Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 20
Filtrar
Mais filtros










Intervalo de ano de publicação
1.
Endocrinol. diabetes nutr. (Ed. impr.) ; 66(6): 385-392, jun.-jul. 2019. tab
Artigo em Inglês | IBECS | ID: ibc-182855

RESUMO

Purpose: Gender affirming hormone therapy (HT) in transgender men both improves and impairs several surrogate cardiovascular risk markers. However, few prospective works with long follow-up and control group are available. In this context, this work aimed to assess the changes in the metabolic and cardiovascular risk pattern after 12 months of HT in transgender men. Furthermore, we aimed to investigate early effects on target tissues that may reflect an initial vascular damage. Methods: Prospective observational study, including 20 transgender men, attended in the Gender Identity Unit (UIG) of the Hospital Clinic from July 2013 to November 2015. Anthropometric and body composition by dual-energy X-ray absorptiometry (DXA), hormonal, metabolic and coagulation parameters, endothelial dysfunction by flow-mediated dilation (FMD) and intima-media thickness (IMT) by carotid ultrasound, were assessed at baseline, at 6 and 12 months of HT. Results: We observed an impairment of lipid profile, and increase of homocysteine and leucocytes count, as well as changes in body composition with increased total lean mass together with decreased total fat mass. In addition, higher mean-maximum common IMT was observed after 12 months of HT. Conclusion: Our work shows changes in metabolic and inflammatory parameters after HT after short-medium follow-up, which could increase cardiovascular risk in this setting, together with initial evidence of vascular changes


Objetivo: En los transexuales masculinos (FtM) el tratamiento hormonal (TH) cruzado produce cambios tanto positivos como negativos en diversos marcadores subrogados de riesgo cardiovascular. Por otro lado, existen pocos estudios prospectivos con un grupo control y con un seguimiento prolongado que valoren los cambios en el perfil del riesgo cardiovascular. En este contexto, nuestro trabajo tiene como objetivo evaluar los cambios en el patrón de riesgo metabólico y cardiovascular tras 12 meses de TH en transexuales masculinos. Además, estudiamos los cambios tempranos en tejidos diana que puedan reflejar un daño vascular inicial. Metodología: Estudio observacional prospectivo en 20 transexuales masculinos atendidos en la unidad de identidad de género (UIG) del Hospital Clínic desde julio de 2013 a noviembre de 2015. Se valoraron los cambios antropométricos y de composición corporal mediante una absorciometría de rayos X de doble energía (DXA), así como las variaciones en los parámetros metabólicos y trombóticos. La disfunción endotelial fue evaluada mediante la dilatación mediada por flujo (FMD), y el grosor de íntima-media carotídea (IMT) a través de una ecografía carotídea, a los 6 y 12 meses del TH. Resultados: Observamos un deterioro en el perfil lipídico, y un aumento de los niveles de homocisteína y del recuento de leucocitos, así como cambios en la composición corporal con aumento de la masa magra y disminución de la masa grasa. Además, se observó un incremento en el grosor de la IMT tras 12 meses del TH. Conclusión: En un seguimiento a mediano-corto plazo tras TH, nuestro trabajo muestra cambios en los parámetros metabólicos inflamatorios que podrían incrementar el riesgo cardiovascular en los transexuales masculinos, sumado a la evidencia de cambios vasculares incipientes


Assuntos
Humanos , Masculino , Hormônios Esteroides Gonadais/uso terapêutico , Doenças Cardiovasculares/induzido quimicamente , Pessoas Transgênero , Hormônios Esteroides Gonadais/efeitos adversos , Doenças Cardiovasculares/complicações , Estudos Prospectivos , Antropometria , Composição Corporal/efeitos dos fármacos , Absorciometria de Fóton
2.
J Endocrinol ; 242(2): 65-77, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31117053

RESUMO

Excessive and prolonged glucocorticoid (GC) exposure, resulting from either prescribed or endogenous hypercortisolism, is associated with a high cardiovascular and metabolic burden (Cushing's syndrome). Although previous studies in humans and mice have reported heterogeneous data about the persistence of metabolic syndrome features after remission of hypercortisolism, there is still controversy as to whether this is due to the deleterious changes induced by GCs during active disease or the result of various other factors interfering in the recovery period. In order to study metabolic effects after remission, we used a reversible mouse model of corticosterone (CORT) (100 µg/mL) administration in drinking water for 5 weeks, followed by a 10-week recovery period. We compared CORT-induced effects at these time points with a high-fat diet-treated group (HFD 45%) and a vehicle group (VEH). Plasma CORT, 11ß-HSD activity, food intake, glucose levels, interscapular brown adiposity, hepatic triglycerides and muscle mass were found altered during CORT treatment but normalized after recovery. Although hyperinsulinemia and insulin resistance were increased during CORT and HFD treatment, insulin homeostasis remained altered following the recovery period only in CORT-treated mice. Subcutaneous and visceral adipose tissues (SAT and VAT) were enlarged during HFD and CORT treatment as measured by MRI. However, increased muscle lipid content, adiposity and macrophage infiltration in VAT were only present in the CORT group following recovery. Taken together, CORT-induced insulin alterations were more potent than HFD-induced ones during the same period of treatment, and also more persistent long term. Moreover, we demonstrated that CORT treatment induces more long-lasting VAT enlargement than HFD.

3.
Endocrinol Diabetes Nutr ; 66(6): 385-392, 2019.
Artigo em Inglês, Espanhol | MEDLINE | ID: mdl-30704917

RESUMO

PURPOSE: Gender affirming hormone therapy (HT) in transgender men both improves and impairs several surrogate cardiovascular risk markers. However, few prospective works with long follow-up and control group are available. In this context, this work aimed to assess the changes in the metabolic and cardiovascular risk pattern after 12 months of HT in transgender men. Furthermore, we aimed to investigate early effects on target tissues that may reflect an initial vascular damage. METHODS: Prospective observational study, including 20 transgender men, attended in the Gender Identity Unit (UIG) of the Hospital Clinic from July 2013 to November 2015. Anthropometric and body composition by dual-energy X-ray absorptiometry (DXA), hormonal, metabolic and coagulation parameters, endothelial dysfunction by flow-mediated dilation (FMD) and intima-media thickness (IMT) by carotid ultrasound, were assessed at baseline, at 6 and 12 months of HT. RESULTS: We observed an impairment of lipid profile, and increase of homocysteine and leucocytes count, as well as changes in body composition with increased total lean mass together with decreased total fat mass. In addition, higher mean-maximum common IMT was observed after 12 months of HT. CONCLUSION: Our work shows changes in metabolic and inflammatory parameters after HT after short-medium follow-up, which could increase cardiovascular risk in this setting, together with initial evidence of vascular changes.


Assuntos
Doenças Cardiovasculares/induzido quimicamente , Doenças Cardiovasculares/epidemiologia , Hormônios Esteroides Gonadais/efeitos adversos , Doenças Metabólicas/induzido quimicamente , Doenças Metabólicas/epidemiologia , Procedimentos de Readequação Sexual/métodos , Adolescente , Adulto , Hormônios Esteroides Gonadais/uso terapêutico , Humanos , Masculino , Estudos Prospectivos , Medição de Risco , Fatores de Tempo , Adulto Jovem
4.
Amyloid ; 25(2): 75-78, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29446975

RESUMO

Several mutations in the gene encoding apolipoprotein AI (apoAI) have been described as a cause of familial amyloidosis. Individuals with apoAI-derived (AApoAI) amyloidosis frequently manifest with liver, kidney, laryngeal, skin and myocardial involvement. Although primary hypogonadism (PH) is considered almost pathognomonic of this disease, until now, primary adrenal insufficiency (PAI) has not been described as a common clinical feature. Here, we report the first kindred with AApoAI amyloidosis in which PAI is well-documented. All family members with the Leu60_Phe71delins60Val_61Thr heterozygous mutation who were regularly followed-up at our centre were considered. Nineteen individuals had the confirmed APOA1 deletion/insertion mutation, with detailed medical records available in 11 cases. Of these, 6 had PAI and 3 (all males) had PH. Among them, one 47-year-old man, not previously diagnosed with PAI, developed adrenal crisis after liver transplantation, precipitated by an opportunistic infection. Transplantation due to organ failure, which necessitates use of immunosuppressive medication such as corticosteroids, is frequently required during the course of hereditary amyloidosis. Consequently, PAI can remain masked, being discovered only when an adrenal crisis develops. Therefore, according to the present evidence, patients with AApoAI amyloidosis should be submitted to regular testing of corticotrophin and cortisol levels in order to avoid delaying corticosteroid replacement.


Assuntos
Insuficiência Adrenal/metabolismo , Amiloidose Familiar/metabolismo , Apolipoproteína A-I/metabolismo , Hipogonadismo/metabolismo , Transplante de Fígado , Corticosteroides/uso terapêutico , Insuficiência Adrenal/sangue , Insuficiência Adrenal/genética , Insuficiência Adrenal/cirurgia , Hormônio Adrenocorticotrópico/sangue , Adulto , Idoso , Amiloidose Familiar/sangue , Amiloidose Familiar/genética , Amiloidose Familiar/cirurgia , Apolipoproteína A-I/genética , Feminino , Humanos , Hidrocortisona/sangue , Hipogonadismo/sangue , Hipogonadismo/genética , Hipogonadismo/cirurgia , Masculino , Pessoa de Meia-Idade
5.
Clin Endocrinol (Oxf) ; 88(3): 415-424, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29154455

RESUMO

OBJECTIVE: Sustained evidence from observational studies indicates that after remission of Cushing syndrome (CS) a cardiovascular risk phenotype persists. Here, we performed a translational study in active CS and CS in remission (RCS) to evaluate the subclinical cardiometabolic burden and to explore the direct pro-inflammatory and prothrombotic potential of their sera on the endothelium in an in vitro translational atherothrombotic cell model. PATIENTS: Cross sectional study. The groups were (n = 9/group): I. RCS; II. Active CS (ACS) and III. Controls (CTR), all matched for age, body mass index, sex, without other hormonal deficits. DESIGN: We evaluated in vivo: cardiometabolic profile; endothelial markers (sVCAM-1, NO); endothelial dysfunction (FMD); intima-media thickness and body composition (DEXA). In vitro endothelial cells (EC) were exposed to sera taken from the different subjects to evaluate inflammatory EC response (tisVCAM) and thrombogenicity of the generated extracellular matrix (ECM): von Willebrand factor (VWF) and platelet reactivity. RESULTS: Three of the 9 RCS subjects were on glucocorticoid replacement therapy (GC-RT). Patients on GC-RT had a shorter period of time in stable remission. In vivo analysis ACS showed typically metabolic features, while cardiometabolic markers reached statistical significance for RCS only for Hs-CRP (P < .01). In vitro:EC exposed to ACS and RCS sera displayed increased tisVCAM-1 (P < .01 for ACS and P < .05 for RCS vs CTR), VWF (P < .01 for ACS and P < .05 for RCS vs CTR) and platelet adhesion on ECM (P < .01 for ACC and P < .05 for RCS vs CTR). No statistically significant differences were observed between GC-RT RSC and RCS without GC-RT. CONCLUSIONS: The sera of premenopausal women with CS in remission, without atherothrombotic disease, contain circulatory endothelial deleterious factors with a direct thrombogenic and pro-inflammatory endothelial effect that could increase cardiovascular risk.


Assuntos
Doenças Cardiovasculares/etiologia , Síndrome de Cushing/sangue , Endotélio/lesões , Adulto , Biomarcadores/sangue , Estudos de Casos e Controles , Estudos Transversais , Síndrome de Cushing/complicações , Síndrome de Cushing/patologia , Endotélio/patologia , Feminino , Humanos , Inflamação/etiologia , Masculino , Pessoa de Meia-Idade , Pós-Menopausa , Indução de Remissão , Trombose/etiologia , Pesquisa Médica Translacional , Adulto Jovem
6.
Int J Endocrinol ; 2017: 2912763, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29213284

RESUMO

Glucocorticoids (GC) induce cardiometabolic risk while atherosclerosis is a chronic inflammation involving immunity. GC are immune suppressors, and the adrenocorticotrophic hormone (ACTH) has immune modulator activities. Both may act in atherothrombotic inflammation involving immune cells (IMNC). Aim. To investigate adhesion and activation surface cell markers (CDs) of peripheral IMNC in endogenous Cushing syndrome (CS) and the immune modulator role of ACTH. Material and Methods. 16 ACTH-dependent CS (ACTH-D), 10 ACTH-independent (ACTH-ID) CS, and 16 healthy controls (C) were included. Leukocytes (Leuc), monocytes (MN), lymphocytes (Lym), and neutrophils (N) were analyzed by flow cytometry for atherosclerosis previously associated with CDs. Results. Leuc, N, and MN correlated with CS (p < 0.05), WC (p < 0.001), WHR (p = 0.003), BMI (p < 0.001), and hs-CRP (p < 0.001). CD14++CD16+ (p = 0.047); CD14+CD16++ (p = 0.053) MN; CD15+ (p = 0.027); CD15+CD16+ (p = 0.008) N; and NK-Lym (p = 0.019) were higher in CS. CD14+CD16++ MN were higher in ACTH-ID (8.9 ± 3.5%) versus ACTH-D CS (4.2 ± 1.9%) versus C (4.9 ± 2.3%). NK-Lym correlated with c-LDL (r = 0.433, p = 0.039) and CD15+ N with hs-CRP (r = 0.446, p = 0.037). In multivariate analysis, Leuc, N, and MN depended on BMI (p = 0.021), WC (p = 0.002), and WHR (p = 0.014), while CD15+ and CD15+CD16+ N on hypercortisolism and CS (p = 0.035). Conclusion. In CS, IMNC present changes in activation and adhesion CDs implicated in atherothrombotic inflammation. ACTH-IDCS presents a particular IMNC phenotype, possibly due to the absence of the immune modulator effect of ACTH.

7.
Endocrinol Diabetes Nutr ; 64(1): 26-33, 2017 Jan.
Artigo em Inglês, Espanhol | MEDLINE | ID: mdl-28440767

RESUMO

INTRODUCTION: Cushing syndrome (CS), an endogenous hypercortisolemic condition with increased cardiometabolic morbidity, leads to development of abdominal obesity, insulin resistance, diabetes and proatherogenic dyslipidemia. Zinc alpha-2 glycoprotein (ZAG) is a recently characterized lipolytic adipokine implicated in regulation of adipose tissue metabolism and fat distribution. In vitro and animal studies suggest that glucocorticoids interact with ZAG secretion and action. To assess the relationship between ZAG and glucocorticoids in a human model of hypercortisolism, circulating ZAG levels were tested in patients with CS and its counterpart controls. METHODS: An observational, cross-sectional study on 39 women, 13 with active CS and 26 controls matched by age and body mass index. Plasma ZAG levels (µg/ml) were measured by ELISA and correlated with hypercortisolism, metabolic, and phenotypic parameters. RESULTS: Plasma ZAG levels were significantly higher in patients with CS compared to controls (64.3±16.6 vs. 44.0±16.1, p=0.002). In a univariate analysis, ZAG levels positively correlated to 24-h urinary free cortisol (p=0.001), body mass index (p=0.02), non-esterified fatty acids (p=0.05), glucose (p=0.003), LDL-C (p=0.028), and type 2 diabetes mellitus (p=0.016), and were inversely related to total adiponectin levels (p=0.035). In a multivariate analysis, after adjusting for CS, ZAG levels only correlated with body mass index (p=0.012), type 2 diabetes mellitus (p=0.004), and glucose (p<0.001). CONCLUSION: This study provides initial evidence that plasma ZAG levels are higher in patients with CS as compared to controls. The close relationship of ZAG with metabolic and phenotypic changes in CS suggests that ZAG may play a significant role in adipose tissue changes in hypercortisolism.


Assuntos
Proteínas de Transporte/sangue , Síndrome de Cushing/sangue , Glicoproteínas/sangue , Adulto , Glicemia/análise , Índice de Massa Corporal , Proteínas de Transporte/metabolismo , Estudos de Casos e Controles , Comorbidade , Estudos Transversais , Síndrome de Cushing/epidemiologia , Síndrome de Cushing/fisiopatologia , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/epidemiologia , Ácidos Graxos não Esterificados/sangue , Feminino , Glucocorticoides/metabolismo , Glicoproteínas/metabolismo , Humanos , Hidrocortisona/sangue , Hidrocortisona/urina , Resistência à Insulina , Gordura Intra-Abdominal/metabolismo , Lipólise , Síndrome Metabólica/sangue , Síndrome Metabólica/epidemiologia , Síndrome Metabólica/fisiopatologia , Pessoa de Meia-Idade , Circunferência da Cintura
8.
Endocrinol. diabetes nutr. (Ed. impr.) ; 64(1): 26-33, ene. 2017. graf, tab
Artigo em Inglês | IBECS | ID: ibc-171235

RESUMO

Introduction: Cushing syndrome (CS), an endogenous hypercortisolemic condition with increased cardiometabolic morbidity, leads to development of abdominal obesity, insulin resistance, diabetes and proatherogenic dyslipidemia. Zinc alpha-2 glycoprotein (ZAG) is a recently characterized lipolytic adipokine implicated in regulation of adipose tissue metabolism and fat distribution. In vitro and animal studies suggest that glucocorticoids interact with ZAG secretion and action. To assess the relationship between ZAG and glucocorticoids in a human model of hypercortisolism, circulating ZAG levels were tested in patients with CS and its counterpart controls. Methods: An observational, cross-sectional study on 39 women, 13 with active CS and 26 controls matched by age and body mass index. Plasma ZAG levels (μg/ml) were measured by ELISA and correlated with hypercortisolism, metabolic, and phenotypic parameters. Results: Plasma ZAG levels were significantly higher in patients with CS compared to controls (64.3±16.6 vs. 44.0±16.1, p=0.002). In a univariate analysis, ZAG levels positively correlated to 24-h urinary free cortisol (p=0.001), body mass index (p=0.02), non-esterified fatty acids (p=0.05), glucose (p=0.003), LDL-C (p=0.028), and type 2 diabetes mellitus (p=0.016), and were inversely related to total adiponectin levels (p=0.035). In a multivariate analysis, after adjusting for CS, ZAG levels only correlated with body mass index (p=0.012), type 2 diabetes mellitus (p=0.004), and glucose (p<0.001). Conclusion: This study provides initial evidence that plasma ZAG levels are higher in patients with CS as compared to controls. The close relationship of ZAG with metabolic and phenotypic changes in CS suggests that ZAG may play a significant role in adipose tissue changes in hypercortisolism (AU)


Introducción: El síndrome de Cushing (SC) es un estado de hipercortisolismo endógeno en el que se observa un incremento del riesgo cardiovascular asociado al desarrollo de obesidad abdominal, insulinorresistencia, diabetes y dislipidemia aterogénica. La zinc alfa-2 glucoproteína (ZAG) es una adipocina lipolítica recientemente caracterizada que está implicada en la regulación del metabolismo del tejido adiposo y la distribución de la grasa. Estudios in vitro y en animales indican que los glucocorticoides interaccionan con la secreción y acción de ZAG. Para evaluar la relación entre ZAG y los glucocorticoides en un modelo humano de hipercortisolismo, se analizaron los niveles circulantes de ZAG en pacientes con SC y sus correspondientes controles. Métodos: Estudio observacional en 39 mujeres, 13 con SC activo y 26 controles pareadas por edad e índice de masa corporal. Los niveles plasmáticos de ZAG (μg/ml) se determinaron mediante ELISA y se correlacionaron con los parámetros de hipercortisolismo, metabólicos y fenotípicos. Resultados: Las concentraciones plasmáticas de ZAG fueron significativamente más elevadas en los pacientes con SC (64,3±16,6 vs. 44±16,1; p=0,002). En el análisis univariante los niveles de ZAG se correlacionaron positivamente con cortisol libre urinario (p=0,001), índice de masa corporal (p=0,02), ácidos grasos no esterificados (p=0,05), glucosa (p=0,003), c-LDL (p=0,028) y diabetes mellitus (p=0,016) e inversamente con adiponectina total (p=0,035). En el análisis multivariante, después de ajustar por el SC, los niveles de ZAG solo se correlacionaron con el índice de masa corporal (p=0,012), la diabetes mellitus tipo 2 (p=0,004) y la glucosa (p<0,001). Conclusión: Nuestro estudio proporciona la primera evidencia de las concentraciones plasmáticas de ZAG en el SC. Los pacientes con SC presentan concentraciones más elevadas de ZAG que los controles. La estrecha relación de ZAG con las alteraciones metabólicas y fenotípicas del SC indica que ZAG podría desempeñar un papel importante en las alteraciones del tejido adiposo en el hipercortisolismo (AU)


Assuntos
Humanos , Feminino , Adulto , Pessoa de Meia-Idade , alfa-Macroglobulinas/análise , Síndrome de Cushing/complicações , Síndrome de Cushing/diagnóstico , Lipólise , Glucocorticoides/análise , Índice de Massa Corporal , Ensaio de Imunoadsorção Enzimática/métodos , Tecido Adiposo , Estudos Transversais/métodos , Antropometria/métodos
9.
Lipids Health Dis ; 15: 78, 2016 Apr 18.
Artigo em Inglês | MEDLINE | ID: mdl-27090218

RESUMO

BACKGROUND: Nutrition therapy is the cornerstone of treating diabetes mellitus. The inclusion of fish (particularly oily fish) at least two times per week is recommended by current international dietary guidelines for type 2 diabetes. In contrast to a large number of human studies examining the effects of oily fish on different cardiovascular risk factors, little research on this topic is available in patients with type 2 diabetes. The aims of this pilot study were to investigate the effects of a sardine-enriched diet on metabolic control, adiponectin, inflammatory markers, erythrocyte membrane fatty acid (EMFA) composition, and gut microbiota in drug-naïve patients with type 2 diabetes. METHODS: 35 drug-naïve patients with type 2 diabetes were randomized to follow either a type 2 diabetes standard diet (control group: CG), or a standard diet enriched with 100 g of sardines 5 days a week (sardine group: SG) for 6 months. Anthropometric, dietary information, fasting glycated hemoglobin, glucose, insulin, adiponectin, inflammatory markers, EMFA and specific bacterial strains were determined before and after intervention. RESULTS: There were no significant differences in glycemic control between groups at the end of the study. Both groups decreased plasma insulin (SG: -35.3%, P = 0.01, CG: -22.6%, P = 0.02) and homeostasis model of assessment--insulin resistance (HOMA-IR) (SG: -39.2%, P = 0.007, CG: -21.8%, P = 0.04) at 6-months from baseline. However only SG increased adiponectin in plasma compared to baseline level (+40.7%, P = 0.04). The omega-3 index increased 2.6% in the SG compared to 0.6% in the CG (P = 0.001). Both dietary interventions decreased phylum Firmicutes (SG and CG: P = 0.04) and increased E. coli concentrations (SG: P = 0.01, CG: P = 0.03) at the end of the study from baseline, whereas SG decreased Firmicutes/Bacteroidetes ratio (P = 0.04) and increased Bacteroides-Prevotella (P = 0.004) compared to baseline. CONCLUSIONS: Although enriching diet with 100 g of sardines 5 days a week during 6 months to a type 2 diabetes standard diet seems to have neutral effects on glycemic control in drug-naïve patients with type 2 diabetes, this nutritional intervention could have beneficial effects on cardiovascular risk. Furthermore, both dietary interventions decreased HOMA-IR and altered gut microbiota composition of drug-naïve patients with type 2 diabetes. TRIAL REGISTRATION: Trial number and name of the registry: NCT02294526, ClinicalTrials.gov.


Assuntos
Diabetes Mellitus Tipo 2/dietoterapia , Diabetes Mellitus Tipo 2/microbiologia , Peixes , Microbioma Gastrointestinal , Adiponectina/sangue , Animais , Biomarcadores/sangue , Composição Corporal/efeitos dos fármacos , Membrana Eritrocítica/química , Membrana Eritrocítica/efeitos dos fármacos , Ácidos Graxos/análise , Ácidos Graxos/sangue , Ácidos Graxos Ômega-3/sangue , Feminino , Produtos Pesqueiros , Humanos , Inflamação/sangue , Masculino , Pessoa de Meia-Idade , Projetos Piloto
10.
PLoS One ; 11(1): e0147851, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26815533

RESUMO

The in vivo optical and hemodynamic properties of the healthy (n = 22) and pathological (n = 2) human thyroid tissue were measured non-invasively using a custom time-resolved spectroscopy (TRS) and diffuse correlation spectroscopy (DCS) system. Medical ultrasound was used to guide the placement of the hand-held hybrid optical probe. TRS measured the absorption and reduced scattering coefficients (µa, µs') at three wavelengths (690, 785 and 830 nm) to derive total hemoglobin concentration (THC) and oxygen saturation (StO2). DCS measured the microvascular blood flow index (BFI). Their dependencies on physiological and clinical parameters and positions along the thyroid were investigated and compared to the surrounding sternocleidomastoid muscle. The THC in the thyroid ranged from 131.9 µM to 144.8 µM, showing a 25-44% increase compared to the surrounding sternocleidomastoid muscle tissue. The blood flow was significantly higher in the thyroid (BFIthyroid = 16.0 × 10-9 cm2/s) compared to the muscle (BFImuscle = 7.8 × 10-9 cm2/s), while StO2 showed a small (StO2, muscle = 63.8% to StO2, thyroid = 68.4%), yet significant difference. Two case studies with thyroid nodules underwent the same measurement protocol prior to thyroidectomy. Their THC and BFI reached values around 226.5 µM and 62.8 × 10-9 cm2/s respectively showing a clear contrast to the nodule-free thyroid tissue as well as the general population. The initial characterization of the healthy and pathologic human thyroid tissue lays the ground work for the future investigation on the use of diffuse optics in thyroid cancer screening.


Assuntos
Hemodinâmica , Glândula Tireoide/irrigação sanguínea , Glândula Tireoide/patologia , Nódulo da Glândula Tireoide/irrigação sanguínea , Nódulo da Glândula Tireoide/patologia , Adulto , Feminino , Humanos , Masculino , Análise Espectral
11.
J Steroid Biochem Mol Biol ; 152: 53-61, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-25913395

RESUMO

The presence of two cysteinyl progestogens, 16-cysteinyl-progesterone (16-Cys-Prog) and 16-cysteinyl-pregnenolone (16-Cys-Preg), in human urine is described for the first time. Their occurrence was unequivocally confirmed by comparison with synthesized material by using mass spectrometric detectors. Several experiments were performed in order to clarify their origin. The adrenal origin of both 16-Cys-Prog and 16-Cys-Preg can be inferred from the increase in their concentrations after ACTH stimulatory test, together with their circadian variation similar to the one observed for cortisol. Moreover, the notable increase in excretions of 16-Cys-Prog during the luteal phase of the menstrual cycle points towards an ovarian production for this progestogen. However, the analysis of samples during the course of two pregnancies revealed that, in spite of the large amounts of progesterone produced during gestation, the human placenta lacks the capacity to make 16-Cys-Prog. The adrenal and ovarian origin has been further indicated by the absence of both metabolites in samples collected from a subject with bilateral adrenalectomy and hypogonadotrophyic hypogonadism. Regarding liver action, in vitro studies with hepatocytes and progesterone indicate that, although the liver is able to metabolize progesterone to 6-dehydroprogesterone, it has not the enzymatic machinery for the generation of 16-dehydroprogesterone. Taken together, these results open the possibility for a noninvasive test for the simultaneous evaluation of progesterone biosynthesis in different organs.


Assuntos
Cisteína/análogos & derivados , Fígado/metabolismo , Ovário/metabolismo , Placenta/metabolismo , Pregnenolona/análogos & derivados , Progesterona/análogos & derivados , Progestinas/urina , Hormônio Adrenocorticotrópico/farmacologia , Adulto , Linhagem Celular Tumoral , Criança , Cisteína/urina , Feminino , Células Hep G2 , Hepatócitos/metabolismo , Humanos , Hidrocortisona/farmacologia , Fase Luteal , Masculino , Gravidez , Pregnenolona/urina , Progesterona/urina
12.
PLoS One ; 9(11): e111678, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25365257

RESUMO

Clock gene expression was associated with different components of metabolic syndrome (MS) in human adipose tissue. However, no study has been done to compare the expression of clock genes in visceral adipose tissue (VAT) from lean and obese subjects and its clinical implications. Therefore, we studied in lean and obese women the endogenous 24 h expression of clock genes in isolated adipocytes and its association with MS components. VAT was obtained from lean (BMI 21-25 kg/m2; n = 21) and morbidly obese women (BMI >40 kg/m2; n = 28). The 24 h pattern of clock genes was analyzed every 6 hours using RT-PCR. Correlation of clinical data was studied by Spearman analysis. The 24 h pattern of clock genes showed that obesity alters the expression of CLOCK, BMAL1, PER1, CRY2 and REV-ERB ALPHA in adipocytes with changes found in CRY2 and REV-ERB ALPHA throughout the 24 h period. The same results were confirmed in VAT and stromal cells (SC) showing an upregulation of CRY2 and REV-ERB ALPHA from obese women. A positive correlation was observed for REV-ERB ALPHA gene expression with BMI and waist circumference in the obese population. Expression of ROR ALPHA was correlated with HDL levels and CLOCK with LDL. Obese subjects with MS exhibited positive correlation in the PER2 gene with LDL cholesterol, whereas REV-ERB ALPHA was correlated with waist circumference. We identified CRY2 and REV-ERB ALPHA as the clock genes upregulated in obesity during the 24 h period and that REV-ERB ALPHA is an important gene associated with MS.


Assuntos
Relógios Circadianos , Regulação da Expressão Gênica , Gordura Intra-Abdominal/metabolismo , Síndrome Metabólica/metabolismo , Obesidade/metabolismo , Adulto , Feminino , Humanos , Gordura Intra-Abdominal/patologia , Síndrome Metabólica/patologia , Obesidade/patologia
13.
PLoS One ; 9(7): e101616, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24988226

RESUMO

Autoimmune polyglandular syndrome type 1 (APS-1, OMIM 240300) is a rare autosomal recessive disorder, characterized by the presence of at least two of three major diseases: hypoparathyroidism, Addison's disease, and chronic mucocutaneous candidiasis. We aim to identify the molecular defects and investigate the clinical and mutational characteristics in an index case and other members of a consanguineous family. We identified a novel homozygous mutation in the splice site acceptor (SSA) of intron 5 (c.653-1G>A) in two siblings with different clinical outcomes of APS-1. Coding DNA sequencing revealed that this AIRE mutation potentially compromised the recognition of the constitutive SSA of intron 5, splicing upstream onto a nearby cryptic SSA in intron 5. Surprisingly, the use of an alternative SSA entails the uncovering of a cryptic donor splice site in exon 5. This new transcript generates a truncated protein (p.A214fs67X) containing the first 213 amino acids and followed by 68 aberrant amino acids. The mutation affects the proper splicing, not only at the acceptor but also at the donor splice site, highlighting the complexity of recognizing suitable splicing sites and the importance of sequencing the intron-exon junctions for a more precise molecular diagnosis and correct genetic counseling. As both siblings were carrying the same mutation but exhibited a different APS-1 onset, and one of the brothers was not clinically diagnosed, our finding highlights the possibility to suspect mutations in the AIRE gene in cases of childhood chronic candidiasis and/or hypoparathyroidism otherwise unexplained, especially when the phenotype is associated with other autoimmune diseases.


Assuntos
Mutação , Poliendocrinopatias Autoimunes/genética , Sítios de Splice de RNA , Fatores de Transcrição/genética , Sequência de Bases , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Moleculares , Dados de Sequência Molecular
14.
PLoS One ; 9(6): e99310, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24914535

RESUMO

TCF7L2 is the susceptibility gene for Type 2 diabetes (T2D) with the largest effect on disease risk that has been discovered to date. However, the mechanisms by which TCF7L2 contributes to the disease remain largely elusive. In addition, epigenetic mechanisms, such as changes in DNA methylation patterns, might have a role in the pathophysiology of T2D. This study aimed to investigate the differences in terms of DNA methylation profile of TCF7L2 promoter gene between type 2 diabetic patients and age- and Body Mass Index (BMI)- matched controls. We included 93 type 2 diabetic patients that were recently diagnosed for T2D and exclusively on diet (without any pharmacological treatment). DNA was extracted from whole blood and DNA methylation was assessed using the Sequenom EpiTYPER system. Type 2 diabetic patients were more insulin resistant than their matched controls (mean HOMA IR 2.6 vs 1.8 in controls, P<0.001) and had a poorer beta-cell function (mean HOMA B 75.7 vs. 113.6 in controls, P<0.001). Results showed that 59% of the CpGs analyzed in TCF7L2 promoter had significant differences between type 2 diabetic patients and matched controls. In addition, fasting glucose, HOMA-B, HOMA-IR, total cholesterol and LDL-cholesterol correlated with methylation in specific CpG sites of TCF7L2 promoter. After adjustment by age, BMI, gender, physical inactivity, waist circumference, smoking status and diabetes status uniquely fasting glucose, total cholesterol and LDL-cholesterol remained significant. Taken together, newly diagnosed, drug-naïve type 2 diabetic patients display specific epigenetic changes at the TCF7L2 promoter as compared to age- and BMI-matched controls. Methylation in TCF7L2 promoter is further correlated with fasting glucose in peripheral blood DNA, which sheds new light on the role of epigenetic regulation of TCF7L2 in T2D.


Assuntos
Metilação de DNA/genética , DNA/sangue , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/genética , Regiões Promotoras Genéticas , Proteína 2 Semelhante ao Fator 7 de Transcrição/genética , Idoso , Estudos de Casos e Controles , Ilhas de CpG/genética , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/metabolismo , Feminino , Humanos , Masculino , Metabolômica
15.
Diabetologia ; 57(6): 1219-31, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24633677

RESUMO

AIMS/HYPOTHESIS: Comprehensive characterisation of the interrelation between the peripancreatic adipose tissue and the pancreatic islets promises novel insights into the mechanisms that regulate beta cell adaptation to obesity. Here, we sought to determine the main pathways and key molecules mediating the crosstalk between these two tissues during adaptation to obesity by the way of an integrated inter-tissue, multi-platform analysis. METHODS: Wistar rats were fed a standard or cafeteria diet for 30 days. Transcriptomic variations by diet in islets and peripancreatic adipose tissue were examined through microarray analysis. The secretome from peripancreatic adipose tissue was subjected to a non-targeted metabolomic and proteomic analysis. Gene expression variations in islets were integrated with changes in peripancreatic adipose tissue gene expression and protein and metabolite secretion using an integrated inter-tissue pathway and network analysis. RESULTS: The highest level of data integration, linking genes differentially expressed in both tissues with secretome variations, allowed the identification of significantly enriched canonical pathways, such as the activation of liver/retinoid X receptors, triacylglycerol degradation, and regulation of inflammatory and immune responses, and underscored interaction network hubs, such as cholesterol and the fatty acid binding protein 4, which were unpredicted through single-tissue analysis and have not been previously implicated in the peripancreatic adipose tissue crosstalk with beta cells. CONCLUSIONS/INTERPRETATION: The integrated analysis reported here allowed the identification of novel mechanisms and key molecules involved in peripancreatic adipose tissue interrelation with beta cells during the development of obesity; this might help the development of novel strategies to prevent type 2 diabetes.


Assuntos
Tecido Adiposo/metabolismo , Ilhotas Pancreáticas/metabolismo , Obesidade/metabolismo , Animais , Masculino , Proteômica , Ratos , Ratos Wistar , Triglicerídeos/metabolismo
16.
Obesity (Silver Spring) ; 21(12): E616-25, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-23595969

RESUMO

OBJECTIVE: Persistent inflammation and impaired adipogenesis are frequent features of obesity and underlie the development of its complications. However, the factors behind adipose tissue dysfunction are not completely understood. Previously it was shown that histone demethylase KDM1A is required for adipogenesis. DESIGN AND METHODS: Kdm1a expression was knocked down in 3T3-L1 preadipocytes by siRNA transfection and whole-genome expression profiling was performed by microarray hybridization. The role of NF-κß and C/EBPß was analyzed by incubation with the inhibitor parthenolide and by cebpb knockdown, respectively. RESULTS: Knockdown of kdm1a or rcor2 in 3T3-L1 preadipocytes results in impaired differentiation and induction of inflammatory gene expression. Enhanced expression of il6 in kdm1a knocked down preadipocytes is associated with increased recruitment of C/EBPß and the NF-κß subunit RelA to the il6 promoter. Cebpb knockdown attenuates the induction of il6 expression in kdm1a knocked down cells, whereas simultaneous cebpb knockdown and NF-κß inhibition abrogates it. Dietary-induced and genetic mouse models of obesity display decreased KDM1A in adipose tissue, and this correlates with increased expression of proinflammatory genes and C/EBPß. CONCLUSION: KDM1A represses the expression of inflammatory genes in preadipocytes. Dysregulated kdm1a expression in preadipocytes may thus participate in the development of obesity-associated inflammation.


Assuntos
Adipócitos/metabolismo , Regulação da Expressão Gênica , Histona Desmetilases/metabolismo , Oxirredutases N-Desmetilantes/metabolismo , Células 3T3-L1 , Adipogenia/fisiologia , Tecido Adiposo/metabolismo , Animais , Proteína beta Intensificadora de Ligação a CCAAT/genética , Proteína beta Intensificadora de Ligação a CCAAT/metabolismo , Diferenciação Celular , Linhagem Celular , Células Endoteliais/metabolismo , Perfilação da Expressão Gênica , Técnicas de Silenciamento de Genes , Histona Desmetilases/genética , Humanos , Interleucina-6/genética , Interleucina-6/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , NF-kappa B/genética , NF-kappa B/metabolismo , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Oxirredutases N-Desmetilantes/genética , Regiões Promotoras Genéticas , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo
17.
Cell Physiol Biochem ; 29(1-2): 61-4, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22415075

RESUMO

BACKGROUND/AIMS: Stimulation of insulin release by D-glucose is accompanied by Cl(-) and HCO(3)(-) efflux from pancreatic islet cells. The efflux of these anions may involve volume-regulated anion channels, including possibly TMEM16A, and the Na(+)-HCO(3)(-)-cotransporter SLC4A4. The present study was designed to explore the expression of both TMEM16A and SLC4A4 in human pancreatic islets. METHODS: Pancreases were obtained from human cadaveric donors. Immunodetection of TMEM16A and SLC4A4 was performed by immunohistochemistry on sections of fixed pancreas, while real-time PCR for the study of corresponding gene expression was performed on RNA extracted from both total pancreatic pieces and isolated pancreatic islets. RESULTS: RT-PCR yielded lower levels of SLC4A4 in isolated islets than in the total pancreas, whilst a mirror image prevailed for TMEM16A mRNA. Immunohistochemistry of human pancreas, however, indicated comparable immunostaining of SLC4A4 in insulin-producing cells and exocrine pancreatic cells, whilst that of TMEM16A appeared less pronounced in insulin-producing cells than in exocrine cells. CONCLUSION: The present findings support the view that, in humans like in rodent, the regulation of anion fluxes in insulin-producing cells may involve both SLC4A4 and TMEM16A.


Assuntos
Canais de Cloreto/metabolismo , Regulação da Expressão Gênica , Ilhotas Pancreáticas/metabolismo , Proteínas de Neoplasias/metabolismo , Simportadores de Sódio-Bicarbonato/metabolismo , Animais , Anoctamina-1 , Canais de Cloreto/genética , Humanos , Imuno-Histoquímica , Ilhotas Pancreáticas/patologia , Camundongos , Proteínas de Neoplasias/genética , RNA Mensageiro/metabolismo , Simportadores de Sódio-Bicarbonato/genética
18.
Endocrinology ; 153(1): 177-87, 2012 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-22067319

RESUMO

In obesity an increase in ß-cell mass occurs to cope with the rise in insulin demand. This ß-cell plasticity is essential to avoid the onset of hyperglycemia, although the molecular mechanisms that regulate this process remain unclear. This study analyzed the role of adipose tissue in the control of ß-cell replication. Using a diet-induced model of obesity, we obtained conditioned media from three different white adipose tissue depots. Only in the adipose tissue depot surrounding the pancreas did the diet induce changes that led to an increase in INS1E cells and the islet replication rate. To identify the factors responsible for this proliferative effect, adipose tissue gene expression analysis was conducted by microarrays and quantitative RT-PCR. Of all the differentially expressed proteins, only the secreted ones were studied. IGF binding protein 3 (Igfbp3) was identified as the candidate for this effect. Furthermore, in the conditioned media, although the blockage of IGFBP3 led to an increase in the proliferation rate, the blockage of IGF-I receptor decreased it. Taken together, these data show that obesity induces specific changes in the expression profile of the adipose tissue depot surrounding the pancreas, leading to a decrease in IGFBP3 secretion. This decrease acts in a paracrine manner, stimulating the ß-cell proliferation rate, probably through an IGF-I-dependent mechanism. This cross talk between the visceral-pancreatic adipose tissue and ß-cells is a novel mechanism that participates in the control of ß-cell plasticity.


Assuntos
Tecido Adiposo/fisiopatologia , Proteína 3 de Ligação a Fator de Crescimento Semelhante à Insulina/fisiologia , Células Secretoras de Insulina/patologia , Células Secretoras de Insulina/fisiologia , Obesidade/patologia , Obesidade/fisiopatologia , Tecido Adiposo/patologia , Animais , Sequência de Bases , Contagem de Células , Linhagem Celular , Proliferação de Células , Meios de Cultivo Condicionados , Dieta/efeitos adversos , Modelos Animais de Doenças , Proteína 3 de Ligação a Fator de Crescimento Semelhante à Insulina/genética , Masculino , Obesidade/etiologia , Obesidade/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Ratos Wistar , Receptor Cross-Talk/fisiologia
19.
J Biol Chem ; 285(39): 30034-41, 2010 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-20656681

RESUMO

Epigenetic mechanisms, in particular the enzymatic modification of histones, are a crucial element of cell differentiation, a regulated process that allows a precursor cell basically to turn into a different cell type while maintaining the same genetic equipment. We have previously described that the promoters of adipogenic genes display significant levels of dimethylation at the Lys(4) of histone H3 (H3K4) in preadipocytes, where these genes are still silenced, thus maintaining the chromatin of the precursor cell in a receptive state. Here, we show that the expression of several histone demethylases and methyltransferases increases during adipogenesis, suggesting an important role for these proteins in this process. Knockdown of the H3K4/K9 demethylase LSD1 results in markedly decreased differentiation of 3T3-L1 preadipocytes. This outcome is associated with decreased H3K4 dimethylation and increased H3K9 dimethylation at the promoter of transcription factor cebpa, whose expression must be induced >200-fold upon stimulation of differentiation. Thus, our data suggest that LSD1 acts to maintain a permissive state of the chromatin in this promoter by opposing the action of a H3K9 methyltransferase. Knockdown of H3K9 methyltransferase SETDB1 produced the opposite results, by decreasing H3K9 dimethylation and increasing H3K4 dimethylation levels at the cebpa promoter and favoring differentiation. These findings indicate that the histone methylation status of adipogenic genes as well as the expression and function of the proteins involved in its maintenance play a crucial role in adipogenesis.


Assuntos
Adipócitos/metabolismo , Adipogenia/fisiologia , Diferenciação Celular/fisiologia , Epigênese Genética/fisiologia , Oxirredutases N-Desmetilantes/metabolismo , Células-Tronco/metabolismo , Células 3T3-L1 , Adipócitos/citologia , Animais , Proteínas Estimuladoras de Ligação a CCAAT/genética , Proteínas Estimuladoras de Ligação a CCAAT/metabolismo , Cromatina/genética , Cromatina/metabolismo , Técnicas de Silenciamento de Genes , Histona Desmetilases , Histona-Lisina N-Metiltransferase , Histonas/genética , Histonas/metabolismo , Camundongos , Oxirredutases N-Desmetilantes/genética , Regiões Promotoras Genéticas/fisiologia , Metiltransferases de Proteína/genética , Metiltransferases de Proteína/metabolismo , Células-Tronco/citologia
20.
Fertil Steril ; 94(6): 2389-92, 2010 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-20493471

RESUMO

To assess the role of the insulin receptor gene in polycystic ovary syndrome (PCOS) we performed a case-control study in a female population (n=226) from Central Europe by examining the genetic associations of single nucleotide polymorphisms (rs8107575, rs2245648, rs2245649, rs2963, rs2245655, and rs2962) and inferred haplotypes around exon 9 of this gene. The ancestral T allele of single nucleotide polymorphism rs2963 or the corresponding haplotype (GGTC-C) showed association with PCOS with odds ratio 2.99, 95% confidence interval 1.4-6.3, independent of obesity but related to the presence of Acanthosis nigricans and insulin resistance, metabolic syndrome, or hyperandrogeny, thus providing a frame for future fine mapping of the susceptibility loci in PCOS.


Assuntos
Síndrome do Ovário Policístico/genética , Polimorfismo de Nucleotídeo Único , Receptor de Insulina/genética , Estudos de Casos e Controles , Europa (Continente) , Feminino , Frequência do Gene , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Desequilíbrio de Ligação , Filogenia , População
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA