: Maternal hypertension, type 2 diabetes (T2D) and obesity are associated with an increased risk of having offspring with conotruncal heart defects (CTDs). Prior studies have identified sets of single nucleotide polymorphisms (SNPs) that are associated with risk for each of these three adult phenotypes. We hypothesized that these same SNPs are associated with maternal risk of CTDs in offspring. METHODS AND RESULTS: We evaluated the parents of children with a CTD ascertained from the Children's Hospital of Philadelphia (n = 466) and by the Pediatric Cardiac Genomic Consortium (n = 255). We used a family-based design to assess the association between CTDs and the maternal genotype for individual hypertension, T2D, and obesity-related SNPs and found no association between CTDs and the maternal genotype for any individual SNP. In addition, we calculated genetic risk scores (GRS) for hypertension, T2D, and obesity using previously published GRS formulas. When comparing the GRS of mothers to fathers, there were no statistically significant differences in the mean for the combined GRS or the GRS for each individual condition. However, when we categorized the mothers and fathers of cases with CTDs as having high (>95th percentile) or low (≤95th percentile) scores, compared to fathers, mothers had almost two times the odds of having a high GRS for hypertension (OR 1.7, 95% CI 1.0, 2.8) and T2D (OR 1.8, 95% CI 1.1, 3.1). CONCLUSIONS: Our results support a link between maternal genetic risk for hypertension/T2D and CTDs in their offspring. These associations might be independent of maternal phenotype at conception.
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Diabetes Mellitus Tipo 2/genética , Cardiopatías Congénitas/genética , Hipertensión/genética , Obesidad Materna/genética , Polimorfismo de Nucleótido Simple , Complicaciones Cardiovasculares del Embarazo/genética , Embarazo en Diabéticas/genética , Adulto , Diabetes Mellitus Tipo 2/patología , Diabetes Mellitus Tipo 2/fisiopatología , Femenino , Cardiopatías Congénitas/patología , Cardiopatías Congénitas/fisiopatología , Humanos , Hipertensión/patología , Hipertensión/fisiopatología , Masculino , Obesidad Materna/patología , Obesidad Materna/fisiopatología , Embarazo , Complicaciones Cardiovasculares del Embarazo/patología , Complicaciones Cardiovasculares del Embarazo/fisiopatología , Embarazo en Diabéticas/patología , Embarazo en Diabéticas/fisiopatología , Factores de RiesgoRESUMEN
Diabetes in pregnancy constitutes an unfavorable environment for embryonic and fetal development, where the child has a higher risk of perinatal morbidity and mortality, with high incidence of congenital malformations and predisposition to long-term metabolic diseases that increase with a hypercaloric diet. To analyze whether hyperglycemia differentially affects proliferation, apoptosis, and mRNA expression in cells from children of normoglycemic pregnancies (NGPs) and diabetes mellitus pregnancies (DMPs), we used umbilical cord Wharton jelly cells as a research model. Proliferation assays were performed to analyze growth and determine the doubling time, and the rate of apoptosis was determined by flow cytometry-annexin-V assays. AMPK, BNIP3, HIF1α, and p53 mRNA gene expression was assessed by semi-quantitative RT-PCR. We found that hyperglycemia decreased proliferation in a statistically significant manner in NGP cells treated with 40â¯mM D-glucose and in DMP cells treated with 30 and 40â¯mM D-glucose. Apoptosis increased in hyperglycemic conditions in NGP and DMP cells. mRNA expression of BNIP3 and p53 was significantly increased in cells from DMPs but not in cells from NGPs. We found evidence that maternal irregular metabolic conditions, like diabetes with hyperglycemia in culture, affect biological properties of fetal cells. These observations could be a constituent of fetal programming.
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Apoptosis/genética , Hiperglucemia/genética , Proteínas de la Membrana/genética , Embarazo en Diabéticas/genética , Embarazo en Diabéticas/patología , Proteínas Proto-Oncogénicas/genética , Proteína p53 Supresora de Tumor/genética , Cordón Umbilical/patología , Gelatina de Wharton/metabolismo , Adenilato Quinasa/genética , Adenilato Quinasa/metabolismo , Proliferación Celular/genética , Femenino , Humanos , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Proteínas de la Membrana/metabolismo , Embarazo , Proteínas Proto-Oncogénicas/metabolismo , ARN Mensajero/metabolismo , Proteína p53 Supresora de Tumor/metabolismoRESUMEN
AIMS: Maternal type 2 diabetes (T2D) can result in adverse pathological outcomes to both the mother and fetus. The present study aimed to investigate the pathological effects of maternal T2D on the gene expression patterns and functions of fetal human umbilical vein endothelial cells (HUVECs), a representative of fetal vascular cells. METHODS: Cell proliferation, apoptosis, mitochondrial ROS production and cell cycle were measured using flowcytometry. Genome-wide expression was measured using Affymetrix microarray. Gene expression of CCND2, STAT1, ITGB8, ALDH2, and ADAMTS5 was measured using real-time PCR. RESULTS: HUVECs derived from T2D mothers (T2D-HUVECs) showed elevated levels of mitochondrial superoxide anions, reduced cell proliferation, and increased apoptosis rates relative to HUVECs derived from healthy control mothers (C.HUVECs). In addition , T2D-HUVECs showed a decreased proportion of cells in G0/G1 and cell cycle arrest at the S phases relative to controls. Interestingly, microarray experiments revealed significant differences in genome-wide expression profiles between T2D-HUVECs and C.HUVECs. In particular, the analysis identified 90 upregulated genes and 42 downregulated genes. The upregulated genes CCND2, STAT1, ITGB8, ALDH2, and ADAMTS5 were validated as potential biomarkers for fetal endothelial dysfunction. Functional network analysis revealed that these genes are the important players that participate in the pathogenesis of endothelial dysfunction, which in turn influences the inflammatory response, cellular movement, and cardiovascular system development and function. CONCLUSION: Sustained alterations in the overall function of T2D-HUVEC and gene expression profiles provided insights into the role of maternal T2D on the pathophysiology of the fetal endothelial dysfunction.
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Diabetes Mellitus Tipo 2/genética , Feto/metabolismo , Regulación del Desarrollo de la Expresión Génica , Células Endoteliales de la Vena Umbilical Humana/fisiología , Embarazo en Diabéticas/genética , Adulto , Apoptosis/genética , Estudios de Casos y Controles , Proliferación Celular/genética , Células Cultivadas , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/metabolismo , Femenino , Perfilación de la Expresión Génica , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Humanos , Análisis por Micromatrices , Embarazo , Embarazo en Diabéticas/metabolismo , Embarazo en Diabéticas/patologíaAsunto(s)
Diabetes Mellitus Tipo 1/diagnóstico , Retinopatía Diabética/diagnóstico , Complicaciones del Embarazo/diagnóstico , Embarazo en Diabéticas/diagnóstico , Vitreorretinopatía Proliferativa/diagnóstico , Adulto , Anticuerpos Monoclonales/administración & dosificación , Diabetes Mellitus Tipo 1/complicaciones , Diabetes Mellitus Tipo 1/terapia , Retinopatía Diabética/patología , Retinopatía Diabética/terapia , Femenino , Angiografía con Fluoresceína , Humanos , Hallazgos Incidentales , Inyecciones Intravítreas , Fotocoagulación , Edema Macular/complicaciones , Edema Macular/diagnóstico , Edema Macular/terapia , Embarazo , Complicaciones del Embarazo/terapia , Embarazo en Diabéticas/patología , Embarazo en Diabéticas/terapia , Tomografía de Coherencia Óptica , Factor A de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Factor A de Crecimiento Endotelial Vascular/inmunología , Vitreorretinopatía Proliferativa/patología , Vitreorretinopatía Proliferativa/terapiaRESUMEN
This study was based on the hypothesis that IL-1ß and its central regulator, the inflammasome, may play a role in the inflammatory condition exhibited by placental tissues from mothers with different gestational hyperglycemia levels. Pregnant women were classified according to the glycemic reference as non-diabetic (nâ¯=â¯15), mild gestational hyperglycemia (nâ¯=â¯15), gestational diabetes mellitus (nâ¯=â¯15) and type 2 diabetes mellitus (nâ¯=â¯15). We investigated levels of pro-inflammatory factors in maternal plasma and placental tissues (by ELISA or immunohistochemistry) and, NFKB activity (by electrophoretic mobility shift assay) and inflammasome protein expression (by Western blot) in chorionic villous. Maternal plasma and placental levels of inflammatory factors (IL-1ß, IL-6, and MCP-1) were increased during all hyperglycemic conditions. Villous stroma cells showed strong immunoreactivity to CD68. In addition, with syncytiotrophoblast, the villous stroma cells were also stained to detect iNOS, MCP-1, TLR2, and TLR4. Although the levels of protein had fluctuated in the groups, NLRP1, NLRP3, ASC, and Caspase 1 were up-regulated in all hyperglycemic groups suggesting the inflammasome may be assembled in these pregnant women. The NFKB activity also exhibited higher levels in hyperglycemic groups, which might imply in pro-inflammatory cytokines production. In summary, increased maternal glucose levels during pregnancy changed systemic and placental inflammatory patterns, which occurred in parallel with the expression of inflammasome factors and processing and secretion of the pro-inflammatory cytokine IL-1ß. These results suggest an inflammatory condition in all gestational hyperglycemic conditions, even in hyperglycemia that is less severe than gestational or overt diabetes, likely associated with inflammasome activation and inflammatory cytokine secretion. Inflammasome activation as a possible source of inflammatory factors may be an important target to be considered while managing hyperglycemia and preventing adverse pregnancy outcomes.
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Vellosidades Coriónicas/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Gestacional/metabolismo , Hiperglucemia/metabolismo , Mediadores de Inflamación/metabolismo , Embarazo en Diabéticas/metabolismo , Adulto , Vellosidades Coriónicas/patología , Diabetes Mellitus Tipo 2/patología , Diabetes Gestacional/patología , Femenino , Humanos , Hiperglucemia/patología , Embarazo , Embarazo en Diabéticas/patologíaRESUMEN
This paper aims to investigate the influence of lipoprotein-associated phospholipase A2 (Lp-PLA2) inhibitor, darapladib, on insulin resistance (IR) in streptozotocin (STZ)-induced diabetic pregnant rats. The rat models were divided into Control (normal pregnancy), STZ + saline (STZ-induced diabetic pregnant rats), STZ + Low-dose and STZ + High-dose darapladib (STZ-induced diabetic pregnant rats treated with low-/high-dose darapladib) groups. Pathological changes were observed by Hematoxylin-eosin (HE) and Immunohistochemistry staining. Lp-PLA2 levels were determined by enzyme-linked immunosorbent assay (ELISA). An automatic biochemical analyzer was used to measure the serum levels of biochemical indicators, and homeostatic model assessment for insulin resistance (HOMA-IR) and insulin sensitivity index (ISI) were calculated. Western blot was applied to determine levels of inflammatory cytokines. Compared with Control group, rats in the STZ + saline group were significantly decreased in body weight, the number of embryo implantation, the number of insulin positive cells and pancreatic islet size as well as the islet endocrine cells, and high-density lipoprotein (HDL-C) level, but substantially increased in Lp-PLA2, low-density lipoprotein (LDL-C), fatty acids (FFA), serum total cholesterol (TC), triglyceride (TG) levels. Moreover, the increased fasting plasma glucose (FPG) and HOMA-IR and inflammatory cytokines but decreased fasting insulin (FINS) and ISI were also found in diabetic pregnant rats. On the contrary, rats in the darapladib-treated groups were just opposite to the STZ + saline group, and STZ + High-dose group improved better than STZ + Low-dose group. Thus, darapladib can improve lipid metabolism, and enhance insulin sensitivity of diabetic pregnant rats by regulating inflammatory cytokines.
Asunto(s)
1-Alquil-2-acetilglicerofosfocolina Esterasa/antagonistas & inhibidores , Benzaldehídos/farmacología , Diabetes Mellitus Experimental/metabolismo , Inhibidores Enzimáticos/farmacología , Resistencia a la Insulina , Oximas/farmacología , Embarazo en Diabéticas/metabolismo , Animales , Benzaldehídos/uso terapéutico , Glucemia/metabolismo , Diabetes Mellitus Experimental/inducido químicamente , Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Experimental/patología , Femenino , Insulina/sangre , Islotes Pancreáticos/efectos de los fármacos , Islotes Pancreáticos/metabolismo , Masculino , Oximas/uso terapéutico , Embarazo , Embarazo en Diabéticas/tratamiento farmacológico , Embarazo en Diabéticas/patología , Ratas , Ratas Sprague-Dawley , EstreptozocinaRESUMEN
The purpose of this study is to analyze the morphological, histological, immunohistochemical and ultrasound findings in the placenta of maternal type 1 and gestational diabetes, to compare the pathological changes of the placental structure in the two types of metabolic disruptions, but also to establish correlations with the expression of these findings, influenced by different associated conditions. This multicenter study includes 53 pregnancies, of which 37 with pregestational and 16 with gestational diabetes. All cases undergone specific obstetric ultrasound assessment and detailed placental scan. There were assessed 49 singleton and four twin pregnancies, all of which having live births as fetal outcome. Maternal preexisting hypertension, preeclampsia and obesity were the main associated conditions. Placental ultrasound scan revealed increased placental thickness even from the second trimester, with significant increases in the first half, and placentomegaly at the end of the third trimester. Macroscopic analysis of the placentas and umbilical cords has shown that the placentas of women with diabetes are heavier, and abnormal cord insertion has been also found. Gross analysis of maternal and fetal surfaces of the placentas revealed certain changes in both metabolic conditions. We observed 14 types of placental pathological findings in pregestational and 11 in gestational diabetes. In diabetic placenta, it is not appropriate to discuss about specific changes, but rather about a pathological diabetic pattern, influenced by associated conditions. Preconceptional and first trimester glycemic control is the key element, and euglycemia throughout pregnancy is a purpose whose accomplishment depends the maternal-fetal outcome.
Asunto(s)
Embarazo en Diabéticas/diagnóstico por imagen , Embarazo en Diabéticas/diagnóstico , Ultrasonografía/métodos , Adulto , Femenino , Humanos , Placenta/patología , Embarazo , Embarazo en Diabéticas/patología , Adulto JovenRESUMEN
The urethral muscle of diabetic pregnant rats is affected by long-term mild diabetes and short-term severe diabetes, which plays a crucial role in the pathogenesis of pelvic floor disorders. We hypothesized that muscles outside the pelvis are subject to similar changes. The current study aimed at analyzing the effects of long-term mild and short-term severe diabetes on the structure and ultrastructure of fiber muscles and collagen in rats' rectus abdominis (RA) muscle. Therefore, the RA muscle of virgin, pregnant, long-term mild diabetic, short-term severe diabetic, long-term mild diabetic pregnant and short-term severe diabetic pregnant 3-month-old Wistar rats were collected. The structure was analyzed by picrosirius red staining, immunohistochemistry for fast and slow muscle fibers and transmission electron microscopy. We investigated two levels of STZ- induced diabetes: long-term mild diabetes (blood glucose level: 120-200 mg/dL) and short-term severe diabetes (blood glucose level >300 mg/dL). Long-term mild diabetic pregnant and short-term severe diabetic pregnant rats had decreased fast fibers and increased slow fibers, disrupted areas of sarcomere, intermyofibrillar mitochondria and myelin figures in the RA muscle. Both groups enabled us to analyze the specific influence of pregnancy, separately from diabetes. The current study demonstrated that diabetes and pregnancy induced intramuscular transformation and reorganization of RA muscle with a switch of fiber type adjusting their architecture according to intensity and duration of hyperglycemic insult within pregnancy.
Asunto(s)
Colágeno/ultraestructura , Diabetes Mellitus Experimental/patología , Fibras Musculares Esqueléticas/ultraestructura , Embarazo en Diabéticas/patología , Recto del Abdomen/ultraestructura , Animales , Femenino , Inmunohistoquímica , Embarazo , Ratas , Ratas Wistar , Índice de Severidad de la EnfermedadRESUMEN
BACKGROUND: Hyperglycemic mothers have increased oxidative stress during pregnancy, which can adversely affect the outcome in their neonates. OBJECTIVES: To measure the oxidative stress and DNA damage in newborns born to mothers with hyperglycemia and correlate their immediate outcome with the amount of oxidative stress and DNA damage. METHODS: This prospective cohort study conducted in a tertiary care teaching hospital, South India included three groups - newborns born to pregestational diabetic mothers, gestational diabetic mothers, and euglycemic mothers with 24 newborns in each. Oxidative stress parameters - malondialdehyde (MDA), total antioxidant capacity (TAC), and DNA damage (comet assay) were assessed in umbilical cord blood. Association between these parameters and immediate neonatal outcome among three groups were studied. RESULTS: Newborns born to diabetic mothers had more MDA levels and DNA damage compared to euglycemic mothers. There was a positive correlation between comet parameters and MDA levels. There was an inverse correlation between comet parameters and TAC. Newborns born to diabetic mothers were at high risk to develop respiratory distress syndrome, hypoglycemia, and sepsis. CONCLUSIONS: Newborns born to diabetic mothers had increased oxidative stress and DNA damage compared to those born to mothers with euglycemia.
Asunto(s)
Daño del ADN , Hiperglucemia/metabolismo , Recién Nacido/metabolismo , Estrés Oxidativo/fisiología , Complicaciones del Embarazo/metabolismo , Adulto , Antioxidantes/metabolismo , Estudios de Casos y Controles , Diabetes Gestacional/metabolismo , Diabetes Gestacional/patología , Femenino , Sangre Fetal/metabolismo , Humanos , Hiperglucemia/patología , India , Masculino , Malondialdehído/sangre , Madres , Embarazo , Complicaciones del Embarazo/patología , Embarazo en Diabéticas/metabolismo , Embarazo en Diabéticas/patología , Adulto JovenRESUMEN
BACKGROUND: Expression of the intermediate filament protein vimentin has been recently observed in the pancreatic islet ß- and α-cells of humans with type 2 diabetes mellitus. It was suggested that the presence of vimentin in endocrine cells may indicate islet tissue renewal, or potentially represent the dedifferentiation of endocrine cells, which could contribute to the onset of type 2 diabetes or islet cell dysfunction. AIM: To analyze the expression of vimentin in pancreatic ß- and α-cells of macrosomic infants of diabetic and nondiabetic mothers. SUBJECTS: Pancreatic samples of five macrosomic infants (gestational age 34-40weeks) from three diabetic and two nondiabetic mothers were compared to six control infants (32-40weeks, weight appropriate for gestational age) from normoglycemic mothers. METHODS: Pancreatic autopsy samples were examined by double immunofluorescent labeling with antibodies against vimentin and either insulin or glucagon. Alterations in the endocrine pancreas were measured using morphometric methods, then data were statistically analyzed. RESULTS: In the pancreatic islets of macrosomic infants from diabetic and nondiabetic mothers, we observed vimentin-positive cells, some of which simultaneously contained insulin or glucagon. We also quantitatively showed that the presence of such cells was associated with hypertrophy and hyperplasia of the islets, and with an increase in ß- and α-cell density. CONCLUSIONS: We speculate that the appearance of vimentin-positive islet cells may reflect induction of differentiation in response to the increased insulin demand, and vimentin may serve as an early marker of endocrine pancreas disorders.
Asunto(s)
Diabetes Mellitus Tipo 2/metabolismo , Macrosomía Fetal/metabolismo , Células Secretoras de Glucagón/metabolismo , Células Secretoras de Insulina/metabolismo , Embarazo en Diabéticas/metabolismo , Vimentina/metabolismo , Adulto , Biomarcadores/metabolismo , Estudios de Casos y Controles , Diabetes Mellitus Tipo 2/patología , Femenino , Macrosomía Fetal/patología , Humanos , Recién Nacido , Masculino , Embarazo , Embarazo en Diabéticas/patologíaRESUMEN
The urethral muscle of diabetic pregnant rats is affected by long-term mild diabetes and short-term severe diabetes, which plays a crucial role in the pathogenesis of pelvic floor disorders. We hypothesized that muscles outside the pelvis are subject to similar changes. The current study aimed at analyzing the effects of long-term mild and short-term severe diabetes on the structure and ultrastructure of fiber muscles and collagen in rats' rectus abdominis (RA) muscle. Therefore, the RA muscle of virgin, pregnant, long-term mild diabetic, short-term severe diabetic, long-term mild diabetic pregnant and short-term severe diabetic pregnant 3-month-old Wistar rats were collected. The structure was analyzed by picrosirius red staining, immunohistochemistry for fast and slow muscle fibers and transmission electron microscopy. We investigated two levels of STZ- induced diabetes: long-term mild diabetes (blood glucose level: 120-200 mg/dL) and short-term severe diabetes (blood glucose level >300 mg/dL). Long-term mild diabetic pregnant and short-term severe diabetic pregnant rats had decreased fast fibers and increased slow fibers, disrupted areas of sarcomere, intermyofibrillar mitochondria and myelin figures in the RA muscle. Both groups enabled us to analyze the specific influence of pregnancy, separately from diabetes. The current study demonstrated that diabetes and pregnancy induced intramuscular transformation and reorganization of RA muscle with a switch of fiber type adjusting their architecture according to intensity and duration of hyperglycemic insult within pregnancy.
Asunto(s)
Animales , Femenino , Embarazo , Ratas , Embarazo en Diabéticas/patología , Colágeno/ultraestructura , Recto del Abdomen/ultraestructura , Fibras Musculares Esqueléticas/ultraestructura , Diabetes Mellitus Experimental/patología , Índice de Severidad de la Enfermedad , Inmunohistoquímica , Ratas WistarRESUMEN
STUDY QUESTION: How does a maternal diabetic hyperadiponectineamia affect signal transduction and lipid metabolism in rabbit preimplantation blastocysts? SUMMARY ANSWER: In a diabetic pregnancy increased levels of adiponectin led to a switch in embryonic metabolism towards a fatty acid-dependent energy metabolism, mainly affecting genes that are responsible for fatty acid uptake and turnover. WHAT IS KNOWN ALREADY: Although studies in cell culture experiments have shown that adiponectin is able to regulate lipid metabolism via 5'-AMP-activated protein kinase (AMPK) and peroxisome proliferator-activated receptor α (PPARα), data on the effects of adiponectin on embryonic lipid metabolism are not available. In a diabetic pregnancy in rabbits, maternal adiponectin levels are elevated fourfold and are accompanied by an increase in intracellular lipid droplets in blastocysts, implying consequences for the embryonic hormonal and metabolic environment. STUDY DESIGN, SIZE, DURATION: Rabbit blastocysts were cultured in vitro with adiponectin (1 µg/ml) and with the specific AMPK-inhibitor Compound C for 15 min, 1 h and 4 h (N ≥ 3 independent experiments: for RNA analysis, n ≥ 4 blastocysts per treatment group; for protein analysis three blastocysts pooled per sample and three samples used per experiment). Adiponectin signalling was verified in blastocysts grown in vivo from diabetic rabbits with a hyperadiponectinaemia (N ≥ 3 independent experiments, n ≥ 4 samples per treatment group, eight blastocysts pooled per sample). PARTICIPANTS/MATERIALS, SETTING, METHODS: In these blastocysts, expression of molecules involved in adiponectin signalling [adaptor protein 1 (APPL1), AMPK, acetyl-CoA carboxylase (ACC), p38 mitogen-activated protein kinases (p38 MAPK)], lipid metabolism [PPARα, cluster of differentiation 36 (CD36), fatty acid transport protein 4 (FATP4), fatty acid binding protein (FABP4), carnitine palmityl transferase 1 (CPT1), hormone-senstive lipase (HSL), lipoprotein lipase (LPL)] and members of the insulin/insulin-like growth factor (IGF)-system [IGF1, IGF2, insulin receptor (InsR), IGF1 receptor (IGF1R)] were analyzed by quantitative RT-PCR and western blot. Analyses were performed in both models, i.e. adiponectin stimulated blastocysts (in vitro) and in blastocysts grown in vivo under increased adiponectin levels caused by a maternal diabetes mellitus. MAIN RESULTS AND THE ROLE OF CHANCE: In both in vitro and in vivo models adiponectin increased AMPK and ACC phosphorylation, followed by an activation of the transcription factor PPARα, and CPT1, the key enzyme of ß-oxidation (all P < 0.05 versus control). Moreover, mRNA levels of the fatty acid transporters CD36, FATP4 and FABP4, and HSL were upregulated by adiponectin/AMPK signalling (all P < 0.05 versus control). Under diabetic developmental conditions the amount of p38 MAPK was upregulated (P < 0.01 versus non-diabetic), which was not observed in blastocysts cultured in vitro with adiponectin, indicating that the elevated p38 MAPK was not related to adiponectin. However, a second effect of adiponectin has to be noted: its intensification of insulin sensitivity, by regulating IGF availability and InsR/IGF1R expression. LARGE SCALE DATA: Not applicable. LIMITATIONS REASONS FOR CAUTION: There are two main limitations for our study. First, human and rabbit embryogenesis can only be compared during blastocyst development. Therefore, the inferences from our findings are limited to the embryonic stages investigated here. Second, the increased adiponectin levels and lack of maternal insulin is only typical for a diabetes mellitus type one model. WIDER IMPLICATIONS OF THE FINDINGS: This is the first mechanistic study demonstrating a direct influence of adiponectin on lipid metabolism in preimplantation embryos. The numbers of young women with a diabetes mellitus type one are increasing steadily. We have shown that preimplantation embryos are able to adapt to changes in the uterine milieu, which is mediated by the adiponectin/AMPK signalling. A tightly hormonal control during pregnancy is essential for survival and proper development. In this control process, adiponectin plays a more important role than known so far. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by the German Research Council (DFG RTG ProMoAge 2155), the EU (FP7 Epihealth No. 278418, FP7-EpiHealthNet N°317146), COST Action EpiConcept FA 1201 and SALAAM BM 1308. The authors have no conflict(s) of interest to disclose.