RESUMEN
OBJECTIVE: To model breastfed infant growth and body composition patterns over the first 4 months with multiple bioactive components of human milk (HM) and clinical factors (including maternal BMI status), which are related to growth. METHODS: Longitudinal observation of infant growth and body composition from 0 to 4 months among 41 predominantly breastfed infants (25 mothers of Normal-weight and 16 mothers with overweight/obesity). Fasted morning HM samples were collected at 5 time-points. Macronutrients, leptin, adiponectin, ghrelin, insulin, cytokines and n-6:n-3 esterified fatty acid ratio were measured. Infant weight-for-length Z-score (WLZ) trajectory, fat-free mass (FFM) gain, fat mass gain and %fat gain were modelled controlling for clinical covariates. RESULTS: HM insulin negatively associated with WLZ trajectory among infants of NW mothers (P = 0.028), but not associated with WLZ trajectory among infants of OW/Ob mothers. HM glucose (P < 0.001) was associated with slower rates of infant FFM gain. Infants of mothers with OW/Ob exhibited slower rates of FFM gain. HM protein, adiponectin and insulin concentrations, and n-6:n-3 ratio were all significant predictors in the model of infant fat mass gain (P < 0.03). Any amount of formula supplementation was associated with faster fat gain (P = 0.002). The model of %fat gain was similar to that of fat mass gain, excepting HM adiponectin was not a significant covariate, and a trend for maternal OW/Ob to correlate with faster %fat gain (P = 0.056). CONCLUSIONS: Bioactive components in HM may contribute to regulation of partitioning of body composition, and these contributions may differ between mothers of normal-weight vs. with OW/Ob.
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Composición Corporal/fisiología , Índice de Masa Corporal , Desarrollo Infantil/fisiología , Leche Humana/metabolismo , Obesidad/metabolismo , Adiponectina/metabolismo , Adulto , Lactancia Materna , Citocinas/metabolismo , Ácidos Grasos/metabolismo , Femenino , Ghrelina/metabolismo , Glucosa/metabolismo , Humanos , Lactante , Recién Nacido , Insulina/metabolismo , Leptina/metabolismo , Estudios Longitudinales , Masculino , Madres , Nutrientes/metabolismoRESUMEN
BACKGROUND/OBJECTIVES: The impact of maternal BMI and insulin sensitivity on bioactive components of human milk (HM) is not well understood. As the prevalence of obesity and diabetes rises, it is increasingly critical that we understand how maternal BMI and hormones associated with metabolic disease relate to concentrations of bioactive components in HM. SUBJECTS/METHODS: This longitudinal cohort design followed 48 breastfeeding mothers through the first four months of lactation, collecting fasting morning HM samples at 2-weeks and 1, 2, 3 and 4-months, and fasting maternal blood at 2-weeks and 4-months. Insulin, glucose, adipokines leptin and adiponectin, appetite regulating hormone ghrelin, marker of oxidative stress 8OHdG and inflammatory cytokines (IL-6, IL-8, and TNF-a) were measured in HM and maternal plasma. RESULTS: A total of 26 normal weight (NW) (BMI=21.4±2.0 kg/m2) and 22 overweight/obese (OW/Ob) (BMI=30.4±4.2 kg/m2) were followed. Of all HM analytes measured, only insulin and leptin were different between groups - consistently higher in the OW/Ob group (leptin: P<0.001; insulin: P<0.03). HM insulin was 98% higher than maternal plasma insulin at 2-weeks and 32% higher at 4-months (P<0.001). Maternal fasting plasma insulin and HOMA-IR were positively related to HM insulin at 2-weeks (P<0.001, R2⩾0.38, n=31), and 4-months (P⩽0.005, R2⩾0.20, n=38). CONCLUSIONS: The concentrations of insulin in HM are higher than in maternal plasma and are related to maternal BMI and insulin sensitivity. With the exception of leptin, there were minimal other differences observed in HM composition across a wide range in maternal BMI.
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Lactancia Materna , Insulina/metabolismo , Leche Humana/metabolismo , Adulto , Índice de Masa Corporal , Estudios de Cohortes , Femenino , Hemoglobina Glucada/metabolismo , Humanos , Recién Nacido , Insulina/sangre , Estudios Longitudinales , Masculino , Embarazo , Estudios Prospectivos , Encuestas y CuestionariosRESUMEN
BACKGROUND/OBJECTIVES: Excessive infant weight gain in the first 6-month of life is a powerful predictor of childhood obesity and related health risks. In mice, omega-6 fatty acids (FAs) serve as potent ligands driving adipogenesis during early development. The ratio of omega-6 relative to omega-3 (n-6/n-3) FA in human milk (HM) has increased threefold over the last 30 years, but the impact of this shift on infant adipose development remains undetermined. This study investigated how maternal obesity and maternal dietary FA (as reflected in maternal red blood cells (RBCs) composition) influenced HM n-6 and n-3 FAs, and whether the HM n-6/n-3 ratio was associated with changes in infant adipose deposition between 2 weeks and 4 months postpartum. SUBJECTS/METHODS: Forty-eight infants from normal weight (NW), overweight (OW) and obese (OB) mothers were exclusively or predominantly breastfed over the first 4 months of lactation. Mid-feed HM and maternal RBC were collected at either transitional (2 weeks) or established (4 months) lactation, along with infant body composition assessed using air-displacement plethysmography. The FA composition of HM and maternal RBC was measured quantitatively by lipid mass spectrometry. RESULTS: In transitional and established HM, docosahexaenoic acid (DHA) was lower (P=0.008; 0.005) and the arachidonic acid (AA)/DHA+eicosapentaenoic acid (EPA) ratio was higher (P=0.05; 0.02) in the OB relative to the NW group. Maternal prepregnancy body mass index (BMI) and AA/DHA+EPA ratios in transitional and established HM were moderately correlated (P=0.018; 0.001). Total infant fat mass was increased in the upper AA/DHA+EPA tertile of established HM relative to the lower tertile (P=0.019). The amount of changes in infant fat mass and percentage of body fat were predicted by AA/EPA+DHA ratios in established HM (P=0.038; 0.010). CONCLUSIONS: Perinatal infant exposures to a high AA/EPA+DHA ratio during the first 4 months of life, which is primarily reflective of maternal dietary FA, may significantly contribute to the way infants accumulate adipose.
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Adiposidad/fisiología , Lactancia Materna/estadística & datos numéricos , Ácidos Grasos Omega-3/metabolismo , Ácidos Grasos Omega-6/metabolismo , Leche Humana/química , Madres , Obesidad/epidemiología , Adulto , Peso al Nacer , Composición Corporal , Colorado/epidemiología , Conducta Alimentaria , Femenino , Humanos , Lactante , Recién Nacido , Lactancia/fisiología , Masculino , Fenómenos Fisiologicos Nutricionales Maternos , Obesidad/metabolismo , Obesidad/fisiopatología , Periodo Posparto/fisiología , Embarazo , Aumento de PesoRESUMEN
BACKGROUND/OBJECTIVES: Poor maternal diet in pregnancy can influence fetal growth and development. We tested the hypothesis that poor maternal diet quality during pregnancy would increase neonatal adiposity (percent fat mass (%FM)) at birth by increasing the fat mass (FM) component of neonatal body composition. METHODS: Our analysis was conducted using a prebirth observational cohort of 1079 mother-offspring pairs. Pregnancy diet was assessed via repeated Automated Self-Administered 24-h dietary recalls, from which Healthy Eating Index-2010 (HEI-2010) scores were calculated for each mother. HEI-2010 was dichotomized into scores of ⩽57 and >57, with low scores representing poorer diet quality. Neonatal %FM was assessed within 72 h after birth with air displacement plethysmography. Using univariate and multivariate linear models, we analyzed the relationship between maternal diet quality and neonatal %FM, FM, and fat-free mass (FFM) while adjusting for prepregnancy body mass index (BMI), physical activity, maternal age, smoking, energy intake, preeclampsia, hypertension, infant sex and gestational age. RESULTS: Total HEI-2010 score ranged between 18.2 and 89.5 (mean: 54.2, s.d.: 13.6). An HEI-2010 score of ⩽57 was significantly associated with higher neonatal %FM (ß=0.58, 95% confidence interval (CI) 0.07-1.1, P<0.05) and FM (ß=20.74; 95% CI 1.49-40.0; P<0.05) but no difference in FFM. CONCLUSIONS: Poor diet quality during pregnancy increases neonatal adiposity independent of maternal prepregnancy BMI and total caloric intake. This further implicates maternal diet as a potentially important exposure for fetal adiposity.
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Adiposidad/fisiología , Fenómenos Fisiologicos Nutricionales Maternos , Madres , Adulto , Peso al Nacer/fisiología , Glucemia , Índice de Masa Corporal , Dieta , Encuestas sobre Dietas , Ingestión de Energía , Conducta Alimentaria , Femenino , Desarrollo Fetal/fisiología , Humanos , Recién Nacido , Estudios Longitudinales , Embarazo , Fenómenos Fisiologicos de la Nutrición Prenatal , Estados Unidos/epidemiologíaRESUMEN
BACKGROUND: Infant adiposity better predicts childhood obesity/metabolic risk than weight, but technical challenges fuel controversy over the accuracy of adiposity estimates. OBJECTIVE: We prospectively measured adiposity (%fat) in term newborns (NB) at 2 weeks (n = 41) and 1 year (n = 30). METHODS: %fat was measured by dual X-ray absorptiometry (DXA), PEAPOD and skin-folds (SF). DXAs were analyzed using Hologic Apex software 3.2(DXAv1) and a new version 5.5.2(DXAv2). RESULTS: NB %fat by DXAv2 was 55% higher than DXAv1 (14.2% vs. 9.1%), 45% higher than SF (9.8%), and 36% higher than PEAPOD (10.4%). Among NB, Pearson correlations were 0.73-0.89, but agreement (intra-class correlations) poor between DXAv2 and DXAv1 (0.527), SF (0.354) and PEAPOD (0.618). At 1 year, %fat by DXAv2 was 51% higher than DXAv1 (33.6% vs. 22.4%), and twice as high compared with SF (14.6%). Agreement was poor between DXAv2 and DXAv1 (0.204), and SF (0.038). The absolute increase in %fat from 2 weeks to 1 year was 19.7% (DXAv2), 13.6% (DXAv1) and only 4.8% by SF. CONCLUSION: Analysis of the same DXA scans using new software yielded considerably higher adiposity estimates at birth and 1 year compared with the previous version. Using different modalities to assess body composition longitudinally is problematic. Standardization is gravely needed to determine how early life exposures affect childhood obesity/metabolic risk.
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Absorciometría de Fotón/métodos , Adiposidad , Composición Corporal , Pletismografía/métodos , Tejido Adiposo/metabolismo , Antropometría , Peso Corporal , Femenino , Humanos , Lactante , Recién Nacido , Masculino , Obesidad Infantil/metabolismo , Estudios Prospectivos , Programas InformáticosRESUMEN
BACKGROUND: Maternal obesity increases adult offspring risk for cardiovascular disease; however, the role of offspring adiposity in mediating this association remains poorly characterized. OBJECTIVE: To investigate the associations of maternal pre-pregnant body mass index (maternal BMI) and gestational weight gain (GWG) with neonatal cardiometabolic markers independent of fetal growth and neonatal adiposity. METHODS: A total of 753 maternal-infant pairs from the Healthy Start study, a large multiethnic pre-birth observational cohort were used. Neonatal cardiometabolic markers included cord blood glucose, insulin, glucose-to-insulin ratio (Glu/Ins), total and high-density lipoprotein cholesterol (HDL-c), triglycerides, free fatty acids and leptin. Maternal BMI was abstracted from medical records or self-reported. GWG was calculated as the difference between the first pre-pregnant weight and the last weight measurement before delivery. Neonatal adiposity (percent fat mass) was measured within 72 h of delivery using whole-body air-displacement plethysmography. RESULTS: In covariate adjusted models, maternal BMI was positively associated with cord blood insulin (P=0.01) and leptin (P<0.001) levels, and inversely associated with cord blood HDL-c (P=0.05) and Glu/Ins (P=0.003). Adjustment for fetal growth or neonatal adiposity attenuated the effect of maternal BMI on neonatal insulin, rendering the association nonsignificant. However, maternal BMI remained associated with higher leptin (P<0.0011), lower HDL-c (P=0.02) and Glu/Ins (P=0.05), independent of neonatal adiposity. GWG was positively associated with neonatal insulin (P=0.02), glucose (P=0.03) and leptin levels (P<0.001) and negatively associated with Glu/Ins (P=0.006). After adjusting for neonatal adiposity, GWG remained associated with higher neonatal glucose (P=0.02) and leptin levels (P=0.02) and lower Glu/Ins (P=0.048). CONCLUSIONS: Maternal weight prior and/or during pregnancy is associated with neonatal cardiometabolic makers including leptin, glucose and HDL-c at delivery, independent of neonatal adiposity. Our results suggest that intrauterine exposure to maternal obesity influences metabolic processes beyond fetal growth and fat accretion.
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Enfermedades Cardiovasculares/etiología , Obesidad/complicaciones , Pletismografía/métodos , Aumento de Peso , Adiposidad , Adulto , Peso al Nacer , Glucemia/metabolismo , Índice de Masa Corporal , Enfermedades Cardiovasculares/sangre , Enfermedades Cardiovasculares/epidemiología , Enfermedades Cardiovasculares/prevención & control , Colorado/epidemiología , Femenino , Desarrollo Fetal , Humanos , Recién Nacido , Insulina/sangre , Leptina/sangre , Lipoproteínas HDL/sangre , Estudios Longitudinales , Obesidad/sangre , Obesidad/epidemiología , Obesidad/prevención & control , Embarazo , Factores de Riesgo , Triglicéridos/sangreRESUMEN
Cytochrome P4501A1 (CYP1A1), an important drug metabolizing enzyme, is expressed in human placenta throughout gestation as well as in fetal liver. Obesity, a chronic inflammatory condition, is known to alter CYP enzyme expression in non-placental tissues. In the present study, we test the hypothesis that maternal obesity alters the distribution of CYP1A1 activity in feto-placental unit. Placentas were collected from non-obese (BMI < 30) and obese (BMI > 30) women at term. Livers were collected from gestation day 130 fetuses of non-human primates fed either control diet or high-fat diet (HFD). Cytosol and microsomes were collected using differential centrifugation, and incubated with 7-ethoxyresorufin. The CYP1A1 specific activity (pmoles of resorufin formed/min/mg of protein) was measured at excitation/emission wavelength of 530/590 nm. Placentas of obese women had significantly reduced microsomal CYP1A1 activity compared to non-obese women (0.046 vs. 0.082; p < 0.05); however no such effect was observed on cytosolic activity. Similarly, fetal liver from HFD fed mothers had significantly reduced microsomal CYP1A1 activity (0.44 ± 0.04 vs. 0.20 ± 0.10; p < 0.05), with no significant difference in cytosolic CYP1A1 activity (control, 1.23 ± 0.20; HFD, 0.80 ± 0.40). Interestingly, multiple linear regression analyses of placental efficiency indicate cytosolic CYP1A1 activity is a main effect (5.67 ± 2.32 (ß ± SEM); p = 0.022) along with BMI (-0.57 ± 0.26; p = 0.037), fetal gender (1.07 ± 0.26; p < 0.001), and maternal age (0.07 ± 0.03; p = 0.011). In summary, while maternal obesity affects microsomal CYP1A1 activity alone, cytosolic activity along with maternal BMI is an important determinant of placental efficiency. Together, these data suggest that maternal lifestyle could have a significant impact on CYP1A1 activity, and hints at a possible role for CYP1A1 in feto-placental growth and thereby well-being of fetus.
Asunto(s)
Citocromo P-450 CYP1A1/metabolismo , Regulación hacia Abajo , Hígado/enzimología , Obesidad/enzimología , Placenta/enzimología , Complicaciones del Embarazo/enzimología , Animales , Índice de Masa Corporal , Citocromo P-450 CYP1A1/química , Citosol/enzimología , Dieta Alta en Grasa/efectos adversos , Femenino , Humanos , Hígado/embriología , Macaca , Microsomas/enzimología , Microsomas Hepáticos/enzimología , Obesidad/etiología , Obesidad/metabolismo , Oxazinas/metabolismo , Embarazo , Complicaciones del Embarazo/metabolismo , Distribución Aleatoria , SolubilidadRESUMEN
Phosphoinositide 3-kinase is a key signaling intermediate necessary for the metabolic actions of insulin. In this study, we assessed the effects of in vivo knockdown of the p85alpha subunit of phosphoinositide 3-kinase on insulin sensitivity, using an antisense oligonucleotide, in lean mice, diet-induced obese mice, and obese leptin-deficient Lep (ob/ob) mice. Mice were injected with either p85alpha-targeted antisense oligonucleotide or saline twice weekly for 4 weeks. Fasting levels of glycemia and insulinemia and insulin and glucose tolerance tests were used to determine insulin sensitivity. Western blot analysis and real-time polyacrylamide chain reaction were used to assess p85alpha protein and mRNA expression. IN VIVO administration of antisense oligonucleotide resulted in 50 and 60% knockdown of liver p85alpha protein and mRNA, respectively, in the lean, diet-induced obese and Lep (ob/ob) mice. This was associated with increased phosphoinositide 3-kinase activity and improved insulin sensitivity in diet-induced obese and Lep (ob/ob) mice. Thus, p85alpha could be an important therapeutic target to ameliorate insulin resistance.
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Resistencia a la Insulina/fisiología , Obesidad/metabolismo , Oligonucleótidos Antisentido/farmacología , Fosfatidilinositol 3-Quinasas/metabolismo , Animales , Glucemia/análisis , Western Blotting , Prueba de Tolerancia a la Glucosa , Insulina/sangre , Hígado/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Obesos , Músculo Esquelético/metabolismo , Fosfatidilinositol 3-Quinasas/genética , ARN , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
Indomethacin has been suggested for the treatment of Alzheimer's disease (AD), but its use is limited by gastrointestinal and renal toxicity. To overcome this limitation, D-Pharm Ltd. (Rehovot, Israel) developed DP-155 (mixture of 1-steroyl and 1-palmitoyl-2-{6-[1-(p-chlorobenzoyl)-5-methoxy-2-methyl-3-indolyl acetamido] hexanoyl}-Sn-glycero-3-phosophatidyl [corrected] choline), a lecithin derivative of indomethacin. Safety was tested by daily oral administration of DP-155 or indomethacin to rats in a dose range of 0.007 to 0.28 mmol/kg. The prevalence of gastrointestinal ulceration was significantly lower (10-fold) for DP-155 than for indomethacin, and the ulcerations were delayed. Signs of renal toxicity, namely reduced urine output and increased urine N-acetyl glycosaminidase to creatinine ratio, were 5-fold lower for DP-155. Indomethacin, but not an equimolar dose of DP-155, reduced urine bicyclo-prostaglandin E(2). An equimolar oral dose of DP-155 or indomethacin, administered every 4 h for 3 days, was equally efficacious in reducing the levels of Abeta42 in the brains of Tg2576 mice. Indomethacin was the principal metabolite of DP-155 in the serum. After DP-155 oral administration, indomethacin's half-life in the serum and the brain was 22 and 93 h, respectively, compared with 10 and 24 h following indomethacin oral administration. The brain to serum ratio was 3.5 times higher for DP-155 than indomethacin. This finding explains the efficacy of DP-155 in reducing Abeta42 brain levels, despite the low systemic blood concentrations of indomethacin derived from DP-155. In conclusion, compared with indomethacin, DP-155 has significantly lower toxicity in the gut and kidney while maintaining similar efficacy to indomethacin in lowering Abeta42 in the brains of Tg2576 mice. This superior safety profile highlights DP-155's potential as an improved indomethacin-based therapy for AD.
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Enfermedad de Alzheimer/tratamiento farmacológico , Péptidos beta-Amiloides/análisis , Química Encefálica/efectos de los fármacos , Indometacina/análogos & derivados , Fragmentos de Péptidos/análisis , Fosfatidilcolinas/uso terapéutico , Animales , Área Bajo la Curva , Encéfalo/metabolismo , Dinoprostona/biosíntesis , Combinación de Medicamentos , Tracto Gastrointestinal/efectos de los fármacos , Tracto Gastrointestinal/patología , Indometacina/farmacocinética , Indometacina/farmacología , Indometacina/uso terapéutico , Indometacina/toxicidad , Riñón/efectos de los fármacos , Masculino , Ratones , Ratones Transgénicos , Fosfatidilcolinas/farmacocinética , Fosfatidilcolinas/toxicidad , Ratas , Ratas Sprague-DawleyRESUMEN
OBJECTIVE: The human Herpesvirus type-6 (HHV-6) has been implicated in multiple sclerosis (MS). Valacyclovir is an antiviral agent with an excellent safety profile. A two-year placebo-controlled, double-blind study was conducted to (1) ascertain if high-dose, prolonged treatment with valacyclovir would be safe and (2) observe if valacyclovir would delay the progression of MS clinically or by magnetic resonance imaging (MRI). DESIGN/METHODS: Fifty-eight patients were stratified as to severity and randomly assigned to receive valacyclovir (3000 mg/day) or placebo for a period of two years. Patients were followed clinically over the two-year period by means of the Expanded Disability Status Scale (EDSS), the Ambulation Index (AI) and brain MRI scans. Patients underwent routine lab studies every three months. Patients continued on the medication for two years unless they had a sustained progression or repeated exacerbations. RESULTS: No patient discontinued the study due to side effects or toxicity. In Relative Ranking of Progression, time to first attack, attack rate, and time to withdrawal there were trends (but not statistically significant) toward drug effect over placebo in the Severe clinical category. MRI evaluation showed no significant drug effect. CONCLUSIONS: Although not statistically significant, positive trends were detected for acyclovir by clinical measures, but not by MRI.
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Aciclovir/análogos & derivados , Aciclovir/administración & dosificación , Antivirales/administración & dosificación , Herpesvirus Humano 6 , Esclerosis Múltiple Crónica Progresiva/tratamiento farmacológico , Esclerosis Múltiple Recurrente-Remitente/tratamiento farmacológico , Infecciones por Roseolovirus/tratamiento farmacológico , Valina/análogos & derivados , Valina/administración & dosificación , Aciclovir/efectos adversos , Adolescente , Adulto , Anciano , Antivirales/efectos adversos , Evaluación de la Discapacidad , Femenino , Marcha , Humanos , Inmunoglobulina M/sangre , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Esclerosis Múltiple Crónica Progresiva/patología , Esclerosis Múltiple Crónica Progresiva/virología , Esclerosis Múltiple Recurrente-Remitente/patología , Esclerosis Múltiple Recurrente-Remitente/virología , Proyectos Piloto , Infecciones por Roseolovirus/complicaciones , Infecciones por Roseolovirus/inmunología , Valaciclovir , Valina/efectos adversosRESUMEN
Amino acids have multiple functions in fetoplacental development. The supply of amino acids to the fetus involves active transport across and metabolism within the trophoblast. Transport occurs through various amino acid transport systems located on both the maternal and fetal facing membranes, many of which have now been documented to be present in rat, sheep and human placentas. The capacity of the placenta to supply amino acids to the fetus develops during pregnancy through alterations in such factors as surface area and specific time-dependent transport system expression. In intrauterine growth restriction (IUGR), placental surface area and amino acid uptakes are decreased in human and experimental animal models. In an ovine model of IUGR, produced by hyperthermia-induced placental insufficiency (PI-IUGR), umbilical oxygen and essential amino acid uptake rates are significantly reduced in the most severe cases in concert with decreased fetal growth. These changes indicate that severe IUGR is likely associated with a shift in amino acid transport capacity and metabolic pathways within the fetoplacental unit. After transport across the trophoblast in normal conditions, amino acids are actively incorporated into tissue proteins or oxidized. In the sheep IUGR fetus, however, which is hypoxic, hypoglycemic and hypoinsulinemic, there appear to be net effluxes of amino acids from the liver and skeletal muscle, suggesting changes in amino acid metabolism. Potential changes may be occurring in the insulin/IGF-I signaling pathway that includes decreased production and/or activation of specific signaling proteins leading to a reduced protein synthesis in fetal tissues. Such observations in the placental insufficiency model of IUGR indicate that the combination of decreased fetoplacental amino acid uptake and disrupted insulin/IGF signaling in liver and muscle account for decreased fetal growth in IUGR.
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Aminoácidos/metabolismo , Retardo del Crecimiento Fetal/metabolismo , Animales , Transporte Biológico Activo , Modelos Animales de Enfermedad , Femenino , Feto/metabolismo , Humanos , Insulina/metabolismo , Factor I del Crecimiento Similar a la Insulina/metabolismo , Hígado/embriología , Hígado/metabolismo , Intercambio Materno-Fetal , Modelos Biológicos , Músculo Esquelético/embriología , Músculo Esquelético/metabolismo , Placenta/metabolismo , Embarazo , Transducción de SeñalAsunto(s)
Proteínas Portadoras , Proteínas de Drosophila , Péptidos y Proteínas de Señalización Intracelular , Receptor de Insulina/metabolismo , Transducción de Señal/fisiología , Envejecimiento/fisiología , Animales , Femenino , Humanos , Proteínas de Insectos/genética , Proteínas de Insectos/metabolismo , Proteínas Sustrato del Receptor de Insulina , Receptor IGF Tipo 1/genética , Receptor IGF Tipo 1/metabolismo , Receptor de Insulina/genética , Levaduras/fisiologíaRESUMEN
Gestational diabetes mellitus (GDM) results from an interaction between susceptibility genes and the diabetogenic effects of pregnancy. During pregnancy, mice heterozygous for the lepin receptor (db/+) gain more weight, are glucose intolerant, and produce macrosomic fetuses compared with wild-type (+/+) mothers, suggesting that an alteration in leptin action may play a role in GDM and fetal overgrowth. To investigate whether leptin administration or pair-feeding can reduce adiposity and thereby prevent GDM and neonatal overgrowth, we examined energy balance, glucose and insulin tolerance, and fetal growth in pregnant db/+ and +/+ mice treated with recombinant human leptin-IgG during late pregnancy. Leptin reduced food intake and adiposity in pregnant db/+ mice to levels similar to pregnant +/+ mice and significantly reduced maternal weight gain. Maternal glucose levels were markedly lower during glucose and insulin challenge tests in leptin-treated db/+ mice relative to db/+ and pair-fed controls. Despite reduced energy intake and improved glucose tolerance, leptin administration did not reduce fetal overgrowth in offspring from db/+ mothers. Fetal and placental leptin levels were 1.3- to 1.5-fold higher in offspring from db/+ mothers and remained unchanged with leptin administration, whereas leptin treatment in +/+ mothers or pair-feeding decreased placental leptin concentration and reduced fetal birth weight. Our results provide evidence that leptin administration during late gestation can reduce adiposity and improve glucose tolerance in the db/+ mouse model of spontaneous GDM. However, fetal and placenta leptin levels are higher in db/+ mothers and are subject to reduced negative feedback in response to leptin treatment. These data suggest that alterations in placenta leptin may contribute to the regulation of fetal growth independently of maternal glucose levels.
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Proteínas Portadoras/genética , Diabetes Gestacional/genética , Diabetes Gestacional/prevención & control , Heterocigoto , Leptina/farmacología , Receptores de Superficie Celular , Proteínas Recombinantes/farmacología , Animales , Diabetes Gestacional/sangre , Desarrollo Embrionario y Fetal/efectos de los fármacos , Femenino , Feto/fisiología , Intolerancia a la Glucosa/etiología , Intolerancia a la Glucosa/fisiopatología , Humanos , Insulina/fisiología , Leptina/metabolismo , Ratones , Ratones Endogámicos C57BL/genética , Músculo Esquelético/fisiopatología , Placenta/efectos de los fármacos , Placenta/metabolismo , Embarazo , Complicaciones del Embarazo , Receptores de Leptina , Transducción de Señal/efectos de los fármacosRESUMEN
Fifty percent of the mice homozygous for a deletion in the gene for CCAAT/enhancer-binding protein beta (C/EBP beta-/- mice; B phenotype) die within 1 to 2 h after birth of hypoglycemia. They do not mobilize their hepatic glycogen or induce the cytosolic form of phosphoenolpyruvate carboxykinase (PEPCK). Administration of cAMP resulted in mobilization of glycogen, induction of PEPCK mRNA, and a normal blood glucose; these mice survived beyond 2 h postpartum. Adult C/EBP beta-/- mice (A phenotype) also had difficulty in maintaining blood glucose levels during starvation. Fasting these mice for 16 or 30 h resulted in lower levels of hepatic PEPCK mRNA, blood glucose, beta-hydroxybutyrate, blood urea nitrogen, and gluconeogenesis when compared with control mice. The concentration of hepatic cAMP in these mice was 50% of controls, but injection of theophylline, together with glucagon, resulted in a normal cAMP levels. Agonists (glucagon, epinephrine, and isoproterenol) and other effectors of activation of adenylyl cyclase were the same in liver membranes isolated from C/EBP beta-/- mice and littermates. The hepatic activity of cAMP-dependent protein kinase was 80% of wild type mice. There was a 79% increase in the concentration of RI alpha and 27% increase in RII alpha in the particulate fraction of the livers of C/EBP beta-/- mice relative to wild type mice, with no change in the catalytic subunit (C alpha). Thus, a 45% increase in hepatic cAMP (relative to the wild type) would be required in C/EBP beta-/- mice to activate protein kinase A by 50%. In addition, the total activity of phosphodiesterase in the livers of C/EBP beta-/- mice, as well as the concentration of mRNA for phosphodiesterase 3A (PDE3A) and PDE3B was approximately 25% higher than in control animals, suggesting accelerated degradation of cAMP. C/EBP beta influences the regulation of carbohydrate metabolism by altering the level of hepatic cAMP and the activity of protein kinase A.
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Proteína beta Potenciadora de Unión a CCAAT/deficiencia , Proteína beta Potenciadora de Unión a CCAAT/metabolismo , Metabolismo de los Hidratos de Carbono , AMP Cíclico/farmacología , Eliminación de Gen , Hígado/efectos de los fármacos , Hígado/metabolismo , Ácido 3-Hidroxibutírico/sangre , Adenilil Ciclasas/metabolismo , Amoníaco/sangre , Animales , Proteína beta Potenciadora de Unión a CCAAT/genética , AMP Cíclico/metabolismo , Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo , Privación de Alimentos , Glucagón/farmacología , Glucosa/biosíntesis , Glucosa/metabolismo , Glucosa-6-Fosfatasa/genética , Hipoglucemia/genética , Hígado/enzimología , Ratones , Ratones Noqueados , Nitrógeno/sangre , Fenotipo , Fosfoenolpiruvato Carboxiquinasa (ATP)/genética , Hidrolasas Diéster Fosfóricas/genética , Hidrolasas Diéster Fosfóricas/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Urea/sangreRESUMEN
OBJECTIVE: We compared the insulin-mimetic effects of vanadate, a protein-tyrosine phosphatase inhibitor, with the effects of insulin on skeletal muscle glucose transport and insulin receptor and insulin receptor substrate 1 phosphorylation to test the hypothesis that protein-tyrosine phosphatases participate in pregnancy-induced insulin resistance. STUDY DESIGN: Skeletal muscle fiber strips were obtained from the rectus abdominis during cesarean delivery in 7 patients with gestational diabetes mellitus, 11 pregnant women with normal glucose tolerance (pregnant control group), and 11 nonpregnant women undergoing elective surgery (nonpregnant control group). Muscle tissues were incubated in vitro for 15 to 60 minutes with or without maximal insulin (100 nmol/L) or sodium vanadate (6 micromol/L). Insulin receptor and insulin receptor substrate 1 tyrosine phosphorylation were measured, as was 2-deoxyglucose transport. The levels of protein-tyrosine phosphatase 1B were measured by Western blot analysis. RESULTS: Vanadate stimulated maximal 2-deoxyglucose transport more than did insulin alone in all samples (P<.05), but the value was still less in muscle tissues from pregnant control subjects and patients with gestational diabetes mellitus (P<.05). In muscle tissues from pregnant control subjects vanadate increased tyrosine phosphorylation of the insulin receptor and insulin receptor substrate 1 to levels similar to those in muscle tissues from nonpregnant control subjects. In patients with gestational diabetes mellitus vanadate increased insulin receptor and insulin receptor substrate 1 tyrosine phosphorylation, but these values remained less than in muscle tissues from nonpregnant control subjects (P<.05). Protein-tyrosine phosphatase 1B levels were not significantly different in skeletal muscles from each group. CONCLUSION: Vanadate did not restore normal glucose transport activity during pregnancy complicated by gestational diabetes mellitus, which indicates that decreased glucose uptake is probably not caused by impaired tyrosine phosphorylation events alone. Increased serine kinase activity and impaired glucose transporter 4 translocation probably contribute to insulin signaling abnormalities associated with pregnancy, especially in patients with gestational diabetes mellitus.
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Diabetes Gestacional/metabolismo , Glucosa/metabolismo , Músculo Esquelético/metabolismo , Obesidad/metabolismo , Complicaciones del Embarazo/metabolismo , Receptor de Insulina/metabolismo , Vanadatos/farmacología , Transporte Biológico/efectos de los fármacos , Femenino , Humanos , Proteínas Sustrato del Receptor de Insulina , Fosfoproteínas/metabolismo , Fosforilación/efectos de los fármacos , Embarazo , Proteína Tirosina Fosfatasa no Receptora Tipo 1 , Proteínas Tirosina Fosfatasas/metabolismo , Valores de Referencia , Tirosina/metabolismoRESUMEN
Recent studies suggest that the serine/threonine kinase protein kinase B (PKB or Akt) is involved in the pathway for insulin-stimulated glucose transporter 4 (GLUT4) translocation and glucose uptake. In this study we examined the components of the Akt signaling pathway in skeletal muscle and adipose tissue in vivo from C57BL/KsJ-Lepr(db/db) mice (db/db), a model of obesity, insulin resistance, and type II diabetes. There were no changes in the protein levels of GLUT4, p85alpha, or Akt in tissues from db/db mice compared with non-diabetic littermate controls (+/+). In response to acute insulin administration, GLUT4 recruitment to the plasma membrane increased twofold in muscle and adipose tissue from +/+ mice, but was significantly reduced by 42-43% (P<0.05) in both tissues from db/db mice. Insulin increased Akt-Ser(473) phosphorylation by two- to fivefold in muscle and adipose tissue from all mice. However, in db/db mice, maximal Akt-Ser(473) phosphorylation was decreased by 32% (P<0.05) and 69% (P<0.05) in muscle and adipose tissue respectively. This decreased phosphorylation in db/db mice corresponded with a significant decrease in maximal Akt kinase activity using a glycogen synthase kinase-3 fusion protein as a substrate (P<0.05). The level of insulin-stimulated tyrosine phosphorylation of p85alpha from phosphatidylinositol 3 (PI 3)-kinase, which is upstream of Akt, was also reduced in muscle and adipose tissue from db/db mice (P<0.05); however, there was no change in extracellular signal-regulated kinase-1 or -2 phosphorylation. These data implicate decreased insulin-stimulated Akt kinase activity as an important component underlying impaired GLUT4 translocation and insulin resistance in tissues from db/db mice. However, impaired insulin signal transduction appears to be specific for the PI 3-kinase pathway of insulin signaling, while the MAP kinase pathway remained intact.
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Diabetes Mellitus Experimental/enzimología , Diabetes Mellitus Tipo 2/enzimología , Resistencia a la Insulina/fisiología , Proteínas Musculares , Proteínas Proto-Oncogénicas/metabolismo , Animales , Glucemia/análisis , Diabetes Mellitus Experimental/fisiopatología , Diabetes Mellitus Tipo 2/fisiopatología , Femenino , Transportador de Glucosa de Tipo 4 , Insulina/sangre , Masculino , Ratones , Ratones Endogámicos C57BL , Proteína Quinasa 1 Activada por Mitógenos/metabolismo , Proteína Quinasa 3 Activada por Mitógenos , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Proteínas de Transporte de Monosacáridos/metabolismo , Obesidad/enzimología , Obesidad/fisiopatología , Fosfatidilinositol 3-Quinasas/metabolismo , Fosforilación , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt , Transducción de Señal/fisiologíaRESUMEN
The bursa of Fabricius is critical to normal B-lymphocyte development in birds. During embryonic life, B-cell precursors migrate to the bursal rudiment and those which have undergone productive V(D)J recombination colonize lymphoid follicles and undergo immunoglobulin V gene diversification by gene conversion. The chicken surface IgM complex appears structurally and functionally equivalent to its mammalian counterpart, with homologs to CD79a and CD79b. Expression of a truncated Igmu chain is sufficient to drive the early stages of B-cell development in the embryo bursa. Bursal cells expressing the truncated mu receptor complex proliferate in bursal follicles, and those which contain V gene rearrangements undergo V gene diversification by gene conversion. The bursa is a gut-associated organ and antigen is focused to bursal lymphoid follicles after hatch. While expression of the truncated mu chain is sufficient to support B-cell development in the embryo, B cells expressing this receptor are rapidly eliminated after hatch. We suggest the possibility that B-cell development in the bursa after hatch is driven by encounter with antigen leading to redistribution of B cells within the lymphoid follicle, B-cell proliferation and V gene repertoire development by gene conversion.
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Linfocitos B/inmunología , Bolsa de Fabricio/inmunología , Embrión de Pollo , Receptores de Antígenos de Linfocitos B/inmunología , Alelos , Secuencia de Aminoácidos , Animales , Diversidad de Anticuerpos , Antígenos CD/química , Virus de la Leucosis Aviar/genética , Antígenos CD79 , Linaje de la Célula , Conversión Génica , Reordenamiento Génico de Linfocito B , Genes de Inmunoglobulinas , Vectores Genéticos , Inmunoglobulina M/química , Inmunoglobulina M/genética , Región Variable de Inmunoglobulina/genética , Sustancias Macromoleculares , Datos de Secuencia Molecular , Receptores de Antígenos de Linfocitos B/química , Alineación de SecuenciaRESUMEN
The cellular mechanisms for the insulin resistance of pregnancy and gestational diabetes mellitus (GDM) are unknown. The membrane protein plasma cell membrane glycoprotein-1 (PC-1) has been identified as an inhibitor of insulin receptor tyrosine kinase (IRTK) activity. We investigated insulin receptor function and PC-1 levels in muscle from three groups of obese subjects: women with GDM, pregnant women with normal glucose tolerance, and nonpregnant control subjects. Subjects (n = 6 for each group) were similar in age and degree of obesity (body fat >30%). IRTK activity, insulin receptor tyrosine phosphorylation, and protein levels of membrane glycoprotein PC-1 were determined in rectus abdominus muscle biopsies obtained at the time of either elective cesarean section or gynecological surgery. No significant differences were evident in basal insulin receptor tyrosine phosphorylation or IRTK activity in the three groups. After maximal insulin (10(-7) mol/l) stimulation, IRTK activity measured with the artificial substrate poly(Glu,Tyr) increased in all subjects but was lower in women with GDM by 25% (P < 0.05) and 39% (P < 0.001) compared with pregnant and nonpregnant control subjects, respectively. Similarly, insulin receptor tyrosine phosphorylation was significantly decreased in subjects with GDM (P < 0.05) compared with pregnant and nonpregnant control subjects. Treatment of the insulin receptors with alkaline phosphatase to dephosphorylate serine/threonine residues increased insulin-stimulated IRTK activity significantly in pregnant control and GDM subjects (P < 0.05), but these rates were still lower compared with nonpregnant control subjects (P < 0.05). PC-1 content in muscle from GDM subjects was increased by 63% compared with pregnant control subjects (P < 0.05) and by 206% compared with nonpregnant control subjects (P < 0.001). PC-1 content was negatively correlated with insulin receptor phosphorylation (r = -0.55, P < 0.05) and IRTK activity (r = -0.66, P < 0.05). These results indicate that pregnant control and GDM subjects had increased PC-1 content and suggest excessive phosphorylation of serine/threonine residues in muscle insulin receptors and that both may contribute to decreased IRTK activity. These changes worsen in women with GDM when controlling for obesity. These postreceptor defects in insulin signaling may contribute to the pathogenesis of GDM and the increased risk for type 2 diabetes later in life.
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Diabetes Mellitus/metabolismo , Diabetes Gestacional/metabolismo , Expresión Génica , Glicoproteínas de Membrana/genética , Músculo Esquelético/metabolismo , Obesidad , Hidrolasas Diéster Fosfóricas , Pirofosfatasas , Receptor de Insulina/metabolismo , Fosfatasa Alcalina/farmacología , Biopsia , Glucemia/metabolismo , Femenino , Humanos , Insulina/farmacología , Glicoproteínas de Membrana/metabolismo , Músculo Esquelético/química , Fosforilación , Fosfotirosina/metabolismo , Embarazo , Receptor de Insulina/análisisRESUMEN
CCAAT/enhancer-binding protein beta (C/EBPbeta) controls gene transcription and metabolic processes in a variety of insulin-sensitive tissues; however, its role in regulating insulin responsiveness in vivo has not been investigated. We performed hyperinsulinemic-euglycemic clamps in awake, non-stressed, chronically catheterized adult mice homozygous for a deletion in the gene for C/EBPbeta (C/EBPbeta(-/-)). Fasting plasma insulin, glucose, and free fatty acid (FFA) levels were significantly lower in C/EBPbeta(-/-) mice compared with wild-type (WT) controls. Acute hyperinsulinemia (4 h) suppressed hepatic glucose production, phosphoenolpyruvate carboxykinase mRNA, and plasma FFA to a similar extent in WT and C/EBPbeta(-/-) mice, suggesting that C/EBPbeta deletion does not alter the metabolic and gene regulatory response to insulin in liver and adipose tissue. In contrast, using submaximal (5 milliunits/kg/min) and maximal (20 milliunits/kg/min) insulin infusions, whole-body glucose disposal was 77% (p < 0.01) and 33% (p < 0.05) higher in C/EBPbeta(-/-) mice, respectively, compared with WT mice. Maximal insulin-stimulated 3-O-methylglucose uptake in isolated soleus muscle was 54% greater in C/EBPbeta(-/-) mice (p < 0.05). Furthermore, insulin-stimulated insulin receptor and Akt Ser(473) phosphorylation and phosphatidylinositol 3-kinase activity were 1.6-2.5-fold greater in skeletal muscle from C/EBPbeta(-/-) mice compared with WT mice. The level of insulin receptor substrate-1 protein was increased 2-fold in skeletal muscle from C/EBPbeta(-/-) mice. These results demonstrate that C/EBPbeta deletion decreases plasma FFA levels and increases insulin signal transduction specifically in skeletal muscle, and both contribute to increased whole-body insulin sensitivity.