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1.
Diabetes Technol Ther ; 21(6): 322-328, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31157566

RESUMO

Background: This multicenter crossover study investigated the potential beneficial effect of an automated bolus calculator (ABC) in children and adolescents with type 1 diabetes (T1D) treated with multiple daily injections (MDI). Methods: Participants were randomized to either begin or end with a 5 months intervention versus their regular treatment regimen (control), separated by a 2 months washout period. During the intervention participants were carefully instructed to use the ABC (Accu-Check Aviva Expert) versus manual insulin calculations during the control period. Participants between 8 and 18 years of age with T1D were recruited from clinics in Denmark, Belgium, and Spain. Inclusion criteria included T1D for >1 year, a minimum of 3 months MDI treatment before inclusion, and HbA1c of 7.5%-11% (57-97 mmol/mol). Improvement in HbA1c was the main outcome, and improved quality of life (QoL) and glucose variability (time spent in target glucose) were secondary outcomes. Results: A total of 65 patients with a mean age of 13.25 years and a mean HbA1c of 8.25% (66.7 mmol/mol) were included. Midway evaluation after 2 months of intervention showed no significant difference from the standard care (0.297, 95% confidence interval [CI]: -0.645 to 0.054; P = 0.10). The difference remained insignificant after the 5 months of intervention (-0.143 [95% CI: -0.558 to 0.272; P = 0.51]). Using the ABC did not change the time spent in target glucose range, nor did it change the QoL. Conclusions: Our study did not demonstrate beneficial additive effects of an ABC in children and adolescents with T1D treated with MDI neither in HbA1c, nor in any other endpoint investigated.

2.
Obesity (Silver Spring) ; 26(10): 1603-1610, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30204940

RESUMO

OBJECTIVE: Early lifestyle interventions in children with obesity decrease risk of obesity and metabolic disorders during adulthood. This study aimed to identify metabolic signatures associated with lifestyle intervention in urine samples from prepubertal children with obesity. METHODS: Thirty-four prepubertal children with obesity were studied before and after a 6-month lifestyle intervention program, and anthropometric, metabolic, and nutritional variables were collected. A nuclear magnetic resonance approach was applied to obtain the metabolomic profile from urine samples. Partial least squares-discriminant analysis (PLS-DA) was used to achieve group classification and variable importance on projection (VIP) for biomarker selection. RESULTS: The intervention reduced caloric intake by 10% (P < 0.05) and BMI standard deviation score by 0.47 SD (P < 0.001). PLS-DA identified trimethylamine N-oxide (TMAO, VIP = 2.21) as the metabolite with the highest discrimination properties between groups. Urine TMAO levels were reduced after the intervention (P < 0.05). TMAO is a biomarker of cardiovascular disease risk and is a product of gut microbiota-dependent metabolism of certain dietary compounds, including choline. Notably, changes in TMAO levels after the intervention did not correlate to differences in choline intake but were inversely associated with fiber intake (P < 0.05). CONCLUSIONS: These results indicate that lifestyle intervention decreases TMAO levels in children with obesity.


Assuntos
Biomarcadores/urina , Metabolômica/métodos , Metilaminas/urina , Obesidade Pediátrica/terapia , Comportamento de Redução do Risco , Criança , Feminino , Humanos , Masculino
3.
FASEB J ; : fj201700717RR, 2018 May 29.
Artigo em Inglês | MEDLINE | ID: mdl-29812971

RESUMO

Postnatal overfeeding increases the risk of chronic diseases later in life, including obesity, insulin resistance, hepatic steatosis, and type 2 diabetes. Epigenetic mechanisms might underlie the long-lasting effects associated with early nutrition. Here we aimed to explore the molecular pathways involved in early development of insulin resistance and hepatic steatosis, and we examined the potential contribution of DNA methylation and histone modifications to long-term programming of metabolic disease. We used a well-characterized mouse model of neonatal overfeeding and early adiposity by litter size reduction. Neonatal overfeeding led to hepatic insulin resistance very early in life that persisted throughout adulthood despite normalizing food intake. Up-regulation of monoacylglycerol O-acyltransferase ( Mogat) 1 conceivably mediates hepatic steatosis and insulin resistance through increasing intracellular diacylglycerol content. Early and sustained deregulation of Mogat1 was associated with a combination of histone modifications that might favor Mogat1 expression. In sum, postnatal overfeeding causes extremely rapid derangements of hepatic insulin sensitivity that remain relatively stable until adulthood. Epigenetic mechanisms, particularly histone modifications, could contribute to such long-lasting effects. Our data suggest that targeting hepatic monoacylglycerol acyltransferase activity during early life might provide a novel strategy to improve hepatic insulin sensitivity and prevent late-onset insulin resistance and fatty liver disease.-Ramon-Krauel, M., Pentinat, T., Bloks, V. W., Cebrià, J., Ribo, S., Pérez-Wienese, R., Vilà, M., Palacios-Marin, I., Fernández-Pérez, A., Vallejo, M., Téllez, N., Rodríguez, M. À., Yanes, O., Lerin, C., Díaz, R., Plosch, T., Tietge, U. J. F., Jimenez-Chillaron, J. C. Epigenetic programming at the Mogat1 locus may link neonatal overnutrition with long-term hepatic steatosis and insulin resistance.

4.
Front Aging Neurosci ; 9: 268, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28848425

RESUMO

Mutations in human collagen VI genes cause a spectrum of musculoskeletal conditions in children and adults collectively termed collagen VI-related myopathies (COL6-RM) characterized by a varying degree of muscle weakness and joint contractures and which include Ullrich Congenital Muscular Dystrophy (UCMD) and Bethlem Myopathy (BM). Given that collagen VI is one of the most abundant extracellular matrix proteins in adipose tissue and its emerging role in energy metabolism we hypothesized that collagen VI deficiency might be associated with alterations in adipose tissue distribution and adipokines serum profile. We analyzed body composition by means of dual-energy X-ray absorptiometry in 30 pediatric and adult COL6-RM myopathy patients representing a range of severities (UCMD, intermediate-COL6-RM, and BM). We found a distinctive pattern of regional adipose tissue accumulation which was more evident in children at the most severe end of the spectrum. In particular, the accumulation of fat in the android region was a distinguishing feature of UCMD patients. In parallel, there was a decrease in lean mass compatible with a state of sarcopenia, particularly in ambulant children with an intermediate phenotype. All children and adult patients that were sarcopenic were also obese. These changes were significantly more pronounced in children with collagen VI deficiency than in children with Duchenne Muscular Dystrophy of the same ambulatory status. High molecular weight adiponectin and leptin were significantly increased in sera from children in the intermediate and BM group. Correlation analysis showed that the parameters of fat mass were negatively associated with motor function according to several validated outcome measures. In contrast, lean mass parameters correlated positively with physical performance and quality of life. Leptin and adiponectin circulating levels correlated positively with fat mass parameters and negatively with lean mass and thus may be relevant to the disease pathogenesis and as circulating markers. Taken together our results indicate that COL6-RM are characterized by specific changes in total fat mass and distribution which associate with disease severity, motor function, and quality of life and which are clinically meaningful and thus should be taken into consideration in the management of these patients.

5.
Anal Chem ; 88(19): 9821-9829, 2016 10 04.
Artigo em Inglês | MEDLINE | ID: mdl-27584001

RESUMO

Gas chromatography coupled to mass spectrometry (GC/MS) has been a long-standing approach used for identifying small molecules due to the highly reproducible ionization process of electron impact ionization (EI). However, the use of GC-EI MS in untargeted metabolomics produces large and complex data sets characterized by coeluting compounds and extensive fragmentation of molecular ions caused by the hard electron ionization. In order to identify and extract quantitative information on metabolites across multiple biological samples, integrated computational workflows for data processing are needed. Here we introduce eRah, a free computational tool written in the open language R composed of five core functions: (i) noise filtering and baseline removal of GC/MS chromatograms, (ii) an innovative compound deconvolution process using multivariate analysis techniques based on compound match by local covariance (CMLC) and orthogonal signal deconvolution (OSD), (iii) alignment of mass spectra across samples, (iv) missing compound recovery, and (v) identification of metabolites by spectral library matching using publicly available mass spectra. eRah outputs a table with compound names, matching scores and the integrated area of compounds for each sample. The automated capabilities of eRah are demonstrated by the analysis of GC-time-of-flight (TOF) MS data from plasma samples of adolescents with hyperinsulinaemic androgen excess and healthy controls. The quantitative results of eRah are compared to centWave, the peak-picking algorithm implemented in the widely used XCMS package, MetAlign, and ChromaTOF software. Significantly dysregulated metabolites are further validated using pure standards and targeted analysis by GC-triple quadrupole (QqQ) MS, LC-QqQ, and NMR. eRah is freely available at http://CRAN.R-project.org/package=erah .


Assuntos
Androgênios/sangue , Hiperinsulinismo/sangue , Metabolômica , Software , Adolescente , Algoritmos , Cromatografia Gasosa-Espectrometria de Massas , Humanos , Análise Multivariada
6.
Proc Nutr Soc ; 75(1): 78-89, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26573376

RESUMO

In today's world, there is an unprecedented rise in the prevalence of chronic metabolic diseases, including obesity, insulin resistance and type 2 diabetes (T2D). The pathogenesis of T2D includes both genetic and environmental factors, such as excessive energy intake and physical inactivity. It has recently been suggested that environmental factors experienced during early stages of development, including the intrauterine and neonatal periods, might play a major role in predisposing individuals to T2D. Furthermore, several studies have shown that such early environmental conditions might even contribute to disease risk in further generations. In this review, we summarise recent data describing how parental nutrition during development increases the risk of diabetes in the offspring. We also discuss the potential mechanisms underlying transgenerational inheritance of metabolic disease, with particular emphasis on epigenetic mechanisms.

7.
Adv Ther ; 32(2): 148-56, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25667132

RESUMO

INTRODUCTION: An initial Phase III clinical trial has evaluated the efficacy and safety of biosimilar recombinant human growth hormone (rhGH; Omnitrope(®), Sandoz) in Spanish children with growth hormone deficiency (GHD). At the end of the study, those patients still growing were offered to remain on treatment (as in usual clinical practice), and continued to be monitored. The aim of this study was to determine the adult height achieved by the Spanish children who participated in the initial Phase III clinical trial, and to evaluate the long-term safety of rhGH treatment. METHODS: This study was a multicenter, observational, retrospective follow-up study of patients who participated in the Phase III clinical trial (70 patients recruited). Auxological parameters [including height, height velocity, and their associated height standard deviation scores (HSDS)] were obtained from 39 patients. Safety was assessed by recording any adverse events (AEs). RESULTS: In total, 27 men and 12 women provided auxological data. At the start of the follow-up study, the mean age of the patients was 12.5 ± 2.7 years, mean height was 144.8 ± 13.9 cm and mean HSDS was -1.16 ± 0.63. By the end of the follow-up period, mean height had increased to 163.1 ± 7.6 cm (n = 36; men 165.5 ± 7.8 cm, women 157.6 ± 3.2 cm) and mean HSDS also increased to -1.01 ± 0.59 (n = 36; men -1.07 ± 0.52, women -0.86 ± 0.72). In terms of safety, no treatment-related AEs were reported during the study. CONCLUSION: This cohort of Spanish patients with GHD showed a positive response to rhGH treatment, achieving adult height within the local normal ranges. In addition, rhGH treatment was well tolerated, with no new or additional safety concerns.


Assuntos
Medicamentos Biossimilares/uso terapêutico , Estatura , Transtornos do Crescimento/tratamento farmacológico , Hormônio do Crescimento Humano/uso terapêutico , Adolescente , Criança , Feminino , Seguimentos , Humanos , Masculino , Estudos Retrospectivos
8.
J Pediatr ; 165(6): 1146-1153.e2, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25260622

RESUMO

OBJECTIVE: To determine if very preterm (VPT) babies are capable of maintaining glucose levels within normal ranges at or near term postmenstrual age. STUDY DESIGN: Glucose levels were intermittently or continuously monitored during 48 hours in a cohort of 60 VPT infants near hospital discharge. Hypoglycemic (≤45 mg/dL, 2.5 mmol/L) and hyperglycemic (≥140 mg/dL or 7.8 mmol/L, severe if ≥180 mg/dL or 10 mmol/L) episodes were considered relevant if they lasted longer than 30 minutes. Feeding regimes followed current practice. RESULTS: With intermittent capillary, 2 hypoglycemic values and another 3 that were abnormally high were detected. With continuous monitoring, 6 babies (10.0%) had isolated hypoglycemia ≤45 mg/dL (2.5 mmol/L) (3 of them reaching 40 mg/dL, 2.2 mmol/L), 14 (23.3%) had isolated hyperglycemia, and 8 (13.3%) had episodes of both. The mean duration of hypoglycemia per patient was 2.8 ± 2.9 hours and 4.68 ± 4.35 hours in the case of hyperglycemia, with 12 infants becoming severely hyperglycemic. Of the 12 severely hyperglycemic patients, 5 also developed severe hypoglycemia. No specific characteristics identified the hypoglycemic babies. A history of intrauterine growth restriction (P = .037) and female sex (P = .063) seemed to increase the risk of severe hyperglycemia. CONCLUSIONS: VPT infants continue to have abnormal glucose values, especially hyperglycemia, by the time of hospital discharge. No specific factors identify babies at higher risk for hypoglycemia, and intrauterine growth restriction and female sex seemed to predispose to hyperglycemia.


Assuntos
Glicemia/análise , Homeostase/fisiologia , Recém-Nascido Prematuro/fisiologia , Comorbidade , Nutrição Enteral , Feminino , Retardo do Crescimento Fetal/epidemiologia , Retardo do Crescimento Fetal/fisiopatologia , Humanos , Hiperglicemia/epidemiologia , Hipoglicemia/epidemiologia , Masculino , Fatores de Risco
9.
Cell Metab ; 19(6): 941-51, 2014 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-24794974

RESUMO

Obesity and type 2 diabetes have a heritable component that is not attributable to genetic factors. Instead, epigenetic mechanisms may play a role. We have developed a mouse model of intrauterine growth restriction (IUGR) by in utero malnutrition. IUGR mice developed obesity and glucose intolerance with aging. Strikingly, offspring of IUGR male mice also developed glucose intolerance. Here, we show that in utero malnutrition of F1 males influenced the expression of lipogenic genes in livers of F2 mice, partly due to altered expression of Lxra. In turn, Lxra expression is attributed to altered DNA methylation of its 5' UTR region. We found the same epigenetic signature in the sperm of their progenitors, F1 males. Our data indicate that in utero malnutrition results in epigenetic modifications in germ cells (F1) that are subsequently transmitted and maintained in somatic cells of the F2, thereby influencing health and disease risk of the offspring.


Assuntos
Metilação de DNA , Metabolismo dos Lipídeos/fisiologia , Fígado/metabolismo , Desnutrição/metabolismo , Receptores Nucleares Órfãos/genética , Envelhecimento , Animais , Células Cultivadas , Epigênese Genética , Feminino , Retardo do Crescimento Fetal/metabolismo , Intolerância à Glucose/genética , Lipogênese/genética , Receptores X do Fígado , Masculino , Camundongos , Camundongos Endogâmicos ICR , Obesidade/genética , Receptores Nucleares Órfãos/biossíntese , Gravidez , Espermatozoides/citologia , Proteína de Ligação a Elemento Regulador de Esterol 1/genética
11.
Child Obes ; 9(3): 252-60, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23705885

RESUMO

BACKGROUND: Fatty liver is highly prevalent among obese children and represents a major risk factor for chronic liver diseases and severe metabolic complications. METHODS: We randomly assigned 17 obese children 8-17 years of age with fatty liver to either an experimental low-glycemic-load or conventional low-fat diet for 6 months. Participants in both groups received nutrition education and behavioral counseling of equal intensity. The primary outcome was hepatic lipid content measured by proton magnetic resonance spectroscopy. Secondary outcomes included change in visceral fat, BMI, anthropometrics, alanine aminotransferase (ALT), and insulin resistance. RESULTS: A total of 16 participants completed the study. Reported glycemic load decreased in the low-glycemic-load group and reported dietary fat decreased in the low-fat group. At baseline, liver fat was 23.8% [standard deviation (SD) 12.2] in the low-glycemic-load group and 29.3% (14.1) in the low-fat group. Liver fat decreased substantially in both groups at 6 months expressed as absolute percentage change, with no between-group differences [-8.8 (standard error (SE) 4.1) vs. -10.5 (3.7)%, respectively, p=0.76 for group×time interaction]. Secondary outcomes also improved on both diets, with no between-group differences. Baseline and change in ALT were strongly associated with hepatic fat content. CONCLUSIONS: Weight-reducing diets focused either on glycemic load or dietary fat improved hepatic steatosis over 6 months. Additional research is needed to determine whether these diets differ in effectiveness over the long term. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00480922.


Assuntos
Glicemia/metabolismo , Dieta com Restrição de Gorduras , Fígado Gorduroso/sangue , Resistência à Insulina , Lipídeos/sangue , Obesidade/sangue , Perda de Peso , Adiposidade , Adolescente , Alanina Transaminase , Criança , Dieta Redutora , Carboidratos da Dieta , Fígado Gorduroso/epidemiologia , Fígado Gorduroso/etiologia , Feminino , Índice Glicêmico , Humanos , Gordura Intra-Abdominal , Masculino , Massachusetts/epidemiologia , Obesidade/complicações , Obesidade/epidemiologia , Resultado do Tratamento
12.
Biochimie ; 94(11): 2242-63, 2012 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-22771843

RESUMO

Nutrition plays a key role in many aspects of health and dietary imbalances are major determinants of chronic diseases including cardiovascular disease, obesity, diabetes and cancer. Adequate nutrition is particularly essential during critical periods in early life (both pre- and postnatal). In this regard, there is extensive epidemiologic and experimental data showing that early sub-optimal nutrition can have health consequences several decades later. The hypothesis that epigenetic mechanisms may link such nutritional imbalances with altered disease risk has been gaining acceptance over recent years. Epigenetics can be defined as the study of heritable changes in gene expression that do not involve alterations in the DNA sequence. Epigenetic marks include DNA methylation, histone modifications and a variety of non-coding RNAs. Strikingly, they are plastic and respond to environmental signals, including diet. Here we will review how dietary factors modulate the establishment and maintenance of epigenetic marks, thereby influencing gene expression and, hence, disease risk and health.


Assuntos
Dieta , Epigênese Genética , Saúde , Animais , Epigenômica , Humanos
13.
Endocrinology ; 151(12): 5617-23, 2010 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-20943806

RESUMO

Epidemiological and clinical data show that rapid weight gain early in life is strongly associated with several components of the metabolic syndrome. Strikingly, abnormal growth rates in early life can additionally influence diabetes risk in subsequent generations. Here we aim to study whether neonatal overgrowth induces diabetes in offspring and grand-offspring of affected individuals using a mouse model of neonatal overfeeding. We induced neonatal overgrowth (ON-F0) by culling offspring to four pups per dam during lactation. By age 4 months, ON-F0 mice developed many features of the metabolic syndrome, including obesity, insulin resistance, and glucose intolerance. We then studied whether male offspring (ON-F1) and grand-offspring (ON-F2) of ON-F0 male mice, which were not overfed during lactation, developed features of the metabolic syndrome with aging. ON-F1 mice developed fed and fasting hyperinsulimemia, hypertryglyceridemia, insulin resistance, and glucose intolerance, but not obesity, by age 4 months. In contrast, ON-F2 male mice showed a more moderate phenotype and only developed fasting hyperglycemia and glucose intolerance by age 4 months. Impaired glucose tolerance in ON-F1 and ON-F2 mice appeared to be accounted for primarily by peripheral insulin resistance, because beta-cell function remained normal or even increased in these cohorts. Nutritional challenges occurring during sensitive periods of development may have adverse metabolic consequences well beyond the lifespan of affected individuals and manifest in subsequent generations. Transgenerational progression of metabolic phenotypes through the male lineage supports a potential role for epigenetic mechanisms in mediating these effects.


Assuntos
Intolerância à Glucose/genética , Hipernutrição/complicações , Envelhecimento/fisiologia , Animais , Animais Recém-Nascidos , Glicemia/genética , Feminino , Intolerância à Glucose/metabolismo , Hiperglicemia/genética , Resistência à Insulina/genética , Resistência à Insulina/fisiologia , Tamanho da Ninhada de Vivíparos , Masculino , Síndrome Metabólica/genética , Camundongos , Camundongos Endogâmicos ICR , Obesidade/genética , Caracteres Sexuais
14.
Pediatr. catalan ; 64(1): 34-36, ene.-feb. 2004. ilus
Artigo em Espanhol | IBECS | ID: ibc-142907

RESUMO

La síndrome toràcica aguda és una complicació freqüent en els pacients afectes de drepanocitosi i representa el segon motiu d’ingrés hospitalari. És una complicació amb una elevada morbi-mortalitat responsable del 25% de les morts d’aquests pacients. Múltiples factors juguen un paper important en la etiopatogènesi d’aquest procés entre els que destaquen l’etiologia infecciosa i l’embòlia grassa. El diagnòstic precoç i l’inici d’un tractament de soport adecuat amb una bona hidratació, oxigenació i cobertura antibiòtica correcta disminueix la severitat del procés i la mortalitat. En molts casos la exanguinotransfusió resulta un tractament vital i és el tractament d’elecció en pacients amb un ràpid deteriorament clínic, gran afectació de la funció respiratoria i en pacients amb fracàs multiorgànic. Presentem el cas d’una nena de 13 anys d’origen marroquí afecta de drepanocitosi que ingressa a la UCI-P per síndrome toràcica aguda greu. L’evolució va ser favorable després de practicar l’exanguinotransfusió (AU)


El síndrome torácico agudo es una complicación frecuente en los pacientes afectos de drepanocitosis y representa el segundo motivo de ingreso hospitalario. Es una complicación con una elevada morbi-mortalidad responsable del 25% de las muertes de estos pacientes. Múltiples factores juegan un papel importante en la etiopatogénesis de este proceso entre los que destacan la etiología infecciosa y la embolia grasa. El diagnóstico precoz y el inicio de un tratamiento de soporte adecuado con una buena hidratación, oxigenación y cobertura antibiótica correcta disminuye la severidad del proceso y la mortalidad. En muchos casos la exanguinotransfusión resulta un tratamiento vital y es el de elección en pacientes con rápido deterioro clínico, gran afectación de la función respiratoria y en pacientes con fracaso multiorgánico. Presentamos el caso de una niña de 13 años de origen marroquí afecta de drepanocitosi que ingresa en la UCI-P por síndrome torácico agudo grave. Su evolución fue favorable tras exanguinotransfusión (AU)


Acute chest syndrome (ACS) is a frequent complication of sickle cell disease and the second leading cause of hospitalization in patients with this disease. ACS is associated with very high morbidity and is responsible for 25% of deaths in sickle cell patients. The most frequent causes of ACS are respiratory infections and pulmonary fat embolism syndrome. Early diagnosis and appropriate supportive treatment, including judicious management of hydration and oxygenation, and proper empirical antimicrobial coverage, may limit its severity and prevent death. In many cases, exchange transfusion proves to be a life-saving procedure. Exchange transfusion is indicated in patients with rapid clinical deterioration, diffuse pulmonary involvement, or multi-organ failure. We present the case of a 13 year-old Moroccan girl with sickle cell disease who was admitted to the PICU with severe ACS. The patient responded favorably to exchange transfusion (AU)


Assuntos
Adolescente , Feminino , Humanos , Anemia Falciforme/complicações , Doenças Torácicas/etiologia , Transfusão de Sangue , Dor no Peito/etiologia , Insuficiência Respiratória/etiologia
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